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Arquivos Brasileiros de Endocrinologia & Metabologia

On-line version ISSN 1677-9487

Arq Bras Endocrinol Metab vol.58 no.5 São Paulo July 2014

http://dx.doi.org/10.1590/0004-2730000003456 

Revisões

Trabecular bone score: perspectives of an imaging technology coming of age

Escore de osso trabecular: perspectivas de um método de imagem em aprimoramento

Barbara C. Silva 1  

John P. Bilezikian 2  

1Medical School, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil

2 Metabolic Bone Diseases Unit, Division of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, United States


ABSTRACT

The trabecular bone score (TBS) is a new method to describe skeletal microarchitecture from the dual energy X-ray absorptiometry (DXA) image of the lumbar spine. While TBS is not a direct physical measurement of trabecular microarchitecture, it correlates with micro-computed tomography (µCT) measures of bone volume fraction, connectivity density, trabecular number, and trabecular separation, and with vertebral mechanical behavior in ex vivo studies. In human subjects, TBS has been shown to be associated with trabecular microarchitecture and bone strength by high resolution peripheral quantitative computed tomography (HRpQCT). Cross-sectional and prospective studies, involving a large number of subjects, have both shown that TBS is associated with vertebral, femoral neck, and other types of osteoporotic fractures in postmenopausal women. Data in men, while much less extensive, show similar findings. TBS is also associated with fragility fractures in subjects with secondary causes of osteoporosis, and preliminary data suggest that TBS might improve fracture prediction when incorporated in the fracture risk assessment system known as FRAX. In this article, we review recent advances that have helped to establish this new imaging technology.

Key words: Trabecular bone score; osteoporosis; fracture risk; bone mineral density; microarchitecture

RESUMO

TBS (do inglês, “trabecular bone score”) é um novo método que estima a microarquitetura óssea a partir de uma imagem de densitometria óssea (DXA) da coluna lombar. Apesar de o TBS não ser uma medida física direta da microarquitetura trabecular, ele correlaciona-se com o volume ósseo, densidade da conectividade trabecular, número de trabéculas e separação trabecular medidos por microtomografia computadorizada (µCT), e com medidas mecânicas da resistência óssea vertebral em estudos ex vivo. Estudos em humanos confirmaram que o TBS associa-se a microarquitetura trabecular e resistência óssea medidas por tomografia computadorizada quantitativa periférica de alta resolução (HRpQCT). Estudos transversais e prospectivos, envolvendo um grande número de indivíduos, mostraram que o TBS é associado com fratura vertebral, de colo de fêmur e com outros tipos de fraturas osteoporóticas em mulheres na pós-menopausa. Dados em homens, apesar de escassos, mostram resultados semelhantes. Além disso, o TBS foi associado a fraturas por fragilidade em indivíduos com diversas causas secundárias de osteoporose e, dados preliminares, sugerem que o uso do TBS pode melhorar a previsão de fratura quando incorporado ao sistema de avaliação de risco de fratura (FRAX). Este artigo faz uma revisão de avanços recentes que têm ajudado a estabelecer esse novo método de imagem.

Palavras-Chave: TBS; osteoporose; risco de fratura; densidade mineral óssea; microarquitetura

INTRODUCTION

Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength, predisposing to an increased risk of fracture (1). The major determinants of bone strength are both bone mineral density (BMD) and skeletal microarchitecture. While BMD can be readily measured by dual-energy X-ray absorptiometry (DXA), the technologies used to determine skeletal microarchitecture, such as histomorphometric analysis and micro-computed tomography (µCT) of the transiliac crest bone biopsy (2,3), high resolution peripheral quantitative computed tomography (HRpQCT) (4), and magnetic resonance imaging (MRI) (5) are not routinely available. To this end, and based upon previous studies using 2D X-ray images to estimate bone microstructure (6-8), the trabecular bone score (TBS), a new approach for assessing skeletal microarchitecture from 2D DXA images (9-11), has been developed.

TBS is an indirect index of trabecular microarchitecture based upon evaluating pixel gray-level variations in the DXA image. TBS is not a direct physical measurement of trabecular microarchitecture, but rather an overall descriptor of bone quality (9). A low TBS value is associated with fewer, less well-connected and more widely distributed trabeculae, while high TBS values are correlated with better trabecular structure (11). TBS can be readily applied to a DXA image through the use of a specific software, and has an attractive feature which is the possibility of being retrospectively calculated from an existing DXA image without the need for further imaging (12).

