conclusion slides
DESCRIPTION
Source:. Conclusion Slides. Review:. Reviewer Memo:. Slide Modified:. Memo:. Source:. Bone Quality. Review:. Bone quality is an integral component of bone strength Maintaining or restoring bone architecture is required for optimal bone quality - PowerPoint PPT PresentationTRANSCRIPT
June 2004
Conclusion Slides
June 2004
• Bone quality is an integral component of bone strength
• Maintaining or restoring bone architecture is required for optimal bone quality
• Bone turnover rate affects the degree of mineralization of bone
• Optimal collagen/mineral matrix properties contribute to bone quality
Bone Quality
June 2004
• Bone quality is an integral component of bone strength
• Maintaining or restoring bone architecture is required for optimal bone quality
• Bone turnover rate affects the degree of mineralization of bone
Bone Quality
June 2004
Raloxifene: Summary of Bone Quality Effects
• Changes in BMD explain only a small proportion of vertebral fracture risk reduction shown with raloxifene
• Raloxifene reduces bone turnover to the premenopausal range allowing
• Repair of microdamage
• Preservation of heterogeneous mineral distribution
• A modest increase in mineralization
June 2004
Possible Contributing Factors to the Antifracture Efficacy of Antiresorptives
• Increase bone mineral density
• Decrease bone turnover
• Preserve bone microarchitecture
• Decrease number of remodeling sites
• Maintain trabecular thickness and connectivity
• Decrease number of trabecular perforations
June 2004
• Biochemical markers and bone turnover significantly reduced to premenopausal range
• Normal bone turnover allows adequate repair of microdamage
• No adverse effect on bone histology
Bone Quality Raloxifene
June 2004
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
June 2004
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• A moderate increase in mineralization and
preservation of heterogeneous mineral distribution• Long-term efficacy with sustained fracture reduction
in the fourth year of treatment• Favorable effects on femoral neck geometry
June 2004
• Architecture • Increase trabecular thickness and connectivity• Increase cortical thickness and improves cortical geometry• Favorable effects on femoral neck geometry
• Turnover • Increase formation on quiescent (neutral) surface• Increase in formation is greater than resorption (positive
bone balance)• Transient increase in cortical porosity without impact on bone
strength• Damage Accumulation
• Forms new bone• Increased bone turnover reduces damage accumulation
Bone Quality ConclusionsTeriparatide
June 2004
• Architecture • Increase trabecular thickness and connectivity• Increase cortical thickness and improves cortical geometry• Favorable effects on femoral neck geometry
• Turnover • Increase formation on quiescent (neutral) surface• Increase in formation is greater than resorption (positive
bone balance)• Transient increase in cortical porosity without impact on bone
strength
Bone Quality ConclusionsTeriparatide
June 2004
Turnover Reduction
Within normal physiologic range
PreservePreservestrengthstrength
Decreaseresorption
cavities
Decreasestress risers
Decreaseperforations
MaintainHorizontal struts
MaintainPlate-like structure
June 2004
Excessive Turnover ReductionBelow normal physiologic range
Increased Increased fragilityfragility
Insufficient fatiguedamage repair
Microcrack accumulation Microcrack
propagation
Prolonged secondary mineralization
Excessive mineralization + homogeneous bone
?
June 2004
Osteoporosis
Severe Osteoporosis
Normal
Courtesy Dr. A. Boyde
June 2004
Physiological RangePhysiological Range
Sourced from Weinstein RS, J Bone Miner Res 15 621-625, 2000
What Is the Optimal Reduction in Bone Turnover for an Antiresorptive Drug?
Bo
ne S
tre
ng
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
Summary of Bone Quality Effects of Raloxifene Summary of Bone Quality Effects of Raloxifene and Teriparatideand Teriparatide
Raloxifene Teriparatide
Cortical geometry Protect Improve
Trabecular microarchitecture Protect Improve
Turnover Decrease Increase
Bone balance Normal Positive
Mineralization Normal Fresh bone
Mineral heterogeneity Normal Increase
Microdamage
Collagen cross-links
Osteocyte apoptosis
Decrease
?
Decrease
Decrease?
Younger
Decrease
June 2004
June 2004
The Assessment of Bone Quality- Advances in Technology
June 2004
0
2
4
6
8
10
0 1 2 3 4 5 6 7C
om
pre
ssiv
e s
tre
ng
th (
kN)
FFE
(kN)
r2=0.86, SE=0.71 kN
Cadaver Vertebrae: FEM vs. BCT
Experiments QCT
0
2
4
6
8
10
0 50 100 150 200 250
Co
mp
ress
ive
str
en
gth
(kN
)
QCT-BMD x Amin
(mg/mm)
r2=0.65, SE=1.11 kN
Crawford et al, Bone 2003
Str
engt
h (k
N)
BCT
ORS 2004
0 50 100 150 200 250QCT-BMD xA (mg/mm)
min
Model Strength (kN)June 2004
June 2004
Virtual Bone Biopsy
• Wrist detection coils• Microscopy-specific MRI scanner software enhancements• 3D image processing and analysis
June 2004
Supplemental Slides
June 2004
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.
June 2004
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
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
June 2004
June 2004
Urinary Markers of Bone Resorption
Marker Abbreviation
Hydroxyproline HYP
Pyridinoline PYD
Deoxypyridinoline DPD
N-terminal cross-linking telopeptide of type I collagen NTX
C-terminal cross-linking telopeptide of type I collagen CTX
Delmas PD. J Bone Miner Res 16:2370; 2001
June 2004
Serum Markers of Bone Turnover Abbreviation
Formation Bone alkaline phosphatase ALP (BSAP)Osteocalcin OCProcollagen type I C-propeptide PICPProcollagen type I N-propeptide PINP
ResorptionN-terminal cross-linking telopeptide of type I collagen NTXC-terminal cross-linking telopeptide of type I collagen CTXTartrate-resistant acid phosphatase TRAP
Delmas PD. J Bone Miner Res 16:2370, 2001
Effect of Size on Areal BMD
1
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
June 2004
Local Buckling