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
Men
Women
To put in perspective
I would like to make cross comparision LR for different diseases
(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: ; 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
This slide illustrates the location of cortical and trabecular bone using the uCT image of an iliac crest biopsy.
Cortical bone (also called compact bone) is the dense outer layer of bone; it is found predominantly in the shafts of the long bones in the arms and legs.
Cortical bone comprises about 75-85% of the total bone in the body, but because of the relative small remodelling surface area, participates in only ~20% of bone turnover at any given moment.
Remodeling in cortical bone occurs at the periosteal (outer) surface, the endosteal (inner) surface, and within the haversian canal system.
Trabecular bone, although comprising a much smaller percentage of the total bone in the body, has a very large surface area due to its lace-like structure, and participates in ~80% of bone turnover at any given moment.
Remodelling occurs on the surface of the trabeculae.
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
This slide depicts the relative proportions of cortical and trabecular bone at various skeletal sites.
Loss of trabecular bone would predispose to vertebral compression fractures, whereas loss of cortical bone would clearly predispose a patient to fractures at the hip and radius.
Trabecular bone mass begins to decrease in early adulthood, occurring sooner than the decline in cortical bone.
However, it has also been reported by Riggs and Melton (NEJM 14: , 1986) that the acceleration of trabecular bone loss at the time of menopause is not as pronounced as the loss of cortical bone.
Remodeling of trabecular and cortical bone is influenced by the environment of the bone remodeling surfaces.
Bone remodelling cells on the trabecular surface are in contact with the cells of the marrow cavity and are likely influenced by their interaction with osteotropic cytokines.
Cortical bone remodeling is more likely to be influenced by osteotropic hormones such as PTH and 1a,25, dihydroxyvitamin D3 due to the greater distance of the remodeling surface from the marrow cavity.
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. Bone remodeling cycle Endosteal sinus Monocyte Pre-osteoclast
Osteocyte
Osteoclast
Macrophage
Pre-osteoblast
Osteoblast
Bone-lining cell
Osteoid
New bone
Old bone

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

14. Bone loss Bone formation Bone resorption Bone formation

15. 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.

16. Relative Influence of Inner and Outer Diameters on Bone Strength
This figure illustrates the impact of changing the Moment of Inertia on bone strength. Starting from the initial state (A), a moderate degree of endosteal resorption (expansion of the marrow space by 3 units) is balanced by application of 1 unit to the periosteal surface, resulting in no change in bending strength.
Lee CA, Einhorn TA. The Bone Organ System, Form and Function. In Marcus R, Feldman D, Kelsey J, Eds. Osteoporosis, 2nd Edition. Academic Press, San Diego, 2001 Volume 1, pp
(Adapted from Lee CA, and Einhorn TA. Osteoporosis 2nd Ed )

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

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

19. 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: WHO Study Group 1994.

20. Osteoporosis
Normal
Osteopenia
Osteoporosis

21. Normal bone
Osteoporosis

22. 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)

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

24. 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)

25. 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)

26. Effect of Size on Areal BMD
BMC
AREA
BMD 1 1 1 1 1 1 2 2 8 4 2 2 3 3
This slide illustrates the impact of body size on the standard area BMD measurement. Assume the existence of a stone quarry in which all the stone has a true mineral density of 1 gram per cubic centimeter. Assume further that 3 cubes are mined from this quarry, and the cubes are 1, 2, and 3 centimeters on a side. If all cubes are placed on a tray and undergo DXA scanning, the resulting BMC, Area, and BMD results are given in the slide. It can be seen that larger objects are reported as having a systematically increased “BMD,” and smaller objects are systematically low. This means that interpretation of areal BMD measurements in very tall (>5 ft 10 inches) or very short (< 5 ft 2 inches) persons will require some adjustment.
Carter DR, Bouxsein ML, Marcus R. New approaches for interpreting projected bone densitometry data. J Bone Miner Res 1992;7: 27 9 3 3
“TRUE” VALUE = 1 g/cm3
(Adapted from Carter DR, et al. J Bone Miner Res 1992)

27. 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

28. DXA (or DEXA)

29. 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

30. 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)

31. DXA: BMD scan
Spine
Hip
Total body

32. DXA: Femoral neck BMD

33. DXA: Lumbar spine BMD

34. DXA: Hip BMD: Results

35. 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

36. 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.

