Bone Quality PART 1 Introduction Architecture Turnover

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Bone QualityPART 1Introduction
ArchitectureTurnover
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Old Definition of Osteoporosis
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.
Conference Report from the Consensus Development
Conference Am J Med 94 646-650, 1993
3
Relationship Between BMD and Fracture

• 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

4
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

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Age and Bone Mass as Predictors of Fracture
Hui SL et al. J Clin Invest 811804-1809 1988
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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

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Vertebral Fracture Risk Reduction Attributable to
an Increase in BMDAntiresorptive Therapy

• Risedronate1 7 28
• Alendronate2 16
• Raloxifene3 4

• Li et al. Stat Med 203175-88 2001
• Cummings et al. Am J Med 112281-289 2002
• 3. Sarkar et al. J Bone Miner Res 17 1-10 2002

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Randomized Studies of Antiresorptives in

Postmenopausal Osteoporotic Women
Risk of Vertebral Fractures
LS BMD
Relative Risk (95 CI)
Raloxifene
Preexisting vertebral
2.2
1
60 mg/d
fracture (VFx)
No preexisting VFx
2.9
1
Alendronate
Preexisting VFx
6.2
2
5/10 mg/d
No preexisting VFx
6.8
3
Risedronate
Preexisting VFx
4.3
4
5 mg/d
No preexisting VFx
5.9
5
Calcitonin
Preexisting VFx
0.7
6
200 IU/d
0
0.5
1.0
Not head
-
to
-
head comparison, vs placebo
1
Data on file, Eli Lilly Co.
4
Harris ST et al.
JAMA
2821344
-
1352, 1999
2
Black DM et al.
Lancet
3481535
-
1541, 1996
5
Reginster JY et al.
Osteoporosis Int
1183
-
91, 2000
3
Cummings SR et al.
JAMA
2802077
-
2082, 1998
Chesnut CH et al.
Am J Med
109267
-
276, 2000
6
9
Relationship Between Baseline Femoral Neck BMD
and Vertebral Fracture Risk MORE Trial - 3 Years
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Raloxifene (pooled)
Placebo
95 Confidence Interval
Baseline Femoral Neck BMD T-Score (NHANES)
Adapted from Sarkar S et al. J Bone Miner Res
171-10, 2002
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Relationship Between Change in Femoral Neck BMD
and Vertebral Fracture RiskMORE Trial - 3 Years
Raloxifene (pooled)
15
Placebo
13
11
9
Risk of ? 1 New Vertebral Fracture
7
5
3
0
-10
-8
-6
-4
-2
0
2
4
6
8
10
Change in Femoral Neck BMD
Adapted from Sarkar S et al. J Bone Miner Res
171-10, 2002
11
Relationship Between Change in Femoral Neck BMD
and Vertebral Fracture Risk
MORE Trial 3 Years
Raloxifene (pooled)
Placebo
Risk of ? 1 New Vertebral Fractureat 3 Years ()
-
-
-
-
-
Change in Femoral Neck BMD at 3 Years
Adapted from Sarkar S et al. J Bone Miner Res
171-10, 2002
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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

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Current Definition of 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.
Normal bone Osteoporosis
NIH Consensus Development Panel on Osteoporosis
JAMA 285785-95 2001
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Shifting the Osteoporosis Paradigm Bone
StrengthNIH Consensus Statement 2000
Bone Quality
Bone Mineral Density
Bone Strength
and
Architecture Turnover rate Damage
Accumulation Degree of Mineralization Properties
of the collagen/mineral matrix
Adapted from NIH Consensus Development Panel on
Osteoporosis. JAMA 285785-95 2001
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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 162163-2172,
2001 NIH Consensus Development Panel on
Osteoporosis. JAMA 285785-952001
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Bone Quality
Architecture Turnover Rate Damage
Accumulation Degree of Mineralization Properties
of the collagen/mineral matrix
Adapted from NIH Consensus Development Panel on
Osteoporosis. JAMA 285785-95 2001
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Distribution of Cortical and Trabecular Bone
Thoracic and 75 trabecular Lumbar Spine 25
cortical
1/3 Radius gt95 Cortical
Femoral Neck 25 trabecular 75 cortical
Ultradistal Radius 25 trabecular 75 cortical
Hip Intertrochanteric Region 50 trabecular 50
cortical
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Cortical and Trabecular Bone
Cortical Bone

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

Trabecular Bone

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

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Relevance of Architecture
Normal Loss of Loss of Quantity Quantity
and Quantity and Architecture Architecture
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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

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Structural Role of TrabeculaeCompressive
strength of connected and disconnected trabeculae
1
16 X
Bell et al. Calcified Tissue Research 1 75-86,
1967
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Resorption Cavities as Mechanical Stress Risers
Adapted from Parfitt A.M. et al. Am J Med 91,
Suppl 5B 5B-34S
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Strain Distribution in Relation to Trabecular
Perforations

