bone quality part 3 collagen/mineral matrix conclusions supplemental slides
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Bone Quality
PART 3Collagen/Mineral Matrix
ConclusionsSupplemental Slides
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
Bone Cells and Matrix
• Properties of collagen and mineral matrix• Suppressed turnover and accumulation of
microdamage• Altered mechanosensation• State of mineralization
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
20
30
40
50
60
4505-92TR2COLL X
0
0.4000
0.8000
1.200
1.600
2.000
X Axis Title
Y A
xis
Title
IR-spectrometer
Bone section
FTIR Imaging – Mineral Crystallinity
E. Paschalis et al. 2003 (in press).
BaselinePi
xel P
opul
atio
n Di
strib
utio
n
Mineral CrystallinityPi
xel P
opul
atio
n Di
strib
utio
n
2 Year Estrogen Therapy
Mineral Crystallinity
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
ion
Dist
ribut
ion
Mineral Matrix
FTIR Imaging – Collagen Cross-Link Ratio
E. Paschalis et al. 2003 (in press).
10 20 30 40 50 60
10
20
30
40
50
60
0
0.4000
0.8000
1.200
1.600
2.000
0.0 0.5 1.0 1.5 2.00
50
100
150
Y A
xis
Title
Axis
collxtr3
Pixe
l Pop
ulat
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Dist
ribut
ion
Pyr/DHLNL
Baseline
0.0 0.5 1.0 1.5 2.00
50
100
150
Y A
xis
Title
X Axis Title
collxtr2
10 20 30 40 50 60
10
20
30
40
50
60
4505-92TR2COLL X
0
0.4000
0.8000
1.200
1.600
2.000
X Axis Title
Y A
xis
Title
Pixe
l Pop
ulat
ion
Dist
ribut
ion
Pyr/DHLNL
2 Year Estrogen Therapy
Conclusion Slides
• 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
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
• 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
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
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
• 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
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
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
Osteoporosis
Severe Osteoporosis
Normal
Courtesy Dr. A. Boyde
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
Supplemental Slides
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
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.
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
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
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
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