Bone Quality PART 2 Damage Accumulation Degree of Mineralization Biomechanics Bone Quality Architecture Turnover Rate Damage Accumulation Degree of Mineralization Properties of the Collagen/Mineral Matrix Adapted from NIH Consensus Development.
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Bone Quality PART 2 Damage Accumulation Degree of Mineralization Biomechanics 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 Dogs Treated with High Doses of Bisphosphonates Microcrack Surface Density (m/mm2) Mean ± SEM 20 15 ** * 10 5 0 Reproduced with permission from Mashiba T et al. J Bone Miner Res 15:613-620; 2000 *P<.05 vs placebo **P<.01 vs placebo Microcracks Risedronate Microcrack in the right femoral neck cortex from a risedronate treated dog Alendronate Microcracks in the third lumbar vertebral body from an alendronate treated dog Reproduced with permission from Mashiba T et al. Bone 28:524-531, 2001 Effect of Long-Term Bisphosphonate Treatment - Incadronate Reproduced with permission from Komatsubara S. J Bone Miner Res 18: 512-520, 2003 Microcrack Analysis in Monkey Vertebrae Microcrack Surface Density * * * Crack Surface Density (Cr.S.Dn.) 90 80 70 60 50 40 30 20 10 0 Ovx CEE Ralox 1 Ralox 2 Burr DB. Osteoporo Int 13, Suppl 3, S73-74; 2002 Sham * p<0.05 CEE-conjugated equine estrogens Ralox 1 – 1 mg/kg Ralox 2 – 5 mg/kg 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 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 Bone Mineralization of the Basic Multicellular Unit Degree of Mineralization (%) 100 - 50 - 0- Time Secondary mineralization (years) Primary mineralization (3 months) Ott S. Advances in Osteoporotic Fracture Management 2: 48-54, 2003 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 Homogeneous vs. Heterogeneous Mineralization Heterogeneous Homogeneous Low mineralization High mineralization Adapted with permission from Boivin et al. Bone 27:687-694; 2000 Heterogeneous Mineral Distribution in Iliac Bone Reproduced with permission from Boivin GJ. Musculoskel Neuron Interact 2: 538-543, 2002. 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 Effects of Alendronate on Bone Mineralization in Ovariectomized Monkeys 2000 Number of Measurements 1750 ALN 1500 OVX CTRL 1250 1000 750 500 250 0 .2 .4 .6 .8 1.0 1.2 1.4 Degree of Mineralization (g mineral/cm3) Meunier and Boivin. Bone 21:373-7, 1997 1.6 1.8 Alendronate Increases Bone Mineralization in Women with Osteoporosis Degree Mineralization of cancellous Bone (g. mineral/cm3 bone) 5 1.6 1.5 1.4 1.3 1.2 1.0 0 .90 1.6 1.5 1.4 1.3 1.2 1.0 .90 .80 .70 .60 0 10 .80 5 15 .70 10 20 .60 15 13 PLA 3 yrs. (N=12057) 16 ALN 3 yrs. (N=136313) .50 20 % of the number of measurements Three Years 15 PLA 2 yrs (N=11872) 9 ALN 2 yrs (N=6220) .50 % of the number of measurements Two Years Degree Mineralization of cancellous Bone (g. mineral/cm3 bone) Adapted with permission from Boivin et al. Bone 27:687-694; 2000 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 % Distribution Total Iliac Bone – Placebo Baseline Endpoint Degree of Mineralization (g mineralization/cm3 bone) Boivin G. ECTS Meeting, P190, 2003. % Distribution Total Iliac Bone – RLX60 Baseline Endpoint Degree of Mineralization (g mineralization/cm 3 bone) Biomechanics 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 Biomechanical Evaluation Biomechanical Evaluations Biomechanical Evaluations of Whole Bone Biomechanical Evaluations Compression test Compression Compression testtest of femoral neck of femoral neck of femoral neck Mixture of cancellous Mixtureand of cancellous cortical bone Compression test and cortical bone of femoral neck Mixture of cancellous and cortical bone Compression test of Compression test of lumbar vertebral body lumbar vertebral body cancellous bone cancellous bone cortical bone Compression cortical bone test of Compression test of lumbar vertebral vertebral body lumbar body cancellous bone cortical bone Three-point bending Three-point bending Three-point bending of femoral midshaft of femoral midshaft corticalmidshaft bone offemoral cortical bone Ø cancellous bone Three-point Ø cancellous bending bone of femoral midshaft cortical bone Ø cancellous bone Whole Bone Properties • Strength • Stiffness • Brittleness • Energy (work to failure) A Pharmacological Agent Should Increase Bone Strength While Also Decreasing Brittleness Treated Force * *Untreated Displacement Turner CH et al. Osteoporos Int 13:97-104; 2002 * Point of Failure Mineralization Affects Brittleness hyperX mineralized (osteopetrosis) Force X optimum hypoX mineralized (osteomalacia) Displacement Turner CH et al. Osteoporos Int 13:97-104; 2002 Impact of Remodeling Lacunae on Mechanical Stress Distribution Transmission of mechanical stress stress “riser” Adapted from Parfitt AM. Am J Med, 1987 Cross-Sectional Moment of Inertia CSMI = A d2 A dx z dz x Cross-Sectional Moment of Inertia CSMI = /4 (r4 outer – r4 inner) Area (cm2) CSMI (cm4) Bending Strength 2.77 0.61 100% 2.77 1.06 149% 2.77 1.54 193% Cross-Sectional Moment of Inertia Adapted from Lee CA, and Einhorn TA. Osteoporosis 2nd Ed. 2001 Relative Influence of Inner and Outer Diameters on Bone Strength Adapted from Lee CA, and Einhorn TA. Osteoporosis 2nd Ed. 2001 Local Buckling ro Buckling Ratio = t thickness radius Local buckling in hollow tubes becomes likely when the buckling ratio is > 10 Local Buckling Analysis Of Hip Cortical Bone Narrow Neck Intertrochanteric Bone Mass (g/cm2) Shaft 0 1 2 3 Distance (cm) 4 5 Reprinted with Permission Beck TJ J Bone Miner Res 15: 2297-2304, 2000 Beck TJ J Bone Miner Res 16: 1108-1119, 2001 Material Properties of Bone • Material strength • Elastic modulus (Young’s modulus) • Toughness Biomechanics: General Deformation Plastic Force/area (Stress) Elastic Failure AUC = toughness Deformation (Strain) Adapted from, Lee and Einhorn, 2001 Biomechanics: Examples Taffy Deformation (Strain) Plastic Deformation Failure Deformation (Strain) Adapted from, Lee and Einhorn, 2001 Force/area (Stress) Failure Bone Failure Force/area (Stress) Force/area (Stress) Glass Elastic Deformation Deformation (Strain) 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 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 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 bone collagen mineral Toughness Bone is Tough and Stiff Stiffness