Added value of trabecular bone score over bone mineral density for identification of vertebral fractures in patients with areal bone mineral density in the non-osteoporotic range

ORIGINAL ARTICLE

Added value of trabecular bone score over bone mineral density for identification of vertebral fractures in patients with areal bone mineral density in the non-osteoporotic range

K. Nassar _& S. Paternotte _& S. Kolta _& J. Fechtenbaum _&

C. Roux _& K. Briot

Received: 6 May 2013 / Accepted: 3 September 2013 / Published online: 1 October 2013

# International Osteoporosis Foundation and National Osteoporosis Foundation 2013

Abstract

Summary Detection of patients with vertebral fracture is sim- ilar for areal bone mineral density (aBMD) and trabecular bone score (TBS) in patients with non-vertebral fracture. In non-osteoporotic patients, TBS adds information to lumbar spine aBMD and is related to an index of spine deterioration.

Introduction Vertebral fractures (VFs) are more predictive of future fracture than aBMD. The number and severity of VFs are related to microarchitecture deterioration. TBS has been shown to be related to microarchitecture. The study aimed at evaluating TBS in the prediction of the presence and severity of VFs.

Methods Patients were selected from a Fracture Liaison Service (FLS): aBMD and vertebral fracture assessment (VFA) were assessed after the fracture, using dual-energy X- ray-absorptiometry (DXA). VFs were classified using Genant's semiquantitative method and severity, using the spinal defor- mity index (SDI). TBS was obtained after analysis of DXA scans. Performance of TBS and aBMD was assessed using areas under the curves (AUCs).

Results A total of 362 patients (77.3 % women; mean age 74.3±

11.7 years) were analysed. Prevalence of VFs was 36.7 %, and 189 patients (52.2 %) were osteoporotic. Performance of TBS was similar to lumbar spine (LS) aBMD and hip aBMD for the identification of patients with VFs. In the population with aBMD in the non-osteoporotic range ( n =173), AUC of TBS for the discrimination of VFs was higher than the AUC of LS aBMD (0.670 vs 0.541, p =0.035) but not of hip aBMD; there was a negative correlation between TBS and SDI ( r = −0.31;

p < 0.0001).

Conclusion Detection of patients with vertebral fracture is similar for aBMD and TBS in patients with non-vertebral fracture. In patients with aBMD in the non-osteoporotic range, TBS adds information to lumbar spine aBMD alone and is related to an index of spine deterioration.

Keywords Bone mineral density . Fracture . Osteoporosis . TBS

Introduction

Osteoporosis is a skeletal disorder characterized by compromised bone strength leading to an increased risk of fracture [1]. Whereas low areal bone mineral density (aBMD) is among the strongest risk factors for fracture, studies have shown that up to one half of patients with fragility fractures have aBMD above the diagnostic threshold of osteoporosis, i.e. T-score ≤−2.5 [2–6]. Among post- menopausal women having risk factors for osteoporosis, but with T-scores higher than the −2.5 threshold, 20 % already have vertebral fractures [7]. Vertebral fractures are the hallmark of bone fragility [8] and are more predictive of future fracture than aBMD; moreover, the risk of subsequent fractures increases with the number and the severity of prior vertebral fractures [9–11]. There is a link between severity of vertebral fractures and alterations of bone microarchitecture assessed at the iliac crest [12].

Assessment of patients with vertebral fractures (VF) is challenging; most of them do not come to clinical attention [13–15]. Use of conventional radiology is unattractive on the ground of costs and radiation exposure. Vertebral fracture as- sessment (VFA) is a radiographic method using dual-energy X- ray-absorptiometry (DXA) to diagnose vertebral fractures, val- idated for reproducibility, sensitivity and specificity as compared K. Nassar : S. Paternotte : S. Kolta : J. Fechtenbaum : C. Roux :

K. Briot ( * )

Rheumatology Department, Cochin Hospital, Paris Descartes University, Paris, France

e-mail: karine.briot@cch.aphp.fr

with spine radiographs, with low radiation exposure [16–19].

