June 2004
Bone Quality 2004
June 2004
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
June 2004
• 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
June 2004
What May Contribute to an Increase in BMD?
• Improvements in mineral and matrix composition• Increased bone tissue per unit of bone volume:
• Filling in remodeling space• Widening existing trabeculae• Creating new trabeculae
• Increased bone size
June 2004
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+
June 2004
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
June 2004
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 S et al. Am J Med 112:281-289; 20023. Sarkar Set al. J Bone Miner Res 17: 1-10; 2002
June 2004
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
June 2004Sourced 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
June 2004Sourced 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
Placebo
Raloxifene (pooled)
% Change in Femoral Neck BMD
% R
isk
of
1 N
ew
V
ert
eb
ral F
ract
ure
95% confidence interval13
7
5
3
9
11
15
-10 -8 -6 -4 -2 0 2 4 6 8 100
June 2004
Placebo
Raloxifene (pooled)
Sourced 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
June 2004
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• Matrix quality (collagen, mineral)• Microscopic damage (e.g. microcracks)• Bone geometry
June 2004
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
June 2004
aBMD (areal) = g/cm2
vBMD (volumetric) = g/cm3
BoneQualityBone
Quality BoneStrength and
MicroarchitectureGeometryTurnover RateDamage AccumulationDegree of MineralizationProperties of the Collagen/mineral Matrix
Shifting the Osteoporosis Paradigm Bone Strength
NIH Consensus Statement 2000
Sourced from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95; 2001
Bone MineralDensity
June 2004
BONE QUALITY CONCEPT
Bone Mass
Distribution of MassGeometry
Architecture
Bone Strength
Tur
nove
r
Material PropertiesMineralizationMatrix QualityMicrodamage
June 2004
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
Fracture
BoneStrength
Bone Mass Nutrition
FallsShape &
ArchitectureHormones
Exercise &Lifestyle
Material Properties
PosturalReflexes
Soft TissuePadding
Reproduced with permission from Heaney RP. Bone 33:457-465, 2003
Factors Leading to Osteoporotic Fracture: Role of Bone Mass
June 2004
June 2004
Bone Quality
Sourced 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
June 2004
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
June 2004
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
June 2004
Relevance of Architecture
Normal Loss of Loss of QuantityQuantity and Quantity and Architecture Architecture
June 2004
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
June 2004
Structural Role of Trabeculae
Compressive strength of connected and disconnected trabeculae
16 X1
Bell GH et al. Calcif Tissue Res 1: 75-86, 1967
June 2004
Resorption Cavities as Mechanical Stress Risers
Sourced from Parfitt AM et al. Am J Med 91, Suppl 5B: 42S-46S
Normal Osteoporotic
June 2004
Strain Distribution in Relation to Trabecular Perforations
Reprinted with Permission from Van der Linden JC 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
June 2004
Trabecular Perforations
Seeman E Lancet 359, 1841-1850, 2002.
Reprinted with Permission from Mosekilde L. Bone Miner 10: 13-35, 1990
June 2004
Antiresorptive Agents Help to Preserve Supporting Ties
Reprinted with Permission from Mosekilde L. Bone 9: 247-250, 1988
June 2004
Bone ArchitectureCortical Bone
Key Variables Associated With Cortical Bone Strength
•Bone turnover
•Cortical thickness
•Geometry and Dimensions
June 2004
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
June 2004
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. J Bone Miner Res 18, 539-534, 2003
periosteal
endosteal
Possible Mechanism for Reduced BMD Response to TPTD Among Alendronate-Pretreated Patients
Pretreatment
bone mass
remodeling space
BMD
TPTD Treatment
endosteal porosity periosteal new bone
cortical area
BMD
AfterAlendronate
mineralization
porosity
June 2004
June 2004
Increases thickness
Improves geometry-Increases diameter
Teriparatide - Effect on Cortical Bone
FACT Trial Lumbar Spine BMD
Areal (DXA) and Volumetric (QCT)
Pe
rce
nt c
ha
ng
e a
t 6 m
on
ths QCT Subset
*
*
*
†
†
Within treatment: *P<0.01 Treatment difference: †P<0.01
TPTD (n = 16)ALN (n = 19)
McClung MR et al. Osteoporos Int 13(Suppl 3):S18, 2002
June 2004
June 2004
Teriparatide Effects on the Femoral Midshaft of Ovariectomized Monkeys
Ovx PTH5WPTH1W
Sham PTH 1 PTH 5
Sourced from Sato et al., JBMR 2004 19 623-629 and Data on file, Eli Lilly & Company
Teriparatide Improves Skeletal Architecture
Patient treated with teriparatide 20 µg
Female, age 65Duration of therapy: 637 days (approx 21 mos)BMD Change: Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%) Total Hip: +5.2% (group mean = 2.6 ± 4.9%)Sourced from Jiang et al. J Bone
Miner Res 18:1932-1941, 2003
Baseline Follow up Jiang UCSF
Structural IndicesQuantitative Analysis-significant Changes
Trabecular bone volume
Structure model index
Connectivity density
Cortical thickness
P<0.05
P<0.05
P<0.001
P<0.05
Sourced from Jiang et al. J Bone Miner Res 18:1932-1941, 2003
June 2004
June 2004
• Teriparatide-induced changes in trabecular and cortical bone morphology:
• contribute to increased biomechanical competence
• may explain the persistent reduction of vertebral and nonvertebral fractures with teriparatide treatment
Sourced from Jiang et al. J Bone Miner Res 18:1932-1941, 2003
Teriparatide Has Positive Effects on Bone Structure
Summary