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Assessment of Skeleton Health. Tuan Van Nguyen and Nguyen Dinh Nguyen Garvan Institute of Medical Research Sydney, Australia. 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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Assessment of skeleton health

Assessment of Skeleton Health

Tuan Van Nguyen and Nguyen Dinh Nguyen

Garvan Institute of Medical Research

Sydney, Australia


Overview
Overview

  • Background

  • Normal bone and bone remodelling

  • Bone loss and age

  • Definitions

  • Measurements of bone strength:

    • Bone mass and DXA, QUS

    • Bone turnover markers


Background
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


Residual lifetime risk of different diseases
Residual lifetime risk of different diseases

Women

Men

(Source: Nguyen ND et al, 2006, under review process)


Survival probability and fracture
Survival probability and fracture

Women

Men

Cumulative survival rate

Age (y)

(Soure: Center J, Nguyen TV et al., Lancet 1999;353:878-82)


Burden of osteoporotic fractures
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)


Cortical and trabecular bone
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


Cortical compact bone
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


Trabecular cancellous bone
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.


Distribution of cortical and trabecular bone
Distribution of Cortical and Trabecular Bone

Thoracic and 75% trabecular

Lumbar Spine 25% cortical

1/3 Radius

>95% Cortical

Femoral Neck 25% trabecular 75% cortical

Ultradistal Radius

25% trabecular

75% cortical

Hip Intertrochanteric Region 50% trabecular

50% cortical


How does bone loss happen
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.


Endosteal sinus

Monocyte

Pre-osteoclast

Pre-osteoblast

Osteoclast

Osteoblast

Bone-lining cell

Osteocyte

Macrophage

Osteoid

New bone

Old bone

Bone remodeling cycle


Bone remodeling cycle

Pre-osteoblasts

Monocytes

Osteoblasts

Osteoclasts

Osteocytes


Bone loss
Bone loss

Bone formation

Bone resorption

Bone formation

Bone resorption


Bone remodelling normal and osteoporosis
Bone Remodelling:Normal and Osteoporosis


Bone mass declines with age
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.


Relative Influence of Inner and Outer Diameters on Bone Strength

(Adapted from Lee CA, and Einhorn TA. Osteoporosis 2nd Ed. 2001)


Gain and loss of Bone throughout the lifespan Strength

Pubertal Growth Spurt

Menopause

BMD

Resorption

Formation

Age (Years)


Relationship between BMD and Age Strength

(VN 2006, unpublished data)


Definition of osteoporosis who
Definition of Osteoporosis Strength(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.


Normal Strength

Osteopenia

Osteoporosis

Osteoporosis


Osteoporosis Strength

Normal bone


Definition of Osteoporosis Strength(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)


BONE STRENGTH Strength

BONE MINERAL

DENSITY

BONE QUALITY

Bone

architecture

Gram of

mineral

per area

Bone

turnover

Bone

size &

geometry


Bone quality
Bone Quality Strength

  • 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)


Bone mass bone mineral density bmd
Bone mass, Bone mineral density (BMD) Strength

  • Bone mass = the amount of bone tissue as the total of protein and mineral or the amount of mineralin the whole skeletonor in a particular segment of bone. (unmeasurable)

  • BMD = the average concentration of mineral per unit area  assessed in 2 dimensions (measurable)


Effect of size on areal bmd
Effect of Size on Areal BMD Strength

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)


Bone densitometry
Bone Densitometry Strength

  • 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


DXA (or DEXA) Strength


Dxa or dexa
DXA (or DEXA) Strength

  • 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


DXA Technology Strength

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)


DXA: BMD scan Strength

Spine

Hip

Total body





Which Skeletal Sites Should Be Measured? Strength

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


Bmd measurement subject to variability
BMD measurement: subject to variability Strength

  • 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.


