Transcript Assessment of Skeleton Health Tuan Van Nguyen and Nguyen Dinh Nguyen Garvan Institute of Medical Research Sydney, Australia Vietnam Osteoporosis Workshop, HCMC 2006

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
• Chúng tôi xin chân thành cám
ơn Công ty Dược phẩm
Bridge Healthcare, Australia là
nhà tài trợ cho hội thảo.
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Thank you!
Vietnam Osteoporosis Workshop, HCMC 2006