Bone Quality: A Major Determinant of Fracture Risk

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Bone Quality A Major Determinant of Fracture
Risk

• Jean Yves REGINSTER
• WHO Collaborating Center for Public Health
  Aspects of Rheumatic Diseases
• University of Liege
• BELGIUM

AFEM Paris 2004
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Definition of Osteoporosis
Osteoporosis is defined as a skeletal disorder
characterized by compromised bone strength
predisposing a person to an increased risk of
fracture. Bone strength primarily reflects the
integration of bone density and bone quality. NIH
Consensus Conference 2001
Normal bone Osteoporosis
NIH Consensus Development Panel on Osteoporosis.
JAMA 285 (2001) 785-95
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Treatment of osteoporosis Challenges of a
chronic treatment
Efficacy on fractures Long term safety Long
term compliance
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What makes our skeleton resistant to fractures?
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Factors Affecting Bone Strength and Fracture Risk
Bone Strength
Fracture
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Determinants of Intrinsic Material Properties

• Properties of the mineral
• Properties of the collagen
• Microdamage accumulation

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Matrix Mineralization
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Relationship between Mineralization Density and
Biomechanical Properties
Load (Stress)
Deformation (Strain)
Bouxsein ASBMR Lilly GMC 2003
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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

Adapted from Weinstein RS, J Bone Miner Res
2000 15 621.
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16 PMOP-ALN 3yrs (N13631) MDMB 1.19 0.02
13 PMOP-PLA 3 yrs (N12057) MDMB 1.06 0.01
20
15
of the number of measurements
10
5
.
0
1.40
1.50
0.50
0.60
0.70
0.80
0.90
1.00
1.10
1.20
1.30
1.60
Degree of Mineralization of Cancellous Bone (g.
mineral/cm3 bone)
Boivin et al, Bone 2000
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Microdamage Accumulation
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Structure
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Microcracks in Bone Structure
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Stopping Crack Growth Can Prevent Fracture
Typically, very tough materials are those in
which cracks do not grow to critical size
Martin Burr, 1989
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Bone Microcrack Density vs. Age
Zioupos, P
Schaffler MB et al.
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Resorption Removing a Microcrack
Burr 2001
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Regression Analysis of Activation Frequency
(Ac.F) and Microdamage Parameters
Mashiba et al. JBMR 2000
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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

Adapted from Weinstein RS, J Bone Miner Res
2000 15 621.
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Remodeling Suppression Increases Microcrack
Accumulation
Risedronate
Alendronate
Incadronate
Beagle dogs treated 3 years with 2.5 x the
clinical dose
Beagle dogs treated 1 year with 6x the clinical
dose
Mashiba T et al. Bone 28524-531, 2001
Komatsubara S. J Bone Miner Res 18 512-520, 2003
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Dogs Treated with High Doses of Bisphosphonates
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Microcrack Surface Density(?m/mm2) Mean SEM
10
5
0
Placebo
Risedronate
Alendronate
Plt.05 vs placebo Plt.01 vs placebo
Mashiba T et al. J Bone Miner Res 15613-620
2000
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New Vertebral Fracture Incidencevs. 3 to 6 Month
CTX Change From Baselinein Postmenopausal
Women Treated with Risedronate
Incidence ()
25
20
15
10
5
Fracture incidence at 1 yr
0
-70
-60
-50
-40
-30
-20
-10
0
5
D CTX at 3-6 mth
CTX T-score à 3-6 mth
Placebo
Risedronate 5mg
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Effects of Raloxifene and Alendronate in
Postmenopausal WomenReduction in Bone Turnover
Mean Serum CTX (ng/L)
Mean Serum PINP (?g/L)
50
500
40
400
Premenopausal
Premenopausal
Mean SD
Mean SD
30
300

20
200

10
100
0
0
Alendronate 10 mg/d
Raloxifene 60 mg/d
Raloxifene 60 mg/d
Alendronate 10 mg/d
plt 0.01 compared to premenopausal levels
Stepan JJ et al. J Bone Miner Res 17 (Suppl
1)S233, 2002
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Relation of BMD to Fracture Risk

• How important is change in BMD with treatment?
• In untreated patients,
• Low BMDhigh fracture risk
• Treatments for osteoporosis increase BMD reduce
  risk
• Is the reduction in fracture risk with treatment
  due to the increase in BMD?

