Post menopausal osteoporosis

Submitted by-Amit KochharBOT 2nd yearPt DDU IPH

Osteoporosis

PATHOGENESIS

DIAGNOSIS

TREATMENT

Two components of the bone

Cortical Bone Dense and compact Runs the length of the long bones forming a

hollow cylinder

Trabecular bone Has a light honeycomb structure Trabeculae are arranged in the directions of tension

and compression Occurs in the heads of the long bones Also makes up most of the bone in the vertebrae

Osteons

Principal organizing feature of compact bone Haversian canal ndash place for the nerve blood

and lymphatic vessels Lamellae ndash collagen deposition pattern Lacunae ndash holes for osteocytes Canaliculi ndash place of communication between

osteocytes

Bone cells

Osteocytes - derived from osteoprogenitor cells Osteoblasts Osteoclasts

Osteocytes

Trapped osteoblasts1048708 In lacunae

Keep bone matrix in good condition and can release calcium ions from bone matrix when calcium demands increase1048708 Osteocytic osteolysis

Osteoblasts

Make collagenActivate nucleation of hydroxyapatite

crystallization onto the collagen matrix forming new bone

As they become enveloped by the collagenous matrix they produce they transform into osteocytes

Stimulate osteoclast resorptive activity

Osteoclasts

Resorbe bone matrix from sites where it is deteriorating or not needed

Digest bone matrix componentsFocal decalcification and extracellular

digestion by acid hydrolases and uptake of digested material

Disappear after resorptionAssist with mineral homeostasis

Chemistry of the bone

Matrix Mineral

Matrix - osteoid

Collagen type I and IVLayers of various orientations (add to the

strength of the matrix)Other proteins 10 of the bone protein

1048708 Direct formation of fibers1048708 Enhance mineralization1048708 Provide signals for remodeling

Mineral

A calcium phosphatecarbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2

1048708 Hydroxyapatite crystals1048708 Imperfect1048708 Contain Mg Na K

Mineralization of the bone

Calcification occurs by extracellular deposition of hydroxyapatite crystalsTrapping of calcium and phosphate ions in

concentrations that would initiate deposition of calcium phosphate in the solid phase followed by its conversion to crystalline hydroxyapatite

Mechanisms exist to both initiate and inhibit calcification

Bone remodeling process

Proceeds in cycles ndash first resorption than bone formation

The calcium content of bone turns over with a half-life of 1-5 years

Bone remodeling process

Coordination of Resorption and Formation

Phase ISignal from osteoblastsStimulation of osteoblastic precursor cells to

become osteoclastsProcess takes 10 days

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Osteoporosis

PATHOGENESIS

DIAGNOSIS

TREATMENT

Two components of the bone

Cortical Bone Dense and compact Runs the length of the long bones forming a

hollow cylinder

Trabecular bone Has a light honeycomb structure Trabeculae are arranged in the directions of tension

and compression Occurs in the heads of the long bones Also makes up most of the bone in the vertebrae

Osteons

Principal organizing feature of compact bone Haversian canal ndash place for the nerve blood

and lymphatic vessels Lamellae ndash collagen deposition pattern Lacunae ndash holes for osteocytes Canaliculi ndash place of communication between

osteocytes

Bone cells

Osteocytes - derived from osteoprogenitor cells Osteoblasts Osteoclasts

Osteocytes

Trapped osteoblasts1048708 In lacunae

Keep bone matrix in good condition and can release calcium ions from bone matrix when calcium demands increase1048708 Osteocytic osteolysis

Osteoblasts

Make collagenActivate nucleation of hydroxyapatite

crystallization onto the collagen matrix forming new bone

As they become enveloped by the collagenous matrix they produce they transform into osteocytes

Stimulate osteoclast resorptive activity

Osteoclasts

Resorbe bone matrix from sites where it is deteriorating or not needed

Digest bone matrix componentsFocal decalcification and extracellular

digestion by acid hydrolases and uptake of digested material

Disappear after resorptionAssist with mineral homeostasis

Chemistry of the bone

Matrix Mineral

Matrix - osteoid

Collagen type I and IVLayers of various orientations (add to the

strength of the matrix)Other proteins 10 of the bone protein

1048708 Direct formation of fibers1048708 Enhance mineralization1048708 Provide signals for remodeling

Mineral

A calcium phosphatecarbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2

1048708 Hydroxyapatite crystals1048708 Imperfect1048708 Contain Mg Na K

Mineralization of the bone

Calcification occurs by extracellular deposition of hydroxyapatite crystalsTrapping of calcium and phosphate ions in

concentrations that would initiate deposition of calcium phosphate in the solid phase followed by its conversion to crystalline hydroxyapatite

