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

2. 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

3. Vietnam Osteoporosis Workshop, HCMC 2006 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. Vietnam Osteoporosis Workshop, HCMC 2006 Residual lifetime risk of different diseases WomenMen (Source: Nguyen ND et al, 2006, under review process)

5. Vietnam Osteoporosis Workshop, HCMC 2006 Survival probability and fracture Age (y) WomenMen Cumulative survival rate (Soure: Center J, Nguyen TV et al., Lancet 1999;353:878-82)

6. Vietnam Osteoporosis Workshop, HCMC 2006 Burden of Osteoporotic fractures Annual cost of all osteoporotic fractures: $20 billion in USA and ~$30 billion on EU 1. Worldwide direct and indirect cost of hip fracture: US$131.5 billion 2. (Sources: 1 Cummings et al., Lancet 2002;359:1761-67; 2 Johnell O, Am J Med 1997;103:20S-26)

7. Vietnam Osteoporosis Workshop, HCMC 2006 Cortical and Trabecular Bone 80% of all the bone in the body 20% of bone turnover 20% of all bone in the body 80% of bone turnover Cortical Bone Trabecular Bone

8. Vietnam Osteoporosis Workshop, HCMC 2006 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. Vietnam Osteoporosis Workshop, HCMC 2006 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. Vietnam Osteoporosis Workshop, HCMC 2006 Distribution of Cortical and Trabecular Bone Thoracic and75% trabecular Lumbar Spine25% cortical Femoral Neck25% trabecular 75% cortical Hip Intertrochanteric Region 50% trabecular 50% cortical 1/3 Radius >95% Cortical Ultradistal Radius 25% trabecular 75% cortical

11. Vietnam Osteoporosis Workshop, HCMC 2006 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. Vietnam Osteoporosis Workshop, HCMC 2006 Bone remodeling cycle Endosteal sinus Monocyte Pre-osteoclast Osteocyte Osteoclast Macrophage Pre-osteoblast OsteoblastBone-lining cell Osteoid New bone Old bone

13. Vietnam Osteoporosis Workshop, HCMC 2006 Osteoclasts Monocytes Pre-osteoblasts Osteoblasts Osteocytes Bone remodeling cycle

14. Vietnam Osteoporosis Workshop, HCMC 2006 Bone loss Bone formation Bone resorption Bone formation Bone resorption

15. Vietnam Osteoporosis Workshop, HCMC 2006 Bone Remodelling: Normal and Osteoporosis

16. Vietnam Osteoporosis Workshop, HCMC 2006

23. 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.

24. Vietnam Osteoporosis Workshop, HCMC 2006 Relative Influence of Inner and Outer Diameters on Bone Strength (Adapted from Lee CA, and Einhorn TA. Osteoporosis 2nd Ed. 2001)

25. Vietnam Osteoporosis Workshop, HCMC 2006 Gain and loss of Bone throughout the lifespan Age (Years) Pubertal Growth Spurt Menopause BMD Resorption Formation

26. Vietnam Osteoporosis Workshop, HCMC 2006 (VN 2006, unpublished data) Relationship between BMD and Age

27. Vietnam Osteoporosis Workshop, HCMC 2006 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 Osteoporosis (WHO) Consensus Development Conference: Diagnosis, Prophylaxis, and Treatment of Osteoporosis, Am J Med 1993;94:646-650. WHO Study Group 1994.

28. Vietnam Osteoporosis Workshop, HCMC 2006 Osteoporosis NormalOsteopeniaOsteoporosis

29. Vietnam Osteoporosis Workshop, HCMC 2006 Osteoporosis Normal bone

30. Vietnam Osteoporosis Workshop, HCMC 2006 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 Osteoporosis (NIH)

31. Vietnam Osteoporosis Workshop, HCMC 2006 Gram of mineral per area Bone architecture Bone size & geometry Bone turnover BONE QUALITY BONE MINERAL DENSITY BONE STRENGTH

32. Vietnam Osteoporosis Workshop, HCMC 2006 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

33. Vietnam Osteoporosis Workshop, HCMC 2006 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)

34. Vietnam Osteoporosis Workshop, HCMC 2006 Effect of Size on Areal BMD 1 1 1 2 2 2 3 3 3 BMC 111 AREABMD 842 2793 “TRUE” VALUE = 1 g/cm 3 (Adapted from Carter DR, et al. J Bone Miner Res 1992)

35. Vietnam Osteoporosis Workshop, HCMC 2006 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

36. Vietnam Osteoporosis Workshop, HCMC 2006 DXA (or DEXA)

37. Vietnam Osteoporosis Workshop, HCMC 2006 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

38. Vietnam Osteoporosis Workshop, HCMC 2006 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

39. Vietnam Osteoporosis Workshop, HCMC 2006 DXA: BMD scan Total body Spine Hip

40. Vietnam Osteoporosis Workshop, HCMC 2006 DXA: Femoral neck BMD

41. Vietnam Osteoporosis Workshop, HCMC 2006 DXA: Lumbar spine BMD

42. Vietnam Osteoporosis Workshop, HCMC 2006 DXA: Hip BMD: Results

43. Vietnam Osteoporosis Workshop, HCMC 2006 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

44. Vietnam Osteoporosis Workshop, HCMC 2006 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.

45. Vietnam Osteoporosis Workshop, HCMC 2006 In vivo/In situ BMD inaccuracy X-RAY PATHS Extra-Osseous Fat+Lean tissue Cortical region Trabeculaae + Marrow Bone region Lateral region REGION OF INTEREST (Adapted from Bolotin HH, Med Phys 2004;31:774-88)

