Dr Nicola Crabtree's presentation from Osteoporosis 2016: DXA and beyond. Find out more at: https://nos.org.uk/conference

1. Dr Nicola Crabtree
Principal Clinical Scientist & NIHR Post Doctoral Research Fellow
Birmingham Children’s Hospital / Queen Elizabeth Hospital Birmingham
Fracture Risk Assessment -
DXA and Beyond

2. Osteoporosis – Conceptual definition
 “a skeletal disease, characterised by low bone
mass and micro-architectural deterioration of
bone tissue, with a consequent increase in bone
fragility and susceptibility to fracture”
Consensus development conference: diagnosis, prophylaxis and treatment of osteoporosis. Am J Med. 1993

3. Osteoporosis – Operational definition
 Operationally defined by dual-energy X-ray
absorptiometry as 2.5 standard deviations or more
below the young adult female mean (T-Score ≤ -2.5)
measured at the femoral neck, total hip, or lumbar
spine.
World Health Organisation. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis (1994)

4. Dual-Energy X-ray Absorptiometry
 DXA
 Widely available
 2-D Projection modality
 Short scan times
 Good precision
 Reliable reference ranges
 Low radiation exposure
 Inversely related to fracture

5. DXA and Osteoporosis

6. 0
20
40
60
80
100
120
1 0,5 0 -0,5 -1 -1,5 -2 -2,5 -3 -3,5 -4 -4,5 -5 -5,5
Femoral neck BMD (T-score Nhanes)
0
20
40
60
80
100
120
140
160
EPISEM study; 6862 postmenopausal white women ≥70 years, randomly
selected from population based listing - Mean f/u of 3.2 yrs. 678 OP fractures
(hip, distal forearm, proximal humerus)
BMD distribution
No of women with fractures
Fracture rate
Fracturerateper1000Person-years
Noofwomenwithfractures
Courtesy of D Hans & MA Krieg – Adapted from the EPISEM Study
BMD overlaps in women with & without fracture

7. Normal Bone Density BUT Vertebral Fracture

8. High Bone Density & Vertebral Fracture

9. Dual energy x-ray absorptiometry
BMD as measured by DXA represents an amalgamation of volumetric bone
density, bone size, microarchitecture and the material properties of bone.
DXA = areal Bone mineral Density (g/cm2)

10. DXA Beyond BMD
 re-visit conceptual definition
 “a skeletal disease, characterised by low bone
mass and micro-architectural deterioration
of bone tissue, with a consequent increase in
bone fragility and susceptibility to fracture”

11. Bone Microarchitecture?
 Histomorphometry of trans illiac bone biopsy
 HRpQCT
 MRI
Not easily assessed clinically

12. CAN WE ESTIMATE BONE
MICRO-ARCHITECTURE
IN-VIVO?

13. Trabecular Bone Score

14. Trabecular Bone Score (TBS)
 Gray-level textural metric extracted from the two-dimensional
lumbar spine dual-energy absorptiometry
 TBS is related to bone microarchitecture and provides skeletal
information that is not captured from the standard bone
density measurement
 Based on experimental variograms of the projected DXA
image.
 TBS has the potential to discern differences between DXA
scans that have similar BMD
 High TBS = Better skeletal micro structure
 Low TBS = Weaker micro structure

15. Trabecular Bone Score (TBS)
Reproduced from Silva BC et al. JBMR 2014 [29], 3, 518-530

16. Can’t see the wood for the trees?
High TBS
Low TBS

17. Clinical Trabecular Bone Score (TBS)
 TBS is processed in the
same region of interest as
BMD.
Bousson et al. Osteoporosis International 2011

18. TBS – Manitoba Study
 29,407 women over 50
years of age
 BMD Hip & spine
 4.7 years follow up
 TBS
 1668 osteoporotic
fractures
 BMD & TBS predicted
fractures equally well
 Combining BMD & TBS
improves the prediction
Hans et al. JBMR 2011

19. TBS and Fracture
Silva BC et al. 2013 JBMR
Women Men
Prospective suggest that the TBS predicts risk of fracture
even after adjustment for BMD.