TRABECULAR BONE SCORE: TECHNICAL ASPECTS

TBS takes into account the pixel gray-level variations in the DXA image. The basic principles of TBS include the following points: a 2D projection image of a porous trabecular structure has a low number of pixel value variations of high amplitude, whereas the projection of a well-structured trabecular bone onto a plane produces an image with a large number of pixel value variations of small amplitude (9). TBS is derived from an experimental variogram of those projected images, calculated as the sum of the squared gray-level differences between pixels at a specific distance and angle. TBS is then calculated as the slope of the log-log transform of the 2D variogram. A low TBS value is associated with worse bone structure, while high TBS values are correlated with better bone structure (11). Table 1 shows the TBS cutoff points in postmenopausal women as suggested by expert opinion (13). Equivalent ranges for TBS in men have not yet been proposed.

Table 1 TBS cutoff points in postmenopausal women proposed by an international working group of TBS users (13) 

TBS value (unitless) Classification
≤ 1.200 Degraded microarchitecture
1.200 to 1.350 Partially degraded microarchitecture
≥ 1.350 Normal

TBS: trabecular bone score.

TBS, typically measured at the lumbar spine (LS), has a short-term in vivo precision of 1.12% - 2.1% (14-17). The TBS result is given for each vertebra and for the overall lumbar spine, as is done for the calculation of BMD. Fractured vertebrae are excluded from the TBS calculation. While a previous study has suggested that osteoarthritic changes of the LS have little effect on TBS (14), vertebrae with overt osteoarthritic changes are also excluded from the TBS analysis.

Several technical limitations of TBS analyses should be noted. As TBS is computed from DXA images, any image “noise” can influence the TBS evaluation. Additionally, TBS results may not be comparable across different densitometers, unless a TBS cross-calibration process utilizing a gray-level TBS phantom is utilized. Finally, excessive soft tissue in the abdomen, overlying the region of interest, may reduce the TBS estimate. In order to mitigate this problem in vivo, the TBS calculation is adjusted for body mass index (BMI). The use of BMI, however, is limited since it can not distinguish central abdominal weight accumulation, which would influence TBS derived from LS DXA, from adiposity at other sites. Of note, the adjustment in TBS for BMI is optimized when BMI is between 15 and 35 kg/m2.

ASSOCIATION OF TBS WITH 3D MEASUREMENTS OF TRABECULAR MICROSTRUCTURE AND BONE STRENGTH

TBS results derived from both simulated 2D-projection µCT images and LS DXA images were compared, in ex vivo studies, with 3D indices of bone microarchitecture assessed by µCT (9-11,18). In general, TBS directly correlates with µCT measures of bone volume fraction (BV/TV) (10,11,18), connectivity density (Conn. D) (10,11), and trabecular number (Tb.N) (10,11), and inversely associated with µCT indices of trabecular separation (Tb.Sp) (10,11) and structural model index (SMI) (18). Surprisingly, TBS was either not associated (18) or negatively correlated (11) with trabecular thickness (Tb.Th). These reported associations between TBS and µCT parameters were not adjusted for age, and it remains unclear whether or not age-adjusted correlations would remain significant. Of note, TBS was also correlated with vertebral mechanical behavior in an ex vivo study of 16 human L3 lumbar vertebrae (18).

Studies by our group examined, for the first time in vivo, the correlations between TBS and 3D microarchitecture parameters (19,20). We assessed TBS from spine DXA images and correlated it with HRpQCT measurements at the radius and tibia in 22 postmenopausal women with primary hyperparathyroidism (PHPT) and in 115 pre- and postmenopausal Chinese-American and Caucasian women. The study of subjects with PHPT revealed significant correlations between LS TBS and HRpQCT measurements of Tb.N (r = 0.505), Tb.Sp (r = -0.492), cortical thickness (r = 0.453), volumetric densities (r = 0.476 to 0.507), and whole bone stiffness (r = 0.442) at the radius (all p < 0.05) (19). TBS was also positively associated with measures of cortical thickness (r = 0.515), volumetric densities (r = 0.471 to 0.619), and whole bone stiffness at the tibia (r = 0.516; all p < 0.05), but its association with Tb.N and Tb.Sp was significant only after controlling for body weight (r = 0.573 and r = -0.524, respectively). TBS was not associated with Tb.Th or trabecular stiffness at either the radius or the tibia.

In the study of Chinese-American and Caucasian women (71 pre- and 44 postmenopausal), all HRpQCT indices at the radius and tibia, except cortical thickness at the radius and Tb.Th at the tibia, were correlated with LS TBS. These correlations, however, were weak to moderate (r = 0.20 to 0.52; all p < 0.05) (20). In this cohort, we have also examined the associations between LS TBS and indices of central quantitative computed tomography (QCT) at the LS and femur. TBS was directly associated with QCT parameters of LS trabecular volumetric BMD (r = 0.664), with trabecular and cortical volumetric densities and with an estimate of cortical thickness at the femoral neck (r = 0.641, 0.346, and 0.540 respectively) and total hip (r = 0.547, 0.491, and 0.541, respectively) (all p < 0.001). Adjustment for weight or BMI did not change the direction or significance of the correlations. The combination of TBS with LS aBMD better predicted the variance in QCT measures than aBMD alone.