However, not all DXA machines are equipped with VFA software, and coverage of VFA has not been embraced by health insurance in all countries. Thus, there is a need in clinical setting for a tool able to predict the presence of vertebral fracture and to indicate appropriately spine imaging in selected patients.

The trabecular bone score (TBS) is a bone texture analysis derived from the DXA image of the lumbar spine [20]. The ex vivo studies conducted on bone specimens (vertebrae, radius and femoral neck) show that TBS positively correlates with 3D bone microarchitecture parameters, such as connec- tivity, density and trabecular number, and negatively with trabecular separation [21–24]. In vivo, this texture parameter analyses the grey-level variations in DXA images, in the same bone region as in lumbar spine aBMD. In clinical practice, lower TBS scores indicate greater fracture susceptibility.

Cross-sectional studies showed that TBS was lower in post- menopausal women with previous fragility fracture compared to those without fracture [25] and was lower in women with fractures irrespective of whether their bone mineral density (BMD) met the criteria for osteoporosis or osteopenia [26, 27]. Two retrospective historical cohort studies showed that lumbar spine TBS and aBMD predicted major fractures similarly; and that the combination of lumbar spine TBS and aBMD improves fracture risk prediction in women with aBMD in the non-osteoporotic range [27, 28]. We have shown previously in patients with rheumatoid arthritis that TBS has a better discrimination than lumbar spine aBMD for prediction of the presence of vertebral fractures [29].

Thus, the purpose of our study was to evaluate the value of TBS, alone or added to aBMD, in the prediction of the presence and severity of vertebral fractures in a cohort of patients included in a Fracture Liaison Service.

Patients and methods

Patient selection

Patients were selected from the Fracture Liaison Service (FLS) of Cochin Hospital. This FLS was established to pro- vide routine assessment for osteoporosis to all men and wom- en over the age of 50 years who had sustained a low-trauma non-vertebral fracture and are hospitalized in the orthopaedic surgery department. Low-trauma fractures are defined as those sustained in falls from standing height or less. Exclusion criteria are pathological and traumatic fractures, outpatients and severe impaired cognitive functions.

A senior physician, dedicated to the task of identifying patients with fragility fractures, selects these patients in the orthopaedic surgery department and prescribes DXA scanning and VFA.

Clinical assessment includes demographic data: age, height, weight, BMI (body mass index) (in kilogram per square metre), when standing position is possible, and infor- mation on anti-osteoporotic treatment in the previous year.

BMD and VFA assessment

These measurements are performed 4–90 days after the hospitalization for fracture. aBMD (in gram per square centimetre) is assessed by DXA (Hologic®, QDR 4500A, software version 12.6; Bedford, MA) at the lumbar spine (L2–L4) and hip (total hip and femoral neck). The small detectable difference (SDD) for the device was 0.034, 0.036 and 0.027 g/cm

for the lumbar spine, femoral neck and total hip, respectively [30]. The quality control protocol for the DXA device includes daily scanning of a phantom.

A single device was used for the whole current study. The World Health Organization (WHO) classification was used to define osteoporosis as T-score ≤− 2.5 at the lumbar spine, total hip or femoral neck. Vertebral fractures from T4 to L4 were evaluated using VFA software on the DXA device. They were classified with the Genant semiquantitative approach [31].

Patients with at least one grade 1 fracture were considered as fractured. Spinal deformity index (SDI), an assessment tool for vertebral fracture prediction [10, 32] was calculated by summing the grade of each fractured vertebra from T4 to L4;

the SDI value can vary between 0 (no fracture) and 39 (all the assessed vertebrae are grade 3). The diagnosis was directly assessed on the screen, by one single reader (JF), an expert in this field.

