OsteoporosisOsteoporosis

TAREK NASRALLA, MDTAREK NASRALLA, MD

RHEUMATOLOGY RHEUMATOLOGY DEPARTMENT, AL AZHAR DEPARTMENT, AL AZHAR

OsteoporosisOsteoporosis

TAREK NASRALLA, MDTAREK NASRALLA, MD

RHEUMATOLOGY RHEUMATOLOGY DEPARTMENT, AL AZHAR DEPARTMENT, AL AZHAR

IntroductionIntroduction

• Most common bone diseaseMost common bone disease• Major risk factor for fractureMajor risk factor for fracture

DefinitionDefinition

A systemic skeletal disease A systemic skeletal disease characterized by 2 main elementscharacterized by 2 main elements

low bone mass low bone mass microarchitectural deterioration of microarchitectural deterioration of

bone tissue with a consequent bone tissue with a consequent increase in bone fragility and increase in bone fragility and susceptibility to fracturesusceptibility to fracture

bone present is normally mineralized bone present is normally mineralized

MECHANISMS OF MECHANISMS OF OSTEOPOROSISOSTEOPOROSIS

‘‘High turnover’ – excessive bone resorption > High turnover’ – excessive bone resorption > excessive bone formationexcessive bone formation

- estrogen deficiency (menopause)- estrogen deficiency (menopause) - hypogonadism (testosterone deficiency)- hypogonadism (testosterone deficiency) - hyperparathyroidism- hyperparathyroidism - hyperthyroidism- hyperthyroidism ‘‘Low turnover’ – decreased bone formation Low turnover’ – decreased bone formation

>decreased bone resorption>decreased bone resorption - liver disease (primarily primary biliary cirrhosis)- liver disease (primarily primary biliary cirrhosis) - heparin- heparin - alcoholism- alcoholism Increased bone resorption and decreased bone Increased bone resorption and decreased bone

formationformation - Glucocorticoids- Glucocorticoids

PATHOGENESIS PATHOGENESIS ROLE OF SYSTEMIC ROLE OF SYSTEMIC

HORMONESHORMONES Calcium-regulating hormonesCalcium-regulating hormones – –

Calcitonin, parathyroid hormone, Vitamin DCalcitonin, parathyroid hormone, Vitamin D Estrogen - Estrogen - inhibits bone resorption inhibits bone resorption deficiency (menopause) - increased bone deficiency (menopause) - increased bone

resorption and rapid bone loss. resorption and rapid bone loss. Androgens - Androgens - deficiency results in bone loss deficiency results in bone loss

with increased bone turnover similar to with increased bone turnover similar to estrogen deficiencyestrogen deficiency

Growth hormone/insulin-like growth Growth hormone/insulin-like growth factorfactor - major determinant of skeletal growth - major determinant of skeletal growth

PATHOGENESISPATHOGENESISLOCAL CYTOKINES AND LOCAL CYTOKINES AND

PROSTAGLANDINSPROSTAGLANDINS CytokinesCytokines - IL-I , IL-6 and TNF-a - potent - IL-I , IL-6 and TNF-a - potent

stimulators of bone resorption and can also inhibit stimulators of bone resorption and can also inhibit bone formation. bone formation.

- IL-4 and IL-13 inhibit bone resorption- IL-4 and IL-13 inhibit bone resorption ProstaglandinsProstaglandins – particularly E2, increase both – particularly E2, increase both

bone resorption and formation bone resorption and formation - many of the local and systemic factors that - many of the local and systemic factors that

regulate bone metabolism also affect prostaglandin regulate bone metabolism also affect prostaglandin synthesis in bone synthesis in bone

Local Growth factors - Local Growth factors - IGFs - important in IGFs - important in maintaining the differentiation and function of maintaining the differentiation and function of osteoblasts osteoblasts

- Others: TGF-beta, PTHrP, Fibroblast growth factor - Others: TGF-beta, PTHrP, Fibroblast growth factor

RISK FACTORS FOR RISK FACTORS FOR OSTEOPOROSISOSTEOPOROSIS

AGEAGE Bone mass decreases with ageBone mass decreases with age Age-related bone loss begins in the 4th or Age-related bone loss begins in the 4th or

