June 2004

Bone Quality 2004

June 2004

A systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.

Old Definition of Osteoporosis

Conference Report from the Consensus Development Conference. Am J Med 94: 646-650, 1993

June 2004

• Low baseline bone mineral density (BMD) predicts increased risk of subsequent fractures

• The magnitude of the increases in BMD with antiresorptive therapies differs greatly, yet the vertebral fracture risk reductions are similar

• There is only a weak relationship between changes in BMD with antiresorptive therapy and the reduction in risk of new fractures

Relationship Between BMD and Fracture

June 2004

What May Contribute to an Increase in BMD?

• Improvements in mineral and matrix composition• Increased bone tissue per unit of bone volume:

• Filling in remodeling space• Widening existing trabeculae• Creating new trabeculae

• Increased bone size

June 2004

Age and Bone Mass as Predictors of Fracture

Hui SL et al. J Clin Invest 81:1804-1809; 1988

Forearm Bone Mass (g/cm2)

Fra

ctur

e R

isk

/ 10

00 P

erso

n Y

ear

Age (Years)

0

20

40

60

80

100

120

140

160

>1.0 0.90-0.99 0.80-0.89 0.70-0.79 0.60-0.69 <0.60

<45

50-5445-49

55-5960-6465-69

70-74

75-79

80+

June 2004

BMD Change and Fracture Risk Reduction with Antiresorptive Therapy

• Fracture Risk decreases by 6-12 months, before maximum BMD response has occurred

• Treatment may reduce fracture risk with little or no change in BMD

• From regression analyses, only a small proportion of fracture risk reduction is attributable to an increase in BMD

June 2004

Vertebral Fracture Risk Reduction Attributable to an Increase in BMD

Antiresorptive Therapy

Risedronate1 7 – 28%

Alendronate2 16%

Raloxifene3 4%

1. Li et al. Stat Med 20:3175-88; 20012. Cummings S et al. Am J Med 112:281-289; 20023. Sarkar Set al. J Bone Miner Res 17: 1-10; 2002

June 2004

Randomized Studies of Antiresorptives in Postmenopausal Osteoporotic Women*

Risk of Vertebral Fractures

1Data on file, Eli Lilly & Co.2Black DM et al. Lancet 348:1535-1541, 19963Cummings SR et al. JAMA 280:2077-2082, 1998

4Harris ST et al. JAMA 282:1344-1352, 19995Reginster JY et al. Osteoporosis Int 11:83-91, 20006 Chesnut CH et al. Am J Med 109:267-276, 2000

LS BMD** Relative Risk (95% CI)

Raloxifene60 mg/d

Preexisting vertebral fracture (VFx)1

No preexisting VFx1

2.2

2.9

Alendronate

5/10 mg/d

Preexisting VFx2

No preexisting VFx3

6.2

6.8

Risedronate5 mg/d

Preexisting VFx4

No preexisting VFx5

4.35.9

Calcitonin200 IU/d

Preexisting VFx6 0.7

*Not head -to-head comparison, **vs placebo 0.5 1.00

June 2004Sourced from Sarkar S et al. J Bone Miner Res 17:1-10, 2002

Relationship Between Baseline Femoral Neck BMD and Vertebral Fracture Risk

MORE Trial - 3 Years

Baseline Femoral Neck BMD T-Score (NHANES)

Placebo

Raloxifene (pooled)

95% Confidence Interval

22%

Risk

of

1 N

ew

Verte

bral

Fra

ctur

e at

3 Y

ears 20

18

1614

12

10

864

2

-3.2 -2.8 -2.8 -2.6 -2.4 -2.2 -2.0 -1.8 -1.60

June 2004Sourced from Sarkar S et al. J Bone Miner Res 17:1-10, 2002

Relationship Between Change in Femoral Neck BMD and Vertebral Fracture Risk

MORE Trial - 3 Years

Placebo

Raloxifene (pooled)

