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Bone Quality

Source:. Bone Quality. Review:. Architecture Turnover Rate Damage Accumulation Degree of Mineralization Properties of the collagen/mineral matrix. Reviewer Memo:. Sourced from NIH Consensus Development Panel on Osteoporosis. JAMA 285: 785-95; 2001. Slide Modified:. Memo:.

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Bone Quality

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  1. Source: Bone Quality Review: Architecture Turnover Rate Damage Accumulation Degree of Mineralization Properties of the collagen/mineral matrix Reviewer Memo: Sourced from NIH Consensus Development Panel on Osteoporosis. JAMA 285: 785-95; 2001 Slide Modified: Memo:

  2. Osteoclasts Resorption Cavities Lining Cells Bone Osteoblasts Lining Cells Mineralized Bone Osteoid Source: Bone Remodeling Process Review: Reviewer Memo: Slide Modified: Memo:

  3. Perforations Stress Risers Source: High Bone Turnover Leads to Development of Stress Risers and Perforations Osteoclasts Review: Reviewer Memo: Bone Slide Modified: Memo:

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

  5. Source: Consequences of an Imbalance in Bone Turnover Review: Reviewer Memo: Osteoporotic Bone Normal Bone Mechanism of Action Animation of Bone Remodeling Process, 2002, Eli Lilly & Company Slide Modified: Memo:

  6. Source: Bone Turnover, Mineralization, and Bone Quality Review: • There is a complex relationship between bone turnover and bone quality • A decrease of bone turnover increases mineralization and permits filling of remodeling space Reviewer Memo: Excessive suppression Increased mineralization Accumulation Increased brittleness of microcracks Skeletal fragility June 2004 Slide Modified: Memo:

  7. Antiresorptive Agent Remodeling space Increased Mineralization Newly formed bone Source: Antiresorptive Agents Increase BMD by Decreasing Remodeling Space and/or Prolonging Mineralization Review: Reviewer Memo: Slide Modified: Memo:

  8. Source: Rate of Bone Turnover Review: Clinical paradigm: Bone turnover is an essential physiological mechanism for repairing microdamage and replacing “old” bone by “new” bone. Healthy bone is a living tissue. Reviewer Memo: Clinical question: Can excessive reduction in bone turnover be harmful for bone? How much suppression is too much? Slide Modified: Memo:

  9. Source: Changes in Biochemical Markers Predict an Increase in Bone Mineral Density During Antiresorptive Therapy Review: • 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 Reviewer Memo: Sourced from Looker AC et al. Osteoporos Int 11:467-480; 2000 Slide Modified: Memo:

  10. Source: Bone Turnover Markers Review: • 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. Reviewer Memo: Slide Modified: Memo:

  11. Source: Relationship Between Changes in Bone Resorption Markers and Vertebral Fracture Risk VERT Study Review: • 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 Reviewer Memo: Sourced from Eastell R et al. Osteoporos Int 13:520; 2002 Slide Modified: Memo:

  12. Mean Serum CTX Mean Serum PINP 50 500 40 400 PINP (μg/L) ±1 SD Premenopausal† Premenopausal† 30 300 CTX (ng/L) ±1 SD * 20 200 * 10 100 0 0 ALN ALN RLX RLX Source: Raloxifene and Alendronate Reduce Bone Turnover in Women with Osteoporosis Review: Reviewer Memo: *p< 0.01 compared to premenopausallevels †The area between the dotted lines is + 2SD of the mean premenopausal value Sourced from Stepan JJ et al. J Bone Miner Res 17 (Suppl 1):S233; 2002 Slide Modified: Memo:

  13. Placebo Raloxifene 60 mg/d Alendronate 10 mg/d Source: Effects of Raloxifene and Alendronate on Markers of Bone ResorptionC-Telopeptide/Creatinine Ratio Review: *† 60 Reviewer Memo: 40 Median % change at 1 Year 20 0 % of Women Below Lower Limit of Premenopausal Range (52 µg/mmol) at 1 Year -20 -40 * -60 -80 *† *p <0.05 vs. PL †p <0.05 vs. RLX -100 Sourced from Johnell O et al. J Clin Endocrinol Metab 87:985-992, 2002 Slide Modified: Memo:

  14. Source: Bone Turnover Effects Bone Quality Review: • 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 Reviewer Memo: Slide Modified: Memo:

  15. 6 6 6 6 6 6 4 4 4 4 4 4 Placebo Raloxifene (pooled) 2 2 2 2 2 2 * * * * † † † † * * * * * * * * *p *p *p *p value <0.05 value <0.05 value <0.05 value <0.05 % Change of BMD p p p p † † † † value <0.10 value <0.10 value <0.10 value <0.10 0 0 0 0 0 0 † † - - - - - - 2 2 2 2 2 2 - - - - - - 4 4 4 4 4 4 Mid Mid Mid Mid Mid Mid Mid Mid Total Total Total Total Total Total Total Total Total Total Total Total Mid Integral Mid Integral Mid Integral Mid Integral Cortical Cortical Cortical Cortical Lumbar Lumbar Lumbar Lumbar Trabecular Trabecular Trabecular Trabecular Integral Integral Integral Integral Trabecular Trabecular Trabecular Trabecular Integral Integral Integral Integral Integral Integral Integral Integral Central Central Central Central Spine BMD Spine BMD Spine BMD Spine BMD ~AP DXA ~LAT DXA ~LAT DXA 2 2 2 2 (g/cm (g/cm (g/cm (g/cm ) ) ) ) Source: Effects of Raloxifene on Trabecular and Cortical BMD Measured by Spinal vQCT MORE Trial - 2 Years Review: Reviewer Memo: -6 vQCT Volumetric quantitative computed tomography DXA Dual x-ray absorptiometry June 2004 Genant H et al. J Bone Miner Res 18(Suppl 2); S383, 2003 Slide Modified: Memo:

  16. Source: Bone Quality Review: Architecture Turnover Rate Damage Accumulation Degree of Mineralization Properties of the Collagen/Mineral Matrix Reviewer Memo: Sourced from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95, 2001 Slide Modified: Memo:

  17. Bisphosphonates Increase Microcracks Incadronate1 Beagle dogs treated 3 years with 2.5 x the clinical dose Dogs Treated with High Doses of Bisphosphonates2 20 ** Risedronate2 * 15 Microcrack Surface Density(m/mm2) Mean ± SEM 10 Beagle dogs treated 1 year with 6x the clinical dose 5 Alendronate2 0 Placebo Risedronate Alendronate *P<.05 vs placebo **P<.01 vs placebo 1Reproduced with permission from Komatsubara S. J Bone Miner Res 18:512-520, 2003 2Reproduced with permission from Mashiba T et al. J Bone Miner Res 15:613-620; 2000 Source: Review: Reviewer Memo: June 2004 Slide Modified: Memo:

  18. Source: Effects of Risedronate and Alendronate on Microcracks Risedronate Alendronate Review: Reviewer Memo: 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 Slide Modified: Memo:

  19. Source: Effect of Long-Term Bisphosphonate Treatment - Incadronate Review: Reviewer Memo: Reproduced with permission from Komatsubara S. J Bone Miner Res 18: 512-520, 2003 Slide Modified: Memo:

  20. Effects of Raloxifene on Microcracks 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 Sourced from Burr DB. Osteoporo Int 13, Suppl 3, S73-74; 2002 Source: Review: Reviewer Memo: Slide Modified: Memo:

  21. Source: Microdamage in Human Trabecular and Cortical Bone Review: Reviewer Memo: Reproduced with permission from Seeman E. Advances in Osteoporotic Fracture Management 2: 2-8, 2002 and Fyhrie DP. Bone 15:105-109,1994 Slide Modified: Memo:

  22. Source: Bone Quality Review: Architecture Turnover Rate Damage Accumulation Degree of Mineralization Properties of the Collagen/Mineral Matrix Reviewer Memo: Sourced from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95, 2001 Slide Modified: Memo:

  23. Source: Bone Mineralization of the Basic Multicellular Unit Review: New bone ~50% mineralized Reviewer Memo: Old bone Primary mineralization (3 months) Sourced from Ott S. Advances in Osteoporotic Fracture Management 2: 48-54, 2003 Slide Modified: Memo:

  24. - - Primary mineralization (3 months) Secondary mineralization (years) Source: Bone Mineralization of the Basic Multicellular Unit Review: - - 100 Bone fully mineralized (%) (%) (%) (%) Reviewer Memo: Mineralization Mineralization Mineralization Mineralization 50 Degree of Degree of Degree of Degree of Old bone 0 Ott S. Advances in Osteoporotic Fracture Management 2: 48-54, 2003 Slide Modified: Memo:

  25. Source: Homogeneous vs. Heterogeneous Mineralization Review: • “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.” Reviewer Memo: Seeman E. Advances in Osteoporotic Fracture Management 2: 2-8, 2002 Slide Modified: Memo:

  26. Source: Homogeneous vs. Heterogeneous Mineralization Review: Heterogeneous Homogeneous Low mineralization Reviewer Memo: High Mineralization Reproduced with permission from Boivin GY et al. Bone 27:687-694; 2000 Slide Modified: Memo:

  27. Source: Heterogeneous Mineral Distribution in Iliac Bone Review: Reviewer Memo: Reproduced with permission from Boivin GY et al. Bone 27:687-694; 2000 Slide Modified: Memo:

  28. Breaking Stress* Modulus of Impact** 25 8 6 20 kg/mm2 4 15 2 10 6 0 63 65 67 69 71 65 66 67 68 Ash Density (%) Ash Density (%) Source: The Relationship Between Mineralization and Bone Strength is Complex Review: Reviewer Memo: *Stiffness **Toughness Reproduced with permission from Seeman E. Advances in Osteoporotic Fracture Management 2: 2-8; 2002 and Currey JD. J Biomechanics 12: 459-469; 1979 June 2004 Slide Modified: Memo:

  29. Source: Distributions of Mineralization Review: Reviewer Memo: Homogeneous Mineralization Heterogeneous Mineralization Slide Modified: Memo:

  30. 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) Source: Alendronate Increases Bone Mineralization in Women with Osteoporosis Review: Two Years Three Years Reviewer Memo: .50 .60 .70 .80 .90 1.0 1.2 1.3 1.4 1.5 1.6 Reproduced with permission from Boivin GY et al. Bone 27:687-694; 2000 Slide Modified: Memo:

  31. Source: Raloxifene Treatment Induces a Normal Pattern of Bone Mineralization Review: Two-year treatment with raloxifene results in a heterogeneous mineral distribution with a modest increase in mineralization Total Iliac Bone - Placebo Total Iliac Bone - Raloxifene 60 mg/d Reviewer Memo: Baseline Baseline Endpoint Baseline Endpoint % Distribution % Distribution Degree of Mineralization (g mineralization/cm3 bone) Sourced from Boivin G et al. J Clin Endocrinol Metab. 2003;88: 4199-4205. Slide Modified: Memo:

  32. Source: Mineralization Distributions with Osteoporosis Agents: RLX Compared to Placebo Review: Baseline Mineralization Reviewer Memo: raloxifene Placebo – Ca VitD Boivin GY et al. J Clin Endocrinol Metab 88:4199-4205, 2003 Homogeneous bone Narrower curvehigher peak Heterogeneous Bone Wider curve Slide Modified: Memo:

  33. Source: Teriparatide Treatment Forms New Not Fully Mineralized Bone Review: Reviewer Memo: Misof et al. J Clin Endocrinol Metab88:1150-6, 2003 Slide Modified: Memo:

  34. Source: Calcium Peak in Male and Female Patients Following Treatment with Intermittent PTH Review: Before PTH After PTD Male Patients Female Patients 23.0 Reviewer Memo: 22.0 Ca Peak [wt%] 21.0 20.0 Cortical Cancellous Cortical Cancellous Bone Bone Bone Bone Male Patients Female Patients 5 4 Ca Width [wt% Ca] 3 2 Cortical Cancellous Cortical Cancellous Bone Bone Bone Bone Misof et al. J Clin Endocrinol Metab88:1150-6, 2003 Slide Modified: Memo:

  35. Source: Overlaid Fluorescence Labeling Lines of Calcium Peak Widths Following Treatment with Intermittent PTH Review: Reviewer Memo: Black Arrow– Ca Peak was 18.19% White Arrow- Interstitial bone Ca Peak was 23.05% Misof et al. J Clin Endocrinol Metab88:1150-6, 2003 Slide Modified: Memo:

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