5th decades5th decades slow loss of cortical and trabecular bone in slow loss of cortical and trabecular bone in

both men and women both men and women Fracture risk also increases with ageFracture risk also increases with age Decreased calcium and vitamin D intake Decreased calcium and vitamin D intake

and reduced sun exposure can lead to and reduced sun exposure can lead to secondary hyperparathyroidism, which may secondary hyperparathyroidism, which may play a role in age-related bone loss play a role in age-related bone loss

Risk FactorsRisk Factors

SEXSEX• More common in women More common in women • Overall fracture rate increased Overall fracture rate increased

threefold in womenthreefold in women• Lower mean peak bone massLower mean peak bone mass• Accelerated bone loss after menopause Accelerated bone loss after menopause • About 75 percent of bone lost after About 75 percent of bone lost after

menopause may be related to estrogen menopause may be related to estrogen deficiency rather than age deficiency rather than age

Risk Factors Risk Factors

RACE RACE Risk of hip fractures is lower in African-American Risk of hip fractures is lower in African-American

women than in Caucasians women than in Caucasians - higher peak bone mass - higher peak bone mass - slower rate of bone loss after menopause - slower rate of bone loss after menopause Asian women have a lower risk of fracture than Asian women have a lower risk of fracture than

Caucasian women. Caucasian women. Though, bone mineral density is lower in Asian Though, bone mineral density is lower in Asian

women - ? due to their smaller body habitus women - ? due to their smaller body habitus Differences in fracture risk across different Differences in fracture risk across different

ethnic groups cannot be explained on the basis of ethnic groups cannot be explained on the basis of differences in bone mineral density alonedifferences in bone mineral density alone

Risk FactorsRisk Factors

GENETICSGENETICS Play a contributory role in bone Play a contributory role in bone

density and fracture riskdensity and fracture risk Vitamin D receptor genotypes – may Vitamin D receptor genotypes – may

affect the ability to bind vitamin Daffect the ability to bind vitamin D Variants in BMP2 gene – identified Variants in BMP2 gene – identified

in families with osteoporosisin families with osteoporosis Variants of estrogen receptor alpha Variants of estrogen receptor alpha

and beta (ESR1 and ESR2) geneand beta (ESR1 and ESR2) gene

Risk FactorsRisk Factors

Sedentary life style (decreased bone Sedentary life style (decreased bone mass and physical functioning)mass and physical functioning)

Slender habitusSlender habitus Low peak bone densityLow peak bone density HypogonadismHypogonadism Pregnancy and Lactation (transient Pregnancy and Lactation (transient

loss)loss) Pernicious anemia - suppression of Pernicious anemia - suppression of

osteoblast activity osteoblast activity

Risk FactorsRisk Factors

Medications Medications – steroids, excess thyroid – steroids, excess thyroid hormone, methotrexate, heparin, hormone, methotrexate, heparin, anticonvulsants, cyclosporineanticonvulsants, cyclosporine

Homocystinuria and high Homocystinuria and high homocysteinehomocysteine levels in adults levels in adults

VitB12 and folate supplementation in VitB12 and folate supplementation in older adults with high homocysteine older adults with high homocysteine level after a stroke has been shown to level after a stroke has been shown to decrease hip fractures (absolute risk decrease hip fractures (absolute risk reduction 7% at 2 years)reduction 7% at 2 years)

Sato Y et al. JAMA 2005 Mar 2;293(9):1082-8.

RISK FACTORS - RISK FACTORS - NUTRITIONNUTRITION

Calcium deficiencyCalcium deficiency Vitamin D deficiencyVitamin D deficiency Protein excess or deficiencyProtein excess or deficiency Phosphoric acid excessPhosphoric acid excess Cigarette Smoking (increases bone Cigarette Smoking (increases bone

loss and decreases intestinal calcium loss and decreases intestinal calcium absorption)absorption)

Excessive caffeine intakeExcessive caffeine intake Vitamin A excessVitamin A excess

DISEASES ASSOCIATED DISEASES ASSOCIATED WITH OSTEOPENIAWITH OSTEOPENIA

PTHPTH HyperthyroidismHyperthyroidism Cushing’sCushing’s MyelomaMyeloma MastocytosisMastocytosis Liver diseaseLiver disease Renal diseaseRenal disease