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Randomized Studies of Antiresorptives in
Postmenopausal Osteoporotic WomenRisk of
Vertebral Fractures
? LS BMD
Relative Risk (95 CI)
Prevalent vertebral fractures (VFx)1
2.2
Raloxifene60 mg/d
2.9
No prevalent VFx1
6.2
Alendronate5/10 mg/d
6.8
Prevalent VFx4
4.3
Risedronate5 mg/d
Prevalent VFx5
5.9
Calcitonin200 IU/d
Prevalent VFx6
0.7
1.0
0
0.5
Not head-to-head comparison vs
placebo. 1Ettinger B, et al. JAMA.
1999282637-645 data on file, Eli Lilly and
Company 2Black DM, et al. Lancet.
19963481535-1541 3Cummings SR, et al. JAMA.
19982802077-2082 4Harris ST, et al. JAMA.
19992821344-1352 5Reginster J-Y, et al.
Osteoporosis Int. 20001183-91 6Chesnut CH, et
al. Am J Med. 2000109267-276.
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NUMBER NEEDED TO TREAT TO PREVENT A VERTEBRAL AND
NONVERTEBRAL FRACTURE OVER A PERIOD OF 2 YEARS.
Cranney et al,Endocrine Reviews.2002,23570-578
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NUMBER NEEDED TO TREAT TO PREVENT A NONVERTEBRAL
FRACTURE OVER A PERIOD OF 2 YEARS.
Cranney et al,Endocrine Reviews.2002,23570-578
and Delmas et al,Bone 2003,33522-32
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Effect of Raloxifene on Spine and Femoral Neck
BMD MORE Trial - 4 Years
Femoral Neck
Lumbar Spine
4
4



3
3

2
2


Mean Change
Mean Change


1
1
0
0
-1
-1
-2
-2
0
12
24
36
48
0
12
24
36
48
Months
Months
Raloxifene 60 mg/d
Plt.001 vs placebo
Delmas PD, et al. J Bone Miner Res. 200015(suppl
1)S556.
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Percentage Change in Femoral Neck BMD at 3 Years
and Risk of New Vertebral Fractures
New Vertebral Fracture
Bone Mineral Density
RR (95 CI)
0.64 (0.52, 0.76) 0.64 (0.52, 0.76) 0.64 (0.51,
0.76)
MORE Trial
Sarkar et al., JBMR 2002
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Percentage of Fracture Risk Reduction Explained
by Changes in BMD
Percentage (95 Conf. Int)
Before Adjustment Excess Relative Odds
(ERO) After Adjustment Corrected Excess
Relative Odds (CERO)
7.2 (95 CI 2.1, 16.5) 9.0 (95 CI 4.3,
22.2)
Watts et al., IBMS 2001
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Relationship Between Percent Change in PINP and
New Vertebral Fracture Risk
0.30
0.27
0.24
0.21
0.18
Risk of New Vertebral Fracture (Risk 95 CI)
0.15
0.12
0.09
0.06
Placebo
0.03
Raloxifene
0
Percent Change in PINP
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Conclusion

• The mechanical properties of bone are determined
  by
• Bone mass
• Geometry
• Intrinsic material properties
• Collagen
• Mineral
• Microdamage accumulation

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Conclusion

• Techniques are available to measure
  properties of the bone matrix

• Broader accessibility and convenience of
  techniques to measure bone quality, and the
  development of new non-invasive techniques, are
  necessary to provide better pre-fracture
  evaluations of tissue quality

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