More recently, the association of TBS with HRpQCT indices was investigated in 72 healthy pre-menopausal women (mean age 33.8 years) (21). TBS was associated with trabecular volumetric BMD (r = 0.49 to 0.57), Tb.N (r = 0.43 to 0.58), Conn.D (r = 0.43 to 0.46), and Tb.Sp (r = -0.43 to -0.57), at the radius and tibia (all p < 0.01). There was a weak correlation between TBS and Tb.Th at the radius (r = 0.37; p < 0.01), but not at the tibia. TBS was either weakly or not associated with HRpQCT measures of cortical density, thickness and porosity.

RELATIONSHIP OF TBS WITH AGE AND MAJOR CLINICAL RISK FACTORS

TBS tends to decline with age as shown in cross-sectional studies (14,22,23). Dufour and cols. observed, in 5,942 Caucasian French women (BMI < 40 kg/m2), a linear decline of 14.5% in L1-L4 TBS between 45 and 85 years of age (14). Age related declines in LS BMD and TBS were also observed in a large cross-sectional study of 29,407 women ≥ 50 years from the province of Manitoba, Canada (22). Similarly, a negative correlation between L2-L4 TBS and age (r = -0.39, p < 0.001) was observed in 4,907 Lebanese women from 20 to 90 years of age (23).

In addition, TBS was associated with many of the risk factors that are predictive of osteoporotic fractures (22). Reduced TBS (lowest versus highest tertile) was associated, after adjusting for age and bone preserving treatment, with prior major fracture, rheumatoid arthritis, chronic obstructive pulmonary disease, recent glucocorticoid use, alcohol or other substance abuse, and higher BMI.

ASSOCIATION OF TBS WITH FRACTURE RISK

A number of cross-sectional (24-29) and prospective (15,16,30,31) studies have shown an association between LS TBS and vertebral, hip, and other types of osteoporotic fractures in postmenopausal women. A recent published cross-sectional study has also demonstrated that TBS is associated with fractures in men (32).

Cross-sectional studies

Table 2 summarizes the data from cross-sectional studies. The studies in postmenopausal women were, in general, retrospective case-control studies, in which cases were women with vertebral fractures [confirmed either by radiographs or vertebral fracture assessment (VFA)] or with a history of hip (27) or other types of osteoporotic fractures (24-26,28,29). Control groups comprised women without evidence of any type of fragility fracture either not matched for age or BMD with cases (27,29), or matched with cases for age (25,26,28) or for age and BMI (24). Overall, TBS was significantly lower in cases than in controls, and both TBS and any BMD measurement were associated with fractures (Table 2). In a few studies, the combination of TBS with LS BMD was a better predictor of vertebral fractures than LS BMD alone (25,26).

Table 2 Summary of cross-sectional studies 

Citation Participants Outcome measure OR (95% CI) for LS TBS OR (95% CI) for LS BMD
Pothuaud and cols. 2009 (24) 135 postmenopausal women (45 Fx subjects and 90 age- and LS BMD-matched controls) For vertebral Fx analyses: (20 Fx subjects and 60 matched controls) Vertebral, hip and other types of osteoporotic Fx (confirmed by radiographs) Unadjusted: All Fx: 1.95 (1.31–2.89); Vertebral Fx: 2.66 (1.46–4.85) Not applicable (cases and controls were matched for BMD)
Winzenrieth and cols. 2010 (25) 243 postmenopausal women with osteopenia at LS (81 subjects with vertebral Fx and 162 age-matched controls) Vertebral Fx (on radiographs) Body weight-adjusted: Vertebral Fx: 1.97 (1.31–2.96) Body weight-adjusted: Vertebral Fx: 1.63 (1.20–2.22)
Rabier and cols. 2010 (26) 168 postmenopausal women with T-score < -1.0 at any site (42 subjects with vertebral Fx and 126 age-matched controls) Vertebral Fx (on radiographs) Body weight-adjusted: Vertebral Fx: 3.81 (2.17–6.72) Body weight-adjusted: Vertebral Fx: 2.48 (1.61–3.83)
Del Rio and cols. 2013 (27) 191 postmenopausal women (83 Fx subjects and 108 not matched controls) Osteoporotic femoral neck Fx (by self-report) Age-adjusted: Femoral neck Fx: 1.71 (1.15-2.79) Age-adjusted: Femoral neck Fx: 1.94 (1.35–2.79)
Krueger and cols. 2014 (28) 429 postmenopausal women (158 Fx subjects, including 91 vertebral Fx, and 271 age-matched controls) Low-energy Fx (by self-report) and vertebral Fx (on VFA) Age and BMI-adjusted: All Fx: 2.46 (1.9–3.1) Vertebral Fx: 2.49 (1.9-3.3) Age and BMI-adjusted: All Fx: 1.36 (1.2–1.6) Vertebral Fx: 1.36 (1.1–1.7)
Lamy and cols. 2012 (29) 631 postmenopausal women (8.4% with vertebral Fx, 17% with major osteoporotic Fx, and 26% with at least 1 osteoporotic Fx) Low-energy Fx (by self-report) and vertebral Fx (on VFA) Age and BMI-adjusted: All Fx: 1.4 (1.1–1.7) Vertebral Fx: 2.0 (1.4–3.0) Major osteoporotic Fx: 1.9 (1.4–2.5) Age and BMI-adjusted: All Fx: 1.3 (1.1–1.6) Vertebral Fx: 1.8 (1.2–2.5) Major osteoporotic Fx: 1.6 (1.2–2.1)
Leib and cols. 2013 (32) 180 men > 40 years old (45 Fx subjects, and 135 age- and LS BMD-matched controls) Low-energy Fx (by self-report) Unadjusted: All Fx: 1.55 (1.09–2.20) Not reported
Nassar and cols. 2014 (33) 362 men and women > 50 years old (77% women) with a low-trauma non-vertebral Fx, including 133 with at least one concurrent vertebral Fx Vertebral Fx (on VFA) Subjects with both non-vertebral and vertebral Fx were compared to subjects with non-vertebral Fx only ORs not reported (see text for detailed results)