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

38. 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
Trabecular-free sites (mid-shaft femur, mid-shaft radius…)
<2
Individual
Type of bone
(Source: Bolotin HH, Med Phys 2004;31:774-88)

39. 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)

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

41. 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)

42. “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)

43. “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)

44. BMD Values From Different Manufacturers Are Not Comparable
Different dual energy methods
Different calibration
Different detectors
Different edge detection software
Different regions of interest

45. Peripheral BMD Testing Accurate & 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.

46. 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

47. 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)

48. Cortical and Trabecular Bone
Cortical Bone
80% of all the bone in the body
20% of bone turnover
Trabecular Bone
This slide illustrates the location of cortical and trabecular bone using the uCT image of an iliac crest biopsy.
Cortical bone (also called compact bone) is the dense outer layer of bone; it is found predominantly in the shafts of the long bones in the arms and legs.
Cortical bone comprises about 75-85% of the total bone in the body, but because of the relative small remodelling surface area, participates in only ~20% of bone turnover at any given moment.
Remodeling in cortical bone occurs at the periosteal (outer) surface, the endosteal (inner) surface, and within the haversian canal system.
Trabecular bone, although comprising a much smaller percentage of the total bone in the body, has a very large surface area due to its lace-like structure, and participates in ~80% of bone turnover at any given moment.
Remodelling occurs on the surface of the trabeculae.
20% of all bone in the body
80% of bone turnover

49. Relevance of Architecture
This figure illustrates the loss of bone strength due to trabecular thinning (loss of quantity) and perforation of trabeculae (loss of architecture).
The strength of a trabecular strut is proportional to the square of its radius.
Preservation of architecture is essential for bone strength.
Normal Loss of Loss of Quantity
Quantity and Quantity and Architecture
Architecture

50. Bone Architecture Trabecular Perforation
The effects of bone turnover on the structural role of trabeculae
Risk of Trabecular Perforation increases with:
Because much of the strength of trabecular bone is caused by its microarchitecture, the loss of trabecular connectivity and other adverse structural consequences of increased osteoclastic activity clearly could predispose to fractures of the vertebrae and other skeletal sites that have a high content of cancellous bone.
Riggs & Melton. JBMR (2002) 17:11-14
Increased bone turnover
Increased erosion depth
Predisposition to trabecular thinning

51. Bell et al. Calcified Tissue Research 1: 75-86, 1967
Structural Role of Trabeculae Compressive strength of connected and disconnected trabeculae 1
16 X
The compressive strength of connected trabeculae is 16-fold greater than disconnected trabeculae.
Bell et al. Calcified Tissue Research 1: 75-86, 1967

52. Resorption Cavities as Mechanical Stress Risers
Normal
Osteoporotic
Resorption cavities occur on trabecular surfaces in normal bone.
In osteoporotic bone, the cavities are more numerous and may be deeper.
Resorption cavities in bone can act as mechanical stress risers, which decrease overall bone strength.
This concept is illustrated on the right with the picture of the cane. The notch in the cane acts as a stress riser, to decrease the overall strength of the cane.
(Adapted from Parfitt A.M. et al. Am J Med 91, Suppl 5B: 5B-34S)

53. 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

54. Cross-Sectional Moment of Inertia CSMI = /4 (r4 outer – r4 inner)
Area (cm2)
CSMI (cm4)
Bending Strength 100% 149% 193%
Courtesy of M. Bouxsein

55. Bone strengh indice: summary
Not well-studied
Derived from BMC, BMD, and several assumptions
Used in research field.

56. 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.

57. 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)

58. Serum Markers of Bone Turnover
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)

59. 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
There is a complex relationship between bone turnover and bone quality.
Suppression of bone turnover is not always good.
Long-term excessive suppression of bone turnover may result in increased skeletal fragility as a result of increased brittleness of bone.
An increase in bone brittleness is due to excessive mineralization which may result in the formation of microcracks and accumulation of microdamage.
Microdamage accumulation is a result of the absence of normal repair mechanisms in bone with very low bone turnover.

60. 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.

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

62. Thank you!