Bone Quality 2004 June 2004 Old Definition of

Bone Quality 2004 June 2004

Old Definition of Osteoporosis 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. Conference Report from the Consensus Development Conference. Am J Med 94: 646 -650, 1993 June 2004

Relationship Between BMD and Fracture • 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 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 Age (Years) Fracture Risk / 1000 Person Year 160 80+ 140 120 75 -79 100 80 70 -74 60 65 -69 60 -64 55 -59 40 50 -54 45 -49 <45 20 0 >1. 0 0. 90 -0. 99 0. 80 -0. 89 0. 70 -0. 79 0. 60 -0. 69 <0. 60 Forearm Bone Mass (g/cm 2) Hui SL et al. J Clin Invest 81: 1804 -1809; 1988 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 Risedronate 1 7 – 28% Alendronate 2 16% Raloxifene 3 4% 1. Li et al. Stat Med 20: 3175 -88; 2001 2. Cummings S et al. Am J Med 112: 281 -289; 2002 3. 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 LS BMD** Raloxifene 60 mg/d Preexisting vertebral fracture (VFx)1 No preexisting VFx 1 2. 2 Alendronate 5/10 mg/d Preexisting VFx 2 No preexisting VFx 3 6. 2 6. 8 Risedronate 5 mg/d Preexisting VFx 4 No preexisting VFx 5 4. 3 5. 9 Calcitonin 200 IU/d Preexisting VFx 6 0. 7 2. 9 0 *Not head -to-head comparison, **vs placebo 1 Data on file, Eli Lilly & Co. 2 Black DM et al. Lancet 348: 1535 -1541, 1996 3 Cummings SR et al. JAMA 280: 2077 -2082, 1998 Relative Risk (95% CI) 0. 5 1. 0 4 Harris ST et al. JAMA 282: 1344 -1352, 1999 JY et al. Osteoporosis Int 11: 83 -91, 2000 6 Chesnut CH et al. Am J Med 109: 267 -276, 2000 5 Reginster June 2004

Relationship Between Baseline Femoral Neck BMD and Vertebral Fracture Risk % Risk of 1 New Vertebral Fracture at 3 Years MORE Trial - 3 Years 22 20 Raloxifene (pooled) 18 Placebo 16 14 95% Confidence Interval 12 10 8 6 4 2 0 -3. 2 -2. 8 -2. 6 -2. 4 -2. 2 -2. 0 -1. 8 -1. 6 Baseline Femoral Neck BMD T-Score (NHANES) Sourced from Sarkar S et al. J Bone Miner Res 17: 1 -10, 2002 June 2004

Relationship Between Change in Femoral Neck BMD and Vertebral Fracture Risk MORE Trial - 3 Years Raloxifene (pooled) 15 Placebo 95% confidence interval % Risk of 1 New Vertebral Fracture 13 11 9 7 5 3 0 -10 -8 -6 -4 -2 0 2 4 6 8 10 % Change in Femoral Neck BMD Sourced from Sarkar S et al. J Bone Miner Res 17: 1 -10, 2002 June 2004

Relationship Between Change in Femoral Neck BMD and Vertebral Fracture Risk of 1 New Vertebral Fracture at 3 Years (%) MORE Trial – 3 Years 15 13 Raloxifene (pooled) Placebo 11 9 7 A B 5 3 B A 0 -10 -8 -6 -4 -2 0 2 4 6 8 10 % Change in Femoral Neck BMD at 3 Years Sourced from Sarkar S et al. J Bone Miner Res 17: 1 -10, 2002 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

Current Definition of 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. Normal bone Osteoporosis NIH Consensus Development Panel on Osteoporosis JAMA 285: 785 -95; 2001 June 2004

Shifting the Osteoporosis Paradigm Bone Strength NIH Consensus Statement 2000 Bone Strength Bone Quality and Bone Mineral Density a. BMD (areal) = g/cm 2 v. BMD (volumetric) = g/cm 3 Microarchitecture Geometry Turnover Rate Damage Accumulation Degree of Mineralization Properties of the Collagen/mineral Matrix Sourced from NIH Consensus Development Panel on Osteoporosis. JAMA 285: 785 -95; 2001 June 2004