46. Vietnam Osteoporosis Workshop, HCMC 2006 In vivo/In situ BMD inaccuracy Under-/or over-estimate BMD (%) NormalOsteopeniaOsteoporosis Typical lumbar vertebral bone site ~25~35Up 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) Individual Type of bone

47. Vietnam Osteoporosis Workshop, HCMC 2006 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

48. Vietnam Osteoporosis Workshop, HCMC 2006 Standard error of rate of change in BMD Individual Group (Source: Nguyen TV et al., JBMR 1997;12:124-34)

49. Vietnam Osteoporosis Workshop, HCMC 2006 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 (Source: Nguyen TV et al., JBMR 1997;12:124-34)

50. Vietnam Osteoporosis Workshop, HCMC 2006 “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)

51. Vietnam Osteoporosis Workshop, HCMC 2006 “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)

52. Vietnam Osteoporosis Workshop, HCMC 2006 “True” level and “True” biological change of BMD 1 st measure2nd measurechange 0.700.735↑ 5.0%Inconclusive 0.700.753↑ 7.5%Possibly biological change 0.730.700↓ 4%Inconclusive 0.730.690↓ 5.5%Possibly biological change

53. Vietnam Osteoporosis Workshop, HCMC 2006 BMD Values From Different Manufacturers Are Not Comparable Different dual energy methods Different calibration Different detectors Different edge detection software Different regions of interest

54. Vietnam Osteoporosis Workshop, HCMC 2006 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.

55. Vietnam Osteoporosis Workshop, HCMC 2006 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)

56. Vietnam Osteoporosis Workshop, HCMC 2006 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

57. Vietnam Osteoporosis Workshop, HCMC 2006 Cortical and Trabecular Bone 80% of all the bone in the body 20% of bone turnover 20% of all bone in the body 80% of bone turnover Cortical Bone Trabecular Bone

58. Vietnam Osteoporosis Workshop, HCMC 2006 Relevance of Architecture NormalLoss ofLoss of Quantity Quantity andQuantityand Architecture Architecture

59. Vietnam Osteoporosis Workshop, HCMC 2006 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

60. Vietnam Osteoporosis Workshop, HCMC 2006 Structural Role of Trabeculae Compressive strength of connected and disconnected trabeculae 16 X 1 Bell et al. Calcified Tissue Research 1: 75-86, 1967

61. Vietnam Osteoporosis Workshop, HCMC 2006 Resorption Cavities as Mechanical Stress Risers (Adapted from Parfitt A.M. et al. Am J Med 91, Suppl 5B: 5B-34S) Normal Osteoporotic

62. Vietnam Osteoporosis Workshop, HCMC 2006 Hip strength indice CSMI (cm 4 ): Cross-sectional moment of inertia CSA (cm 2 ): Cross sectional area Z (cm 3 ): Section modulus= CSMI/distance from the centre of the mass to the superior neck margin. Cstress (N/mm 2 ): 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

63. Vietnam Osteoporosis Workshop, HCMC 2006 Cross-Sectional Moment of Inertia CSMI =  /4 (r 4 outer – r 4 inner) Area (cm 2 )2.772.772.77 CSMI (cm 4 )0.611.061.54 Bending Strength100%149%193%

64. Vietnam Osteoporosis Workshop, HCMC 2006 Bone strengh indice: summary Not well-studied Derived from BMC, BMD, and several assumptions Used in research field.

65. Vietnam Osteoporosis Workshop, HCMC 2006 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.

66. Vietnam Osteoporosis Workshop, HCMC 2006 Urinary Markers of Bone Resorption MarkerAbbreviation HydroxyprolineHYP PyridinolinePYD DeoxypyridinolineDPD N-terminal cross-linking telopeptide of type I collagenNTX C-terminal cross-linking telopeptide of type I collagenCTX (Source: Delmas PD. J Bone Miner Res 16:2370; 2001)

67. Vietnam Osteoporosis Workshop, HCMC 2006 Serum Markers of Bone Turnover Marker Abbreviation Formation Bone alkaline phosphatase ALP (BSAP) OsteocalcinOC Procollagen type I C-propeptidePICP Procollagen type I N-propeptidePINP Resorption N-terminal cross-linking telopeptide of type I collagen NTX C-terminal cross-linking telopeptide of type I collagenCTX Tartrate-resistant acid phosphataseTRAP (Source: Delmas PD. J Bone Miner Res 16:2370, 2001)

68. Vietnam Osteoporosis Workshop, HCMC 2006 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

69. Vietnam Osteoporosis Workshop, HCMC 2006 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.

70. Vietnam Osteoporosis Workshop, HCMC 2006 Lời Cảm tạ Chúng tôi xin chân thành cám ơn Công ty Dược phẩm Bridge Healthcare, Australia là nhà tài trợ cho hội thảo.

71. Vietnam Osteoporosis Workshop, HCMC 2006 Thank you!