TBS: trabecular bone score; OR: odds ratio; Fx: fracture. LS: lumbar spine.

Data in men, while limited, are similar. A retrospective non-randomized case-control study enrolled 180 men ≥ 40 years old (BMI ranging from 17 to 36 kg/cm2), 45 of whom had a history of a low-energy fracture after the age of 40 (32). Study subjects had sustained 59 fractures, including spine (34%), hip (14%), forearm (19), ankle (13%), humerus and rib (5% each) fractures. The control group consisted of 135 age- and LS BMD-matched men without evidence of low-energy fractures by self-report. TBS was lower in men with than in those without fractures (1.102 ± 0.129 vs. 1.159 ± 0.134, respectively; p = 0.013). Unadjusted odds ratios (ORs) for osteoporotic fractures and vertebral fracture (n = 17) were, respectively, 1.55 (95% CI 1.09–2.20), and 2.07 (95% CI 1.14–3.74), for each SD decline in TBS. It is noteworthy that the control men had a TBS score that would be considered to be low for women, underscoring the point that there are not normal TBS standards yet for men.

LS TBS in a group of men and women was also examined in a cross-sectional study that included 362 subjects over 50 years old (77% women, mean age 74 ± 12 years) who had been hospitalized, within 4 to 90 days prior to the enrollment, for the treatment of a low-trauma non-vertebral fracture (33). Vertebral fractures were then assessed by VFA, and subjects were allocated to one of 2 groups based on the absence (n = 229) or presence of at least one vertebral fracture (n = 133; 57 grade 1, 47 grade 2, and 29 grade 3). TBS was significantly lower in patients with vertebral and non-vertebral fractures than in those with non-vertebral fractures only (1.157 ± 0.108 vs. 1.227 ± 0.107; p < 0.0001), as was BMD T-score at the LS, femoral neck, and total hip. TBS, LS BMD and total hip BMD predicted vertebral fractures equally well, with areas under the receiving operator curve (AUCs) of 0.677, 0.669, and 0.692, respectively. The combination of TBS with LS BMD improved vertebral fracture discrimination as compared to LS BMD alone (p = 0.043), but not with total hip alone (p = 0.327). In the 173 subjects with BMD T-scores in the non-osteoporotic range, among whom 38 had a prevalent a vertebral fracture, TBS was a better discriminator of vertebral fractures than LS BMD alone (AUCs of 0.671 vs. 0.541; p = 0.035), but similar to total hip BMD alone (AUCs of 0.670 vs. 0.585; p = 0.264). The small number of cases, however, limits this analysis.

Prospective studies

Data from prospective studies are summarized in table 3 (15,16,30,31). The Manitoba study was the largest one to examine the ability of LS TBS to predict fracture risk (16). The study enrolled 29,407 women ≥ 50 years from the Canadian province of Manitoba, and showed that LS TBS at baseline predicted new clinical vertebral, hip and major osteoporotic fractures over a mean follow-up of 4.7 years. The combination of TBS with any BMD measurement (LS, femoral neck or total hip) was a better predictor of osteoporotic fracture than BMD alone (p < 0.0001). However, the AUC for TBS + BMD was only slightly greater than the AUC for BMD alone (+ 0.02, + 0.01, and + 0.01, compared to LS, femoral neck and total hip, respectively). Of note, LS TBS remained a predictor of fracture even after adjusting for BMD and additional clinical risk factors.

