Bone density and geometry in assessing hip fracture risk in postmenopausal

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1 The British Journal of Radiology, 80 (2007), Bone density and geometry in assessing hip fracture risk in postmenopausal women S GNUDI, MD, E SITTA, MD and N FIUMI, MD Modulo Dipartimentale di Medicina Interna, Istituti Ortopedici Rizzoli, Via Pupilli 1, Bologna, Italy ABSTRACT. We used femoral neck structural parameters (FNSPs), calculated from bone mineral density (BMD) measurements of the femoral neck by dual X-ray absorptiometry, to discriminate osteoporotic fractures of the proximal femur in postmenopausal women. We compared 1646 women without fracture and 429 women with hip fractures, including 273 with femoral neck (FN) and 156 with trochanter (TR) fractures. The association between the studied parameters and the fractures was modelled using multiple logistic regression, and included age, height and weight. Fracture-predicted probability (FPP) was also calculated for each predictor tested. Receiver operating characteristic (ROC) curve areas with their standard errors (SEs) were calculated for the fracture status, having the calculated FPP as a test variable. The areas were compared by the Hanley McNeil test. Hip fracture had lower BMD, cross-sectional area (CSA), section modulus (SM) and cortical thickness (CT), and higher buckling ratio (BR), than controls. To the same extent as FN BMD, BR best predicted the risk for each fracture, showing ROC curve areas of (SE 0.011) for hip fracture, (SE 0.014) for FN fracture, and (SE 0.016) for TR fracture. The association of BR with fracture risk did not differ from that of FN BMD, which has a ROC curve area of (SE 0.011) for hip fracture, (SE 0.014) for FN fracture, and (SE 0.016) for TR fracture. Both FN BMD and BR predicted TR fracture significantly better than they did FN fracture. FNSPs, although interesting in understanding the biomechanics of bone fragility, do not appear to add diagnostic value to the simple measurement of BMD. Received 17 October 2006 Revised 17 January 2007 Accepted 30 January 2007 DOI: /bjr/ The British Institute of Radiology Osteoporotic fractures are an increasing problem for healthcare services because their incidence is high, and therefore they are expensive to treat [1, 2]. Therefore, effective methods are needed to diagnose those at risk in order to target fracture prevention treatment [3 5], particularly with regard to hip fracture, which is the osteoporotic fracture with the worst outcome [6, 7]. Bone mineral density (BMD) has been found to be the best predictor of osteoporotic fracture [8, 9], although other risk factors [10, 11] have also been shown to be important, such as those leading to an increase in the propensity to fall [12 15]. For hip fracture in women, proximal femur geometry (PFG) has also been highlighted as a risk factor [16 19], with particular reference to the hip axis length (HAL) [16], the neck shaft angle (NSA) [18] and the femoral neck diameter (FND) [19]. Recently, femoral neck structural parameters (FNSPs) have also been tested for association with hip fracture risk [20 24]. However, whether their ability to predict hip fracture is better than that of BMD, or whether they can improve the hip fracture risk assessment of the latter parameter, is still debated. As FNSPs are estimable from dual X-ray absorptiometry (DXA), we evaluate in this study the ability of FNSPs to assess hip fracture risk in comparison with, and/or in addition to, BMD, in order to add to the estimation of their potential in predicting future fracture. Address correspondence to: Dr Saverio Gnudi, Istituti Ortopedici Rizzoli, Via Pupilli 1, Bologna, Italy. saverio. gnudi@ior.it Methods and materials After local ethics committee approval, we examined the data of 2075 Italian post-menopausal women living in the district of Bologna who were referred to our centre for DXA examination. They consisted of 1646 consecutive outpatients without medical history of previous fracture, and 429 consecutive women with hip fracture either femoral neck (FN) (n5273) or trochanter (TR) (n5156) fracture which occurred within 30 days of DXA examination. Subjects having a reported history of malignancies, rheumatoid arthritis, hyperthyroidism, hyperparathyroidism, heart, lung, liver or kidney failure, Paget s disease of bone, and those treated with corticosteroids were excluded from the present study. Age, age at menopause, height, weight, BMD, bone mineral content (BMC) and the area of the measured region of interest were recorded for each subject and included in the study data. A pencil-beam densitometer (Norland XR 36; Coopersurgical Co, Fort Atkinson, WI) was used to perform DXA scans of the FN region of the hip in all of the women and to measure their BMD. The women were positioned on the scanning table according to the manufacturer s recommendations with legs internally rotated, which was standardized by using the Norland intra-rotating legs fixture. Densitometry measurements were performed on the left hip or on the contralateral one in patients who had had a fracture of the left hip. At our centre, the repeated measurement coefficient of variation of the FN BMD was 1.9% (standard deviation (SD)50.7) [25]. Calculation of the FNSP was based on the The British Journal of Radiology, November