% Change in Femoral Neck BMD

% R

isk

of

1 N

ew

V

ert

eb

ral F

ract

ure

95% confidence interval13

7

5

3

9

11

15

-10 -8 -6 -4 -2 0 2 4 6 8 100

June 2004

Placebo

Raloxifene (pooled)

Sourced from Sarkar S et al. J Bone Miner Res 17:1-10, 2002

Relationship Between Change in Femoral Neck

BMD and Vertebral Fracture Risk MORE Trial – 3 Years

- - - - -10 8 6 4 2 0 2 4 6 8 10

13

11

15

7

5

3

9

0

B

B

A

A

Ris

k o

f 1

Ne

w V

ert

eb

ral F

ract

ure

at 3

Yea

rs (

%)

% Change in Femoral Neck BMD at 3 Years

June 2004

Many Characteristics of Bone Strength Are Not Reflected in DXA Results

• Reflected in DXA Measurements:• Bone size• Trabecular volume and cortical thickness• Amount of mineralization in bone and surrounding tissues

• Not Reflected in DXA Measurements:• Trabecular connectivity and number• Matrix quality (collagen, mineral)• Microscopic damage (e.g. microcracks)• Bone geometry

June 2004

Normal bone Osteoporosis

Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality.

Current Definition of Osteoporosis

NIH Consensus Development Panel on Osteoporosis JAMA 285:785-95; 2001

June 2004

aBMD (areal) = g/cm2

vBMD (volumetric) = g/cm3

BoneQualityBone

Quality BoneStrength and

MicroarchitectureGeometryTurnover RateDamage AccumulationDegree of MineralizationProperties of the Collagen/mineral Matrix

Shifting the Osteoporosis Paradigm Bone Strength

NIH Consensus Statement 2000

Sourced from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95; 2001

Bone MineralDensity

June 2004

BONE QUALITY CONCEPT

Bone Mass

Distribution of MassGeometry

Architecture

Bone Strength

Tur

nove

r

Material PropertiesMineralizationMatrix QualityMicrodamage

June 2004

Components of Bone Quality

• Architecture• Macroarchitecture (bone geometry)• Microarchitecture (trabecular connectivity and shape)

• Bone turnover• Resorption• Formation

• Material properties

• Collagen properties (cross-linking)• Mineralization (degree and heterogeneity)• Microdamage (microcracks)

Chesnut III CH. J Bone Miner Res 16:2163-2172, 2001NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95;2001

Fracture

BoneStrength

Bone Mass Nutrition

FallsShape &

ArchitectureHormones

Exercise &Lifestyle

Material Properties

PosturalReflexes

Soft TissuePadding

Reproduced with permission from Heaney RP. Bone 33:457-465, 2003

Factors Leading to Osteoporotic Fracture: Role of Bone Mass

June 2004

June 2004

Bone Quality

Sourced from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95; 2001

Architecture

Turnover Rate

Damage Accumulation

Degree of Mineralization

Properties of the collagen/mineral matrix

June 2004

Distribution of Cortical and Trabecular Bone

Thoracic and 75% trabecularLumbar Spine 25% cortical

Femoral Neck 25% trabecular75% cortical

Hip Intertrochanteric Region 50% trabecular

50% cortical

1/3 Radius >95% Cortical

Ultradistal Radius25% trabecular

75% cortical

June 2004

Cortical and Trabecular Bone

• 80% of all the bone in the body • 20% of bone turnover

• 20% of all bone in the body • 80% of bone turnover

Cortical Bone

Trabecular Bone

June 2004

Relevance of Architecture

Normal Loss of Loss of QuantityQuantity and Quantity and Architecture Architecture

June 2004

Bone ArchitectureTrabecular Perforation

The effects of bone turnover on the structural role of trabeculae

Risk of Trabecular Perforation increases with:

• Increased bone turnover• Increased erosion depth• Predisposition to trabecular thinning

