Bone Quality

PART 1Introduction Architecture

Turnover

A systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.

Old Definition of Osteoporosis

Conference Report from the Consensus Development Conference: Am J Med 94: 646-650, 1993

• Low baseline bone mineral density (BMD) predicts increased risk of subsequent fractures

• The magnitude of the increases in BMD with antiresorptive therapies differs greatly, yet the vertebral fracture risk reductions are similar

• There is only a weak relationship between changes in BMD with antiresorptive therapy and the reduction in risk of new fractures

Relationship Between BMD and Fracture

What May Contribute to an Increase in BMD?

• Increased mineralization in existing bone • Increased bone tissue per unit of bone volume:

• Filling in resorption space• Widening existing trabeculae• Creating new trabeculae

• Increased bone size

Age and Bone Mass as Predictors of Fracture

Hui SL et al. J Clin Invest 81:1804-1809; 1988

Forearm Bone Mass (g/cm2)

Fra

ctur

e R

isk

/ 10

00 P

erso

n Y

ear

Age (Years)

0

20

40

60

80

100

120

140

160

>1.0 0.90-0.99 0.80-0.89 0.70-0.79 0.60-0.69 <0.60

<45

50-5445-49

55-5960-6465-69

70-74

75-79

80+

BMD Change and Fracture Risk Reduction with Antiresorptive Therapy

• Fracture Risk decreases by 6-12 months, before maximum BMD response has occurred

• Treatment may reduce fracture risk with little or no change in BMD

• From regression analyses, only a small proportion of fracture risk reduction is attributable to an increase in BMD

Vertebral Fracture Risk Reduction Attributable to an Increase in BMD

Antiresorptive Therapy

Risedronate1 7 – 28%

Alendronate2 16%

Raloxifene3 4%

1. Li et al. Stat Med 20:3175-88; 20012. Cummings et al. Am J Med 112:281-289; 20023. Sarkar et al. J Bone Miner Res 17: 1-10; 2002

Randomized Studies of Antiresorptives in Postmenopausal Osteoporotic Women*

Risk of Vertebral Fractures

1Data on file, Eli Lilly & Co.2Black DM et al. Lancet 348:1535-1541, 19963Cummings SR et al. JAMA 280:2077-2082, 1998

4Harris ST et al. JAMA 282:1344-1352, 19995Reginster JY et al. Osteoporosis Int 11:83-91, 20006 Chesnut CH et al. Am J Med 109:267-276, 2000

LS BMD** Relative Risk (95% CI)

Raloxifene60 mg/d

Preexisting vertebral fracture (VFx)1

No preexisting VFx1

2.2

2.9

Alendronate

5/10 mg/d

Preexisting VFx2

No preexisting VFx3

6.2

6.8

Risedronate5 mg/d

Preexisting VFx4

No preexisting VFx5

4.35.9

Calcitonin200 IU/d

Preexisting VFx6 0.7

*Not head -to-head comparison, **vs placebo 0.5 1.00

Adapted from Sarkar S et al. J Bone Miner Res 17:1-10, 2002

Relationship Between Baseline Femoral Neck BMD and Vertebral Fracture Risk

MORE Trial - 3 Years

Baseline Femoral Neck BMD T-Score (NHANES)

Placebo

Raloxifene (pooled)

95% Confidence Interval

22%

Risk

of

1 N

ew

Verte

bral

Fra

ctur

e at

3 Y

ears 20

18

1614

12

10

864

2

-3.2 -2.8 -2.8 -2.6 -2.4 -2.2 -2.0 -1.8 -1.60

Placebo

Raloxifene (pooled)

% Change in Femoral Neck BMD

% R

isk

of

1 N

ew

V

ert

eb

ral F

ract

ure

95% confidence interval

Adapted from: Sarkar S et al. J Bone Miner Res 17:1-10, 2002

Relationship Between Change in Femoral Neck BMD and Vertebral Fracture Risk

MORE Trial - 3 Years

13

7

5

3

9

11

15

-10 -8 -6 -4 -2 0 2 4 6 8 100

Placebo

Raloxifene (pooled)

Adapted from Sarkar S et al. J Bone Miner Res 17:1-10, 2002

Relationship Between Change in Femoral Neck

BMD and Vertebral Fracture Risk MORE Trial – 3 Years

- - - - -10 8 6 4 2 0 2 4 6 8 10

13

11

15

7

5

3

9

0

B

B

A

A

Ris

k o

f 1

Ne

w V

ert

eb

ral F

ract

ure

at 3

Yea

rs (

%)

% Change in Femoral Neck BMD at 3 Years

Many Characteristics of Bone Strength Are Not Reflected in DXA Results

• Reflected in DXA Measurements:• Bone size• Trabecular volume and cortical thickness• Amount of mineralization in bone and surrounding tissues

• Not Reflected in DXA Measurements:• Trabecular connectivity and number• Collagen quality• Microscopic damage (e.g. microcracks)• Bone geometry

Normal bone 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.

