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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. 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

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  1. 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 1999;353:878-82)

  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: US$131.5 billion2. (Sources: 1Cummings et al., Lancet 2002;359:1761-67; 2Johnell O, Am J Med 1997;103:20S-26)

  7. 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

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. Endosteal sinus Monocyte Pre-osteoclast Pre-osteoblast Osteoclast Osteoblast Bone-lining cell Osteocyte Macrophage Osteoid New bone Old bone Bone remodeling cycle

  13. Bone remodeling cycle Pre-osteoblasts Monocytes Osteoblasts Osteoclasts Osteocytes

  14. Bone loss Bone formation Bone resorption Bone formation Bone resorption

  15. Bone Remodelling:Normal and Osteoporosis

  16. 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.

  17. Relative Influence of Inner and Outer Diameters on Bone Strength (Adapted from Lee CA, and Einhorn TA. Osteoporosis 2nd Ed. 2001)

  18. Gain and loss of Bone throughout the lifespan Pubertal Growth Spurt Menopause BMD Resorption Formation Age (Years)

  19. Relationship between BMD and Age (VN 2006, unpublished data)

  20. 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.

  21. Normal Osteopenia Osteoporosis Osteoporosis

  22. Osteoporosis Normal bone

  23. 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)

  24. BONE STRENGTH BONE MINERAL DENSITY BONE QUALITY Bone architecture Gram of mineral per area Bone turnover Bone size & geometry

  25. 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)

  26. Bone mass, Bone mineral density (BMD) • 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)

  27. 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)

  28. 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

  29. DXA (or DEXA)

  30. 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

  31. 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)

  32. DXA: BMD scan Spine Hip Total body

  33. DXA: Femoral neck BMD

  34. DXA: Lumbar spine BMD

  35. DXA: Hip BMD: Results

  36. 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

  37. 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.

  38. In vivo/In situ BMD inaccuracy 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

  39. In vivo/In situ BMD inaccuracy Individual Type of bone (Source: Bolotin HH, Med Phys 2004;31:774-88)

  40. 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)

  41. Standard error of rate of change in BMD Individual Group (Source: Nguyen TV et al., JBMR 1997;12:124-34)

  42. 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 1997;12:124-34)

  43. “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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