Table 3 Summary of prospective studies 

Citation Participants Mean follow-up period Outcome measure Risk ratio (95% CI) for LS TBS Risk Ratio (95% CI) for LS BMD Risk Ratio (95% CI) TH BMD
Manitoba Hans and cols. 2011 (16) 29,407 postmenopausal women ≥ 50 years (5.7% (1,668) of subjects presented incident osteoporotic Fx, including 1.5% clinical vertebral and 1.0% hip Fx) 4.7 years Incident clinical vertebral, hip and major osteoporotic Fx (assessed in health service records by fracture codes) Age-adjusted: Clinical vertebral Fx: HR = 1.45 (1.32–1.58); Major osteoporotic Fx: HR = 1.35 (1.29–1.42) Hip Fx: 1.46 (1.30–1.63) Age-adjusted: Clinical Vertebral Fx: HR = 1.72 (1.55–1.91); Major osteoporotic Fx: HR = 1.47 (1.39–1.55) Hip Fx: 1.31 (1.16–1.48) Age-adjusted: Clinical Vertebral Fx: HR = 1.75 (1.58–1.96); Major osteoporotic Fx: HR = 1.67 (1.58–1.76) Hip Fx: 2.55 (2.22–2.93)
OFELY Boutroy and cols. 2013 (30) 560 postmenopausal women (94 subjects had an incident fragility Fx at any site) 8.0 years Incident clinical and radiographic vertebral Fx and fragility Fx at any site, except head, toes and fingers (all Fx were confirmed by radiographs) Adjusted for age, weight and prevalent FX at baseline: Any type of osteoporotic Fx: OR = 1.34 (1.04-1.73) Adjusted for age, weight and prevalent FX at baseline: OR = 1.30 (1.06-1.58) Adjusted for age, weight and prevalent FX at baseline: OR = 1.99 (1.52-2.62)
JPOS Iki and cols. 2014 (31) 665 postmenopausal women (92 subjects had an incident vertebral Fx) 8.3 years Incident vertebral Fx (by VFA) Age- and LS BMD-adjusted: Vertebral Fx: OR =1.54 (1.17-2.02) Age- and TBS-adjusted: Vertebral Fx: OR = 1.27 (1.02, 1.59) Not measured
OPUS Briot and cols. 2013 (15) 1,007 postmenopausal women > 50 years (8.1% (82) e 4.6% (46) of subjects presented with incident osteoporotic Fx, and vertebral Fx, respectively) 6.0 years Incident vertebral Fx (by radiographs) and low-trauma FX (by self-report) Unadjusted: Vertebral Fx: OR = 1.54 (1.17-2.03) Clinical osteoporotic Fx: OR = 1.62 (1.30-2.01) Unadjusted: Vertebral Fx: OR =1.75 (1.25-2.48) Clinical osteoporotic Fx: OR =1.47 (1.16-1.89) Unadjusted: Vertebral Fx: OR = 1.73 (1.26–2.38) Clinical osteoporotic Fx: OR = 1.65 (1.30–2.11)

TBS: trabecular bone score; BMD: bone mineral density; OR: odds ratio; HR: hazard ratio; Fx: fracture; LS: lumbar spine; TH: total hip.

In another prospective study, Boutroy and cols. (30) evaluated 560 postmenopausal Caucasian women from the OFELY cohort, and showed that TBS and LS BMD predicted any type of fragility fracture equally well. The association between TBS and fracture remained even after controlling for age, body weight and prevalent fracture at baseline. Thirty-seven percent of fractures occurred in women with LS TBS < 1.209 (lowest quartile), and having a TBS below that threshold was a predictor of fracture risk in non-osteoporotic women [OR 2.75 (95% CI 1.47-5.17)], but not in osteoporotic subjects.

In the prospective study by Iki and cols. (31), TBS was a predictor of incident vertebral fractures on VFA (Table 3). LS BMD, TBS, and LS BMD + TBS predicted vertebral fractures equally well, with AUCs of 0.673, 0.682, and 0.700, respectively. There was a higher incidence rate of vertebral fracture in the lower TBS tertile group in each BMD stratum.

