The ABC of

Trabecular Bone Score (TBS)

From Theory to Clinical Practice

Prof. Didier Hans

Center for Bone diseases, DAL

Lausanne University Hospital, Switzerland

Conflict of interest

Didier Hans is co-owner of the TBS patent and has corresponding

ownership shares into medimaps group as well as chairman of the

Board & part time CEO

Osteoporosis…

Systemic skeletal disease characterised by low

bone mass and a micro-architectural

deterioration of bone tissue

normal osteoporotic

* Consensus Development Conference, Am J Med 94:646-650, 1993

BMD 1 BMD 2=

?

Bone Mineral Density alone?

Bone Quality

Krieg et al ABMR 2007

Normal and major CRF?

History: 70 year-old woman. She came along for medical check-up. The patient is not taking vitamin D and calcium supplement.

Clinical assessment: History of ankle fracture; Glucocorticoid use 5mg/day for 4 months 5 years ago; BMI (26.2 kg/m2); Regular consumption of alcohol (more than 3 unit / day). No other associated risk factors for fracture.

Bone Assessment /Examination: Spine BMD T-score +0.8 SD (severe degenerative artifacts), Total Hip BMD T-score -0.4 SD and Femoral Neck BMD T-score 0.0 SD. No vertebral fractures on VFA.

FRAX hip fracture = 1.5 FRAX MOF = 21

0

5

10

15

20

25

50 55 60 65 70 75 80 85 90

FR

AX

pro

bab

ilit

y o

f fr

actu

re (

%)

Age

IT MOP

IT HF

Pharmaceutical

treatment…?

US FRAX® Intervention threshold

without TBS adjustment

Objectives

What is TBS?

How is it measured and how was it validated?

What are the potential clinical uses of TBS for

fracture risk assessment, treatment decision

making and monitoring?

Are there special populations where TBS might be

more helpful?

How to handle TBS in clinical routine?

The FDA Labeling for TBS

"TBS iNsight is a software provided for use as a

complement to a DXA analysis. … TBS is derived

from the texture of the [PA spine] DXA image and

has been shown to be related to bone

microarchitecture and fracture risk. This data

provides information independent of BMD…”

FDA 510(k) Clearance in 2012

Can we assess bone

micro-architecture in

routine clinical practice?

DXA HR-RX

v-CT / HR-CT

m-MRI / m-CT

h-CT

Research Only

Routine

Time + radiation + cost

TBS Fractal

Adapted (courtesy) from R Muller

How Can TBS Assess Microarchitecture?

Identify each single

Tree from this maze ?

Tricky

Identify all clearings ?

Much easier

Simplified Principle of TBS

TBS BTBS A >

copyright Professor Alan Boyde QMULcopyright Professor Alan Boyde QMUL

Simplified Principle of TBS

TBS a new parameter: Principles

Silva et al. JBMR 2014; Epub.

TBS is a bone texture index

correlated with bone

microarchitecture parameters and

provides information beyond BMD

Micro-architecture evaluation : HR-CT

• 30 dry vertebrae (human, lumbar and

low thoracic)

• HR-CT acquisitions (isotropic 93 µm

voxel size, 3D microarchitecture parameters)

• 2D projection image from 3D model

• Resolution degradation from 93 to 1488

µm pixel size

• Noise addition effects

• TBS analysis

“Study results show that the

correlations between TBSμCT at

93μm and 3D microarchitecture

parameters are weakly impacted by

the degradation of image resolution

and the presence of noise.”.

Winzenrieth R. et al JCD 2012

TBS is related to microarchitecture

parametersTBS is a texture analysis parameter

correlated to the bone micro-architecture parameters: PARFITT

+ TBS is related to:

SMI: r=0.62 (p<0.02)

Stiffness: r=0.64 (p<0.02)

Roux JP et al. ASBMR 2012, Hans et al. JCD 2012, Resch et al. ASBMR2012, Bilezikian JCEM 2013

TBS … Not Just Another BMD29407 Women age 50+, baseline TBS correlates

Leslie WD et al. JCD 2012

Lumbar

spine

BMD

Femoral

neck BMD

Lumbar

spine TBS

Age -0.26 -0.40 -0.31

Height +0.21 +0.27 -0.10

Weight +0.36 +0.40 -0.18

BMI +0.29 +0.32 -0.15

Lumbar spine BMD -- +0.68 +0.33

Femoral neck BMD +0.68 -- +0.27

Lumbar spine TBS +0.33 +0.27 --

Why the BUZZ

1. DXA Scan 2. Software Processing 3s 3. TBS Analysis & Report

An elevated TBS value correlates with better skeletal

microstructure; a low TBS value correlates with

weaker skeletal microstructure.