Mechanisms exist to both initiate and inhibit calcification

Bone remodeling process

Proceeds in cycles ndash first resorption than bone formation

The calcium content of bone turns over with a half-life of 1-5 years

Bone remodeling process

Coordination of Resorption and Formation

Phase ISignal from osteoblastsStimulation of osteoblastic precursor cells to

become osteoclastsProcess takes 10 days

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Two components of the bone

Cortical Bone Dense and compact Runs the length of the long bones forming a

hollow cylinder

Trabecular bone Has a light honeycomb structure Trabeculae are arranged in the directions of tension

and compression Occurs in the heads of the long bones Also makes up most of the bone in the vertebrae

Osteons

Principal organizing feature of compact bone Haversian canal ndash place for the nerve blood

and lymphatic vessels Lamellae ndash collagen deposition pattern Lacunae ndash holes for osteocytes Canaliculi ndash place of communication between

osteocytes

Bone cells

Osteocytes - derived from osteoprogenitor cells Osteoblasts Osteoclasts

Osteocytes

Trapped osteoblasts1048708 In lacunae

Keep bone matrix in good condition and can release calcium ions from bone matrix when calcium demands increase1048708 Osteocytic osteolysis

Osteoblasts

Make collagenActivate nucleation of hydroxyapatite

crystallization onto the collagen matrix forming new bone

As they become enveloped by the collagenous matrix they produce they transform into osteocytes

Stimulate osteoclast resorptive activity

Osteoclasts

Resorbe bone matrix from sites where it is deteriorating or not needed

Digest bone matrix componentsFocal decalcification and extracellular

digestion by acid hydrolases and uptake of digested material

Disappear after resorptionAssist with mineral homeostasis

Chemistry of the bone

Matrix Mineral

Matrix - osteoid

Collagen type I and IVLayers of various orientations (add to the

strength of the matrix)Other proteins 10 of the bone protein

1048708 Direct formation of fibers1048708 Enhance mineralization1048708 Provide signals for remodeling

Mineral

A calcium phosphatecarbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2

1048708 Hydroxyapatite crystals1048708 Imperfect1048708 Contain Mg Na K

Mineralization of the bone

Calcification occurs by extracellular deposition of hydroxyapatite crystalsTrapping of calcium and phosphate ions in

concentrations that would initiate deposition of calcium phosphate in the solid phase followed by its conversion to crystalline hydroxyapatite

Mechanisms exist to both initiate and inhibit calcification

Bone remodeling process

Proceeds in cycles ndash first resorption than bone formation

The calcium content of bone turns over with a half-life of 1-5 years

Bone remodeling process

Coordination of Resorption and Formation

Phase ISignal from osteoblastsStimulation of osteoblastic precursor cells to

become osteoclastsProcess takes 10 days

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Osteons

Principal organizing feature of compact bone Haversian canal ndash place for the nerve blood

and lymphatic vessels Lamellae ndash collagen deposition pattern Lacunae ndash holes for osteocytes Canaliculi ndash place of communication between

osteocytes

Bone cells

Osteocytes - derived from osteoprogenitor cells Osteoblasts Osteoclasts

Osteocytes

Trapped osteoblasts1048708 In lacunae

Keep bone matrix in good condition and can release calcium ions from bone matrix when calcium demands increase1048708 Osteocytic osteolysis

Osteoblasts

Make collagenActivate nucleation of hydroxyapatite

crystallization onto the collagen matrix forming new bone

As they become enveloped by the collagenous matrix they produce they transform into osteocytes

Stimulate osteoclast resorptive activity

Osteoclasts

Resorbe bone matrix from sites where it is deteriorating or not needed

Digest bone matrix componentsFocal decalcification and extracellular

digestion by acid hydrolases and uptake of digested material

Disappear after resorptionAssist with mineral homeostasis

Chemistry of the bone

Matrix Mineral

Matrix - osteoid

Collagen type I and IVLayers of various orientations (add to the

strength of the matrix)Other proteins 10 of the bone protein

1048708 Direct formation of fibers1048708 Enhance mineralization1048708 Provide signals for remodeling

Mineral

A calcium phosphatecarbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2

1048708 Hydroxyapatite crystals1048708 Imperfect1048708 Contain Mg Na K

Mineralization of the bone

Calcification occurs by extracellular deposition of hydroxyapatite crystalsTrapping of calcium and phosphate ions in

concentrations that would initiate deposition of calcium phosphate in the solid phase followed by its conversion to crystalline hydroxyapatite