Celiac diseaseCeliac disease R.A.R.A. Osteogenesis Osteogenesis

imperfectaimperfecta AIDSAIDS IBSIBS Others Others

Protective factorsProtective factors

higher body mass indexhigher body mass index black raceblack race estrogen estrogen diuretic therapy (thiazides)diuretic therapy (thiazides) exerciseexercise Moderate alcohol ingestion (associated Moderate alcohol ingestion (associated

with increased bone mineral density), with increased bone mineral density), data relating to fracture risk - mixed data relating to fracture risk - mixed

SYMPTOMS OF SYMPTOMS OF OSTEOPOROSISOSTEOPOROSIS

AsymptomaticAsymptomatic Pain with fracture (or not)Pain with fracture (or not) Decreased heightDecreased height ““Dowager’s hump”- kyphosisDowager’s hump”- kyphosis Look for risk factorsLook for risk factors symptoms and signs of associated symptoms and signs of associated

conditionsconditions

LABORATORY LABORATORY EVALUATION EVALUATION

To exclude secondary causes of To exclude secondary causes of osteoporosisosteoporosis

Calcium, phosphorus, BUN, Cr., TSH, Calcium, phosphorus, BUN, Cr., TSH, CBC, alkaline phosphataseCBC, alkaline phosphatase

Consider:Consider: PTH, serum 25-hydroxyvitamin D PTH, serum 25-hydroxyvitamin D

levels - secondary hyperparathyroidismlevels - secondary hyperparathyroidism SPEP, UPEP – multiple myelomaSPEP, UPEP – multiple myeloma In men, serum free testosteroneIn men, serum free testosterone

DIAGNOSIS OF DIAGNOSIS OF OSTEOPOROSISOSTEOPOROSIS

PLAIN RADIOGRAPHS PLAIN RADIOGRAPHS Detectable changes with 30-50% bone lossDetectable changes with 30-50% bone loss Trabecular thinning Trabecular thinning Compression fracturesCompression fractures BONE DENSITOMETRYBONE DENSITOMETRY Single-photon absorptiometry – screening, Single-photon absorptiometry – screening,

used at peripheral sites (radius, calcaneus)used at peripheral sites (radius, calcaneus) Dual x-ray absorptiometry (DEXA) -GOLD Dual x-ray absorptiometry (DEXA) -GOLD

STANDARD, precise measurements at hip STANDARD, precise measurements at hip and spineand spine

OTHER METHODS – Quantitative computed OTHER METHODS – Quantitative computed tomography, Ultrasoundtomography, Ultrasound

WHOWHO Diagnostic Criteria for Diagnostic Criteria for Osteopenia and Osteoporosis Osteopenia and Osteoporosis

Based on Bone Mass Based on Bone Mass MeasurementsMeasurements CategoryCategory

NormalNormal

OsteopeniaOsteopenia

OsteporosisOsteporosis

Bone massBone mass BMD within one BMD within one

standard deviation of standard deviation of the young adult the young adult reference mean (T-reference mean (T-score)score)

BMD between 1- 2.5 BMD between 1- 2.5 standard deviations standard deviations below the young adult below the young adult reference meanreference mean

BMD BMD >>2.5 standard 2.5 standard deviations below the deviations below the young adult reference young adult reference mean or presence of mean or presence of >> one fragility fracturesone fragility fractures

Indications for bone Indications for bone densitometrydensitometry

Estrogen-deficient women at clinical Estrogen-deficient women at clinical risk of osteoporosisrisk of osteoporosis

Vertebral abnormalitiesVertebral abnormalities Long-term steroid useLong-term steroid use Primary hyperparathyroidismPrimary hyperparathyroidism Monitoring response to therapyMonitoring response to therapy Every 2 years (controversial)Every 2 years (controversial)

NOF TREATMENT NOF TREATMENT GUIDELINESGUIDELINES

Postmenopausal women with Postmenopausal women with vertebral or hip fracturesvertebral or hip fractures

T-score less than –2 with no risk T-score less than –2 with no risk factorsfactors

