Comparison of Hip Geometry, Strength, and Estimated Fracture Risk in Women With Anorexia Nervosa and Overweight/Obese Women

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1 ORIGINAL Endocrine ARTICLE Research Comparison of Hip Geometry, Strength, and Estimated Fracture Risk in Women With Anorexia Nervosa and Overweight/Obese Women Katherine Neubecker Bachmann, ouneh K. Fazeli, Elizabeth A. Lawson, Brian M. Russell, Ariana D. Riccio, Erinne Meenaghan, Anu V. Gerweck, Kamryn Eddy, Tara Holmes, Mark Goldstein, Thomas Weigel, Seda Ebrahimi, Diane Mickley, Suzanne Gleysteen, Miriam A. Bredella, Anne Klibanski, and Karen K. Miller Neuroendocrine Unit (K.N.B.,.K.F., E.A.L., A.K., K.K.M.), Departments of sychiatry (K.E.) and Radiology (M.A.B.), Massachusetts General Hospital and Harvard Medical School, and Neuroendocrine Unit (B.M.R., A.D.R., E.M., A.V.G.), Clinical Research Center (T.H.), Massachusetts General Hospital, and Division of Adolescent Medicine (M.G.), Massachusetts General Hospital for Children and Harvard Medical School, Boston, Massachusetts 02114; Klarman Center (T.W.), McLean Hospital and Harvard Medical School, Belmont, Massachusetts 02478; Cambridge Eating Disorders Center (S.E.), Cambridge, Massachusetts 02138; Wilkins Center for Eating Disorders (D.M.), Greenwich, Connecticut 06831; and Beth Israel Deaconess Medical Center (S.G.) and Harvard Medical School, Boston, Massachusetts Context: Data suggest that anorexia nervosa (AN) and obesity are complicated by elevated fracture risk, but skeletal site-specific data are lacking. Traditional bone mineral density (BMD) measurements are unsatisfactory at both weight extremes. Hip structural analysis (HSA) uses dual-energy X-ray absorptiometry data to estimate hip geometry and femoral strength. Factor of risk () is the ratio of force applied to the hip from a fall with respect to femoral strength; higher values indicate higher hip fracture risk. Objective: The objective of the study was to investigate hip fracture risk in AN and overweight/ obese women. Design: This was a cross-sectional study. Setting: The study was conducted at a Clinical Research Center. atients: atientsincluded368women(aged19 45y): 246AN, 53overweight/obese, and69leancontrols. Main Outcome Measures: HSA-derived femoral geometry, peak factor of risk for hip fracture, and factor of risk for hip fracture attenuated by trochanteric soft tissue ( attenuated ) were measured. Results: Most HSA-derived parameters were impaired in AN and superior in obese/overweight women vs controls at the narrow neck, intertrochanteric, and femoral shaft (.03). The attenuated was highest in AN and lowest in overweight/obese women (.0001). Lean mass was associated with superior, and duration of amenorrhea with inferior, HSA-derived parameters and attenuated (.05). Mean attenuated (.036), but not femoral neck BMD or HSA-estimated geometry, was impaired in women who had experienced fragility fractures. Conclusions: Femoral geometry by HSA, hip BMD, and factor of risk for hip fracture attenuated by soft tissue are impaired in AN and superior in obesity, suggesting higher and lower hip fracture risk, respectively. Only attenuated factor of risk was associated with fragility fracture prevalence, suggesting that variability in soft tissue padding may help explain site-specific fracture risk not captured by BMD. (J Clin Endocrinol Metab 99: , 2014) ISSN rint X ISSN Online rinted in U.S.A. Copyright 2014 by the Endocrine Society Received April 17, Accepted July 9, First ublished Online July 25, 2014 Abbreviations: AN, anorexia nervosa; BMD, bone mineral density; BMI, body mass index; BR, buckling ratio; CSA, cross-sectional area; CSMI, cross-sectional moment of inertia; CT, computed tomography; DXA, dual-energy X-ray absorptiometry; FN, femoral neck; FS, femoral shaft; HSA, hip structural analysis; IT, intertrochanteric region; LBM, lean body mass; NN, narrow neck;, factor of risk; attenuated, attenuated factor of risk; peak, peak factor of risk; Z, section modulus jcem.endojournals.org J Clin Endocrinol Metab, December 2014, 99(12): doi: /jc

2 doi: /jc jcem.endojournals.org 4665 Fracture risk is elevated in anorexia nervosa (AN) and at certain skeletal sites in obesity, but specific data regarding risk of hip fracture are lacking in both disorders. Low body mass index (BMI) has been established as a risk factor for fracture (1, 2), and higher fracture rates have been reported in AN (3, 4). Obesity was previously thought to be protective against fractures, although this has been challenged by recent data (1, 2, 5, 6). Up to 28% of postmenopausal women with low-trauma fractures are obese (5), suggesting that high BMI may not be protective against fracture. Data regarding fracture risk at specific skeletal sites in AN and obesity are limited. Higher fracture rates have been reported in AN (7), but most studies have lacked the power to determine