Mechanisms exist to both initiate and inhibit calcification

Bone remodeling process

Proceeds in cycles ndash first resorption than bone formation

The calcium content of bone turns over with a half-life of 1-5 years

Bone remodeling process

Coordination of Resorption and Formation

Phase ISignal from osteoblastsStimulation of osteoblastic precursor cells to

become osteoclastsProcess takes 10 days

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Bone cells

Osteocytes - derived from osteoprogenitor cells Osteoblasts Osteoclasts

Osteocytes

Trapped osteoblasts1048708 In lacunae

Keep bone matrix in good condition and can release calcium ions from bone matrix when calcium demands increase1048708 Osteocytic osteolysis

Osteoblasts

Make collagenActivate nucleation of hydroxyapatite

crystallization onto the collagen matrix forming new bone

As they become enveloped by the collagenous matrix they produce they transform into osteocytes

Stimulate osteoclast resorptive activity

Osteoclasts

Resorbe bone matrix from sites where it is deteriorating or not needed

Digest bone matrix componentsFocal decalcification and extracellular

digestion by acid hydrolases and uptake of digested material

Disappear after resorptionAssist with mineral homeostasis

Chemistry of the bone

Matrix Mineral

Matrix - osteoid

Collagen type I and IVLayers of various orientations (add to the

strength of the matrix)Other proteins 10 of the bone protein

1048708 Direct formation of fibers1048708 Enhance mineralization1048708 Provide signals for remodeling

Mineral

A calcium phosphatecarbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2

1048708 Hydroxyapatite crystals1048708 Imperfect1048708 Contain Mg Na K

Mineralization of the bone

Calcification occurs by extracellular deposition of hydroxyapatite crystalsTrapping of calcium and phosphate ions in

concentrations that would initiate deposition of calcium phosphate in the solid phase followed by its conversion to crystalline hydroxyapatite

Mechanisms exist to both initiate and inhibit calcification

Bone remodeling process

Proceeds in cycles ndash first resorption than bone formation

The calcium content of bone turns over with a half-life of 1-5 years

Bone remodeling process

Coordination of Resorption and Formation

Phase ISignal from osteoblastsStimulation of osteoblastic precursor cells to

become osteoclastsProcess takes 10 days

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Osteocytes

Trapped osteoblasts1048708 In lacunae

Keep bone matrix in good condition and can release calcium ions from bone matrix when calcium demands increase1048708 Osteocytic osteolysis

Osteoblasts

Make collagenActivate nucleation of hydroxyapatite

crystallization onto the collagen matrix forming new bone

As they become enveloped by the collagenous matrix they produce they transform into osteocytes

Stimulate osteoclast resorptive activity

Osteoclasts

Resorbe bone matrix from sites where it is deteriorating or not needed

Digest bone matrix componentsFocal decalcification and extracellular

digestion by acid hydrolases and uptake of digested material

Disappear after resorptionAssist with mineral homeostasis

Chemistry of the bone

Matrix Mineral

Matrix - osteoid

Collagen type I and IVLayers of various orientations (add to the

strength of the matrix)Other proteins 10 of the bone protein

1048708 Direct formation of fibers1048708 Enhance mineralization1048708 Provide signals for remodeling

Mineral

A calcium phosphatecarbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2

1048708 Hydroxyapatite crystals1048708 Imperfect1048708 Contain Mg Na K

Mineralization of the bone

Calcification occurs by extracellular deposition of hydroxyapatite crystalsTrapping of calcium and phosphate ions in

concentrations that would initiate deposition of calcium phosphate in the solid phase followed by its conversion to crystalline hydroxyapatite

Mechanisms exist to both initiate and inhibit calcification

Bone remodeling process

Proceeds in cycles ndash first resorption than bone formation

The calcium content of bone turns over with a half-life of 1-5 years

Bone remodeling process

Coordination of Resorption and Formation

Phase ISignal from osteoblastsStimulation of osteoblastic precursor cells to

become osteoclastsProcess takes 10 days

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Osteoblasts

Make collagenActivate nucleation of hydroxyapatite

crystallization onto the collagen matrix forming new bone

As they become enveloped by the collagenous matrix they produce they transform into osteocytes

