Bone Quality PART 3 Collagen/Mineral Matrix Conclusions Supplemental Slides

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

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4505-92TR2COLL X

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IR-spectrometer

Bone section

FTIR Imaging – Mineral Crystallinity

E. Paschalis et al. 2003 (in press).

BaselinePi

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Mineral CrystallinityPi

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2 Year Estrogen Therapy

Mineral Crystallinity

FTIR Imaging – Mineral:Matrix Ratio


Baseline

Mineral Matrix

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Mineral Matrix

FTIR Imaging – Collagen Cross-Link Ratio


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collxtr3

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Pyr/DHLNL

Baseline

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collxtr2

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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


• Histomorphometry• No woven bone• No marrow fibrosis• No mineralization defect• No cellular toxicity (light microscopy)• Normal histologic appearance


• 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.


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


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


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

Bone Quality PART 3 Collagen/Mineral Matrix Conclusions Supplemental Slides

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