Assessment of Skeleton Health
Tuan Van Nguyen and Nguyen Dinh Nguyen
Garvan Institute of Medical Research
Sydney, Australia
Vietnam Osteoporosis Workshop, HCMC 2006
Overview
• Background
• Normal bone and bone remodelling
• Bone loss and age
• Definitions
• Measurements of bone strength:
– Bone mass and DXA, QUS
– Bone turnover markers
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Background
• Aging population: fastest growing age group
• Osteoporosis and osteoporotic fracture: agerelated disorders
• Osteoporosis and osteoporotic fracture:
– Common
– Cause serious disability and excess mortality
– Major economic burden on healthcare system
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Residual lifetime risk of different diseases
Women
Men
Any fracture**
Any fracture
1/3
fracture**
Hip
Hip fracture
1/14
3/5
1/6
fracture**
Vertebral
Vertebral fracture
1/8
~ 1/4
sites)****
Cancer (all
Cancer (all sites)
Diabetes Mellitus++
Diabetes Mellitus
2/5
1/2
1/3
Breast cancer**
3/7
1/8
Prostate cancer**
1/8
Coronary heart ++
Coronary heart
1/3
1/4
Lung/bronchus****
Lung/bronchus
1/16
1/16
0
10
20
30
40
50
60
Residual lifetime risk (%)
(*, from age 60y; **, from birth, ++ from age 50)
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(Source: Nguyen ND et al, 2006, under review
process)
Survival probability and fracture
Men
Cumulative survival rate
Women
Age (y)
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(Soure: Center J, Nguyen TV et al., Lancet
1999;353:878-82)
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: US$131.5 billion2.
(Sources: 1Cummings et al., Lancet 2002;359:1761-67; 2Johnell O, Am J Med 1997;103:20S-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
Lumbar Spine
75% trabecular
25% cortical
1/3 Radius
>95% Cortical
Femoral Neck 25% trabecular
75% cortical
Hip Intertrochanteric Region
50% trabecular
50% cortical
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Ultradistal Radius
25% trabecular
75% cortical
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
Endosteal sinus
Monocyte
Pre-osteoclast
Pre-osteoblast
Osteoclast
Osteocyte
Macrophage
Osteoblast
Bone-lining cell
Osteoid
New bone
Old bone
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Bone remodeling cycle
Pre-osteoblasts
Monocytes
Osteoclasts
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Osteoblasts
Osteocytes
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)
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Gain and loss of Bone throughout the
lifespan
Pubertal
Growth Spurt
Menopause
BMD
Resorption
Formation
5
15
25
35
45
55
Age (Years)
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65
75
85
Relationship between BMD and Age
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(VN 2006, unpublished data)
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 1993;94:646-650. WHO Study Group 1994.
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Osteoporosis
Normal
Osteopenia
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Osteoporosis
Normal bone
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Osteoporosis
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 285:785-95; 2001)
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BONE STRENGTH
BONE MINERAL
DENSITY
BONE QUALITY
Gram of
mineral
per area
Bone
architecture
Bone
turnover
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Bone
size &
geometry
Bone Quality
•
•
•
•
•
Architecture
Turnover Rate
Damage Accumulation
Degree of Mineralization
Properties of the collagen/mineral matrix
( NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95; 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
1
1
1
2
AREA
BMD
1
1
1
8
4
2
27
9
3
2
2
3
BMC
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.
Patient
Photons
Very little scatter radiation to
technologist
Collimator
(pinhole for pencil beam, slit for fan beam)
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
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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
Some Patients
• Forearm (33% Radius)
– If hip or spine cannot be
measured
– Hyperparathyroidism
– Very obese
– Trochanter
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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
Fat+Lean tissue
X-RAY PATHS
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Cortical region
(Adapted from Bolotin HH, Med Phys
2004;31:774-88)
In vivo/In situ BMD inaccuracy
Individual
Type of bone
Typical lumbar vertebral
bone site
Distal radius, femur
Under-/or over-estimate BMD (%)
Normal Osteopenia Osteoporosis
~25
~35
Up to 50
~20
~25
~35
Trabecular-free sites
(mid-shaft femur, midshaft radius…)
<2
(Source: Bolotin HH, Med Phys 2004;31:774-88)
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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 1997;12:124-34)
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Standard error of rate of change in BMD
Individual
Group
(Source: Nguyen TV et al., JBMR 1997;12:124-34)
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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 (BMDfracture).
• 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:
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2006Nguyen TV et al., JBMR 1997;12:124-34)
“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 2004;31:774-88; Nguyen TV et al., JBMR 1997;12:124-34; Nguyen TV et al,
JCD 2000;3:107-19)
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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 2000;3:107-19)
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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 Testing
Accurate & 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 285:785-95; 2001)
Vietnam Osteoporosis Workshop, HCMC 2006
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
Quantity and
Architecture
Loss of
Quantity
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Loss of Quantity
and Architecture
Bone Architecture
Trabecular 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 Trabeculae
Compressive strength of connected
and disconnected trabeculae
1
Bell et al. Calcified Tissue Research 1: 75-86, 1967
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16 X
Resorption Cavities as Mechanical
Stress Risers
Normal
Osteoporotic
(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)
CSMI (cm4)
Bending Strength
2.77
0.61
100%
2.77
1.06
149%
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2.77
1.54
193%
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 16:2370; 2001)
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Serum Markers of Bone Turnover
Marker
Abbreviation
Formation
Bone alkaline phosphatase
Osteocalcin
Procollagen type I C-propeptide
Procollagen type I N-propeptide
ALP (BSAP)
OC
PICP
PINP
Resorption
N-terminal cross-linking telopeptide
of type I collagen
C-terminal cross-linking telopeptide
of type I collagen
Tartrate-resistant acid phosphatase
NTX
CTX
TRAP
(Source: Delmas PD. J Bone Miner Res 16:2370, 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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Lời Cảm tạ
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ơn Công ty Dược phẩm
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nhà tài trợ cho hội thảo.
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Thank you!
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