Stimulate osteoclast resorptive activity

Osteoclasts

Resorbe bone matrix from sites where it is deteriorating or not needed

Digest bone matrix componentsFocal decalcification and extracellular

digestion by acid hydrolases and uptake of digested material

Disappear after resorptionAssist with mineral homeostasis

Chemistry of the bone

Matrix Mineral

Matrix - osteoid

Collagen type I and IVLayers of various orientations (add to the

strength of the matrix)Other proteins 10 of the bone protein

1048708 Direct formation of fibers1048708 Enhance mineralization1048708 Provide signals for remodeling

Mineral

A calcium phosphatecarbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2

1048708 Hydroxyapatite crystals1048708 Imperfect1048708 Contain Mg Na K

Mineralization of the bone

Calcification occurs by extracellular deposition of hydroxyapatite crystalsTrapping of calcium and phosphate ions in

concentrations that would initiate deposition of calcium phosphate in the solid phase followed by its conversion to crystalline hydroxyapatite

Mechanisms exist to both initiate and inhibit calcification

Bone remodeling process

Proceeds in cycles ndash first resorption than bone formation

The calcium content of bone turns over with a half-life of 1-5 years

Bone remodeling process

Coordination of Resorption and Formation

Phase ISignal from osteoblastsStimulation of osteoblastic precursor cells to

become osteoclastsProcess takes 10 days

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Osteoclasts

Resorbe bone matrix from sites where it is deteriorating or not needed

Digest bone matrix componentsFocal decalcification and extracellular

digestion by acid hydrolases and uptake of digested material

Disappear after resorptionAssist with mineral homeostasis

Chemistry of the bone

Matrix Mineral

Matrix - osteoid

Collagen type I and IVLayers of various orientations (add to the

strength of the matrix)Other proteins 10 of the bone protein

1048708 Direct formation of fibers1048708 Enhance mineralization1048708 Provide signals for remodeling

Mineral

A calcium phosphatecarbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2

1048708 Hydroxyapatite crystals1048708 Imperfect1048708 Contain Mg Na K

Mineralization of the bone

Calcification occurs by extracellular deposition of hydroxyapatite crystalsTrapping of calcium and phosphate ions in

concentrations that would initiate deposition of calcium phosphate in the solid phase followed by its conversion to crystalline hydroxyapatite

Mechanisms exist to both initiate and inhibit calcification

Bone remodeling process

Proceeds in cycles ndash first resorption than bone formation

The calcium content of bone turns over with a half-life of 1-5 years

Bone remodeling process

Coordination of Resorption and Formation

Phase ISignal from osteoblastsStimulation of osteoblastic precursor cells to

become osteoclastsProcess takes 10 days

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Chemistry of the bone

Matrix Mineral

Matrix - osteoid

Collagen type I and IVLayers of various orientations (add to the

strength of the matrix)Other proteins 10 of the bone protein

1048708 Direct formation of fibers1048708 Enhance mineralization1048708 Provide signals for remodeling

Mineral

A calcium phosphatecarbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2

1048708 Hydroxyapatite crystals1048708 Imperfect1048708 Contain Mg Na K

Mineralization of the bone

Calcification occurs by extracellular deposition of hydroxyapatite crystalsTrapping of calcium and phosphate ions in

concentrations that would initiate deposition of calcium phosphate in the solid phase followed by its conversion to crystalline hydroxyapatite

Mechanisms exist to both initiate and inhibit calcification

Bone remodeling process

Proceeds in cycles ndash first resorption than bone formation

The calcium content of bone turns over with a half-life of 1-5 years

Bone remodeling process

Coordination of Resorption and Formation

Phase ISignal from osteoblastsStimulation of osteoblastic precursor cells to

become osteoclastsProcess takes 10 days

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Matrix - osteoid

Collagen type I and IVLayers of various orientations (add to the

strength of the matrix)Other proteins 10 of the bone protein

1048708 Direct formation of fibers1048708 Enhance mineralization1048708 Provide signals for remodeling

Mineral

A calcium phosphatecarbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2

1048708 Hydroxyapatite crystals1048708 Imperfect1048708 Contain Mg Na K

Mineralization of the bone

Calcification occurs by extracellular deposition of hydroxyapatite crystalsTrapping of calcium and phosphate ions in

concentrations that would initiate deposition of calcium phosphate in the solid phase followed by its conversion to crystalline hydroxyapatite