June 2004

Structural Role of Trabeculae

Compressive strength of connected and disconnected trabeculae

16 X1

Bell GH et al. Calcif Tissue Res 1: 75-86, 1967

June 2004

Resorption Cavities as Mechanical Stress Risers

Sourced from Parfitt AM et al. Am J Med 91, Suppl 5B: 42S-46S

Normal Osteoporotic

June 2004

Strain Distribution in Relation to Trabecular Perforations

Reprinted with Permission from Van der Linden JC et al. J Bone Miner Res 16:457-465; 2001

• Trabeculae under low strain (blue) can tolerate bone loss better than traceculae under high strain (red)

• Resorption of trabeculae causes a larger decrease in stiffness than does thinning of trabeculae

June 2004

Trabecular Perforations

Seeman E Lancet 359, 1841-1850, 2002.

Reprinted with Permission from Mosekilde L. Bone Miner 10: 13-35, 1990

June 2004

Antiresorptive Agents Help to Preserve Supporting Ties

Reprinted with Permission from Mosekilde L. Bone 9: 247-250, 1988

June 2004

Bone ArchitectureCortical Bone

Key Variables Associated With Cortical Bone Strength

•Bone turnover

•Cortical thickness

•Geometry and Dimensions

June 2004

Effects of Antiresorptive Drugs

Fracture at a Stress RiserStress Risers

High turnover state: endosteal resorption and increased porosity

Low turnover state: reduced endosteal resorption and porosity

June 2004

Effect of Teriparatide [rh PTH(1-34)] on Radial BMD

• Periosteal apposition of new bone that is not yet fully mineralized

• Endosteal resorption of normal or highly mineralized bone

BMD

Zanchetta JR et al. J Bone Miner Res 18, 539-534, 2003

periosteal

endosteal

Possible Mechanism for Reduced BMD Response to TPTD Among Alendronate-Pretreated Patients

Pretreatment

bone mass

remodeling space

BMD

TPTD Treatment

endosteal porosity periosteal new bone

cortical area

BMD

AfterAlendronate

mineralization

porosity

June 2004

June 2004

Increases thickness

Improves geometry-Increases diameter

Teriparatide - Effect on Cortical Bone

FACT Trial Lumbar Spine BMD

Areal (DXA) and Volumetric (QCT)

Pe

rce

nt c

ha

ng

e a

t 6 m

on

ths QCT Subset

*

*

*

†

†

Within treatment: *P<0.01 Treatment difference: †P<0.01

TPTD (n = 16)ALN (n = 19)

McClung MR et al. Osteoporos Int 13(Suppl 3):S18, 2002

June 2004

June 2004

Teriparatide Effects on the Femoral Midshaft of Ovariectomized Monkeys

Ovx PTH5WPTH1W

Sham PTH 1 PTH 5

Sourced from Sato et al., JBMR 2004 19 623-629 and Data on file, Eli Lilly & Company

Teriparatide Improves Skeletal Architecture

Patient treated with teriparatide 20 µg

Female, age 65Duration of therapy: 637 days (approx 21 mos)BMD Change: Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%) Total Hip: +5.2% (group mean = 2.6 ± 4.9%)Sourced from Jiang et al. J Bone

Miner Res 18:1932-1941, 2003

Baseline Follow up Jiang UCSF

Structural IndicesQuantitative Analysis-significant Changes

Trabecular bone volume

Structure model index

Connectivity density

Cortical thickness

P<0.05

P<0.05

P<0.001

P<0.05

Sourced from Jiang et al. J Bone Miner Res 18:1932-1941, 2003

June 2004

June 2004

• Teriparatide-induced changes in trabecular and cortical bone morphology:

• contribute to increased biomechanical competence

• may explain the persistent reduction of vertebral and nonvertebral fractures with teriparatide treatment

Sourced from Jiang et al. J Bone Miner Res 18:1932-1941, 2003

Teriparatide Has Positive Effects on Bone Structure

Summary