BONE QUALITY CONCEPT Turnover Bone Mass Distribution of Mass Geometry Architecture Bone Strength Material Properties Mineralization Matrix Quality Microdamage 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, 2001 NIH Consensus Development Panel on Osteoporosis. JAMA 285: 785 -95; 2001 June 2004

Factors Leading to Osteoporotic Fracture: Role of Bone Mass Shape & Architecture Falls Hormones Fracture Bone Strength Postural Reflexes Bone Mass Nutrition Material Properties Soft Tissue Padding Exercise & Lifestyle June 2004 Reproduced with permission from Heaney RP. Bone 33: 457 -465, 2003

Bone Quality Architecture Turnover Rate Damage Accumulation Degree of Mineralization Properties of the collagen/mineral matrix Sourced from NIH Consensus Development Panel on Osteoporosis. JAMA 285: 785 -95; 2001 June 2004

Distribution of Cortical and Trabecular Bone Thoracic and Lumbar Spine 75% trabecular 25% cortical 1/3 Radius >95% Cortical Femoral Neck 25% trabecular 75% cortical Ultradistal Radius 25% trabecular 75% cortical Hip Intertrochanteric Region 50% trabecular 50% cortical June 2004

Cortical and Trabecular Bone Cortical Bone • 80% of all the bone in the body • 20% of bone turnover Trabecular Bone • 20% of all bone in the body • 80% of bone turnover June 2004

Relevance of Architecture Normal Quantity and Architecture Loss of Quantity and Architecture June 2004

Bone Architecture Trabecular 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 1 Bell GH et al. Calcif Tissue Res 1: 75 -86, 1967 16 X June 2004

Resorption Cavities as Mechanical Stress Risers Normal Osteoporotic Sourced from Parfitt AM et al. Am J Med 91, Suppl 5 B: 42 S-46 S June 2004

Strain Distribution in Relation to Trabecular Perforations • 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 Reprinted with Permission from Van der Linden JC et al. J Bone Miner Res 16: 457 -465; 2001 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 Architecture Cortical Bone Key Variables Associated With Cortical Bone Strength • Bone turnover • Cortical thickness • Geometry and Dimensions June 2004

Effects of Antiresorptive Drugs High turnover state: endosteal resorption and increased porosity Stress Risers Fracture at a Stress Riser 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 periosteal endosteal BMD Zanchetta JR et al. J Bone Miner Res 18, 539 -534, 2003 June 2004

Possible Mechanism for Reduced BMD Response to TPTD Among Alendronate-Pretreated Patients Pretreatment bone mass remodeling space June 2004 After Alendronate TPTD Treatment BMD mineralization porosity endosteal porosity periosteal new bone cortical area

Teriparatide - Effect on Cortical Bone Improves geometry-Increases diameter Increases thickness June 2004

FACT Trial Percent change at 6 months Lumbar Spine BMD Areal (DXA) and Volumetric (QCT) * † TPTD (n = 16) ALN (n = 19) * * Mc. Clung MR et al. Osteoporos Int 13(Suppl 3): S 18, 2002 June 2004 † QCT Subset Within treatment: *P<0. 01 Treatment difference: †P<0. 01

Teriparatide Effects on the Femoral Midshaft of Ovariectomized Monkeys Sham Ovx PTH 1 W Sourced from Sato et al. , JBMR 2004 19 623 -629 and Data on file, Eli Lilly & Company PTH 5 W June 2004

Teriparatide Improves Skeletal Architecture Baseline Patient treated with teriparatide 20 µg Sourced from Jiang et al. J Bone Miner Res 18: 1932 -1941, 2003 Follow up Jiang UCSF Female, age 65 Duration 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%)

Structural Indices Quantitative Analysis-significant Changes Trabecular bone volume P<0. 001 Structure model index P<0. 05 Connectivity density P<0. 05 Cortical thickness P<0. 05 Sourced from Jiang et al. J Bone Miner Res 18: 1932 -1941, 2003 June 2004

Teriparatide Has Positive Effects on Bone Structure Summary • 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 June 2004