skeletal site-specific fracture risk. There have only been two AN cohort studies with longitudinal fracture risk data (3, 4); both found higher risk of overall fracture, spine fractures, and forearm fractures. One of these studies found an increased risk of hip fracture (4), whereas the other study did not, which may have been due to the low number of hip fractures in the cohort (3). Among obese women, higher fracture rates at the humerus, upper arm, elbow, upper leg, and ankle have been reported (1, 2, 6). In contrast, lower risk of hip fracture has been reported in overweight and obese women, although underweight women were not excluded from the control groups, which may have reduced the difference between groups (2, 6). The reason for variability in fracture risk at different skeletal sites is unclear. Bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry (DXA) is limited in its ability to predict fracture risk and can be inaccurate at the extremes of the weight spectrum. The limitations of BMD alone in predicting fracture risk are demonstrated by the finding that as many as half of women who sustain hip fractures do not have osteoporosis by BMD criteria (8). In addition, DXA makes assumptions about ratios of fat to lean tissue, but these ratios can change at both weight extremes (9). Furthermore, low BMI in healthy populations is associated with increased risk of hip fracture, even after adjusting for BMD (2), supporting the concept that factors besides BMD play a role in fracture risk. In obesity, BMD does not fully explain the variability in fracture risk at different skeletal sites, and fracture risk assessments based on T scores can underestimate fracture risk (10). Furthermore, most postmenopausal obese women with low-trauma fractures have normal BMD at the spine and hip (5). The limitations of BMD alone to predict fracture risk have led to the development of additional fracture assessment tools. Imaging modalities to visualize bone microarchitecture provide information about bone structure that may help explain bone fragility. High-resolution peripheral quantitative computed tomography measures bone microarchitecture at the radius and tibia but is not possible at the hip. Hip structural analysis (HSA) is a technique that uses DXA data to estimate geometry and strength indices at the proximal femur. Certain HSA-derived variables predict hip fracture risk (11, 12) and correlate strongly with equivalent measurements assessed by 3-dimensional quantitative computed tomography (13) without exposure to high radiation doses. In addition, the biomechanics of falling and site-specific variations in the amount of soft tissue providing cushioning effects from a fall may contribute to site-specific fracture risk. Factor of risk () is a biomechanically based method to estimate hip fracture risk that has been shown to predict hip fracture, for which higher -values are associated with higher fracture risk (14 16). Factor of risk for hip fracture is the ratio of the force applied to the hip in a sideways fall from standing height divided by the strength of the proximal femur (14, 15, 17). eak factor of risk and attenuated factor of risk are calculated using the peak force and attenuated force applied to the hip, respectively. eak force represents the maximum force applied to the lateral femur during a sideways fall. Attenuated force accounts for cushioning effects from trochanteric soft tissue. The concept of attenuated force is that soft tissue overlying the bone provides cushioning during an impact and decreases the force applied to the bone. Thus, the greater the soft tissue thickness, the lower the attenuated force applied to the bone and consequently the lower the attenuated factor of risk (14). By taking into account both bone strength and loads applied to the bone during a fall, the factor of risk may provide insights into hip fracture risk in populations with widely varying body habitus, in which BMD alone may not capture key elements that influence fracture risk. We hypothesized the following: 1) women with AN would have impaired femoral geometry and strength indices as assessed by HSA and elevated hip fracture risk estimated by attenuated factor of risk, which accounts for soft tissue in addition to bone strength, and in contrast 2) overweight/obese women would have superior femoral geometry and strength indices as assessed by HSA and that the increased force of falling attributable to higher weight would be offset by the cushioning effects of trochanteric soft tissue, leading to lower hip fracture risk estimated by attenuated factor of risk. Therefore, we studied hip geometry as assessed by HSA-derived parameters and estimated hip fracture risk as assessed by factor of risk, both from peak load and attenuated load accounting for cushioning effects of trochanteric soft tissue, in women with AN, overweight/obese women, and lean female controls.