Finally, the Osteoporosis and Ultrasound Study (OPUS) (15) examined the added value of TBS to BMD for prediction of fractures in 1,007 postmenopausal women (Table 3). Women with incident fractures were older than non-fractured subjects. The AUCs for TBS, BMD (at LS, femoral neck, and total hip), and the combination of TBS with any BMD measurement were similar. The performance of TBS, BMD and TBS + BMD for fracture prediction was examined using reassignment analysis assessed by net reclassification improvement (NRI). While for prediction of incident clinical osteoporotic fractures the combination of TBS with LS BMD was similar to LS BMD alone (NRI = 10.5%, p = 0.105), for prediction of vertebral fractures, TBS and LS BMD together increased the performance over LS BMD alone (NRI = 8.6%, p = 0.046).

ROLE OF TBS IN SECONDARY OSTEOPOROSIS

Diabetes mellitus

A retrospective cohort study examined, in the Manitoba cohort described above, 29,407 women ≥ 50 years, including 2,356 (8.1%) who had diabetes mellitus (34). While BMD at all sites was higher among those with diabetes, TBS was consistently lower, in unadjusted and adjusted models (all p < 0.001). Over a mean follow-up period of 4.7 years, and after covariate adjustment, the risk for major osteoporotic fracture was 49% greater (HR 95% CI 1.27–1.74) in women with diabetes than in those without diabetes. While BMD did not predict fracture among the diabetes cohort, TBS was a BMD-independent predictor of fracture, and predicted fractures in those with diabetes (adjusted HR 1.27, 95%CI 1.10-1.46) as well as in nondiabetic women (HR 1.31, 95%CI 1.24-1.38).

Primary hyperparathyroidism

The association of vertebral fracture and TBS was examined in a cross-sectional study of 73 postmenopausal women with primary hyperparathyroidism (PHPT) compared to 74 age-matched healthy women (35). While LS BMD and femoral neck BMD were similar between the groups, TBS was significantly lower in subjects with PHPT (1.19 ± 0.10) than in controls (1.24 ± 0.09, p < 0.01). Total hip and 1/3 radius BMDs were also lower in PHPT subjects (p < 0.01). In the PHPT group, TBS was significantly lower in subjects with (n = 29) than in those without (n = 44) radiographic vertebral fractures (1.14 ± 0.10 vs. 1.22 ± 0.10, respectively; p < 0.01), with an AUC of 0.716 (95%CI: 0.590-0.841; p = 0.002). PHPT patients with (n = 18) and without (n = 55) non-vertebral fractures had similar TBS values.

A prospective observational study has also evaluated TBS in patients with PHPT (n = 92; 74 females; mean age 62.7 ± 10.1 years) and 98 control subjects (36). Vertebral fractures were assessed by radiographs. PHPT subjects had, at baseline, a lower TBS Z-score (-2.39 ± 1.79), and higher prevalence of vertebral fracture (43.5%) than controls (Z-score of -0.98 ± 1.07 and 8.2%, respectively, both p < 0.0001). Compared to controls, subjects with PHPT also had significantly lower BMD measurements at all sites. Among subjects with PHPT, each SD decline in TBS conferred 40% greater risk of vertebral fracture (OR 1.4, 95%CI 1.1-1.9, p = 0.02), regardless of LS BMD, age, BMI and gender. In the PHPT group, 20 subjects who underwent parathyroidectomy were compared with 10 non-surgically treated cases after 24 months. At month 24, TBS improved in surgically treated patients, whereas it remained stable in conservatively treated subjects. A recent study confirmed that TBS improves at 1 year following parathyroidectomy in subjects with PHPT (37).

Rheumatoid arthritis

A cross-sectional study evaluated 185 women (mean age 56 ± 14 years) known to have rheumatoid arthritis (RA) for 15.5 ± 9.9 years (38). Approximately 60% of the study population (n = 112) was in use of glucocorticoids (mean daily dose of 6.4 mg equivalent to prednisone). Both BMD T-scores and TBS were significantly lower among patients with vertebral fracture (n = 33; 17.8%) than in non-fractured individuals. The AUCs for vertebral fracture were similar for TBS (0.704), LS BMD (0.621), femoral neck BMD (0.727), and total hip BMD (0.719).

Adrenal incidentaloma and subclinical hypercortisolism

The association between TBS and fractures was explored in 102 patients with adrenal incidentaloma [AI; 63 females; 34 with subclinical hypercortisolism (SH)], and 70 matched controls (39). In patients, vertebral fractures were assessed by X-rays. Z-scores were used to report TBS and BMD. TBS (-3.18 ± 1.21) was lower in subjects with SH than in patients without SH (-1.70 ± 1.54, p < 0.0001) or controls (-1.19 ± 0.99, p < 0.0001), as was LS BMD and total femur BMD. A low TBS, as defined by a TBS Z–score < -1.5, was associated with the presence of vertebral fracture, regardless of age, BMI, and gender [OR = 4.8 (95% CI 1.85–12.42), p < 0.001]. A subgroup of 40 patients was followed for 24 months, and among them, TBS predicted the occurrence of a new fracture even after adjusting for LS BMD, BMI, and age (OR = 11.2; 95%CI, 1.71–71.41, p < 0.012).

