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

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

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)

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

DXA and Osteoporosis

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 fracturesFracture rate

Frac

ture

rat

e pe

r 10

00 P

erso

n-ye

ars

No of w

omen w

ith fractures

Courtesy of D Hans & MA Krieg – Adapted from the EPISEM Study

BMD overlaps in women with & without fracture

Normal Bone Density BUT Vertebral Fracture

High Bone Density & Vertebral Fracture

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)

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”

Bone Microarchitecture? Histomorphometry of trans illiac bone biopsy HRpQCT MRI

Not easily assessed clinically

CAN WE ESTIMATE BONE MICRO-ARCHITECTURE

IN-VIVO?

Trabecular Bone Score

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

Trabecular Bone Score (TBS)

Reproduced from Silva BC et al. JBMR 2014 [29], 3, 518-530

Can’t see the wood for the trees?

High TBS

Low TBS

Clinical Trabecular Bone Score (TBS)

TBS is processed in the same region of interest as BMD.

Bousson et al. Osteoporosis International 2011

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

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.

TBS FRAX Meta-Analysis: Gradients of Risks per SD change in risk score

Age TBS onlyClinical risk factors

+ BMDClinical risk factors

+ BMD + TBS

Hip fracture50 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 fractures50 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

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

TBS Meta analysis → FRAX

TBS is predictor

of fracture risk

independent of

FRAX and BMD

FRAX + NOGG

FRAX with added TBS

High TBS reduces fracture risk

Low TBS increases fracture risk

FRAX + NOGG + TBSLow TBS High TBS

Disease specific– Type II Diabetes

Vestergaard et al OI 2007

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 diabetesMean (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

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

Adj

uste

d O

R

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

TBS and Osteoporosis Treatment

Popp et al. 2012 JBMR Silva BC et al. 2013 JBMR

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

Hip Geometry

Hip Strength Analysis / Advanced Hip Analysis

θ

Beck et al. 1990

Bone Distribution 74 year old physically active lady

83 year old physically inactive lady

Faster & Stronger

Slower & Weaker

Hip Geometry: Independent of FRAX and BMD Manitoba database, N=50,420 women >40, 1020 incident

hip fractures HR per SDFRAX without BMD

HR per SDFRAX 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

Hip Axis Length

67 year old woman T-scores: Total hip -1.6 FRAX: Major 11% Hip 2.7%

HAL predicts hip fracture independent of FRAX and BMD

Leslie WD et al. JCD 2015

3.7%

Precision of Hip Geometry Parameters

Precision % CV %LSCCSA 1.9 to 7.9 5.3 to 21.9Section Modulus 3.3 to 10.1 9.1 to 28.0Buckling Ratio 2.8 to 30.6 7.8 to 84.8CSMI 3.2 to 11.7 8.9 to 32.4Neck Shaft Angle 0.6 to 2.7 1.7 to 7.5Hip Axis Length 0.4 to 1.8 1.2 to 5.0

Leslie 2015 ISCD

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

Atypical Femoral Fractures

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

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 features1. 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 features1. 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

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 features1. 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 diaphyses2. 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 healingShane et al. JBMR 2014

Example of Atypical Femoral fracture

Shane et al. JBMR 2014

Bone Density and AFF

Whole Femur Imaging with DXA

Beaking – Quantification with DXA