In vivo in situ bmd inaccuracy
In vivo/In situ BMD inaccuracy Strength

REGION OF INTEREST

Lateral region

Lateral region

Bone region

Trabeculaae + Marrow

Extra-Osseous

Fat+Lean tissue

Cortical region

(Adapted from Bolotin HH, Med Phys 2004;31:774-88)

X-RAY PATHS


In vivo/In situ BMD inaccuracy Strength

Individual

Type of bone

(Source: Bolotin HH, Med Phys 2004;31:774-88)


Source of variability in bmd measurements
Source of variability in BMD measurements Strength

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)


Standard error of rate of change in bmd
Standard error of rate of change in BMD Strength

Individual

Group

(Source: Nguyen TV et al., JBMR 1997;12:124-34)


Source of variability in bmd measurements1
Source of variability in BMD measurements Strength

  • 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 1997;12:124-34)


True level and true biological change of bmd
“True” level and “True” biological change of BMD Strength

  • 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)


True level and true biological change of bmd1
“True” level and “True” biological change of BMD Strength

  • 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)



BMD Values From Different Manufacturers Are Not Comparable Strength

  • Different dual energy methods

  • Different calibration

  • Different detectors

  • Different edge detection software

  • Different regions of interest


Peripheral BMD Testing StrengthAccurate & Precise

  • What it can do

    • Predict fracture risk

    • Tool for osteoporosis education

  • What it cannot do

    • Diagnose osteoporosis

    • Monitor therapy

  • A “normal” peripheral test does not necessarily mean that the patient does not have osteoporosis.

  • WHO criteria do not apply to peripheral BMD testing.


Quantitative Ultrasound (QUS) Strength

  • Broad-band ultrasound attenuation or ultrasound velocity

  • No radiation exposure

  • Cannot be used for diagnosis

  • Preferred use in assessment of fracture risk


Bone quality1
Bone Quality Strength

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)


Cortical and trabecular bone1
Cortical and Trabecular Bone Strength

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


Relevance of architecture
Relevance of Architecture Strength

Normal Loss of Loss of Quantity

Quantity and Quantity and Architecture

Architecture


Bone architecture trabecular perforation
Bone Architecture StrengthTrabecular 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


Structural role of trabeculae compressive strength of connected and disconnected trabeculae
Structural Role of Trabeculae StrengthCompressive strength of connected and disconnected trabeculae

1

16 X

Bell et al. Calcified Tissue Research 1: 75-86, 1967


Resorption cavities as mechanical stress risers

Normal Strength

Osteoporotic

Resorption Cavities as Mechanical Stress Risers

(Adapted from Parfitt A.M. et al. Am J Med 91, Suppl 5B: 5B-34S)


Hip strength indice
Hip strength indice Strength

  • 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


Cross sectional moment of inertia csmi 4 r 4 outer r 4 inner
Cross-Sectional Moment of Inertia StrengthCSMI = /4 (r4 outer – r4 inner)

Area (cm2) 2.77 2.77 2.77

CSMI (cm4) 0.61 1.06 1.54

Bending Strength 100% 149% 193%


Bone strengh indice summary
Bone strengh indice: summary Strength

  • Not well-studied

  • Derived from BMC, BMD, and several assumptions

  • Used in research field.


Bone turnover markers
Bone Turnover Markers Strength

  • 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.


Urinary markers of bone resorption
Urinary Markers of Bone Resorption Strength

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)


Serum markers of bone turnover
Serum Markers of Bone Turnover Strength

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 16:2370, 2001)


Bone Turnover Effects Bone Quality Strength

  • Very low turnover excessive mineralization and the accumulation of microdamage

  • Very high turnover  accumulation of perforations and a negative bone balance


Summary
Summary Strength

  • 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.


L i c m t
Lời Cảm tạ Strength

  • Chúng tôi xin chân thành cám ơn Công ty Dược phẩm Bridge Healthcare, Australia là nhà tài trợ cho hội thảo.


Thank you

Thank you! Strength


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