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