Current Definition of Osteoporosis

NIH Consensus Development Panel on Osteoporosis JAMA 285:785-95; 2001

BoneQuality

BoneStrength and

ArchitectureTurnover rateDamage AccumulationDegree of MineralizationProperties of the collagen/mineral matrix

Shifting the Osteoporosis Paradigm Bone Strength

NIH Consensus Statement 2000

Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95; 2001

BoneMineralDensity

Components of Bone Quality

• Architecture• Macroarchitecture (bone geometry)• Microarchitecture (trabecular connectivity and shape)

• Bone turnover• Resorption• Formation

• Material properties

• Collagen properties (cross-linking)• Mineralization (degree and heterogeneity)• Microdamage (microcracks)

Chesnut III CH. J Bone Miner Res 16:2163-2172, 2001NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95;2001

Bone Quality

Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95; 2001

Architecture

Turnover Rate

Damage Accumulation

Degree of Mineralization

Properties of the collagen/mineral matrix

Distribution of Cortical and Trabecular Bone

Thoracic and 75% trabecularLumbar Spine 25% cortical

Femoral Neck 25% trabecular75% cortical

Hip Intertrochanteric Region 50% trabecular

50% cortical

1/3 Radius >95% Cortical

Ultradistal Radius25% trabecular

75% cortical

Cortical and Trabecular Bone

• 80% of all the bone in the body • 20% of bone turnover

• 20% of all bone in the body • 80% of bone turnover

Cortical Bone

Trabecular Bone

Relevance of Architecture

Normal Loss of Loss of QuantityQuantity and Quantity and Architecture Architecture

Bone ArchitectureTrabecular Perforation

The effects of bone turnover on the structural role of trabeculae

Risk of Trabecular Perforation increases with:

• Increased bone turnover• Increased erosion depth• Predisposition to trabecular thinning

Structural Role of Trabeculae

Compressive strength of connected and disconnected trabeculae

16 X1

Bell et al. Calcified Tissue Research 1: 75-86, 1967

Resorption Cavities as Mechanical Stress Risers

Adapted from Parfitt A.M. et al. Am J Med 91, Suppl 5B: 5B-34S

Normal Osteoporotic

Strain Distribution in Relation to Trabecular Perforations

Reprinted with Permission from Van der Linden et al. J Bone Miner Res 16:457-465; 2001

• Trabeculae under low strain (blue) can tolerate bone loss better than traceculae under high strain (red)

• Resorption of trabeculae causes a larger decrease in stiffness than does thinning of trabeculae

Trabecular Perforations

Reprinted with Permission from Mosekilde L. Bone Miner 10: 13-35, 1990

Seeman Lancet 359, 1841-1850, 2002.

Antiresorptive Agents Help to Preserve Supporting Ties

Reprinted with Permission from Mosekilde L. Bone 9: 247-250, 1988

Bone ArchitectureCortical Bone

Fracture Risk Increases With:

• Increased Bone turnover

• Decreased cortical thickness

• Changes in dimensions

Effects of Antiresorptive Drugs

Fracture at a Stress RiserStress Risers

High turnover state: endosteal resorption and increased porosity

Low turnover state: reduced endosteal resorption and porosity

Effect of Teriparatide [rh PTH(1-34)] on Radial BMD

• Periosteal apposition of new bone that is not yet fully mineralized

• Endosteal resorption of normal or highly mineralized bone

BMD

Zanchetta JR et al. JBMR 18, 539-534, 2003

Possible Mechanism for Reduced BMD Response to TPTD Among Alendronate-Pretreated Patients

Pretreatment

bone mass

remodeling space

1Boivin, Bone 2000, 2 Burr, JBMR 2001, 3 Zanchetta, IOF 2001

BMD

TPTD Treatment

endosteal porosity 2

periosteal new bone

cortical area 3

BMD

AfterAlendronate

mineralization

porosity1

Increases thickness

Improves geometry-Increases diameter

Teriparatide - Effect on Cortical Bone

FACT Trial Lumbar Spine BMD

Areal (DXA) and Volumetric (QCT)

