1. Bone Quality PART 1 Introduction Architecture Turnover

2. 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. 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. What May Contribute to an Increase in BMD? Increased mineralization in existing bone Increased bone tissue per unit of bone volume: Filling in resorption space Widening existing trabeculae Creating new trabeculae Increased bone size

5. 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. 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. 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 et al. Am J Med 112:281-289; 2002 3. Sarkar et al. J Bone Miner Res 17: 1-10; 2002

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

11. Placebo Raloxifene (pooled) Adapted 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. 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 Collagen quality Microscopic damage (e.g. microcracks) Bone geometry

13. 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. Bone Quality Bone Strength and Architecture Turnover rate Damage Accumulation Degree of Mineralization Properties of the collagen/mineral matrix Shifting the Osteoporosis Paradigm Bone Strength NIH Consensus Statement 2000 Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95; 2001 Bone Mineral Density

15. 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

16. Bone Quality Adapted 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

17. 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

18. 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

19. Relevance of Architecture NormalLoss ofLoss of Quantity Quantity andQuantityand Architecture Architecture

20. 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

21. Structural Role of Trabeculae Compressive strength of connected and disconnected trabeculae 16 X 1 Bell et al. Calcified Tissue Research 1: 75-86, 1967

22. Resorption Cavities as Mechanical Stress Risers Adapted from Parfitt A.M. et al. Am J Med 91, Suppl 5B: 5B-34S Normal Osteoporotic

23. Strain Distribution in Relation to Trabecular Perforations Reprinted with Permission from Van der Linden 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

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

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

26. Bone Architecture Cortical Bone Fracture Risk Increases With: Increased Bone turnover Decreased cortical thickness Changes in dimensions

27. 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

28. 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. JBMR 18, 539-534, 2003

29. Possible Mechanism for Reduced BMD Response to TPTD Among Alendronate-Pretreated Patients Pretreatment bone mass remodeling space 1 Boivin, Bone 2000, 2 Burr, JBMR 2001, 3 Zanchetta, IOF 2001 BMD TPTD Treatment endosteal porosity 2 periosteal new bone cortical area 3 BMD After Alendronate mineralization porosity 1

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

31. 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 et al. Osteoporos Int. 2002 Jiang UCSF

32. Teriparatide Effects on the Femoral Midshaft of Ovariectomized Monkeys Ovx PTH5W PTH1W Sham PTH 1PTH 5 Data on file, Eli Lilly

33. Eriksen et al ACR 2002 Baseline Follow-up Effect of 20  g Teriparatide on Trabecular and Cortical Architecture

34. 3-D Structural Indices in Women in the Teriparatide Fracture Prevention Trial Quantitative analysis-Significant changes Trabecular bone volume Structure model index Connectivity density Cortical thickness P<0.025 P<0.034 P<0.001 P<0.012 Eriksen et al ACR 2002

35. Effect of 20  g Teriparatide on Bone Histology -Iliac crest bone biopsies Increased trabecular bone volume Shifted trabeculae toward a more plate-like structure Increased trabecular bone connectivity Increased cortical bone thickness with no increase in cortical porosity Eriksen et al ACR 2002

36. Bone Quality Adapted 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

37. Bone Remodeling Process Resorption Cavities Bone Osteoclasts Lining Cells Osteoblasts Osteoid Lining Cells Mineralized Bone

38. High Bone Turnover Leads to Development of Stress Risers and Perforations Lining Cells Bone Osteoclasts Stress Risers Perforations

39. Consequences of an Imbalance in Bone Turnover Normal Bone Osteoporotic Bone Mechanism of Action Animation of Bone Remodeling Process, 2002, Eli Lilly

40. Excessive suppression Increased mineralization AccumulationIncreased brittleness of microcracks Skeletal fragility There is a complex relationship between bone turnover and bone quality A decrease of bone turnover increases mineralization and permits filling of remodeling space Bone Turnover, Mineralization, and Bone Quality

41. Antiresorptive Agents Increase BMD by Decreasing Remodeling Space and/or Prolonging Mineralization Antiresorptive Agent Newly formed bone Increased Mineralization Remodeling space

42. Rate of Bone Turnover Bone turnover is an essential physiological mechanism for repairing microdamage and replacing “old” bone by “new” bone Can excessive reduction in bone turnover be harmful for bone? How much suppression is too much? Clinical paradigm: Clinical question:

43. Changes in Biochemical Markers Predict an Increase in Bone Mineral Density During Antiresorptive Therapy Treatment with antiresorptive agents produce greater proportional changes in bone turnover markers than in BMD Measurable changes in bone turnover markers tend to occur before changes in BMD There are significant correlations between changes in bone turnover markers and changes in BMD Adapted from Looker AC et al. Osteoporos Int 11:467-480; 2000

44. Bone Turnover Markers Bone turnover markers are components of bone matrix or enzymes that are released from cells or matrix during the process of bone remodeling (resorption and formation). Bone turnover markers reflect but do not regulate bone remodeling dynamics.

45. Urinary Markers of Bone Resorption MarkerAbbreviation HydroxyprolineHYP PyridinolinePYD DeoxypyridinolineDPD N-terminal cross-linking telopeptide of type I collagenNTX C-terminal cross-linking telopeptide of type I collagenCTX Delmas PD. J Bone Miner Res 16:2370; 2001

46. Serum Markers of Bone Turnover Abbreviation Formation Bone alkaline phosphatase ALP (BSAP) OsteocalcinOC Procollagen type I C-propeptidePICP Procollagen type I N-propeptidePINP Resorption N-terminal cross-linking telopeptide of type I collagen NTX C-terminal cross-linking telopeptide of type I collagenCTX Tartrate-resistant acid phosphataseTRAP Delmas PD. J Bone Miner Res 16:2370, 2001

47. Relationship Between Changes in Bone Resorption Markers and Vertebral Fracture Risk VERT Study A decrease in urinary CTX and NTX at 3-6 months was associated with vertebral fracture risk at 3 years A decrease in urinary CTX >60% and of urinary NTX >40% gave little added benefit in fracture reduction Adapted from Eastell R et al. Osteoporos Int 13:520; 2002

48. Raloxifene and Alendronate Reduce Bone Turnover in Women with Osteoporosis Mean Serum CTX (ng/L) Mean Serum PINP (  g/L) Adapted from Stepan JJ et al. J Bone Miner Res 17 (Suppl 1):S233; 2002 *p< 0.01 compared to premenopausal levels 0 100 200 300 400 500 ALN RLX * Mean ± SD 0 10 20 30 40 50 ALN RLX * Premenopausal

49. Very low turnover leads to excessive mineralization and the accumulation of microdamage Very high turnover leads to accumulation of perforations and a negative bone balance Bone Turnover Effects Bone Quality