Other conditions

A recent prospective study evaluated the effect of growth hormone (GH) replacement on TBS in 147 subjects with growth hormone deficiency (GHD; mean age 35.1 years; 84 males) (40). Compared to baseline, there was a significant increase in BMD at LS (+14%) and total femur (+7%) at 2 years of GH replacement (both p ≤ 0.001). TBS, obtained in a subgroup of 32 subjects with GHD, was also improved after 2 years of GH replacement. However, the reported result (4% gain at 2 years) was recorded at the level of L4 only, which limits this analysis.

Data reported in abstracts also showed that TBS is related to fractures in individuals with chronic kidney disease (41) and on long-term glucocorticoid (GC) therapy (42). The study of 47 women with CKD (grade not reported), and 94 healthy women (73% postmenopausal) showed that, compared to controls, subjects with CKD have reduced TBS (p < 0.0001) (41). In the CKD group, while no difference was seen for BMD (p = 0.46), TBS was significantly lower in subjects with a prior fracture (number of fractures not reported) than in non-fractured subjects (p = 0.034), with an unadjusted OR of 2.5 (95% CI 1.02-6.15), and AUC of 0.756 (0.609-0.870). Age- or BMI-adjusted ORs were not reported.

Finally, the impact of long-term GC therapy on TBS was explored in 136 women, aged 45 to 80 years, treated with GCs (≥ 5 mg/day) for ≥ 1 year (42). Compared with the age-matched normal values, GC-treated patients had a 4% decrease in TBS (p < 0.0001), but no change in BMD (p = 0.49). In GC treated-patients, the age-adjusted OR for TBS was 1.62 (95% CI 1.02-2.59) for vertebral fracture and 1.60 (95% CI 1.04–2.47) for osteoporotic peripheral fracture. The association between fracture risk and BMD was not significant.

EFFECT OF OSTEOPOROSIS THERAPY ON TBS

The impact of different osteoporosis therapy on TBS has been evaluated (17,43-47) and the results are summarized in table 4. In general, the change in TBS in response to osteoporosis therapy was of smaller magnitude than the change in LS BMD. Additionally, the change in TBS appears to be a function of the therapeutic class, with greater improvements observed upon treatment with teriparatide and strontium ranelate. Overall, the treatment with bisphosphonates led to a slight increase or maintenance of TBS over ~3 years (Table 4). Further research is needed to determine the role of TBS for monitoring treated or untreated osteoporosis and, if this is class-specific, which agents are more likely to show increases in TBS.

Table 4 Summary of studies that evaluated the impact of different osteoporosis therapies on LS TBS 

Citation Participants Mean follow-up period Treatment Number of subjects per treatment group Percent change in LS TBS relative to baseline Percent change in LS BMD relative to baseline
Krieg and cols. 2013 (43) 1,684 women ≥ 50 years old 3.7 years Antiresorptive agents# 534 +0.2 ± 1.9 % / year* +1.86 ± 1.8 % / year*
Untreated subjects 1,150 -0.31 ± 0.06 % / year* -0.36 ± 0.05 % / year*
Popp and cols. (17) 2013 Subset of 107 postmenopausal women from the HORIZON trial 3 years Zoledronic acid 54 At 3 years: +1.41 ± 0.79%* At 3 years: +9.58 ± 0.6%*
Placebo 53 At 3 years: -0.49 ± 0.62% At 3 years: +1.38 ± 0.9%*
Kalder and cols. 2014 (44) Subset of 36 postmenopausal women with hormone-sensitive primary breast cancer from the TEAM trial 2 years Tamoxifene 17 At 2 years: +3.3 ± 1.6%* At 2 years: +1.9 ± 0.8%*
Exemestane 19 At 2 years: -2.3 ± 1.1%* At 2 years: -5.3 ± 0.9%*
McClung and cols. 2012 (45) 285 postmenopausal women from the FREEDOM trial, with LS or total hip BMD T-score < -2.5, and with both > -4.0 3 years Denosumab 157 At 3 years: +2.4%* At 3 years: +9.8%*
Placebo 128 At 3 years: -0.7% At 3 years: +0%
Günther and cols. 2012 (46) 82 postmenopausal women with osteoporosis (open label study) 2 years Teriparatide 82 At 2 years: +4.3%* At 2 years: +7.6%*
Hans and cols. 2012 (47) Subgroup of a 79 postmenopausal women with osteoporosis included in a double blind, double dummy study randomized to strontium ranelate or alendroante 2 years Strontium ranelate Not reported At 2 years: +3.1%* At 2 years: +9.0%*
Alendronate At 2 years: +1.0% At 2 years: +7.6%*

TBS: trabecular bone score; LS: lumbar spine; BMD: bone mineral density; HORIZON trial: Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly; FREEDOM trial: Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months; TEAM Study: Tamoxifene Exemestane Adjuvant Multinational Study.* P < 0.05 compared to baseline. # 86% bisphosphonates, 10% raloxifene, and 4% calcitonin. @ Data reported in abstracts.