TBS

TBS (TBS iNsight® Software version 1.8, Med-Imaps, Pessac, France) was obtained after reanalysis of DXA lumbar spine (L2–L4) scans. The study was conducted independently of the manufacturer. The software uses the AP spine raw image(s) from the densitometer, including the aBMD region of interest (ROI) and edge detection, so that the TBS calcula- tion is performed over exactly the same ROI as the aBMD measurement. For each region of measurement, TBS was evaluated based upon grey-level analysis of the DXA images as the slope at the origin of the log-log representation of the experimental variogram. TBS (L2–L4) was calculated as the mean value of the individual measurements for vertebrae L2–

L4. A BMI between 15 and 35 kg/m

is mandatory for TBS analysis, according to the manufacturer.

Statistical analysis

Characteristics of patients with hip fractures and non-vertebral

non-hip fractures and with and without vertebral fractures

were compared by using chi-square tests or Fisher's exact

tests, or t tests as appropriate. The discriminative values of aBMD at all sites, TBS (L2–L4) and their combination for the presence of vertebral fracture was assessed by determining the area under the receiving operator characteristic (ROC) curve (area under the curve, AUC). All the analysis was performed on SAS 9.1® statistical software.

Results

Patient characteristics

Five hundred and twenty-eight patients were recruited in the FLS between February 2009 and October 2012. VFA was not performed in 113 patients for technical reasons (including inability to raise the upper arm for lateral view of VFA measurement because of humerus and other upper arm frac- tures); TBS was not measured in 115 patients because of the inability to assess height and/or weight (and thus BMI which is requested for TBS calculation) at the time of the DXA scan.

Thus, 362 patients are the basis of the study (77.3 % women;

mean age 74.3 ±11.7 years) (Table 1). One hundred and eighty-six (51.4 %) patients had hip fractures, and 176 (48.6 %) had a non-vertebral non-hip fracture, located at the humerus ( n = 25 (14.2 %)), pelvis ( n =16 (9.3 %)), wrist ( n =85 (49.4 %)) and other sites ( n =50 (28.4 %)). For 296 of them, the non-vertebral fracture was a major fracture (hip, wrist, humerus) according to the FRAX®. Their char- acteristics are shown in Table 1. One hundred and eighty-nine (52.2 %) patients had aBMD in the osteoporotic range (T≤−2.5 at least one the three sites); 110 (30.4 %) patients received calcium and/or vitamin D, and 49 (13.5 %) reported receiving an anti-osteoporotic treatment in the year before the fracture. Prevalence of vertebral fractures by VFA was 36.7 %

( n =133); the mean number of vertebral fractures was 1.7±

1.2. The characteristics of patients according to the presence of vertebral fractures were in Table 2.

Half of our population recruited in the FLS had hip frac- ture. Compared to patients with non-hip non-vertebral fractures, patients with hip fracture were older (77.3±10.9 vs 71.3±11.7 years, p ≤ 0.0001), had frequently more vertebral fractures (44.5 vs 28.9 %, p = 0.002) and osteoporosis (T≤−2.5 at least one the three sites) (62.6 vs 41.7 %, p ≤0.0001). They had lower femoral neck and hip aBMD than patients without hip fractures (0.580±0.11 vs 0.639±0.12 g/cm

and 0.600±0.15 vs 0.769±0.15 g/cm

, p <0.0001).

TBS

TBS was weakly correlated with lumbar spine ( r =0.51) and total hip ( r =0.34) aBMD. TBS was lower in patients with vertebral fractures than in patients without vertebral fractures (1.156±0.108 vs 1.227±0.107, p <0.0001). Mean values of TBS were 1.159±0.115 and 1.153±0.099 in patients with one VF and at least two VFs, respectively.

Vertebral fracture discrimination using TBS

In the whole population, AUC of TBS (0.677) was similar to AUC of lumbar spine (LS) aBMD (0.669, p =0.80) and hip aBMD AUC (0.692, p =0.68) (Fig. 1) for the presence of VF.