Mechanisms exist to both initiate and inhibit calcification

Bone remodeling process

Proceeds in cycles ndash first resorption than bone formation

The calcium content of bone turns over with a half-life of 1-5 years

Bone remodeling process

Coordination of Resorption and Formation

Phase ISignal from osteoblastsStimulation of osteoblastic precursor cells to

become osteoclastsProcess takes 10 days

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Mineral

A calcium phosphatecarbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2

1048708 Hydroxyapatite crystals1048708 Imperfect1048708 Contain Mg Na K

Mineralization of the bone

Calcification occurs by extracellular deposition of hydroxyapatite crystalsTrapping of calcium and phosphate ions in

concentrations that would initiate deposition of calcium phosphate in the solid phase followed by its conversion to crystalline hydroxyapatite

Mechanisms exist to both initiate and inhibit calcification

Bone remodeling process

Proceeds in cycles ndash first resorption than bone formation

The calcium content of bone turns over with a half-life of 1-5 years

Bone remodeling process

Coordination of Resorption and Formation

Phase ISignal from osteoblastsStimulation of osteoblastic precursor cells to

become osteoclastsProcess takes 10 days

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Mineralization of the bone

Calcification occurs by extracellular deposition of hydroxyapatite crystalsTrapping of calcium and phosphate ions in

concentrations that would initiate deposition of calcium phosphate in the solid phase followed by its conversion to crystalline hydroxyapatite

Mechanisms exist to both initiate and inhibit calcification

Bone remodeling process

Proceeds in cycles ndash first resorption than bone formation

The calcium content of bone turns over with a half-life of 1-5 years

Bone remodeling process

Coordination of Resorption and Formation

Phase ISignal from osteoblastsStimulation of osteoblastic precursor cells to

become osteoclastsProcess takes 10 days

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Bone remodeling process

Proceeds in cycles ndash first resorption than bone formation

The calcium content of bone turns over with a half-life of 1-5 years

Bone remodeling process

Coordination of Resorption and Formation

Phase ISignal from osteoblastsStimulation of osteoblastic precursor cells to

become osteoclastsProcess takes 10 days

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Bone remodeling process

Coordination of Resorption and Formation

Phase ISignal from osteoblastsStimulation of osteoblastic precursor cells to

become osteoclastsProcess takes 10 days

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Coordination of Resorption and Formation

Phase ISignal from osteoblastsStimulation of osteoblastic precursor cells to

become osteoclastsProcess takes 10 days

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Coordination of Resorption and Formation

Phase IIOsteoclast resorb bone creating cavity1048708 Macrophages clean up

Phase III1048708 New bone laid down by osteoblasts1048708 Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Hormonal Influence

Vitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Vitamin D

Osteoblast have receptors for (125-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (125-(OH)2-D) represses

gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6 macrophage colony-stimulating factor

secretion Chronic stimulation of the PTH causes hypocalcemia

and leads to resorptive effects of PTH on bone

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Calcitonin

C cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus

of calcitonin secretionPlasma concentration is 10-20 pgml and

half life is 5 min

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Actions of Calcitonin

Osteoclasts are target cells for calcitoninMajor effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Other systemic hormones

Estrogens Increase bone remodeling

Androgens Increase bone formation

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Other systemic hormones

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Local regulators of bone remodeling

Cytokines IL-6 IL-1

ProstaglandinsGrowth factors

IGF-ITGF-β

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Osteoporosis

A disease characterized by low bone massmicroarchitectural deterioration of the bone

tissue

Leading toenhanced bone fragility increase in fracture risk

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

WHO guidelines for determiningosteoporosis

Normal Not less than 1 SD below the avg for young adults

Osteopenia -1 to -25 SD below the mean Osteoporosis More than 25 SD below the

young adult average 70 of women over 80 with no estrogen

replacement therapy qualify

Severe osteoporosis More than 25 SD below with fractures

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Osteoporosis - epidemiology

Disorder of postmenopausal women of northern European descent

Increase in the incidence related to decreasing physical activity

Over 27 million or 1of 3 women are affected with osteoporosis

Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Pathogenesis of EstrogenDeficiency and Bone Loss