Silva et al. J Bone Miner Res. 2014 Jan 20

…few seconds…

…no impact of degenerative diseases…

Padilla, Lamy et al. ESCIM 2014

…retrospective analysis capability…

ASBMR 2011 -- 1 abstracts

ASBMR 2012 -- 19 abstracts

ASBMR 2013 -- 30 abstracts

ASBMR 2014 -- ??

0

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8

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12

14

16

18

20

2009 2010 2011 2012 2013 2014TBS Pubmed 1 2 3 5 14 20

Number

Clinical evidence

• TBS gives lower values in post-menopausal women and in men with

previous fragility fractures than their non-fractured counterparts;

• TBS is complementary to data available by lumbar spine DXA

measurements;

• TBS results are lower in women who have sustained a fragility

fracture but in whom DXA does not indicate osteoporosis or even

osteopenia;

• TBS predicts fracture risk as well as lumbar spine BMD

measurements in postmenopausal women;

• Efficacious therapies for osteoporosis differ in the extent to which

they influence the TBS;

• TBS is associated with fracture risk in individuals with conditions

related to reduced bone mass or bone quality.

Extracted from Silva et al. J Bone Miner Res. 2014 Jan 20

TBS Has a High Fracture

Discrimination Ability in Complement

of BMD in Both Women and Men

0,0 1,0 2,0 3,0 4,0 5,0 6,0

[40]

[44]

[45]

[46]

[48]

[40]

[41]

[42]

[45]

[46]

[47]

[48]

[43]

[49]

TBS Odd Ratios depending on fracture type

I

I

I

I

I

I

I

I

I

I

I

I

I

I

Wo

me

nst

ud

ies

Men study

All fracture types

All fracture types

Vertebral fracture type

Hipfracture type

TBS discriminates OP fractureindependently of BMD and CRF

TBS Can Predict Fractures

Independently and in Conjunction

with BMD

When BMD alone is not enough, the combination of BMD + TBS enables to identify

patients with high risk of fracture likely to have fractures whereas the patients are in

the osteopenic zone

BMD and TBS complementary ?Major OP Fractures – (GEHC-Lunar DXA system)

Hans et al. JBMR 2011

A: TBS identifies Osteoporotic

patients as well as BMD

B-C: Osteopenic patients with a

low TBS have a higher risk of

fracture than osteoporotic

patients with a normal TBS

A

BC

TBS re-classification rate in

osteopenic zone

Hans et al. JBMR 2011

At iso BMD the fracture risk is increasing when TBS is decreasing

A

B

C

685 Japanese women,

mean follow-up 10 years

102 subjects have

sustained a vertebral

fracture

Masayuki Iki et al. JBMR 2013

BMD and TBS complementary ?Vertebral Fractures – (Hologic DXA system)

Popp A., Lippuner K et al. Submitted 2014

BMD and TBS complementary ?ALL OP Fractures – (Hologic DXA system)

0,0 1,0 2,0 3,0

OFELY study

SEMOF study

Manitoba study

Manitoba study

JPOS study

Manitoba study

Hazard Ratio depending on fracture type

I

I

I

I

I

I

All fracture types

Hipfracture type

Vertebral fracture type

TBS predicts OP fracture

independently of BMD and CRF

TBS can be used to monitor changes

across time and particularly for

treatments follow-up.

Differential effect upon the molecule

Manitoba retrospective observational cohort

Paired DXA examinations 3.7 years (exclusion HRT, OTX or CS use)

Untreated n=1,150 vs Treated n=534 (MPR >75%, 86% BP).

TBS & Bisphosphonate vs Placebo

Krieg et al, 2013, OI

HORIZON Berne subset

TBS & Bisphosphonate vs Placebo

Popp et al, 2013, JBMR

No correlation between

changes in BMD and TBS.

Subset FREEDOM Study: 285 women (128 placebo, 157 DMAb) with a

TBS value at baseline and ≥1 post-baseline visit.

TBS & Denosumab vs Placebo

McClung et al, 2012, ASBMR

Month

Perc

en

tag

e C

han

ge F

rom

Baselin

e

Data are LS mean (95% CI). *P ≤ 0.0144 compared with baseline and placebo. Lumbar

spine BMD and TBS were assessed from the same DXA scans.