3 4666 Neubecker Bachmann et al Hip Geometry, Strength, Fracture Risk J Clin Endocrinol Metab, December 2014, 99(12): Materials and Methods Study participants We performed a retrospective analysis of premenopausal women with AN, lean, and overweight/obese women from prior studies who had hip DXAs electronically available. Informed consent had been obtained, and the artners Institutional Review Board had approved all protocols. Because age is an important determinant of skeletal integrity, groups of comparable age range and mean age were chosen based on a predetermined algorithm. BMD data have been previously reported for some study subjects (18 23). HSA and factor-of-risk data have not been reported previously for any subjects. Subjects did not have renal disease, liver disease, untreated thyroid dysfunction, diabetes mellitus, active substance abuse, or prior use of medications known to affect bone metabolism. AN subjects met Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria for diagnosis of AN and had a BMI less than 18.5 kg/m 2. Lean controls had BMIs between 18.5 and 24.9 kg/m 2. Overweight/obese women had BMIs between 25 and 49 kg/m 2. Lean and overweight/obese women were eumenorrheic. AN subjects had eumenorrhea, amenorrhea, or were receiving oral contraceptives. BMD and body composition evaluation All subjects underwent DXA (Hologic Inc) to measure hip BMD, lean body mass (LBM), and fat mass. Hip structural analysis HSA uses properties of hip DXA images to estimate hip geometry and strength indices. The HSA program provides seven parameters: cross-sectional area (CSA; index of resistance to axial forces); cross-sectional moment of inertia (CSMI; estimate of resistance to bending forces in a cross-section); section modulus (Z; index of bending strength); cortical thickness; subperiosteal width; endocortical width; and buckling ratio (BR; index of susceptibility to cortical buckling under compressive loads). Higher values are associated with greater predicted femoral strength for all HSA-derived parameters except for BR, for which higher values are predictive of inferior strength. HSA analyzes the hip at three sites: narrow neck (NN; narrowest part of the femoral neck), femoral shaft (FS; across the shaft 1.5 cm from the NN to the intersection of the neck and shaft axes), and intertrochanteric region (IT; along the bisector of the angle of the axes of NN and FS) (24). Factor of risk () Factor of risk for hip fracture was calculated as the ratio of force applied to the hip in a sideways fall from standing height with respect to femoral strength, as previously published (14, 15) using the following equation: Factor of risk () applied force/femoral Strength Applied force was calculated in two ways, as the peak force and attenuated force, the latter accounting for cushioning effects from trochanteric soft tissue. eak force and attenuated force were used to calculate peak factor of risk ( peak ) and attenuated factor of risk ( attenuated ), respectively. eak force was estimated from each subject s height and weight using a published equation derived from biomechanical modeling of a sideways fall from standing height (25, 26). Attenuated force accounted for the cushioning effects of soft tissue overlying the greater trochanter and was calculated as peak force minus 71 N/mm of trochanteric soft tissue (14, 15, 27). Trochanteric soft tissue thickness was directly measured from whole-body DXA by calculating the horizontal distance from the lateral aspect of the greater trochanter to the lateral aspect of the air-soft tissue boundary (14, 16). Reproducibility of the soft tissue measurements was 0.63%, as assessed by the mean coefficient of variation for repeat measurements of 20 DXA scans. Whole-body DXA scans were available in all lean and overweight/obese subjects and the majority (210 of 246) of the AN subjects. Femoral Strength is a function of the femoral neck (FN) BMD and equals 8207 FN BMD (grams per square centimeter) This equation was derived from the linear regression between the FN BMD and the femoral failure load in cadaveric specimens (15, 28). Fracture Fracture history was obtained by patient report by interview in 240 of 246 AN, 50 of 69 lean, and 32 of 53 overweight/obese women. The standard definition of fragility fractures, those not due to falls from greater than standing height or from highenergy trauma such as motor vehicle collisions and excluding finger, toe, and facial fractures, was used. There was no age cutoff because low-trauma fractures in childhood