T-score –1.5 or below with risk T-score –1.5 or below with risk factorsfactors

TREATMENT OF TREATMENT OF OSTEOPOROSISOSTEOPOROSIS

NON- PHARMACOLOGIC THERAPYNON- PHARMACOLOGIC THERAPY Diet - Calcium and Vit DDiet - Calcium and Vit D ExerciseExercise Smoking cessationSmoking cessationPHARMACOLOGIC THERAPY (postmenopausal PHARMACOLOGIC THERAPY (postmenopausal

with osteopenia or osteoporosis)with osteopenia or osteoporosis) ““Estrogens” Estrogens” BisphosphonatesBisphosphonates Selective estrogen receptor modulatorsSelective estrogen receptor modulators CalcitoninCalcitonin Parathyroid hormoneParathyroid hormone Others – Isoflavones, thiazide, tiboloneOthers – Isoflavones, thiazide, tibolone

CALCIUM AND VITAMIN CALCIUM AND VITAMIN DD

For post menpausal women and older men: For post menpausal women and older men: Daily calcium intake – 1500mg/day Daily calcium intake – 1500mg/day

Shown to decrease fracture rate in Shown to decrease fracture rate in institutionalized and community elderlyinstitutionalized and community elderly

Safe except in those with other causes of Safe except in those with other causes of hypercalcemiahypercalcemia

Probably does not increase risk of kidney Probably does not increase risk of kidney stones.stones.

Take calcium carbonate with food for Take calcium carbonate with food for absorptionabsorption

Ca supplementation may favorably affect Ca supplementation may favorably affect serum lipidsserum lipids

VITAMIN DVITAMIN D

Important for calcium absorption, Important for calcium absorption, affects PTHaffects PTH

Elderly need more—less response to Elderly need more—less response to sunlight, less efficient hydroxylationsunlight, less efficient hydroxylation

Total Vit D 800 IU/day Total Vit D 800 IU/day higher doses may be required with higher doses may be required with

malabsorption or certain meds - malabsorption or certain meds - anticonvulsantsanticonvulsants

Exercise and Smoking Exercise and Smoking CessationCessation

EXERCISEEXERCISE Associated with lower risk of hip fracturesAssociated with lower risk of hip fractures - increased muscular strength- increased muscular strength Associated with improvements in bone Associated with improvements in bone

density:density: 2 – 6%2 – 6% Recommended exercise – 30mins, 3 Recommended exercise – 30mins, 3

days/weekdays/weekSMOKING CESSATIONSMOKING CESSATION Accelerates bone lossAccelerates bone loss One pack/day in adult life associated in 5- One pack/day in adult life associated in 5-

10% reduction in bone density10% reduction in bone density

ESTROGENSESTROGENS Anti-resorptive, can stop bone loss and Anti-resorptive, can stop bone loss and

decrease fracturesdecrease fractures Was considered primary therapy in Was considered primary therapy in

postmenopausal womenpostmenopausal women WHI study of estrogen and WHI study of estrogen and

progesterone stopped early due to progesterone stopped early due to adverse effects - breast cancer, CAD, adverse effects - breast cancer, CAD, stroke and venous thromboembolic stroke and venous thromboembolic eventsevents

No more effective than bisphosphonatesNo more effective than bisphosphonates

BisphosphonatesBisphosphonates Alendronate (fosomax) – treatment dose: Alendronate (fosomax) – treatment dose:

10mg/day or 70mg weekly, prevention dose: 10mg/day or 70mg weekly, prevention dose: 5mg/day or 35mg weekly 5mg/day or 35mg weekly

Risedronate (actonel) – treatment and prevention Risedronate (actonel) – treatment and prevention dose: 5mg/day or 35mg weeklydose: 5mg/day or 35mg weekly

New - IbandronateNew - Ibandronate ( (Boniva)– 150mg monthly Boniva)– 150mg monthly dosedose

Increases bone densityIncreases bone density Decreases vertebral and nonvertebral fracturesDecreases vertebral and nonvertebral fractures Beneficial effects for at least ten yearsBeneficial effects for at least ten years Bone loss after treatment is stoppedBone loss after treatment is stopped Side effects – pill-induced esophagitis, Side effects – pill-induced esophagitis,

hypocalcemiahypocalcemia

Selective estrogen receptor Selective estrogen receptor modulatorsmodulators

Raloxifene (Evista)Raloxifene (Evista) Approved for prevention and treatmentApproved for prevention and treatment Increases BMDIncreases BMD Less effective than estrogen and Less effective than estrogen and

bisphosphonates (though no direct bisphosphonates (though no direct comparisons)comparisons)

