Transcript Bone Quality

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
Adapted from NIH Consensus Development Panel on Osteoporosis.
JAMA 285:785-95; 2001
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
4505-92TR2
COLL X
60
2.000
50
Y Axis Title
1.600
40
1.200
30
0.8000
0.4000
20
0
10
10
20
30
40
X Axis Title
IR-spectrometer
Bone section
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60
0
TRABECULAR CRYSTALLINITY
10
FTIR Imaging
– Mineral
Crystallinity
TRABECULAR
CRYSTALLINITY
10
20
30
40
50
60
X Axis Tit le
3674-90TR2
CRYST
Baseline
2.000
4539/92
1.600
60
1.200
2.000
2 00
1.200
20
0.8000
10
0.4000
20
0.8000
1.600
20
40
0.4000
0
1 00
1 00
30
0.8000
0.4000
20
0
10
10
20
30
1.200
0
0
40
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0.0
0.5
1.0
X Axis Tit le
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X Axis Title
60
0.0
0.5
X Axis Tit le
0.4000
0
1 00
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60
crysttr2
3 00
40
40
2.0 40
X Axis Tit le
crysttr2
2.000
2.000
1.600
1.600
1.200
2 00
1.200
30
Y Axis Title
0.8000
30
3 00
50
50
1.520
60
2 00
Y Axis Tit le
1.200
60
Y Axis Tit le
1.600
4539-92TR2
CRYST
Distribution
Pixel Population
Y Axis Title
539/92
2.000
1.0
Pixel Population
Y Axis Tit leDistribution
4539/92
10
X Axis Title
4539-92TR2
crysttr2
CRYST
3 00
2.0
0
BECULAR CRYSTALLINITY
20
1.5
0.8000
20
0.4000
20
0.8000
0.4000
1 00
0
2 00
1 00
10
0
0
10
0.0
0.5
1.0
1.5
2.0
0
Title
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MineralX Axis
Crystallinity
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20
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20
60
30
X Axis Tit le
X Axis Tit le
E. Paschalis et al. 2003 (in press).
2.000
50
60
0.0
0
0.0
0.5
1.0
X Axis Tit le
crysttr2
3 00
40
0.5
1.5
1.0
2.0
X Axis
1.5
Title
Mineral Crystallinity
2.0
Y Axis Title
1.600
30
30
10
30
2 00
50
Y Axis Title
Y Axis Tit le
40
60
2.000
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Y Axis Tit le
4539-92TR2
crysttr2
CRYST
3 00
50
Y Axis Tit le
674/90
2 Year Estrogen Therapy
60
3674-90TR2
CRYST
Y Axis Tit le
3674/90
crysttr2
3 00
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10
TRABECULAR M/M
FTIR Imaging – Mineral:Matrix
Ratio
TRABECULAR M/M
2 Year Estrogen
Therapy
4771-92TR2
Baseline
4682/90
MIN / MAT
4771/92
10
20
30
40
50
60
X Axis Title
m/m
4682-90tr1
mm
4682-90tr1
60
m /m
4682-90tr1
150
4.000
50
mm
4682-90tr1
60
3.200
150
4.000
4.000
30
2.400
30
20
20
10
1.600
1.600
100
0.8000
0
0.8000
40
50
Y Axis Tit le
Y Axis Title
40
2.400
3.200
Y Axis T itl e
Y Axis Title
50
50
Y Axis T itl e
40
30
100
3.200
Y Axis Title
682/90
60
2.400
1.600
50
0.8000
20
0
0
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X Axis Title
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20
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4771/92
4771-92TR2
MIN / MAT
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4
30
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40
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60
mmtr2
mmtr2
1 50
4.000
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100
Y Axis Tit le
Y Axis Tit le
1 50
30
4.000
3.200
3.200
2.400
Y Axis Title
Pixel Population
Y Axis TDistribution
itl e
0.8000
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X Axis Tit le
4682-90tr1
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40
1.600
3 20
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MIN
mm / MAT
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2.400
10
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4.000
3.200
1
2.400
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1.600
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Pixel Population
Y Axis Distribution
Title
771/92
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X Axis T itl e
X Axis Title
ABECULAR M/M
150
40
0
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0.8000
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1 00
1.600
0.8000
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1 00
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X40Axis Matrix
T itl50
e
Mineral
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X Axis Tit le
X Axis Tit le
E. Paschalis et al. 2003 (in press).
mmtr2
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1
2
X Axis Title
1
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X Axis Title
Mineral Matrix
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4
FTIR Imaging – Collagen Cross-Link Ratio
Baseline
2 Year Estrogen Therapy
4505-92TR2
COLL X
60
60
2.000
2.000
50
50
1.600
1.600
40
40
1.200
0.8000
0.4000
20
Y Axis Title
1.200
30
30
0.8000
0.4000
20
0
10
0
10
10
20
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X Axis Title
collxtr2
collxtr3
150
Distribution
Pixel Population
Y Axis Title
Distribution
Pixel Population
Y Axis Title
150
100
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0
100
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0
0.0
0.5
1.0
Pyr/DHLNL
Axis
1.5
2.0
E. Paschalis et al. 2003 (in press).
0.0
0.5
1.0
X Axis Title
Pyr/DHLNL
1.5
2.0
Conclusion Slides
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
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
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)
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. 14:S279; 1999
Prestwood KM, et al. J Clin Endocrinol Metab. 85:2197-2202; 2000
Ott SM, et al. J Bone Miner Res. 17:341-348; 2002
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
Bone Quality Conclusions
Teriparatide
• 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
Relationship Between Excessive Suppression
Of Bone Turnover and Damage Accumulation
Excessive suppression of bone turnover
Prolonged
mineralization
Insufficient repair
of microdamage
Damage accumulation
Increase in bone fragility
Long-term fracture efficacy and safety?
The Optimal Effect of an Antiresorptive
Agent on Bone Quality
Adequate suppression of bone turnover
Sufficient
mineralization
Physiological repair
of microdamage
Preservation of architecture
Long-term fracture efficacy and safety
Normal
Osteoporosis
Severe Osteoporosis
Courtesy Dr. A. Boyde
What Is the Optimal Reduction in Bone Turnover
for an Antiresorptive Drug?
Bone Strength
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
Physiological Range
Bone Turnover
Adapted from Weinstein RS, J Bone Miner Res 2000; 15 621-625.
Supplemental Slides
Effect of Size on Areal BMD
1
1
1
2
AREA
BMD
1
1
1
8
4
2
27
9
3
2
2
3
BMC
3
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
• 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.
Cao Y et al. J Bone Miner Res 17:2237-46; 2002
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 17:2237-46, 2002
The Effect of Antiresorptive Therapy
on Fracture Healing
Cross-sectional Microradiographs
at the Fracture Plane
6 weeks
16
weeks
Sham
OVX
EE2
RLX
ALN
Reproduced with permission from Cao Y et al. J Bone Miner Res 17:2237-46; 2002
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 17:2237-46, 2002