0

2

4

6

8

10

12

–2

0 12 24 36Month

Perc

en

tag

e C

han

ge F

rom

Baselin

e

*

*

*9.8%

0%

BMD

–2

0

2

4

0

3

1

–1

12 24 36

2.4%

–0.7

*

*

TBS

DenosumabPlacebo

*

Phase 2, Multicenter, Randomized, Double-blind, Double-dummy, Placebo-

controlled, 12-month Pilot Study

SCREENING

Denosumab 60 mg Q6M

BASELINE

VISIT

Alendronate 70 mg QWRando mizatio n

1:1:1

Placebo

0 – 35 Days

END

OF

TREATMENT

12 Months

TBS & Denosumab vs AL vs Placebo

Thomas T et al, 2013, ASBMR

ab

abc

DXA aBMD

p < 0.05 compared with: abaseline, bplacebo, calendronate

–4

–2

0

2

4

6

8

Placebo Alendronate Denosumab

ab

ab

a

QCT vBMD

b

abc

TBS

Perc

enta

ge C

hange a

t 12 m

on

ths F

rom

Baselin

eTBS & Denosumab vs AL vs Placebo

Thomas T et al, 2013, ASBMR

TBS & PTH vs Bisphosphonate

Senn C et al, 2014, Osteoporos Int. 2014

N = 65

N = 122

% of Individuals with significant change

at the spine at 24 months

PTH 1 DMAB ZOL IBAN 1 ALAnti-

resorber

LSC 95% 1 TBS BMD TBS TBS TBS BMD TBS TBS

Significantgain

+3.10% 61.5% 78.5% 44% 35% 26.3% 51.6% 29% 22%

Stability 27.7% 20.0% - - 46.7% 42.6% - -

Significantloss

-3.10% 10.8% 1.5% - - 27.0% 5.8% - -

1 Senn C et al, 2014, Osteoporos Int. 2014

Treatment effects summary on TBS(5 different studies – Not a head to head study)

PTH

ZOL

AL

PLBO

0%

24 months

1%

4%

3%

2%

-1%

No correlation between % change in

BMD and TBS

DMAB

Adapted from Silva et al. JBMR 2014

TBS High Added Value in Case

of Secondary osteoporosis

Utility of TBS in secondary OP: a review

Despite the relative small number of patients evaluated, TBS has been

shown to be associated with fractures in:

diabetes,

primary hyperparathyroidism,

rheumatoid arthritis,

adrenal incidentaloma,

chronic kidney disease,

in individuals on longterm GC therapy.

Moreover, TBS is reduced in patients with ankylosing spondylitis, and

improves after the treatment of endocrinological conditions related to

reduced bone mass, such as Cushing’s disease, and primary

hyperparathyroidism.

Ulivieri FM, Silva BC, Sardanelli F, Hans D, Bilezikian JP, Caudarella R. Endocrine. 2014 May 23.

A TBS decrease is observed even from low dose of GCs (5mg/day)

while no change in BMD values is observed in comparison with the

reference values

TBS & Glucocorticoids: Dose effect

Colson et al, GIO 2011

-3,5%

-4,6%

1,6%

0,4%

-5,0%

-4,0%

-3,0%

-2,0%

-1,0%

0,0%

1,0%

2,0%

Diff

ere

nce

s b

etw

ee

n G

CS

su

bje

cts

an

d re

fere

nce

va

lue

s in

%

ΔTBS L1L4 (%) ΔBMD L1L4 (%)

5mg/day (n=74) >5mg/day (n=62)

p=0.76

p=0.91

p<0,001

p<0,001

-3.5%

-4.6%

Is TBS Helpful in Diabetes?29,407 women ≥50 years with baseline DXA

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)

ANCOVA adjusted for age, BMI, glucocorticoids, prior major fracture, rheumatoid

arthritis, COPD, alcohol abuse and osteoporosis therapy.

Leslie WD et al. JCEM 2013.

TBS is More Sensitive Than BMD to

Diabetes-Related Fracture Risk

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).

LS TBS predicted fractures in those with diabetes (adjusted HR 1.27,

95%CI 1.10-1.46) and without diabetes (HR 1.31, 95%CI 1.24-1.38).

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

Ad

jus

ted

OR

Leslie WD et al. JCEM 2013.

Bone quality assessment in type 2

diabetes mellitus

In T2DM, TBS is lower and associated with poor glycemic control. Abnormal

trabecular microarchitecture may help explain the paradox of increased

fractures at a higher BMD in T2DM.