No increase in breast or endometrial No increase in breast or endometrial cancercancer

Side effects: venous thromboembolismSide effects: venous thromboembolism

CALCITONINCALCITONIN

Intranasal dailyIntranasal daily Can decrease pain of acute Can decrease pain of acute

vertebral fracturevertebral fracture Well-toleratedWell-tolerated Not much effect on BMD or Not much effect on BMD or

fracture riskfracture risk

TERIPARATIDE TERIPARATIDE (FORTEO)(FORTEO)

Parathyroid hormoneParathyroid hormone Intermittent administration stimulates bone Intermittent administration stimulates bone

formation more than resorptionformation more than resorption Daily injectionDaily injection Increases bone mass and decreases fractures Increases bone mass and decreases fractures

(65-70 % in vertebral fractures)(65-70 % in vertebral fractures) Compared to alendronate – greater increase Compared to alendronate – greater increase

in spine bone density and decreased in spine bone density and decreased vertebral riskvertebral risk

Side effects: nausea, headaches, Side effects: nausea, headaches, hypercalcemiahypercalcemia

Reserved for high risk patients: daily Reserved for high risk patients: daily injection, high cost, risk of osteosarcomainjection, high cost, risk of osteosarcoma

OthersOthers Isoflavones – phytoestrogenIsoflavones – phytoestrogen - Commonly found in soy products- Commonly found in soy products -Conflicting results in studies-Conflicting results in studies Thiazides diuretics – useful in postmenopausal Thiazides diuretics – useful in postmenopausal

women with hypertension women with hypertension - modest decrease in bone loss- modest decrease in bone loss Tibolone – synthetic steroid with estrogenic, Tibolone – synthetic steroid with estrogenic,

androgenic, progestagenic propertiesandrogenic, progestagenic properties -increases bone density, has not been shown to -increases bone density, has not been shown to

decrease fracture riskdecrease fracture risk - may increase risk of endometrial hyperplasia, - may increase risk of endometrial hyperplasia,

breast cancerbreast cancer -widely used in Europe, not FDA approved-widely used in Europe, not FDA approved

Potential therapiesPotential therapies Androgen – does not appear to be Androgen – does not appear to be

superior to estrogen, virilizing effectssuperior to estrogen, virilizing effects Growth factors – stimulate bone growth, Growth factors – stimulate bone growth,

useful in growth hormone deficiency, useful in growth hormone deficiency, conflicting trial results with normal conflicting trial results with normal levelslevels

Statins – conflicting data, observational Statins – conflicting data, observational studies report no effects on bone densitystudies report no effects on bone density

- small clinical trial showed modest - small clinical trial showed modest increase in forearm BMDincrease in forearm BMD

Other therapiesOther therapies

Strontium ranelate - increases bone Strontium ranelate - increases bone formation, inhibits bone resorptionformation, inhibits bone resorption

in clinical trials, increased BMD in in clinical trials, increased BMD in spine and femur and decreased spine and femur and decreased fracture.fracture.

side effect – diarrheaside effect – diarrhea

Folate and Vit B12 – may lower fracture Folate and Vit B12 – may lower fracture risk in elderly patients (with elevated risk in elderly patients (with elevated homocysteine level) after a strokehomocysteine level) after a stroke

OSTEOPOROSIS IN MENOSTEOPOROSIS IN MEN Occurs at later ageOccurs at later age Incidence of hip fractures increases Incidence of hip fractures increases

exponentially with ageexponentially with age Mortality associated with hip fractures and Mortality associated with hip fractures and

other major fractures is higher in men other major fractures is higher in men Men are less likely to be evaluated or receive Men are less likely to be evaluated or receive

antiresorptive therapy after a hip fracture antiresorptive therapy after a hip fracture Consider serum free testosterone, SPEP, Consider serum free testosterone, SPEP,

UPEP, PTH, 1,25(OH2)Vitamin D level or UPEP, PTH, 1,25(OH2)Vitamin D level or endocrine consultendocrine consult

Bisphosphonates proven effective in menBisphosphonates proven effective in men

It’s Up To You Now!It’s Up To You Now!

What are you going to do to have What are you going to do to have strong bones that last a lifetime?strong bones that last a lifetime?