bone quality part 3 collagen/mineral matrix conclusions supplemental slides
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Bone Quality PART 3 Collagen/Mineral Matrix Conclusions Supplemental Slides. Bone Quality. Architecture Turnover Rate Damage Accumulation Degree of Mineralization Properties of the Collagen/Mineral Matrix. - PowerPoint PPT PresentationTRANSCRIPT
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Bone Quality
PART 3Collagen/Mineral Matrix
ConclusionsSupplemental Slides
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Bone Quality
Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95; 2001
ArchitectureTurnover RateDamage AccumulationDegree of MineralizationProperties of the Collagen/Mineral Matrix
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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
10 20 30 40 50 60
10
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40
50
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4505-92TR2COLL X
0
0.4000
0.8000
1.200
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X Axis Title
Y A
xis
Title
IR-spectrometer
Bone section
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FTIR Imaging – Mineral Crystallinity
E. Paschalis et al. 2003 (in press).
BaselinePi
xel P
opul
atio
n Di
strib
utio
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Mineral CrystallinityPi
xel P
opul
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n Di
strib
utio
n
2 Year Estrogen Therapy
Mineral Crystallinity
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FTIR Imaging – Mineral:Matrix Ratio
E. Paschalis et al. 2003 (in press).
Baseline
Mineral Matrix
Pixe
l Pop
ulat
ion
Dist
ribut
ion
2 Year Estrogen Therapy
Pixe
l Pop
ulat
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Dist
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Mineral Matrix
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FTIR Imaging – Collagen Cross-Link Ratio
E. Paschalis et al. 2003 (in press).
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0.4000
0.8000
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collxtr3
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Pyr/DHLNL
Baseline
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collxtr2
10 20 30 40 50 60
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4505-92TR2COLL X
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0.4000
0.8000
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2.000
X Axis Title
Y A
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Pixe
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Pyr/DHLNL
2 Year Estrogen Therapy
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Conclusion Slides
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• 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
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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• 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)
Bone Quality -Raloxifene
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Weinstein RS, et al. J Bone Miner Res. 14:S279; 1999Prestwood KM, et al. J Clin Endocrinol Metab. 85:2197-2202; 2000Ott SM, et al. J Bone Miner Res. 17:341-348; 2002
Bone Quality -Raloxifene
• Histomorphometry• No woven bone• No marrow fibrosis• No mineralization defect• No cellular toxicity (light microscopy)• Normal histologic appearance
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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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• 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
Bone Quality ConclusionsTeriparatide
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Relationship Between Excessive Suppression Of Bone Turnover and Damage Accumulation
Excessive suppression of bone turnover
Long-term fracture efficacy and safety?
Prolongedmineralization
Insufficient repairof microdamage
Damage accumulation
Increase in bone fragility
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The Optimal Effect of an Antiresorptive Agent on Bone Quality
Adequate suppression of bone turnover
Sufficientmineralization
Physiological repairof microdamage
Preservation of architecture
Long-term fracture efficacy and safety
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Osteoporosis
Severe Osteoporosis
Normal
Courtesy Dr. A. Boyde
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What Is the Optimal Reduction in Bone Turnover for an Antiresorptive Drug?
Adapted from Weinstein RS, J Bone Miner Res 2000; 15 621-625.
Physiological Physiological RRangeange
Bon
e St
reng
th
Bone Turnover
Excessive turnover• Increase in stress risers (weak zones)• Increase in perforations• Loss of connectivity
Insufficient turnover• Accumulation of microdamage• Increased brittleness due to
excessive mineralization
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Supplemental Slides
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Effect of Size on Areal BMD1
11
2
22
3
3
3
BMC
1 1 1
AREA BMD
8 4 2
27 9 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
Cao Y et al. J Bone Miner Res 17:2237-46; 2002
• Female OVX rats (n=140)
• Five study groups
• Sham control• OVX placebo control• OVX + estrogen• OVX + raloxifene• OVX + alendronate
• Objective: To evaluate the effect of antiresorptives on fracture healing.
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The Effect of Antiresorptive Therapy on Fracture Healing
External Callus Formation
Reproduced with permission from Cao Y et al. J Bone Miner Res 17:2237-46, 2002
• 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
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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 17:2237-46; 2002
6 weeks
16 weeks
Sham OVX EE2 RLX ALN
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The Effect of Antiresorptive Therapy on Fracture Healing
Photomicrographs of the Callus
Reproduced with permission from Cao Y et al. J Bone Miner Res 17:2237-46, 2002
Sham OVX EE2 RLX ALN