1. Bone Quality PART 2 Damage Accumulation Degree of Mineralization Biomechanics

2. 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

3. Dogs Treated with High Doses of Bisphosphonates Reproduced with permission from Mashiba T et al. J Bone Miner Res 15:613-620; 2000 *P<.05 vs placebo **P<.01 vs placebo Microcrack Surface Density (  m/mm 2 ) Mean ± SEM Placebo Risedronate 20 15 10 5 0 * Alendronate **

4. Reproduced with permission from Mashiba T et al. Bone 28:524-531, 2001 Microcracks Microcrack in the right femoral neck cortex from a risedronate treated dog Microcracks in the third lumbar vertebral body from an alendronate treated dog RisedronateAlendronate

5. Effect of Long-Term Bisphosphonate Treatment - Incadronate Reproduced with permission from Komatsubara S. J Bone Miner Res 18: 512-520, 2003

6. Microcrack Analysis in Monkey Vertebrae Microcrack Surface Density Burr DB. Osteoporo Int 13, Suppl 3, S73-74; 2002 0 10 20 30 40 50 60 70 80 90 OvxCEERalox 1Ralox 2Sham * * * Crack Surface Density (Cr.S.Dn.) * p<0.05 CEE-conjugated equine estrogens Ralox 1 – 1 mg/kg Ralox 2 – 5 mg/kg

7. Reproduced with permission from Seeman E. Advances in Osteoporotic Fracture Management 2: 2-8, 2002 and Fyhrie DP. Bone 15:105-109, 1994 Microdamage in Human Trabecular and Cortical Bone

8. 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

9. Bone Mineralization of the Basic Multicellular Unit 3 months Primary mineralization (3 months) Secondary mineralization (years) Time 100 - 50 - 0 - Degree of Mineralization (%) Ott S. Advances in Osteoporotic Fracture Management 2: 48-54, 2003

10. Homogeneous vs. Heterogeneous Mineralization “Microdamage progression is prevented by the roughness (or heterogeneity) of mineral densities and differing directions of mineralized collagen present.” “Cracks require energy to progress through bone, and when the mineral density is high and distribution of the tissue mineral density is homogeneous less energy (derived from deformation) is required for microdamage progression.” Seeman E. Advances in Osteoporotic Fracture Management 2: 2-8, 2002

11. Homogeneous vs. Heterogeneous Mineralization Adapted with permission from Boivin et al. Bone 27:687-694; 2000 Heterogeneous Homogeneous Low mineralization High mineralization

12. Heterogeneous Mineral Distribution in Iliac Bone Reproduced with permission from Boivin GJ. Musculoskel Neuron Interact 2: 538-543, 2002.

13. Reproduced with permission from Seeman E. Advances in Osteoporotic Fracture Management 2: 2-8; 2002 and Currey JD. J Biomechanics 12: 459-469; 1979 The Relationship Between Mineralization and Bone Strength is Complex

14. Meunier and Boivin. Bone 21:373-7, 1997 Effects of Alendronate on Bone Mineralization in Ovariectomized Monkeys.2.4.6.81.01.21.41.61.8 2000 1750 1500 1250 1000 750 500 250 0 Degree of Mineralization (g mineral/cm 3 ) Number of Measurements OVX ALN CTRL

15. Alendronate Increases Bone Mineralization in Women with Osteoporosis Two YearsThree Years Adapted with permission from Boivin et al. Bone 27:687-694; 2000.50.60.70.80.90 1.0 1.2 1.3 1.4 1.5 1.6

16. Raloxifene Treatment Induces a Normal Pattern of Bone Mineralization Boivin G. ECTS Meeting, P190, 2003. Two-year treatment with raloxifene results in a moderate increase in mineralization and preservation of heterogeneous mineral distribution

17. Biomechanics

18. What Contributes to Bone Strength? Quantity of bone Structural Properties Size and shape of bone Trabecular connectivity Trabecular shape Overall Quality Microdamage, etc. Material Properties Collagen/mineral matrix

19. Biomechanical Evaluation of Whole Bone Compression test of femoral neck Compression test of lumbar vertebral body Three-point bending of femoral midshaft

20. Whole Bone Properties Strength Stiffness Brittleness Energy (work to failure)

21. Force Displacement Untreated Treated Turner CH et al. Osteoporos Int 13:97-104; 2002 A Pharmacological Agent Should Increase Bone Strength While Also Decreasing Brittleness * Point of Failure * *

22. Mineralization Affects Brittleness X X X hyper- mineralized (osteopetrosis) optimum hypo- mineralized (osteomalacia) Force Displacement Turner CH et al. Osteoporos Int 13:97-104; 2002

23. Impact of Remodeling Lacunae on Mechanical Stress Distribution Adapted from Parfitt AM. Am J Med, 1987 stress “riser” Transmission of mechanical stress

24. Cross-Sectional Moment of Inertia CSMI =  A  d 2 x dxdx A y dzdz z

25. Cross-Sectional Moment of Inertia CSMI =  /4 (r 4 outer – r 4 inner) Area (cm 2 )2.772.772.77 CSMI (cm 4 )0.611.061.54 Bending Strength100%149%193%

26. Cross-Sectional Moment of Inertia Adapted from Lee CA, and Einhorn TA. Osteoporosis 2nd Ed. 2001

27. Relative Influence of Inner and Outer Diameters on Bone Strength Adapted from Lee CA, and Einhorn TA. Osteoporosis 2nd Ed. 2001

28. Buckling Ratio = r o t Local Buckling Local buckling in hollow tubes becomes likely when the buckling ratio is > 10 thickness radius

29. Local Buckling

30. 01234 5 Intertrochanteric Narrow Neck Distance (cm) Bone Mass (g/cm 2 ) Shaft Analysis Of Hip Cortical Bone Reprinted with Permission Beck TJ J Bone Miner Res 15: 2297-2304, 2000 Beck TJ J Bone Miner Res 16: 1108-1119, 2001

31. Material Properties of Bone Material strength Elastic modulus (Young’s modulus) Toughness

32. Biomechanics: General Adapted from, Lee and Einhorn, 2001 Elastic Plastic Failure AUC = toughness Deformation Deformation (Strain) Force/area (Stress )

33. Biomechanics: Examples Elastic Deformation Failure Glass Plastic Deformation Failure Taffy Bone Failure Adapted from, Lee and Einhorn, 2001 Deformation (Strain) Force/area (Stress ) Deformation (Strain) Force/area (Stress ) Deformation (Strain) Force/area (Stress )

34. Relationship of Mineralization to Toughness Adapted from Wainwright, Biggs, Currey and Gosline. Mechanical Design in Organisms. Princeton Press, 1976 Young’s Modulus (Stiffness) Toughness HypermineralizationHypomineralization Mineral Content

35. Structural Determinants of Bending Strength Adapted from, Lee CA, and Einhorn TA. Osteoporosis 2 nd Ed. 2001 E = Young’s modulus of Elasticity (material property) I = Cross Sectional Moment of Inertia (geometrical property)

36. Reproduced with permission from Seeman E Advances in Osteoporotic Fracture Management 2:2-8; 2002 and Currey JD J Biomechanics 12: 459-469; 1979 Toughness versus Stiffness

37. Bone is Tough and Stiff collagen mineral Osteomalacia Osteopetrosis Stiffness Toughness bone