Combination of TBS and LS aBMD (AUC=0.707) improved VF discrimination as compared to LS aBMD alone ( p =0.043) but not to hip aBMD alone ( p =0.327). Combination of TBS and hip aBMD (AUC=0.713) did not improve VF discrimi- nation as compared to LS aBMD alone ( p =0.088) and to hip aBMD alone ( p =0.327). Results were similar in patients with major fracture according to the FRAX®.

Negative predictive value for vertebral fracture discrimina- tion was 0.76, 0.79, 0.81, 0.84 and 0.82 for LS aBMD, hip aBMD, TBS, combination of TBS with LS aBMD and com- bination of TBS with hip aBMD, respectively. Positive pre- dictive value was 0.43, 0.41, 0.46, 0.47 and 0.42 for LS aBMD, hip aBMD, TBS, combination of TBS with LS aBMD and combination of TBS with hip aBMD, respectively.

TBS according to the severity of vertebral fractures

Among patients with vertebral fractures, 57 (42.9 %), 47 (35.3 %) and 29 (21.8 %) had only grade 1 fracture, at least one grade 2 (without grade 3) and at least one grade 3 fracture.

Thus, in our cohort of patients older than 50 years with a recent non-traumatic fracture, 21 % ( n =76) have moderate and/or severe vertebral fractures. There was no statistically significant difference of TBS among these three subgroups:

1.168±0.115 in only grade 1 group, 1.154±0.104 in patients Table 1 Characteristics of the population (n =362)

Variables

Age (years) (mean ± SD) 74.3±11.7

Female (n , %) 280 (77.3 %)

History of low trauma fracture N (%) 112 (31.4 %)

BMI (kg/m

) (mean ± SD) 23.5±4.3

Lumbar spine T-score (mean ± SD) − 1.48±1.69 Femoral neck T-score (mean ± SD) − 2.30±1.03

Total hip T-score (mean ± SD) − 1.79±1.13

Osteoporosis (T ≤− 2.5 at least one site) (n, %) 189 (52.2 %)

≥ 1 Vertebral fracture (n , %) 133 (36.7 %)

Number of vertebral fracture (mean ± SD) 0.6±1.1 Spinal deformity index (SDI) (mean ± SD) 1.1±2.2

Lumbar spine TBS (mean ± SD) 1.201±0.113

with at least one grade 2, and 1.139±0.104 in patients with at least one grade 3.

There was a negative correlation between SDI and TBS ( r =−0.31 ( p <0.0001)), hip aBMD (−0.32 ( p <0.0001)) and LS aBMD ( r = −0.30 ( p <0.0001)). TBS was not correlated with SDI after adjustment for age, hip aBMD and lumbar spine aBMD.

Seventy-six patients had at least one grade 2 VF. The AUC for discrimination of these patients as compared to the others ( n =286 having no VF or only grade 1 VFs) were 0.665, 0.679, 0.661, 0.712 and 683 for TBS, LS aBMD, hip aBMD, TBS + LS aBMD, and TBS + hip aBMD. In this situation, AUC of TBS for the discrimination of VFs was similar to LS aBMD (0.665 vs 0.679, p =0.712) and to hip aBMD (0.665 vs 0.661 p =0.953). Combination of TBS and LS aBMD or hip aBMD to improve discrimination of patients having at least one grade 2 VF was not significant ( p =0.095 and 0.433, respectively) as compared to these parameters alone. Results were similar in patients for whom the non- vertebral fracture was a major fracture according to the FRAX®.

TBS in patients with aBMD in the non-osteoporotic range In patients with aBMD in the non-osteoporotic range ( n =173) (T> −2.5 at all sites), TBS was significantly lower in patients with vertebral fractures than in patients without VF (1.187±

0.121 vs 1.253±0.104, p =0.001). AUC of TBS for the dis- crimination of VFs was higher than the AUC of LS aBMD (0.671 vs 0.541, p =0.035) but not of hip aBMD (0.670 vs 0.585, p =0.264) (Figs. 2 and 3). TBS was negatively corre- lated to SDI ( r =−0.25 ( p =0.001)). In these patients, LS aBMD and hip aBMD were not correlated with SDI (−0.07 ( p =0.360) and −0.04 ( p =0.618), respectively).

