Bone Quality PART 2 Damage Accumulation Degree of Mineralization Biomechanics

1. Bone QualityPART 2Damage AccumulationDegree of MineralizationBiomechanics

2. Bone Quality Architecture Turnover Rate Damage Accumulation Degree of Mineralization Properties of the Collagen/Mineral Matrix Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95, 2001

3. Dogs Treated with High Doses of Bisphosphonates 20 ** * 15 Microcrack Surface Density(m/mm2) Mean ± SEM 10 5 0 Placebo Risedronate Alendronate Reproduced with permission from Mashiba T et al. J Bone Miner Res 15:613-620; 2000 *P<.05 vs placebo **P<.01 vs placebo

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

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

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

8. Bone Quality Architecture Turnover Rate Damage Accumulation Degree of Mineralization Properties of the Collagen/Mineral Matrix Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95, 2001

9. Bone Mineralization of the Basic Multicellular Unit 100 - 50 - 0 - Degree of Mineralization (%) Time Secondary mineralization (years) Primary mineralization (3 months) 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 Heterogeneous Homogeneous Low mineralization High mineralization Adapted with permission from Boivin et al. Bone 27:687-694; 2000

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

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

14. 2000 1750 1500 1250 1000 750 500 250 0 Effects of Alendronate on Bone Mineralization in Ovariectomized Monkeys ALN OVX CTRL Number of Measurements .2 .4 .6 .8 1.0 1.2 1.4 1.6 1.8 Degree of Mineralization (g mineral/cm3) Meunier and Boivin. Bone 21:373-7, 1997

15. 15 PLA 2 yrs (N=11872) 13 PLA 3 yrs. (N=12057) 16 ALN 3 yrs. (N=136313) 9 ALN 2 yrs (N=6220) 20 20 15 15 .50 .60 .70 .80 .90 1.0 1.2 1.3 1.4 1.5 1.6 % of the number of measurements % of the number of measurements 10 10 5 5 0 0 Degree Mineralization of cancellous Bone Degree Mineralization of cancellous Bone (g. mineral/cm3 bone) (g. mineral/cm3 bone) Alendronate Increases Bone Mineralization in Women with Osteoporosis Two Years Three Years .50 .60 .70 .80 .90 1.0 1.2 1.3 1.4 1.5 1.6 Adapted with permission from Boivin et al. Bone 27:687-694; 2000

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

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 Three-point bending of femoral midshaft Compression test of lumbar vertebral body

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

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

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

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

24. Cross-Sectional Moment of Inertia CSMI =  A  d2 y A dz x dx z

25. Cross-Sectional Moment of Inertia CSMI = /4 (r4 outer – r4 inner) Area (cm2) 2.77 2.77 2.77 CSMI (cm4) 0.61 1.06 1.54 Bending Strength 100% 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. r o Buckling Ratio = Buckling Ratio = t Local Buckling thickness radius Local buckling in hollow tubes becomes likely when the buckling ratio is > 10

29. Local Buckling

30. Analysis Of Hip Cortical Bone Narrow Neck Intertrochanteric Bone Mass (g/cm2) Shaft 0 1 2 3 4 5 Distance (cm) 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. Deformation Plastic Elastic Failure Force/area (Stress) AUC = toughness Deformation (Strain) Biomechanics: General Adapted from, Lee and Einhorn, 2001

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

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

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

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

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