Assessment of Skeleton Health

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Assessment of Skeleton Health

• Tuan Van Nguyen and Nguyen Dinh Nguyen
• Garvan Institute of Medical Research
• Sydney, Australia

2
Overview

• Background
• Normal bone and bone remodelling
• Bone loss and age
• Definitions
• Measurements of bone strength
• Bone mass and DXA, QUS
• Bone turnover markers

3
Background

• Aging population fastest growing age group
• Osteoporosis and osteoporotic fracture
  age-related disorders
• Osteoporosis and osteoporotic fracture
• Common
• Cause serious disability and excess mortality
• Major economic burden on healthcare system

4
Residual lifetime risk of different diseases
Women
Men
(Source Nguyen ND et al, 2006, under review
process)
5
Survival probability and fracture
Women
Men
Cumulative survival rate
Age (y)
(Soure Center J, Nguyen TV et al., Lancet
1999353878-82)
6
Burden of Osteoporotic fractures

• Annual cost of all osteoporotic fractures 20
  billion in USA and 30 billion on EU1.
• Worldwide direct and indirect cost of hip
  fracture US131.5 billion2.

(Sources 1Cummings et al., Lancet
20023591761-67 2Johnell O, Am J Med
199710320S-26)
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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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Cortical (Compact) Bone

• 80 of the skeletal mass
• Provides a protective outer shell around every
  bone in the body
• Slower turnover
• Provides strength and resists bending or torsion

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Trabecular (Cancellous) Bone

• 20 of the skeletal mass, but 80 of the bone
  surface.
• less dense, more elastic, and higher turnover
  rate than cortical bone.
• appears spongy
• found in the epipheseal and metaphysal regions of
  long bones and throughout the interior of short
  bones.
• constitutes most of the bone tissue of the axial
  skeleton (skull, ribs and spine).
• interior scaffolding maintains bone shape despite
  compressive forces.

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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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How does bone loss happen?

• Bone is a living, growing, tissue
• Healthy bones are not quiescent. They are
  constantly being remodeled.
• This is not simply a problem of bony destruction,
  but imbalance between the formation and
  destruction of bone.

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Bone remodeling cycle
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Bone remodeling cycle
Pre-osteoblasts
Monocytes
Osteoblasts
Osteoclasts
Osteocytes
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Bone loss
Bone formation
Bone resorption
Bone formation
Bone resorption
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Bone mass declines with age

• Remodeling occurs at discrete foci called bone
  remodeling units (BRUs).
• Number of active BRUs ? with age ? ? bone
  turnover.
• Osteoblasts not able to completely fill cavities
  created by osteoclasts and less mineralized bone
  is formed.
• Endosteal bone loss partially compensated by
  periosteal bone formation ? trabecular thinning.

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Relative Influence of Inner and Outer Diameters
on Bone Strength
(Adapted from Lee CA, and Einhorn TA.
Osteoporosis 2nd Ed. 2001)
17
Gain and loss of Bone throughout the lifespan
Pubertal Growth Spurt
Menopause
BMD
Resorption
Formation
Age (Years)
18
Relationship between BMD and Age
(VN 2006, unpublished data)
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Definition of Osteoporosis(WHO)

• A systematic skeleton disease characterized by
• low bone mass
• microarchitectural deterioration of bone tissue
• consequent increase in bone fragility and
  susceptibility to fracture

Consensus Development Conference Diagnosis,
Prophylaxis, and Treatment of Osteoporosis, Am J
Med 199394646-650. WHO Study Group 1994.
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Osteoporosis
21
Osteoporosis
Normal bone
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Definition of Osteoporosis(NIH)

• 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.

(Source NIH Consensus Development Panel on
Osteoporosis JAMA 285785-95 2001)
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BONE STRENGTH
BONE MINERAL DENSITY
BONE QUALITY
Bone architecture
Gram of mineral per area
Bone turnover
Bone size geometry
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Bone Quality

• Architecture
• Turnover Rate
• Damage Accumulation
• Degree of Mineralization
• Properties of the collagen/mineral matrix

( NIH Consensus Development Panel on
Osteoporosis. JAMA 285785-95 2001)
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Bone mass, Bone mineral density (BMD)

• Bone mass the amount of bone tissue as the
  total of protein and mineral or the amount of
  mineral in the whole skeleton or in a particular
  segment of bone. (unmeasurable)
• BMD the average concentration of mineral per
  unit area ? assessed in 2 dimensions (measurable)

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Effect of Size on Areal BMD
BMC
AREA
BMD
1
1
1
1
1
1
2
2
8
4
2
2
3
3
27
9
3
3
TRUE VALUE 1 g/cm3
(Adapted from Carter DR, et al. J Bone Miner Res
1992)
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Bone Densitometry

• Non-invasive test for measurement of BMD
• Major technologies
• Dual-energy X-ray Absorptiometry (DXA)
• Quantitative Ultrasound (QUS)
• Quantitative Computerized Tomography (QCT)
• Many manufacturers
• Numerous devices
• Different skeletal sites

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DXA (or DEXA)
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DXA (or DEXA)

• Gold-standard for BMD measurement
• Measures central or axial skeletal sites
  spine and hip
• May measure other sites total body and forearm
• Extensive epidemiologic data
• Correlation with bone strength in-vitro
• Validated in many clinical trials

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DXA Technology
Detector (detects 2 tissue types - bone and soft
tissue)
Very low radiation to patient. Very little
scatter radiation to technologist
Patient
Collimator (pinhole
for pencil beam, slit for fan beam)
Photons
X-ray Source
(produces 2 photon energies with
different attenuation profiles)
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DXA BMD scan
Spine
Hip
Total body
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DXA Femoral neck BMD
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DXA Lumbar spine BMD
34
DXA Hip BMD Results
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Which Skeletal Sites Should Be Measured?