• 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

Reprinted with Permission from Van der Linden et
al. J Bone Miner Res 16457-465 2001
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Trabecular Perforations
Reprinted with Permission from Mosekilde L. Bone
Miner 10 13-35, 1990 Seeman Lancet 359,
1841-1850, 2002.
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Antiresorptive Agents Help to Preserve
Supporting Ties
Reprinted with Permission from Mosekilde L. Bone
9 247-250, 1988
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Bone ArchitectureCortical Bone

• Fracture Risk Increases With
• Increased Bone turnover
• Decreased cortical thickness
• Changes in dimensions

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Effects of Antiresorptive Drugs
High turnover state endosteal resorption and
increased porosity
Stress Risers
Fracture at a Stress Riser
Low turnover state reduced endosteal resorption
and porosity
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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

Zanchetta JR et al. JBMR 18, 539-534, 2003
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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
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Teriparatide - Effect on Cortical Bone
Improves geometry-Increases diameter
Increases thickness
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FACT Trial Lumbar Spine BMD Areal (DXA) and
Volumetric (QCT)
Source RMP.B3DSGHBM.SASPGM(BDS001DD)see
reference in notes
Review David Donley - statistical review WPDF
DWD200210c WPDF for global kit LX200308c (Li
Xie 090403)

QCT Subset

Reviewer Memo

Percent change at 6 months


Within treatment Plt0.01
Treatment difference Plt0.01
McClung et al. Osteoporos Int. 2002
Slide Modified on 9/18/2002 124538 PM SL12
Rev 272on 2/3/2003 22055 PM SL12 Rev
320on 9/4/2003 84421 AM SL25 Rev 47 on
9/25/2003 63858 PM SL1 Rev 128
Memo new notes, changed reference to published
McClung 18Aug03 - MR
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Teriparatide Effects on the Femoral Midshaft of
Ovariectomized Monkeys
Data on file, Eli Lilly
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Effect of 20 mg Teriparatide on Trabecular and
Cortical Architecture
Baseline
Follow-up
Eriksen et al ACR 2002
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3-D Structural Indices in Women in the
Teriparatide Fracture Prevention
TrialQuantitative analysis-Significant changes
Source
Review Hong Ren
Trabecular bone volume
Plt0.001
Reviewer Memo
Structure model index
Plt0.025
Connectivity density
Plt0.034
Cortical thickness
Plt0.012
Eriksen et al ACR 2002
Slide Modified on 10/22/2002 125504 PM
SL11 Rev 147
Memo ACR 2002
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Effect of 20 mg Teriparatide on Bone
Histology-Iliac crest bone biopsies
Source
Review Hong Ren

• 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

Reviewer Memo
Eriksen et al ACR 2002
Slide Modified on 10/22/2002 125508 PM
SL16 Rev 147
Memo ACR 2002
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Bone Quality
Architecture Turnover Rate Damage
Accumulation Degree of Mineralization Properties
of the collagen/mineral matrix
Adapted from NIH Consensus Development Panel on
Osteoporosis. JAMA 285 785-95 2001
37
Bone Remodeling Process
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High Bone Turnover Leads to Development of Stress
Risers and Perforations
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Consequences of an Imbalance in Bone Turnover
Osteoporotic Bone
Normal Bone
Mechanism of Action Animation of Bone Remodeling
Process, 2002, Eli Lilly
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Bone Turnover, Mineralization, and Bone Quality

• There is a complex relationship between bone
  turnover and bone quality
• A decrease of bone turnover increases
  mineralization and permits filling of remodeling
  space

Excessive suppression Increased
mineralization Accumulation Increased
brittleness of microcracks Skeletal
fragility
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Antiresorptive Agents Increase BMD by Decreasing
Remodeling Space and/or Prolonging Mineralization
42
Rate of Bone Turnover
Clinical paradigm

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

Clinical question
Can excessive reduction in bone turnover be
harmful for bone? How much suppression is too
much?
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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
11467-480 2000
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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.

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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 162370 2001
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Serum Markers of Bone Turnover

• Abbreviation
• Formation
• Bone alkaline phosphatase ALP (BSAP)
• Osteocalcin OC
• Procollagen type I C-propeptide PICP
• Procollagen type I N-propeptide PINP
• Resorption
• N-terminal cross-linking telopeptide of
  type I collagen NTX
• C-terminal cross-linking telopeptide of
  type I collagen CTX
• Tartrate-resistant acid phosphatase TRAP

Delmas PD. J Bone Miner Res 162370, 2001
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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 gt60 and of urinary NTX
  gt40 gave little added benefit in fracture
  reduction

Adapted from Eastell R et al. Osteoporos Int
13520 2002
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Raloxifene and Alendronate Reduce Bone Turnover
in Women with Osteoporosis
Mean Serum CTX (ng/L)
Mean Serum PINP (?g/L)
Premenopausal
Mean SD
Mean SD
plt 0.01 compared to premenopausal levels
Adapted from Stepan JJ et al. J Bone Miner Res 17
(Suppl 1)S233 2002
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Bone Turnover Effects Bone Quality

• 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