In patients for whom the non-vertebral fracture was a major fracture according to the FRAX® ( n =132), TBS was signif- icantly lower in patients with vertebral fractures than in pa- tients without VF (1.194±0.112 vs 1.264±0.092, p =0.001).

AUC of TBS for the discrimination of VFs was similar to LS aBMD (0.697 vs 0.545, p = 0.303) and to hip aBMD (0.697 vs 0.588, p =0.264). TBS was negatively correlated to SDI ( r =−0.29 ( p =0.001)). In these patients with aBMD in the non-osteoporotic range, LS aBMD and hip aBMD were not Table 2 Characteristics of pa-

tients according to the presence of vertebral fractures

Vertebral fractures No vertebral fractures p value

N (%) 133 229

Age (years) (mean ± SD) 80.2 (±10.4) 71.0 (±11.1) <0.0001

Female (n, %) 104 (78.2 %) 176 (76.9 %) 0.769

Parents with hip fracture (n, %) 81 (60.9 %) 101 (44.1 %) 0.002

Lumbar spine T-score (mean ± SD) −2.1±1.7 −1.2±1.6 <0.0001

Femoral neck T-score (mean ± SD) − 2.7±1.1 − 2.1±1.0 <0.0001

Total hip T-score (mean ± SD) − 2.3±1.1 − 1.5±1.0 <0.0001

Osteoporosis (T ≤− 2.5 at least one site) (n, %) 95 (71.4 %) 94 (41.1 %) <0.0001

Lumbar spine TBS (mean ± SD) 1.157±0.108 1.227±0.107 <0.0001

ROC curves in the whole population

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

1 - Specificity

Sensitivity

TBS LS BMD Hip BMD TBS + LS BMD TBS + Hip BMD

Fig. 1 Discriminative value of

TBS alone and in combination

with LS and hip aBMD in the

whole population

correlated with SDI (−0.08 ( p =0.344) and −0.06 ( p =0.491), respectively).

Discussion

This study conducted in a population of patients recruited in a Fracture Liaison Service shows that TBS improves the pre- diction of the presence of VFs as compared to lumbar spine aBMD alone, but not to hip aBMD. The same result is observed in patients with aBMD in the non-osteoporotic range. However, in this population, TBS is correlated to the severity of the vertebral fractures, whereas lumbar spine and hip aBMDs are not.

Almost 40 % of our patients having a recent non-traumatic non-vertebral fracture had at least one vertebral fracture, confirming the high prevalence of these VFs not previously diagnosed in this population [33]. Prevalence of VFs differs according to the site of non-vertebral fracture; it is higher in

subjects with hip fractures, explaining the higher prevalence of VFs found in our study as compared to other studies [33]. In these patients with hip fractures, VFs influence functional outcomes [34], illustrating the relevance of the identification of patients with prevalent vertebral fracture.

Our study confirms previous data showing that TBS had an additive value for the discrimination of patients with vertebral fracture when combined with lumbar spine aBMD [24–26]. In patients with rheumatoid arthritis (RA), TBS measured at the lumbar spine has a better discrimination value than lumbar spine aBMD for the prediction of the presence of vertebral fractures. In RA patients with osteopenia, the proportion of patients with vertebral fracture was higher in the lowest tertile of TBS when compared with the highest tertile [29]. In wom- en older than 50 years of the Manitoba study ( n =29 407, mean follow-up of 4.7 years) (10.7 % of major fractures excluding clinical vertebral fractures), TBS and LS aBMD predicted similarly incident fragility fractures (including clin- ical vertebral fractures), and the combination was superior to either measurement alone [27]. In the OFELY cohort (17 % with prevalent fracture), the assessment of TBS in 560 post- menopausal women predicted incident fractures (including clinical vertebral fractures), as well as LS aBMD, but the combination of TBS and LS aBMD added only limited infor- mation in the whole population [28]. In our study on patients with non-vertebral fractures and in the other studies with a lower prevalence of non-vertebral fractures, TBS is superior to LS aBMD for the identification of vertebral fractures.