R. Dhaliwal R. et al. Osteoporos Int. 2014

1

1.05

1.1

1.15

1.2

1.25

1.3

1.35

Non diabetes mellitus(N= 43)

Type II diabetesmellitus (N= 57)

Spine TBS

Spine BMD

1

1.05

1.1

1.15

1.2

1.25

1.3

T2DM with Alc ≤ 7.5% (N=40)

T2DM with Alc >7.5% (N=40)

P< 0.002

ns

P< 0.003

P< 0.02

Adjusted for age and BMI (linear regression)

How to use TBS in Clinical

Routine

TBS: How is the Number Interpreted?

normalT-score > -1

osteoporosisT-score < -2.5

low bone mass-1 < T-score < -2.5

Adapted from Silva et al. JBMR 2014

Patients with same BMD may not have

the same risk of fractureDifferent TBS value

TBS L1-L4: 1.457

TBS L1-L4: 1.132

Age

Age

TB

S L

1-L

4T

BS

L1-L

4

Same BMDDifferent

patient

management ?

Spanish Nomogram Approach

Combining graph of T-score BMD and T-score TBS

Del Rio et al. ECCEO 2014

Possible TBS interpretation table

• Fracture risk assessed by:

BMD alone:

BMD + TBS

Based on Spine

TBS

≥ 1.300

1.200 < > 1.300

≤ 1.200

Based on minimum hip or spine BMD T-score

Normal Osteopenia Osteoporosis

BMD AloneColor Code

Sub-category of risk

of Major osteoporotic

fracture per 1'000

women per year

≤ 4

] 4 - 5 ]

] 5 - 7 ]

] 7- 10 ]

] 10 - 14 ]

] 14 - 20 ]

> 20

Adapted from Table 3 in Hans et al. J Bone Miner Res. 2011 Nov;26(11):2762-9

German approach (DVO Guidelines)

TBS

TBS … BMD Independent Associations

29407 Women age 50+, baseline TBS correlates

Leslie WD et al. JCD 2012

No BMD BMD adjusted

(lumbar spine)

BMD adjusted

(femoral neck)

Age ▼▼ ▼▼ ▼▼

BMI ▼▼ ▼▼ ▼▼

Recent osteoporosis Tx ▲ ▲ ▲

Recent glucocorticoids ▼ ▼ ▼

Prior major fracture ▼▼ ▼ ▼▼

Rheumatoid arthritis ▼ ▼ ▼

COPD ▼▼ ▼▼ ▼▼

Alcohol abuse ▼ ▼ ▼

FRAX adjusted by TBS?

Change to MOP

probability

Change to HF

probability

If L1L4TBS is in the lowest tertile: Increase 25%* Increase 30%*

If L1L4TBS is in the middle tertile

(referent):No change No change

If L1L4TBS is in the highest tertile:Decrease

21%*No change

* WD. Leslie et al.. Lumbar Spine TBS is a FRAX Independent Risk Factor for Fracture: The Manitoba

BMD Cohort. ISCD Annual meeting 2013. Tampa. Florida.

IT

- 75 yo women, BMI 18.4

- Wrist Fracture

- Smoking

- T-score (BMD)

- L1-4 = -2.6

- Femur = -2.5

- GI sensitivity

- Dental surgery in few months

(teeth lossening)

2012 French Recommendations

0

5

10

15

20

25

30

35

40

50 55 60 65 70 75 80 85 90Pro

ba

bilit

yo

f M

OF

at

10

ye

ars

(%)

Age

French FRAX intervention threshold

SIT

TBS = 1.156(Texture highly degraded)

0

5

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15

20

25

30

35

40

50 55 60 65 70 75 80 85 90Pro

ba

bilit

y o

f M

OF

at

10

ye

ars

(%

)

Age

French FRAX intervention threshold

SIT

2012 French Recommendations

- 75 yo women, BMI 18.4

- Wrist Fracture

- Smoking

- T-score (BMD)

- L1-4 = -2.6

- Femur = -2.5

- Adjusted FRAX = 22.5

- TBS 1.159

- GI sensitivity

- Dental surgery in few months

(teeth lossening)

Bisphosphonate or

Strontium Ranelate or Denosumab

Normal and major CRF?

History: 70 year-old woman. She came along for medical check-up. The patient is not taking vitamin D and calcium supplement.

Clinical assessment: History of ankle fracture; Glucocorticoid use 5mg/day for 4 months and then stopped; BMI (26.2 kg/m2); Regular consumption of alcohol (more than 3 unit / day). No other associated risk factors for fracture.

Bone Assessment /Examination: Spine BMD T-score +0.8 SD (severe degenerative artifacts), Total Hip BMD T-score -0.4 SD and Femoral Neck BMD T-score 0.0 SD. No vertebral fractures on VFA.