2 S Gnudi, E Sitta and N Fiumi assumption that density of fully mineralized bone is 1050 mg cm 23 [26] and that the cortical mass proportion (CMP) in the FN is 60% [27 29]. FND was estimated by dividing the area of the FN region by the constant height of 1.5 cm of the region of interest. Subsequently, the structural parameters of the femoral neck geometry (i.e. the cross-sectional area (CSA), the cross-sectional moment of inertia (CSMI), the section modulus (SM), the cortical thickness (CT) and the buckling ratio (BR)) were calculated according to the equations described in a paper by Filardi et al [30]. Statistics The unpaired t-test was used to compare variables between women with hip fractures and those without. One-way analysis of variance (ANOVA) and the Scheffé post hoc test for pairwise comparisons were used to compare variables among women with TR fractures, FN fractures and those without fractures. Pearson s correlation was used to assess the relationship between the studied variables. The association between the BMD and FNSPs (standardized for 1 SD change from the healthy subjects mean value) when tested as predictors, and the dependent variable hip fracture status, were modelled using multiple logistic regression adjusting for age, height and weight. The relative probabilities of fracture were expressed by an odds ratio (OR). The group of predictors giving the best fracture prediction was modelled by logistic regression using the stepwise forward method. From the logistic equations, the subjects fracture-predicted probability (FPP) was calculated for each tested predictor after adjusting for age, weight and height. Receiver operating characteristic (ROC) curves were then constructed by using the presence/absence of fracture as the status variable and the calculated FPP as the test variable. The calculated areas of different ROC curves were compared using the Hanley McNeil [31, 32] test, in order to assess the ability of the fracture predictors to discriminate between subjects with and without fracture. Results The women who had FN or TR fracture were older and lighter than those without fracture. They also had lower BMD, CSA, SM and CT, and higher BR, than controls (Table 1). Women with TR fracture were also smaller and had lower CSMI than controls and had lower BMD, CSA, CSMI, SM and CT, and higher BR, than those with cervical fracture. FN BMD was positively correlated with CT (r50.99), CSA (r50.91), SM (r50.63) and CSMI (r50.43), and negatively with BR (r5 0.90) (p,0.001 for each structural parameter s correlation with FN BMD). Logistic regression showed that, after adjusting for age, weight and height and standardizing for 1 SD decrease in BMD, CSA, CSMI and SM and 1 SD increase in BR, each of these parameters predicted hip fracture and both types of proximal femur fractures, except for CSMI, which was associated with TR but not with FN fracture (Table 2). Table 3 shows the areas of the ROC curves, built by using the FPP (obtained from each of the five logistic models reported in Table 2) as the test variable and the fracture status as the status variable. The ROC curve areas derived from the logistic models having FN BMD and BR as predictors did not differ significantly from each other according to the Hanley McNeil test, but were significantly higher than those derived from models having CSA, CSMI and SM as predictors in hip and FN fractures, and those having CSMI in TR fracture. For each studied parameter, the ROC curve areas of the trochanteric fracture were significantly greater (Hanley McNeil test) than those of the FN fracture (Table 3). When BMD and FNSP were forced together into the logistic forward regression with age, age at menopause, weight and height, only BR among the FNSPs entered the model to predict hip fracture BR: OR 1.73 (95% confidence interval (CI) ); FN BMD: OR 1.82 (95% CI ); age: OR (95% CI ); height: OR 1.03 (95% CI ). The area of the ROC curve, built by using the FPP derived from this forward logistic regression model as the test variable, was (SE 0.011). It was not significantly different (Hanley McNeil test) from the ROC curve areas calculated by using the FPP from the logistic regression testing BR and FN BMD separately. Discussion In this study, we evaluated the ability of FNSPs to discriminate between subjects with and without proximal femur fracture owing to minimal trauma. We found a statistically significant association between hip fracture risk and all of the tested FNSPs, after adjusting for age, age at menopause, weight and height, except for CSMI and FN fracture. Among the tested structural parameters, BR was the best predictor of the fracture risk. It predicted fracture significantly better than all of the other FNSPs and equally as well as FN BMD. These data agree with recent reports by Melton et al [23] and Ahlborg et al [24] who showed a similar ability of standard BMD measurements of the proximal femur and FNSPs to predict the fracture risk in osteoporotic women. The finding that BR is the best FNSP to predict fracture is particularly attractive because it derives from a measurement related to bone mass and femoral neck geometry (i.e. FND), both of which have been shown to influence bone strength [33, 34]. It provides a mechanism to explain the limit of geometric compensation (i.e. FND expansion) by bone cortex thinning, which leads to bone wall instability. Although structural parameters are interesting for understanding the biomechanics of bone fragility, they do not seem to add diagnostic value to the simple measurement of BMD. In fact, by conditional logistic regression, the best model for separating women with and without hip fractures, which contains both BMD and BR as predictors, does not predict fracture better than either considered separately. Conversely, the combined use of BMD and simple geometrical measurements of the FN has been shown to give better results, with modest but statistically significant improvements on the hip fracture prediction by BMD [19, 35 37]. Analysing hip fracture according to anatomical type, differences were found between FN and TR fracture. 894 The British Journal of Radiology, November 2007