However, in clinical practice, measurement of aBMD at two sites including the hip is recommended; our data show that TBS does not add information when the hip aBMD is available.

Identification of subjects with aBMD in the non-osteoporotic range at high risk of fractures is a relevant objective. The OFELY study showed that the combination of normal and osteopenic T-scores with the lowest range of TBS improved ROC curves in the patients with aBMD in the non osteoporotic range

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

1 - Specificity

Sensitivity

TB LS Hip TBS + LS TBS + Hip

Fig. 2 Discriminative value of TBS alone and in combination with LS and hip aBMD in patients with aBMD in the non- osteoporotic range

1.08 1.1 1.12 1.14 1.16 1.18 1.2 1.22 1.24

No VF (n=229)

At least one VF (n=133)

Grade 1 (n=57)

Grade 2 (n=47)

Grade 3 (n=29)

TBS values (mean)

*

Fig. 3 TBS values according to the vertebral fractures status. The aster-

isk indicates that TBS value of patients with at least one VF was lower

than the TBS value of patients without VF (p ≤ 0.05). TBS was not

statistically significant among patients with only grade 1, patients with

at least one grade 2 and patients with at least one grade 3

the identification of a significant proportion of women with aBMD in the non-osteoporotic range with incident fragility fracture [28]. In our study on patients with aBMD in the non- osteoporotic range, TBS added information to LS aBMD for the detection of patients with VFs, but not to hip aBMD. This discrepancy among two studies may be related to the difference in clinical fragility, as all our patients already had a non-vertebral fracture. These results were not confirmed if we performed the analysis in patients with major non-vertebral fractures (hip, wrist, humerus).

Detection of patients with VF is not enough for optimal management, as relevant outcomes (such as risk for subsequent fractures and mortality) are related not only to the presence but also to the severity of the vertebral fractures, i.e. their number and grades [9, 10, 32]. TBS did not add information in this matter in our population of patients with fracture. However, correlation between TBS and the number and severity of ver- tebral fractures assessed by the SDI was significant in patients with aBMD in the non-osteoporotic range; we did not find such a correlation with lumbar spine aBMD and hip a BMD. These results were confirmed for patients with major non-vertebral fractures according to the FRAX®. This suggests that in pa- tients with aBMD in the non-osteoporotic range and peripheral fracture, TBS could reflect the vertebral deterioration, more than aBMD does. Using transiliac biopsies and measurement of bone microarchitecture across different grades of VF sever- ity, Genant et al. showed that vertebral fracture severity is associated with progressive deterioration of cancellous and cortical microarchitecture, and that the assessment of VF se- verity is a surrogate of the microarchitecture status indepen- dently of age and lumbar spine BMD [10]. We did not test the predictive value of FRAX® in our population for several reasons. FRAX® has not been proposed for the prediction of the risk of radiographic vertebral fractures. Moreover FRAX®

is used to calculate the risk of fracture and is not useful in the patients who have just made a recent fracture and who are thus at high immediate risk [35]. In this population, it is the severity (presence of vertebral fractures) assessment which is important.

The main limitation of our study is the fracture severity of the population; half of the patients had hip fractures, and these results have been obtained in a population of patients with a recent fragility fracture. Our results cannot be applied to a population with less severe cases, especially patients without fracture.

This study is the first study which shows a relationship between TBS and severity of VFs using VFA. Detection of patients with vertebral fracture is similar for aBMD and TBS in patients with non-vertebral fracture. In patients with aBMD in the non-osteoporotic range, TBS adds information to lum- bar spine aBMD alone (not to hip aBMD) and is related to an index of spine deterioration.

Conflicts of interest None.

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