Bone Quality PART 3 Collagen/Mineral Matrix Conclusions Supplemental Slides

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Bone QualityPART 3Collagen/Mineral
MatrixConclusionsSupplemental Slides
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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 285785-95 2001
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Bone Cells and Matrix

• Properties of collagen and mineral matrix
• Suppressed turnover and accumulation of
  microdamage
• Altered mechanosensation
• State of mineralization

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Properties of the Collagen/Mineral
Matrix -Antiresorptive Drugs
Fourier Transform Infrared Microscopic Imaging
(FTIRI) of Iliac Crest Bone Sections
IR-spectrometer
Bone section
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FTIR Imaging Mineral Crystallinity
Baseline
2 Year Estrogen Therapy
Pixel Population Distribution
Pixel Population Distribution
Mineral Crystallinity
Mineral Crystallinity
E. Paschalis et al. 2003 (in press).
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FTIR Imaging MineralMatrix Ratio
Pixel Population Distribution
Pixel Population Distribution
Mineral Matrix
Mineral Matrix
E. Paschalis et al. 2003 (in press).
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FTIR Imaging Collagen Cross-Link Ratio

E. Paschalis et al. 2003 (in press).
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Conclusion Slides
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Bone Quality

• Bone quality is an integral component of bone
  strength
• Maintaining or restoring bone architecture is
  required for optimal bone quality
• An imbalance in bone turnover rate affects the
  degree of mineralization of bone
• Optimal collagen/mineral matrix properties
  contribute to bone quality

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Possible Contributing Factors to the Fracture
Efficacy of Antiresorptives

• Increased bone mineral density
• Decreased bone turnover
• Improved bone quality
• Decrease remodeling sites
• Maintain trabecular thickness and connectivity
• Decrease number of trabecular perforations
• Decrease microfractures
• Improve matrix properties

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Bone Quality -Raloxifene

• Biochemical markers and bone turnover
  significantly reduced to premenopausal range
• Normal bone turnover allows adequate repair of
  microdamage
• No adverse effect on bone architecture (iliac
  crest histomorphometry)

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Bone Quality -Raloxifene

• Histomorphometry
• No woven bone
• No marrow fibrosis
• No mineralization defect
• No cellular toxicity (light microscopy)
• Normal histologic appearance

Weinstein RS, et al. J Bone Miner Res. 14S279
1999 Prestwood KM, et al. J Clin Endocrinol
Metab. 852197-2202 2000 Ott SM, et al. J Bone
Miner Res. 17341-348 2002
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Bone Quality -Raloxifene

• No adverse effects on bone histology
• Changes in BMD explain only a small proportion of
  vertebral fracture risk reduction
• Reduces bone turnover to the normal premenopausal
  range allowing
• Adequate repair of microdamage
• A moderate increase in mineralization and
  preservation of heterogeneous mineral
  distribution
• Long-term efficacy with sustained fracture
  reduction in the fourth year of treatment

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Bone Quality ConclusionsTeriparatide

• Architecture
• Increase trabecular thickness and connectivity
• Increases cortical thickness and improves
  cortical geometry
• Turnover
• Increases formation on quiescent (neutral)
  surface
• Increase in formation is greater than resorption
  (positive bone balance)
• Damage Accumulation
• Forms new bone
• Increased bone turnover reduces damage
  accumulation

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Relationship Between Excessive Suppression Of
Bone Turnover and Damage Accumulation

• Excessive suppression of bone turnover

Insufficient repair of microdamage
Prolonged mineralization
Damage accumulation
Increase in bone fragility
Long-term fracture efficacy and safety?
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The Optimal Effect of an Antiresorptive Agent on
Bone Quality
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What Is the Optimal Reduction in Bone Turnover
for an Antiresorptive Drug?

• Insufficient turnover
• Accumulation of microdamage
• Increased brittleness due to excessive
  mineralization

• Excessive turnover
• Increase in stress risers (weak zones)
• Increase in perforations
• Loss of connectivity

Adapted from Weinstein RS, J Bone Miner Res
2000 15 621-625.
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Supplemental Slides
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Effect of Size on Areal BMD
BMC
AREA
BMD
1
1
1
1
1
1
2
2
8
4
2
2
3
3
27
9
3
3
TRUE VALUE 1 g/cm3
Adapted from Carter DR, et al. J Bone Miner Res
1992
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The Effect of Antiresorptive Therapy on Fracture
Healing Study Protocol

• Female OVX rats (n140)
• Five study groups
• Sham control
• OVX placebo control
• OVX estrogen
• OVX raloxifene
• OVX alendronate
• Objective To evaluate the effect of
  antiresorptives on fracture healing.

Cao Y et al. J Bone Miner Res 172237-46 2002
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The Effect of Antiresorptive Therapy on Fracture
Healing External Callus Formation

• 6 Weeks
• Callus formation
• Fracture visible

• 16 Weeks
• OVX Fracture line dissapeared
• ALN fracture line still visible
• Callus width largest in ALN group
• Fracture repair was delayed with ALN treatment

Reproduced with permission from Cao Y et al. J
Bone Miner Res 172237-46, 2002
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The Effect of Antiresorptive Therapy on Fracture
Healing Cross-sectional Microradiographsat the
Fracture Plane
Reproduced with permission from Cao Y et al. J
Bone Miner Res 172237-46 2002
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The Effect of Antiresorptive Therapy on Fracture
Healing Photomicrographs of the Callus
Sham OVX EE2 RLX ALN
Reproduced with permission from Cao Y et al. J
Bone Miner Res 172237-46, 2002