3 Assessing hip fracture risk in postmenopausal women Table 1. Estimated parameters of the studied cases Control (n51646) Hip fracture (n5429) FN-Fr (n5273) TR-Fr (n5156) One-way ANOVA Post hoc Scheffé test (Mean SD) Ctrl vs FN-Fr vs TR-Fr Ctrl vs FN-Fr Ctrl vs TR-Fr FN-fr vs TR-Fr Age (years) * Age at menopause (years) Height (cm) Weight (kg) a FN BMD (mg cm 22 ) a CSA (cm 2 ) a CT (cm) a CSMI (cm 4 ) b SM (cm 3 ) a BR a BR, buckling ratio; FN BMD, femoral neck bone mineral density; CSA, cross-sectional area; CSMI, cross-sectional moment of inertia; CT, cortical thickness; FN-Fr, femoral neck fracture; SM, section modulus; TR-Fr, trochanter fracture. Unpaired t-test for controls vs hip fracture: a p,0.001 vs control group. b p,0.005 vs control group. Table 2. Odds ratios (OR) and 95% confidence interval (95% CI) obtained from five different logistic regressions, each one including age, height, weight and one of the test variables Test variable OR (95% CI) a Hip fracture FN-Fr TR-Fr FN BMD 3.17 ( ) b 2.98 ( ) b 3.60 ( ) b CSA 2.39 ( ) b 2.12 ( ) b 3.36 ( ) b CSMI 1.14 ( ) c 1.03 ( ) d 1.44 ( ) b SM 1.49 ( ) b 1.37 ( ) b 1.77 ( ) b BR 2.47 ( ) b 2.42 ( ) b 2.43 ( ) b BR, buckling ratio; FN BMD, femoral neck bone mineral density; CSA, cross-sectional area; CSMI, cross-sectional moment of inertia; CT, cortical thickness; FN-Fr, femoral neck fracture; SM, section modulus; TR-Fr, trochanter fracture. a OR and 95% CI are expressed for 1 SD decrease of BMD, CSA, CSMI and SM, and 1 SD increase of BR, and then adjusted for age, age at menopause, height and weight. b p,0.001 c p,0.05 d p5not significant Lower FN BMD was found to characterize TR fracture better than FN [38, 39]; statistically significant differences in structural parameters between cervical and trochanteric fractures were also found. It follows, according to others [37], that FN BMD is better at separating women with and without TR fractures than those with and without FN fracture. Perhaps owing to their correlation with BMD, structural parameters are also better predictors of TR fracture than of FN fracture, in agreement with Szulc et al [22]. Among FNSPs, BR was the best Table 3. ROC curve areas estimating the fracture probability by the test variable FPP calculated by logistic models having FN BMD and single FNSPs as predictors (adjusted for age, height and weight). Test variable ROC curve area (SE) Hanley McNeil test (p-value) Hip fracture FN-Fr TR-Fr FN vs TR fracture FPP by FN BMD (0.011) (0.014) (0.016) FPP by CSA (0.013) b (0.016) b (0.017) FPP by CSMI (0.014) a (0.017) a (0.019) a FPP by SM (0.014) a (0.017) a (0.018) FPP by BR (0.011) (0.014) (0.016) BR, buckling ratio; CSA, cross-sectional area; CSMI, cross sectional moment of inertia; CT, cortical thickness; FN BMD, femoral neck bone mineral density; FN-Fr, femoral neck fracture; FNSP, femoral neck structural parameter; FPP, fracture-predicted probability; ROC curve, receiver operating characteristic curve; SE, standard error; SM, section modulus; TR-Fr, trochanter fracture. a Hanley McNeil test: p,0.001 compared with FPP by FN BMD and with FPP by BR. b Hanley McNeil test: p,0.01 compared with FPP by FN BMD and with FPP by BR. The British Journal of Radiology, November

4 S Gnudi, E Sitta and N Fiumi predictor of both FN and TR fractures, but was most accurate at separating TR fracture, thus showing the same fracture prediction pattern as FN BMD. The fact that BR was best at predicting TR fracture highlights the importance of cortical bone instability in this type of fracture that occurs in women with very low bone mass. These data indicate differences in the structural basis of the two different types of proximal femur fracture, which should lead to FN and TR fracture being considered separately when evaluating individuals at risk of fracture. This study has some limitations. The controls were densitometry-referred individuals, and therefore they may not reflect the general population. BMD measurement of women with fractures was performed retrospectively and current BMD may not reflect that at the time of fracture, although the short time that had elapsed between fracture and BMD measurement should have minimized the bias [40]. Measurement of both BMD and FNSPs lacks validation across equipment. In addition, the estimation of structural parameters from a twodimensional image makes some assumptions that are likely to lead to inaccuracy in the evaluation of the structure indices, which could be reduced by using a three-dimensional technique. Despite these limitations, our study shows that some FNSPs and BMD discriminate proximal femur fractures to the same extent, and that their combined use does not significantly improve the predictive ability of each separately. It also shows that both FN BMD and FNSPs are stronger predictors of TR fracture than of FN fracture, and that BR is, among FNSPs, the best predictor of fracture and is equally as good as BMD. Although FNSPs do not predict hip fracture better than BMD, their evaluation has been shown to be useful in understanding the biomechanics of hip fractures. 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