Pe

rce

nt

ch

an

ge

at

6 m

on

ths QCT Subset

*

*

*

†

†

Within treatment: *P<0.01 Treatment difference: †P<0.01

TPTD (n = 16)ALN (n = 19)

McClung et al. Osteoporos Int. 2002

Jiang UCSF

Teriparatide Effects on the Femoral Midshaft of Ovariectomized Monkeys

Ovx PTH5WPTH1W

Sham PTH 1 PTH 5

Data on file, Eli Lilly

Eriksen et al ACR 2002

Baseline Follow-up

Effect of 20 g Teriparatide on Trabecular and Cortical Architecture

3-D Structural Indices in Women in the Teriparatide Fracture Prevention Trial

Quantitative analysis-Significant changes

Trabecular bone volume

Structure model index

Connectivity density

Cortical thickness

P<0.025

P<0.034

P<0.001

P<0.012

Eriksen et al ACR 2002

Effect of 20 g Teriparatide on Bone Histology-Iliac crest bone biopsies

• Increased trabecular bone volume

• Shifted trabeculae toward a more plate-like structure

• Increased trabecular bone connectivity

• Increased cortical bone thickness with no increase in cortical porosity

Eriksen et al ACR 2002

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 Remodeling Process

ResorptionCavities

Bone

Osteoclasts

Lining Cells

Osteoblasts

Osteoid

Lining Cells

MineralizedBone

High Bone Turnover Leads to Development of Stress Risers and Perforations

Lining Cells

Bone

Osteoclasts

Stress Risers

Perforations

Consequences of an Imbalance in Bone Turnover

Normal BoneNormal Bone Osteoporotic BoneOsteoporotic Bone

Mechanism of Action Animation of Bone Remodeling Process, 2002, Eli Lilly

Excessive suppression Increased mineralization

Accumulation Increased brittlenessof microcracks

Skeletal fragility

• There is a complex relationship between bone turnover and bone quality

• A decrease of bone turnover increases mineralization and permits filling of remodeling space

Bone Turnover, Mineralization, and Bone Quality

Antiresorptive Agents Increase BMD by Decreasing Remodeling Space and/or

Prolonging Mineralization

Antiresorptive Agent

Newly formed bone

Increased MineralizationRemodeling space

Rate of Bone Turnover

Bone turnover is an essential physiological mechanism for repairing microdamage and replacing “old” bone by “new” bone

Can excessive reduction in bone turnover be harmful for bone?

How much suppression is too much?

Clinical paradigm:

Clinical question:

Changes in Biochemical Markers Predict an Increase in Bone Mineral

Density During Antiresorptive Therapy

• Treatment with antiresorptive agents produce greater proportional changes in bone turnover markers than in BMD

• Measurable changes in bone turnover markers tend to occur before changes in BMD

• There are significant correlations between changes in bone turnover markers and changes in BMD

Adapted from Looker AC et al. Osteoporos Int 11:467-480; 2000

Bone Turnover Markers

• Bone turnover markers are components of bone matrix or enzymes that are released from cells or matrix during the process of bone remodeling (resorption and formation).

• Bone turnover markers reflect but do not regulate bone remodeling dynamics.

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

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

Relationship Between Changes in Bone Resorption Markers and Vertebral Fracture Risk

VERT Study

• A decrease in urinary CTX and NTX at 3-6 months was associated with vertebral fracture risk at 3 years

• A decrease in urinary CTX >60% and of urinary NTX >40% gave little added benefit in fracture reduction

Adapted from Eastell R et al. Osteoporos Int 13:520; 2002

Raloxifene and Alendronate Reduce Bone Turnover in Women with Osteoporosis

Mean Serum CTX (ng/L) Mean Serum PINP (g/L)

Adapted from Stepan JJ et al. J Bone Miner Res 17 (Suppl 1):S233; 2002

*p< 0.01 compared to premenopausal levels

0

100

200

300

400

500

ALNRLX

*M

ean

± S

D

Mea

n ±

SD

0

10

20

30

40

50

ALN RLX

*

PremenopausalPremenopausal

• Very low turnover leads to excessive mineralization and the accumulation of microdamage

• Very high turnover leads to accumulation of perforations and a negative bone balance

Bone Turnover Effects Bone Quality