Estrogen loss triggers increases in IL-1 IL-6 and TNF due toReduced suppression of gene

transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased

osteoclast development and lifespan

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Osteoclast Differentiation andActivation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

National Osteoporosis Risk Assessment (NORA) Factors Associated With Increased Risk of Osteoporosis

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

NORA Factors Associated With Reduced Risk of Osteoporosis

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

NORA BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formationFailure to complete 3 stages of remodeling

Types of osteoporosisType IType IISecondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Osteoporosis - types

Postmenopausal osteoporosis (type I)Caused by lack of estrogenCauses PTH to over stimulate osteoclastsExcessive loss of trabecular bone

Age-associated osteoporosis (type II)Bone loss due to increased bone turnoverMalabsorptionMineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Secondary osteoporosis

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Osteoporotic vertebra

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Normal vs osteoporotic bone

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Risk Factors

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

When to Measure BMD inPostmenopausal Women

All women 65 years and olderPostmenopausal women lt65 years of

age If result might influence decisions about

interventionOne or more risk factorsHistory of fracture

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

When Measurement of BMD IsNot Appropriate

Healthy premenopausal womenHealthy children and adolescentsWomen initiating ETHT for

menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Prediction of Fracture Risk

All techniques (DXA QCT QUS) predict fracture risk

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD

0

05

1

15

2

25

3

Forea

rm Hip

Verteb

ral

All Site

s

Rel

ativ

e R

isk

Forearm

Hip

Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture riskPopulation surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites

Marshall D et al Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures British Medical Journal 3121254-1259 1996

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

The McCue CUBA Ultrasonometry Technology that can Assess Osteoporosis

OsteoporoticBoneFrequency

BUA110 NormaldBMHz

40dBMHz

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture

0

10

20

30

40

50

60

Fracture No Fracture

BU

A (

dB

sq

MH

z)

Subjects who developed hip fracture showed significantly (plt0001) lower heel BUA results in a two-year follow-up prospective study of 1414 subjects

Porter RW et al Prediction of hip fracture in elderly women a prospective study British Medical Journal 301638-641 1990

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

0

01

02

03

04

05

06

07

08

09

1

Heel BUA Spine BMD Neck BMD Trochanter BMD

Are

a U

nd

er

the C

urv

e

When assessing vertebral osteoporosis there was no statistically significant difference in the discriminating power of Heel BUA or Spine Femur Neck or Trochanter BMD by DXA

Ohishi T et al Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture Journal of Clinical Densitometry 3227-231 2000

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Receiver Operator Characteristic Analysis of Hip Fracture Risk

05

055

06

065

07

075

08

085

09

Heel BUA Femur Neck BMD

Are

a U

nd

er t

he

Cu

rve

Schott AM et al Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density

Journal of Bone and Mineral Research 10243-249 1995

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

0

05

1

15

2

25

3

Hans et al Bauer et al Frost et al

Research Study

Rel

ativ

e R

isk

of

Fra

ctu

re

BUA

BMD

Hans D et al Ultrasonographic heel measurements to predict hip fracture in elderly women the EPIDOS prospective study Lancet 348511-514 1996

Bauer DC et al Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women Archieves of Internal Medicine 157629-634 1997

Frost ML et al A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip Calcified Tissue International 71207-211 2002

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Increased Relative Fracture Risk is Seen With Decreasing BUA

005

115

225

335

445

5

lt10 10 to lt40 40 to lt70 70 to 100

Percentile Category

Rel

ativ

e F

ract

ure

Ris

k

14824 men and women were followed for an average of 19 years to relate BUA to future fracture riskSubjects in the lowest 10th percentile of BUA showed a relative risk of fracture 444 times greater than those in the highest 30th percentile of BUA

Khaw KT et al Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus EPIC-Norfolk prospective study Lancet 363197-202 2004

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Who Should Be Consideredfor Prevention or Treatment

Postmenopausal women with T-score below ndash20 with no risk factors

Postmenopausal women with T-score below ndash15 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

NORA

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

NORA

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Prevention of Bone Loss

Prevention of Bone LossCalciumHRTSERMSCalcitoninBisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary

Forearm BMD

WHI Results

WHI Results

Summary

WHI Results

WHI Results

Summary

WHI Results

Summary

Summary