FRAX hip fracture = 1.5 FRAX MOF = 21

0

5

10

15

20

25

50 55 60 65 70 75 80 85 90

FR

AX

pro

bab

ilit

y o

f fr

actu

re (

%)

Age

US FRAX® Intervention thresholdwithout TBS adjustment

IT MOP

IT HF

Pharmaceutical

treatment…?

TBS L1-L4: 1.352 is normal

FRAX hip fracture = 1.5 (no TBS adjustment)

TBS adjusted FRAX MOF = 16.6

TBS L1-L4: 1.352

0

5

10

15

20

25

50 55 60 65 70 75 80 85 90

FR

AX

pro

bab

ilit

y o

f fr

actu

re (

%)

Age

US FRAX® Intervention thresholdwith TBS adjustment

IT MOP

IT HF

Pharmaceutica

l treatment…?

Fracture rates per 1,000 woman-years

according to FRAX and TBS tertiles

Adapted from WD. Leslie et al. Osteoporos Int. 2014 Jun 21

1 (lowest)

2 (middle)

3 (highest)

0

10

20

30

1(lowest) 2

(middle) 3(highest)

MOF Probability

MO

F r

ate

per

1,0

00 y

ears

TBS Tertile

Association between TBS and OP fracture

and death after multiple adjustments

TBS adjusted forOsteoporotic fracture Death

HR a (95% CI) HR a (95% CI)

Time since baseline and age 1.36 (1.30-1.42) 1.32 (1.26-1.39)

Clinical risk factors * 1.27 (1.21-1.33) 1.23 (1.17-1.29)

Femoral neck BMD 1.24 (1.18-1.30) 1.29 (1.23-1.35)

Clinical risk factors * + FN BMD 1.18 (1.12-1.23) 1.20 (1.14-1.26)

Lumbar spine BMD 1.23 (1.18, 1.30) 1.35 (1.29, 1.42)

Clinical risk factors* + LS BMD 1.17 (1.11, 1.23) 1.26 (1.19, 1.32)

* Body mass index, previous fracture, chronic obstructive pulmonary disease (smoking proxy),

glucocorticoid use > 90 days, rheumatoid arthritis, secondary osteoporosis and high alcohol use.

a HR per SD decrease

WD. Leslie et al. Osteoporos Int. 2014 Jun 21

WD. Leslie et al. Osteoporos Int. 2014 Jun 21

Change in MOF probability according to age and

T-score -2 or +1 SD without CRF

symbol=without TBS, line=10th-90th TBS percentile

0

2

4

6

8

10

12

14

16

18

50 60 70 80

Age (years)

T-score -2

T-score +1

Fracture probability (%)

FRAX Meta-Analysis: Preliminary

Count Percent

JPOS 978 5.7

MissOs HK 1953 11.4

MrOs HK 1924 11.2

MrOs Sweden 1048 6.1

OFELY 498 2.9

OPUS 938 5.5

SEMOF 524 3.1

Rotterdam 2377 13.9

CaMos 2865 16.8

Rotterdam RSI 922 5.4

Rotterdam RSII 240 1.4

FORMEN 1532 9.0

STRAMBO 707 4.1

Geelong 597 3.5

Leslie WD, Kanis J, H Johanson et al, unpublished data

FRAX Meta-Analysis: TBS to Predict

Incident MOFs

HR = 1.40

HR = 1.34

HR = 1.79

HR = 1.55

HR = 1.53

HR = 1.32

Leslie WD, Kanis J, H Johanson et al, unpublished data

0.40

0.60

0.80

1.00

1.20

1.40

1.60

1.80

2.00

0.8 0.9 1 1.1 1.2 1.3 1.4 1.5 1.6

FR

AX

ad

jus

tem

en

t ra

tio

TBS

50 years

60 years

70 years

80 years

90 years

no impact line

Adjusting fracture probability for TBS

Fine Tuning FRAX adjustment to come

Age inte

raction

Leslie WD, Kanis J, H Johanson et al, unpublished data

Conclusions There is sufficient evidence today to use TBS in clinical

routine as one of the risk factors of the fracture

While the optimal threshold for TBS should be confirmed, an

incremental improvement in fracture identification was seen

by using lumbar spine TBS in combination with FRAX.

Once cross-validated in the individual level meta-analysis,

lumbar spine TBS will be integrated into the FRAX model as

an add on.

Such simple way to take TBS into account would allow the

use of current medical society recommendation regarding

osteoporosis management with only minor adaptation.

Thank

you for

your

attention

Density BMD

Macro-Architecture

Micro-Achitecture

Morphometry

Body Composition

BMD

TBS