Vietnam Osteoporosis Workshop, HCMC 2006 Assessment of Skeleton Health Tuan Van Nguyen and Nguyen...

Vietnam Osteoporosis Workshop, HCMC 2006

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


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 (%)0 10 20 30 40 50 60

Any fracture*

Hip fracture*

Vertebral fracture*

Cancer (all sites)**

Diabetes Mellitus+

Breast cancer**

Coronary heart +

Lung/bronchus**

(*, from age 60y; **, from birth, + from age 50)

3/5

~ 1/4

1/6

2/5

1/3

1/8

1/4

1/16

WomenMen

Residual lifetime risk (%)0 10 20 30 40 50 60

Any fracture*

Hip fracture*

Vertebral fracture*

Cancer (all sites)**

Diabetes Mellitus+

Prostate cancer**

Coronary heart +

Lung/bronchus**

(*, from age 60y; **, from birth, + from age 50)

1/3

1/14

1/8

3/7

1/2

1/8

1/3

1/16

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


Survival probability and fracture

Age (y)

Women Men

Cum

ulat

ive

surv

ival

rat

e

(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)


Cortical and Trabecular Bone

• 80% of all the bone in the body

• 20% of bone turnover

• 20% of all bone in the body


Cortical Bone

Trabecular 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•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

Thoracic and 75% trabecularLumbar Spine 25% cortical

Femoral Neck 25% trabecular75% cortical

Hip Intertrochanteric Region 50% trabecular

50% cortical

1/3 Radius >95% Cortical

Ultradistal Radius25% 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.


Bone remodeling cycleBone remodeling cycle

Endosteal sinus

Monocyte

Pre-osteoclast

Osteocyte

Osteoclast

Macrophage

Pre-osteoblast

Osteoblast Bone-lining cell

Osteoid

New bone

Old bone


OsteoclastsMonocytes

Pre-osteoblasts

Osteoblasts

Osteocytes

Bone remodeling cycleBone remodeling cycle


Bone loss

Bone formation Bone resorption

Bone formation Bone resorption


Bone Remodelling:Normal and Osteoporosis


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)


5 15 25 35 45 55 65 75 85

Gain and loss of Bone throughout the lifespan

Age (Years)

Pubertal Growth Spurt Menopause

BMD

Resorption

Formation

Vietnam Osteoporosis Workshop, HCMC 2006 (VN 2006, unpublished data)

Relationship between BMD and Age


A systematic skeleton disease characterized by:

- low bone mass

- microarchitectural deterioration of bone tissue

- consequent increase in bone fragility and susceptibility to fracture

Definition of OsteoporosisDefinition of Osteoporosis(WHO)(WHO)

Consensus Development Conference: Diagnosis, Prophylaxis, and Treatment of Osteoporosis, Am J Med 1993;94:646-650. WHO Study Group 1994.


OsteoporosisOsteoporosis

Normal Osteopenia Osteoporosis


OsteoporosisNormal bone


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)

Definition of OsteoporosisDefinition of Osteoporosis(NIH)(NIH)


Gram of mineral per area

Bone architecture

Bone size &

geometry

Bone turnover

BONE QUALITYBONE MINERALDENSITY

BONE STRENGTH


Bone Quality

( NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95; 2001)

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


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)


Effect of Size on Areal BMD

1

11

2

22

3

3

3

BMC

1 1 1

AREA BMD

8 4 2

27 9 3

“TRUE” VALUE = 1 g/cm3

(Adapted from Carter DR, et al. J Bone Miner Res 1992)


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


DXA (or DEXA)


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


DXA Technology

X-ray Source (produces 2 photon energies with different attenuation profiles)

Photons Collimator (pinhole for pencil beam, slit for fan beam)

Patient

Detector (detects 2 tissue types - bone and soft tissue)

Very low radiation to patient.

Very little scatter radiation to technologist


DXA: BMD scan

Total body

Spine

Hip


DXA: Femoral neck BMD


DXA: Lumbar spine BMD


DXA: Hip BMD: Results


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


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.


In vivo/In situ BMD inaccuracy

X-RAY PATHS

Extra-Osseous Fat+Lean tissue Cortical region

Trabeculaae + Marrow

Bone regionLateral region Lateral region

REGION OF INTEREST

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


In vivo/In situ BMD inaccuracy

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…)

<2

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

IndividualType of bone


Source of variability in BMD measurements

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

Number of measurements per subject required to increase the reliability of measurement for a given coefficient of reliability


Standard error of rate of change in BMDIndividual Group



• 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 of variability in BMD measurements



“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)



• 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)



1st measure 2nd measure change

0.70 0.735 ↑ 5.0% Inconclusive

0.70 0.753 ↑ 7.5% Possibly biological change

0.73 0.700 ↓ 4% Inconclusive

0.73 0.690 ↓ 5.5% Possibly biological change


BMD Values From Different Manufacturers Are Not Comparable

• Different dual energy methods

• Different calibration

• Different detectors

• Different edge detection software

• Different regions of interest


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.


• Broad-band ultrasound attenuation or ultrasound velocity

• No radiation exposure

• Cannot be used for diagnosis

• Preferred use in assessment of fracture risk

Quantitative Ultrasound (QUS)


Bone Quality

( NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95; 2001)

Architecture

Turnover Rate

Damage Accumulation

Degree of Mineralization

Properties of the collagen/mineral matrix


Cortical and Trabecular Bone

• 80% of all the bone in the body


• 20% of all bone in the body


Cortical Bone

Trabecular Bone


Relevance of Architecture

Normal Loss of Loss of QuantityQuantity and Quantity and Architecture Architecture


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


Structural Role of Trabeculae

Compressive strength of connected and disconnected trabeculae

16 X1

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


Resorption Cavities as Mechanical Stress Risers

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

Normal Osteoporotic


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


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 1.54

Bending Strength 100% 149% 193%


Bone strengh indice: summary

• Not well-studied

• Derived from BMC, BMD, and several assumptions

• Used in research field.


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.


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)


Serum Markers of Bone Turnover

Marker Abbreviation

Formation Bone alkaline phosphatase ALP (BSAP)Osteocalcin OCProcollagen type I C-propeptide PICPProcollagen type I N-propeptide PINP

ResorptionN-terminal cross-linking telopeptide of type I collagen NTXC-terminal cross-linking telopeptide of type I collagen CTXTartrate-resistant acid phosphatase TRAP

(Source: Delmas PD. J Bone Miner Res 16:2370, 2001)


• Very low turnover excessive mineralization and the accumulation of microdamage

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

Bone Turnover Effects Bone Quality


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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ơn Công ty Dược phẩm Bridge Healthcare, Australia là nhà tài trợ cho hội thảo.


Thank you!

Vietnam Osteoporosis Workshop, HCMC 2006 Assessment of Skeleton Health Tuan Van Nguyen and Nguyen...

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