• Every Patient
• Spine
• L1-L4 (L2-L4)
• Hip
• Total Proximal Femur
• Femoral Neck
• Trochanter

• Some Patients
• Forearm (33 Radius)
• If hip or spine cannot be measured
• Hyperparathyroidism
• Very obese

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BMD measurement subject to variability

• In vivo/in situ BMD inaccuracy effect of bone
  structure, bone size and shape, and extra-osseous
  soft tissue
• Measurement error within subject and
  between-subject variations.
• Between machine variation.

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In vivo/In situ BMD inaccuracy
REGION OF INTEREST
Lateral region
Lateral region
Bone region
Trabeculaae Marrow
Extra-Osseous FatLean tissue
Cortical region
(Adapted from Bolotin HH, Med Phys 200431774-88)
X-RAY PATHS
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In vivo/In situ BMD inaccuracy
Under-/or over-estimate BMD () Under-/or over-estimate BMD () Under-/or over-estimate BMD ()
Normal Osteopenia Osteoporosis
Typical lumbar vertebral bone site 25 35 Up to 50
Distal radius, femur 20 25 35
Trabecular-free sites (mid-shaft femur, mid-shaft radius) lt2
Individual
Type of bone
(Source Bolotin HH, Med Phys 200431774-88)
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Source of variability in BMD measurements
Number of measurements per subject required to
increase the reliability of measurement for a
given coefficient of reliability
(Source Nguyen TV et al., JBMR 199712124-34)
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Standard error of rate of change in BMD
Individual
Group
(Source Nguyen TV et al., JBMR 199712124-34)
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Source of variability in BMD measurements

• Group level Intra-subject estimation error could
  contribute about 90 of the variability component
  ? ? power of study, and underestimate the RR
  (BMD-fracture).
• Individual level? false ve false ve error
  rates of diagnostic BMD.
• ? measurement error by multiple measurement.
• ? long-term intra-subject variation by ? the
  length of follow-up and/or ? the frequency of
  measurements.
• Studies with 3-5 yrs of follow-up optimal cost
  benefits.
• More than 2 measurements/year not improve the
  precision appreciably.

(Source Nguyen TV et al., JBMR 199712124-34)
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True level and True biological change of BMD

• Factors affect to BMD level and BMD change
• Invivo/in situ BMD inaccuracy
• Random error
• Measurement errors intra- and between-subject
  variability
• Systematic errors
• Effect of regression-toward-the mean

(Sources Bolotin HH, Med Phys 200431774-88
Nguyen TV et al., JBMR 199712124-34 Nguyen TV
et al, JCD 20003107-19)
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True level and True biological change of BMD

• BMD level
• Good agreement between observed and true values
• Individual with low BMD 20 false ve and false
  ve of diagnosis of osteoporosis.
• BMD change
• Overall average increase in BMD of 2 no
  conclusion of significant change for an
  individual.
• An observed ? of at least 5.5 or ? of at least
  7.5 could be a significantly biological change.

(Source Nguyen TV et al, JCD 20003107-19)
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BMD Values From Different Manufacturers Are Not
Comparable

• Different dual energy methods
• Different calibration
• Different detectors
• Different edge detection software
• Different regions of interest

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Peripheral BMD TestingAccurate Precise

• What it can do
• Predict fracture risk
• Tool for osteoporosis education
• What it cannot do
• Diagnose osteoporosis
• Monitor therapy

1. A normal peripheral test does not necessarily
   mean that the patient does not have osteoporosis.
2. WHO criteria do not apply to peripheral BMD
   testing.

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Quantitative Ultrasound (QUS)

• Broad-band ultrasound attenuation or ultrasound
  velocity
• No radiation exposure
• Cannot be used for diagnosis
• Preferred use in assessment of fracture risk

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Bone Quality
Architecture Turnover Rate Damage
Accumulation Degree of Mineralization Properties
of the collagen/mineral matrix
( NIH Consensus Development Panel on
Osteoporosis. JAMA 285785-95 2001)
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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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Hip strength indice

• CSMI (cm4) Cross-sectional moment of inertia
• CSA (cm2) Cross sectional area
• Z (cm3) Section modulus CSMI/distance from the
  centre of the mass to the superior neck margin.
• Cstress (N/mm2) Compressive stress on the
  superior surface of the FN during a fall on the
  greater trochanter. Calculated by combining CSMI
  and CSA.
• FND (cm) Femoral neck Diameter
• Buckling ratio radius/thickness

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Cross-Sectional Moment of Inertia CSMI ?/4
(r4 outer r4 inner)
Area (cm2) 2.77 2.77 2.77 CSMI (cm4) 0.61 1.06 1.5
4 Bending Strength 100 149 193
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Bone strengh indice summary

• Not well-studied
• Derived from BMC, BMD, and several assumptions
• Used in research field.

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Bone Turnover Markers

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

(Source Delmas PD. J Bone Miner Res 162370
2001)
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Serum Markers of Bone Turnover

• Marker 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

(Source Delmas PD. J Bone Miner Res 162370,
2001)
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Bone Turnover Effects Bone Quality

• Very low turnover ?excessive mineralization and
  the accumulation of microdamage
• Very high turnover ? accumulation of perforations
  and a negative bone balance

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Summary

• Osteoporosis and osteoporotic fractures are
  common among aging population
• Gold standard of assessment skeleton health is
  BMD via DXA machine.
• BMD measurement is subject to bias and errors.
• Additional measure of bone health QUS (BMD),
  bone strength indice and bone turnover markers.

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  Bridge Healthcare, Australia là nhà tài tr? cho
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Thank you!