20. TBS FRAX Meta-Analysis:
Gradients of Risks per SD change in risk score
Age TBS only
Clinical risk factors
+ BMD
Clinical risk factors
+ BMD + TBS
Hip fracture
50 1.51 (0.89 - 2.55) 4.03 (2.01 - 8.10) 5.09 (2.45 - 10.55)
60 1.46 (1.01 - 2.11) 3.46 (2.13 - 5.62) 4.90 (2.80 - 8.56)
70 1.41 (1.12 - 1.77) 2.97 (2.23 - 3.97) 4.72 (3.06 - 7.26)
80 1.36 (1.18 - 1.57) 2.55 (2.14 - 3.05) 4.54 (3.06 - 6.74)
90 1.31 (1.06 - 1.62) 2.19 (1.66 - 2.90) 4.37 (2.73 - 7.00)
Other MOP fractures
50 1.54 (1.18 - 2.00) 1.56 (1.18 - 2.05) 1.62 (1.25 - 2.10)
60 1.51 (1.26 - 1.79) 1.52 (1.26 - 1.84) 1.58 (1.33 - 1.88)
70 1.47 (1.32 - 1.64) 1.49 (1.30 - 1.69) 1.54 (1.40 - 1.70)
80 1.44 (1.29 - 1.61) 1.45 (1.28 - 1.65) 1.50 (1.37 - 1.64)
90 1.41 (1.18 - 1.68) 1.42 (1.18 - 1.70) 1.46 (1.25 - 1.71)
EV McCloskey et al. on behalf of the FRAX meta-analysis working group – 2015

21. Can TBS be usefully added to FRAX?
TBS yields risk which is
 independent of BMD
 independent of CRFs
 amenable to intervention
 clinically meaningful
 Sufficient level of evidence (many studies)
 Validation cohort

22. TBS Meta analysis → FRAX
TBS is predictor
of fracture risk
independent of
FRAX and BMD

23. FRAX + NOGG

24. FRAX with added TBS
 High TBS
reduces
fracture risk
 Low TBS
increases
fracture risk

25. FRAX + NOGG + TBS
Low TBS High TBS

26. Disease specific– Type II Diabetes
Vestergaard et al OI 2007

27. TBS – Type II Diabetes
 29,407 women ≥50 years with baseline DXA
 ANCOVA adjusted for age, BMI, glucocorticoids, prior major fracture, rheumatoid, arthritis, COPD,
alcohol abuse and osteoporosis therapy.
Diabetes – No diabetes
Mean (95% CI)
Lumbar spine BMD (g/cm2)
+0.031
(0.024 : 0.038)
Femoral neck BMD (g/cm2)
+0.012
(0.007 : 0.016)
Trochanter BMD (g/cm2)
+0.008
(0.003 : 0.013)
Total hip BMD (g/cm2)
+0.019
(0.014 : 0.025)
Lumbar spine TBS (unitless)
-0.051
(-0.056 : -0.046)
Leslie WD et al. JCEM 2013

28. TBS is More Sensitive Than BMD to
Diabetes-Related Fracture Risk
OR 0.66
OR 2.61
OR 0.68OR 0.80
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
L14 BMD Fem Neck BMD Total Hip BMD L14 TBS
AdjustedOR
Odds ratios (95% CI bars) for lowest vs highest tertile according to presence of diabetes (adjusted for age,
BMI, osteoporosis therapy, glucocorticoids, prior fracture, rheumatoid arthritis, COPD, alcohol abuse).
Leslie WD et al. JCEM 2013

29. TBS and Osteoporosis Treatment
Popp et al. 2012 JBMR Silva BC et al. 2013 JBMR

30. ISCD – PDC 2015
 TBS is associated with vertebral, hip and major osteoporotic fracture risk in
older women (hip and major osteoporotic fracture risk in older men)
 TBS should not be used alone to determine treatment
 TBS can be used in association with FRAX and BMD to adjust FRAX-
probability in older women and men
 TBS is not useful for monitoring bisphosphonate TBS is associated with
major osteoporotic fracture risk in postmenopausal women with type II
diabetes
Shepherd et al. JCD 2015

31. Hip Geometry

32. Hip Strength Analysis / Advanced Hip Analysis
θ
Beck et al. 1990

33. Bone Distribution
 74 year old physically active lady
 83 year old physically inactive lady

34. Faster & Stronger
Slower & Weaker

35. Hip Geometry: Independent of FRAX and BMD
 Manitoba database, N=50,420 women >40, 1020 incident hip
fractures HR per SD
FRAX without BMD
HR per SD
FRAX with BMD
CSA 1.79
(1.66-1.94)
1.11
(1.01-1.22)
Section Modulus 1.47
(1.36-1.58)
1.04
(0.97-1.12)
Buckling Ratio 1.21
(1.15-1.26)
1.21
(1.14-1.28)
CSMI 1.25
(1.16-1.35)
1.05
(0.98)
Neck Shaft Angle 1.23
(1.17-1.30)
1.23
(1.17-1.30)
Hip Axis Length 1.30
(1.22-1.38)
1.30
(1.22-1.38)
Leslie WD et al. 2015 JCEM

