1. June 2004 Bone Quality 2004

2. 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

3. 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

4. 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

5. 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/cm 2 ) Fracture Risk / 1000 Person Year Age (Years) 0 20 40 60 80 100 120 140 160 >1.00.90-0.990.80-0.890.70-0.790.60-0.69<0.60 <45 50-54 45-49 55-59 60-64 65-69 70-74 75-79 80+

6. 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

7. 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

8. June 2004 Randomized Studies of Antiresorptives in Postmenopausal Osteoporotic Women * Risk of Vertebral Fractures 1 Data on file, Eli Lilly & Co. 2 Black DM et al.Lancet348:1535-1541, 1996 3 Cummings SR et al.JAMA280:2077-2082, 1998 4 Harris ST et al.JAMA282:1344-1352, 1999 5 Reginster JY et al.Osteoporosis Int11:83-91, 2000 6 Chesnut CH et al.Am J Med109:267-276, 2000 LS BMD**Relative Risk (95% CI) Raloxifene 60 mg/d Preexisting vertebral fracture (VFx) 1 No preexisting VFx 1 2.2 2.9 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 *Not head-to-head comparison, **vs placebo 0.51.0 0

9. June 2004 Sourced 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 New Vertebral Fracture at 3 Years 20 18 16 14 12 10 8 6 4 2 -3.2-2.8 -2.6-2.4-2.2-2.0-1.8-1.6 0

10. June 2004 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 Placebo Raloxifene (pooled) % Change in Femoral Neck BMD % Risk of  1 New Vertebral Fracture 95% confidence interval 13 7 5 3 9 11 15 -10 -8 -6-4-202468 10 0

11. 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 64202468 13 11 15 7 5 3 9 0 B B A A Risk of  1 New Vertebral Fracture at 3 Years (%) % Change in Femoral Neck BMD at 3 Years

12. 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

13. 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

14. June 2004 aBMD (areal) = g/cm 2 vBMD (volumetric) = g/cm 3 Bone Quality Bone Quality Bone Strength and Microarchitecture Geometry Turnover Rate Damage Accumulation Degree of Mineralization Properties 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 Mineral Density

15. June 2004 BONE QUALITY CONCEPT Bone Mass Distribution of Mass Geometry Architecture Bone Strength Turnover Material Properties Mineralization Matrix Quality Microdamage

16. 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

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

18. 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

19. June 2004 Distribution of Cortical and Trabecular Bone Thoracic and75% trabecular Lumbar Spine25% cortical Femoral Neck25% trabecular 75% cortical Hip Intertrochanteric Region 50% trabecular 50% cortical 1/3 Radius >95% Cortical Ultradistal Radius 25% trabecular 75% cortical

20. 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

21. June 2004 Relevance of Architecture NormalLoss ofLoss of Quantity Quantity andQuantityand Architecture Architecture

22. 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

23. June 2004 Structural Role of Trabeculae Compressive strength of connected and disconnected trabeculae 16 X 1 Bell GH et al. Calcif Tissue Res 1: 75-86, 1967

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

25. 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

26. June 2004 Trabecular Perforations Seeman E Lancet 359, 1841-1850, 2002. Reprinted with Permission from Mosekilde L. Bone Miner 10: 13-35, 1990

27. June 2004 Antiresorptive Agents Help to Preserve Supporting Ties Reprinted with Permission from Mosekilde L. Bone 9: 247-250, 1988

28. June 2004 Bone Architecture Cortical Bone Key Variables Associated With Cortical Bone Strength Bone turnover Cortical thickness Geometry and Dimensions

29. June 2004 Effects of Antiresorptive Drugs Fracture at a Stress Riser Stress Risers High turnover state: endosteal resorption and increased porosity Low turnover state: reduced endosteal resorption and porosity

30. 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

31. 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 After Alendronate mineralization porosity June 2004

32. Increases thickness Improves geometry-Increases diameter Teriparatide - Effect on Cortical Bone

33. FACT Trial Lumbar Spine BMD Areal (DXA) and Volumetric (QCT) Percent change at 6 months 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

34. Teriparatide Effects on the Femoral Midshaft of Ovariectomized Monkeys Ovx PTH5W PTH1W Sham PTH 1PTH 5 Sourced from Sato et al., JBMR 2004 19 623-629 and Data on file, Eli Lilly & Company

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

36. Structural Indices Quantitative Analysis-significant Changes Trabecular bone volume Structure model index Connectivity density Cortical thickness P<0.05 P<0.001 P<0.05 Sourced from Jiang et al. J Bone Miner Res 18:1932-1941, 2003 June 2004

37. 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