CONCLUSIONS – TRABECULAR BONE SCORE: FACTS AND FUTURE

TBS is an indirect index of bone microarchitecture that has a major clinical advantage of being readily available from DXA images. It is associated with 3D direct measures of trabecular microarchitecture, and with direct and indirect measures of bone strength. TBS declines with age, and is correlated with major clinical risk factors that are predictive of osteoporotic fractures. Several cross-sectional and prospective studies, involving a large number of postmenopausal women, have confirmed the association of TBS with vertebral and non-vertebral fractures. Data in men, while much less extensive, show similar findings. There is also evidence that, while TBS and LS BMD predict fracture equally well, TBS slightly improves fracture prediction when combined with any BMD measurement.

Indeed, these results provide support for utilizing TBS in conjunction with BMD to estimate fracture risk. This approach may be especially useful in individuals with BMD values in the osteopenic range. This is of interest, since most individuals with fragility fractures will have BMD values not in the osteoporotic range but rather in the osteopenic or even normal range (48,49). This observation could be explained by other aspects of bone quality, such as bone microarchitecture, or even by readily assessable clinical risk factors that increase fracture risk independent of the BMD measurement. Thus, for those with BMD in the osteopenic range, TBS, when used in combination with the fracture risk assessment system (FRAX®), which incorporates clinical risk factors along with BMD (50), may have a role in fracture risk assessment. In fact, preliminary data have shown that TBS may improve fracture prediction when used in combination with FRAX® (51,52).

In addition to these data in primary osteoporosis, TBS was also shown to be associated with fractures in subjects with diverse secondary causes of osteoporosis. This is particularly attractive in those conditions in which the increase in fracture risk is largely independent of BMD by DXA, such as diabetes mellitus or long-term GC exposure. Similarly, in asymptomatic PHPT, the trabecular bone as assessed by LS BMD appears relatively well preserved, whereas epidemiological studies show increased fracture risk in vertebral and non-vertebral sites. While these unexpected findings between fracture risk and BMD by DXA may be explained by an inferior bone microarchitecture, current methods to assess microstructure are not routinely available, so that TBS could be used, combined with BMD, for fracture-risk assessment in such cases of secondary osteoporosis.

Finally, current data do not support the use of TBS to estimate antifracture effectiveness of diverse osteoporosis treatments, and further research is needed to evaluate the value of TBS for monitoring treatment effect.

There are a number of areas for future research and delineation. A well-established TBS cut-point that classifies normal and abnormal TBS values has not yet been defined. The TBS reference range that has been proposed so far (Table 1), which applies to postmenopausal women only, was recommended by a working group of TBS users. This definition remains to be definitively established across age and gender. Also, as noted before, the use of TBS in subjects with BMI below 15 kg/m2 and over 35 kg/m2 has not been validated.

Additionally, while there are extensive data establishing an association between TBS and fracture risk in postmenopausal women, data in men are limited. Of note, when TBS is derived from DXA images obtained in GE-Lunar densitometers, TBS appears to be lower in men than in women, which is surprising given the previous observations of better trabecular microarchitecture in aging men than in women by histomorphometry and HRpQCT (53,54).

Finally, despite the strong correlations between TBS and 3D measures of trabecular microarchitecture in ex vivo studies, studies in vivo have shown only moderate correlations. Additionally, the majority of the studies did not find an association between TBS and trabecular thickness, indicating that TBS may not fully capture some aspects of bone microstructure assessed by higher resolution imaging modalities.

In conclusion, current data on lumbar spine TBS are promising. If further studies establish TBS cut-points across age and gender, and confirm that TBS improves fracture prediction from FRAX, TBS could become a valuable adjunctive clinical tool in fracture risk assessment, assisting in therapeutic decision-making particularly in those at intermediate risk for fracture.

Acknowledgments

: Barbara C. Silva and John P. Bilezikian met guidelines for authorship: drafting the manuscript and approving its final version. Supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes) (to Barbara C. Silva), and National Institutes of Health grant DK32333 (to John P. Bilezikian).

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Received: May 12, 2014; Accepted: May 22, 2014

Correspondence to: John P. Bilezikian Department of Medicine, College of Physicians and Surgeons 630 W. 168th Street, New York, NY 10032 jpb2@columbia.edu

Disclosure: no potential conflict of interest relevant to this article was reported.

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