36. Hip Axis Length
 67 year old woman
 T-scores: Total hip -1.6
 FRAX: Major 11% Hip 2.7%

37. HAL predicts hip fracture independent of FRAX and BMD
Leslie WD et al. JCD 2015
3.7%

38. Precision of Hip Geometry Parameters
Precision % CV %LSC
CSA 1.9 to 7.9 5.3 to 21.9
Section Modulus 3.3 to 10.1 9.1 to 28.0
Buckling Ratio 2.8 to 30.6 7.8 to 84.8
CSMI 3.2 to 11.7 8.9 to 32.4
Neck Shaft Angle 0.6 to 2.7 1.7 to 7.5
Hip Axis Length 0.4 to 1.8 1.2 to 5.0
Leslie 2015 ISCD

39. ISCD – PDC 2015
 Hip axis length (HAL) derived from DXA is associated with hip fracture risk in
postmenopausal women.
 Other hip geometry parameters derived from DXA should not be used to
assess hip fracture risk.
 Hip geometry parameters derived from DXA should not be used to initiate
treatment.
 Hip geometry parameters derived from DXA should not be used for
monitoring.
Shepherd et al. JCD 2015

40. Atypical Femoral Fractures

41. Atypical Femoral Fractures
 Located in the sub trochanteric region and the diaphysis of the
femur
 Reported in patients in bisphosphonates or denosumad
treatment for osteoporosis
 But do occur in patients NOT taking these drugs
 Absolute risk of AFF in patients on bisphophonates is low
ranging from 3.2 to 50 per 100,000 person-years
 Long-term use of bisphosphonates may be associated with
higher risk approxiamtely 100 per 100,000 person-years
 First reported in 2005 (Odvina et al. JCEM)
Shane et al. JBMR 2014

42. ASBMR Task Force 2013
-Revised Case Definition of AFFs
 The fracture must be located along the femoral diaphysis from just distal to the lesser trochanter to just proximal to
the supracondylar flare.
 In addition, at least four of five Major Features must be present. None of the Minor Features is required but have
sometimes been associated with these fractures.
 Major features
1. The fracture is associated with minimal or no trauma, as in a fall from a standing height or less
2. The fracture line originates at the lateral cortex and is substantially transverse in its orientation, although it may
become oblique as it progresses medially across the femur
3. Complete fractures extend through both cortices and may be associated with a medial spike; incomplete fractures
involve only the lateral cortex
4. The fracture is noncomminuted or minimally comminuted
5. Localized periosteal or endosteal thickening of the lateral cortex is present at the fracture site (“beaking” or “flaring”)
 Minor features
1. Generalized increase in cortical thickness of the femoral diaphyses
2. Unilateral or bilateral prodromal symptoms such as dull or aching pain in the groin or thigh
3. Bilateral incomplete or complete femoral diaphysis fractures
4. Delayed fracture healing
Shane et al. JBMR 2014

43. ASBMR Task Force 2013
-Revised Case Definition of AFFs
 The fracture must be located along the femoral diaphysis from just distal to the lesser trochanter to just proximal to
the supracondylar flare.
 In addition, at least four of five Major Features must be present. None of the Minor Features is required but have
sometimes been associated with these fractures.
 Major features
1. The fracture is associated with minimal or no trauma, as in a fall from a standing height or less
2. The fracture line originates at the lateral cortex and is substantially transverse in its orientation, although it may
become oblique as it progresses medially across the femur
3. Complete fractures extend through both cortices and may be associated with a medial spike; incomplete fractures
involve only the lateral cortex
4. The fracture is noncomminuted or minimally comminuted
5. Localized periosteal or endosteal thickening of the lateral cortex is present at the fracture site (“beaking” or “flaring”)
 Minor features
1. Generalized increase in cortical thickness of the femoral diaphyses
2. Unilateral or bilateral prodromal symptoms such as dull or aching pain in the groin or thigh
3. Bilateral incomplete or complete femoral diaphysis fractures
4. Delayed fracture healing
Shane et al. JBMR 2014

44. Example of Atypical Femoral fracture
Shane et al. JBMR 2014

45. Bone Density and AFF

46. Whole Femur Imaging with DXA

47. Beaking – Quantification with DXA