and adolescence can be associated with low BMD (29). Biochemical analyses Serum IGF-1 levels were available in 22 of 246 AN, 34 of 69 lean, and 32 of 53 overweight/obese women. IGF-1 was measured by the Immulite 2000 immunoassay analyzer (Siemens Medical Solutions Diagnostics) with an intraassay coefficient of variation of less than 4%. Other variables Duration since AN diagnosis and total months of amenorrhea (excluding time on oral contraceptives) were collected from AN subjects during interviews. Durations of AN and amenorrhea were available in 206 and 158 of 246 AN subjects, respectively. Statistical analysis Statistical analyses were performed using JM Statistical Discovery Software, version 10 rofessional (SAS Institute Inc). Variables were tested for normality using the Shapiro-Wilk test. Because not all variables were normally distributed, nonparametric testing was performed. roportions were compared using the Fisher s exact test. Continuous variables were compared among the three groups using the Kruskal-Wallis test, and if the significance value was.05, Wilcoxon pairwise comparisons were performed. Further adjustment for multiple comparisons was not necessary because of the use of a preliminary test of significance among three groups (30). Data are presented as means SD (Table 1). Univariate regressions were performed for HSA-derived parameters and factor of risk, and Spearman -values are reported. values for univariate regressions of HSA-derived parameters (Table 2) and factor of risk (Table 3) were corrected for multiple comparisons by the Bonferroni method. Because there were seven HSA-derived variables analyzed at three sites, values for univariate

4 doi: /jc jcem.endojournals.org 4667 Table 1. Baseline Characteristics regressions of HSA-derived parameters were multiplied by 21. values for univariate regressions of factor of risk were multiplied by 2 to account for the two factor-of-risk variables. We hypothesized a priori that LBM would be associated with favorable femoral geometry, based on prior data showing that LBM is a more significant determinant of BMD than is BMI or fat mass (31). Multivariate regression models on log-transformed data were constructed to determine predictors of HSA-derived variables using stepwise regression analysis. Statistical significance was defined as a two-tailed value of.05. Results Anorexia Nervosa Lean Controls Clinical characteristics Women with AN, lean controls, and overweight/obese females were of comparable mean age (Table 1). As expected, BMI, LBM, and total fat mass were lowest in the AN group and highest in the overweight/obese group. The FN and total hip BMD were lowest in AN and highest in overweight/obese women. Mean serum IGF-1 levels were lower in AN than lean controls. Of the 209 AN subjects with data available for age of AN diagnosis, 59 were diagnosed before 18 years of age, of whom eight were diagnosed between the ages of 9 and 12 years. HSA-derived femoral geometry All HSA-derived parameters, except endocortical width, were impaired in AN and superior in overweight/ obese women compared with lean controls (.03). CSA, CSMI, section modulus, cortical thickness, subperiosteal width, and BR were impaired at all sites (NN, IT, FS) in Overweight/, Obese a AN vs C, AN vs OW, CvsOW Age, y NS NS NS NS BMI, kg/m Total lean mass, kg Total fat mass, kg Illness duration, mo N/A N/A.0001 N/A N/A N/A Amenorrhea N/A duration, mo Estrogen use, mo NS IGF-1, ng/ml NS.036 NS NS revalence of any 43% 46% 28% NS NS NS NS prior fracture, % revalence of 33% 32% 19% NS NS NS NS prior fragility fracture, % FN BMD, g/cm Trochanteric BMD, g/cm 2 IT BMD, g/cm Total hip BMD, g/cm Abbreviations: AN, anorexia nervosa; C, lean controls; NS, not significant; OW, overweight/obese; FN, femoral neck; IT, intertrochanteric. a Overall value. AN compared with lean and overweight/obese women (.02; Figure 1). Overweight/obese women had superior CSA, CSMI, section modulus, and cortical thickness at all sites and BR at IT and FS, compared with lean and AN females (.03). Thus, bone size estimates (cortical thickness, subperiosteal width) as well as strength estimates (CSA, CSMI, section modulus, BR) were inferior in AN and superior in overweight/obese women. Factor of risk for hip fracture () The peak (Figure 2A) was higher in overweight/obese than lean controls (.007) and trended toward being higher in overweight/obese than AN (.057). The peak did not differ between AN and lean females. The attenuated (Figure 2B) was highest in AN and lowest in overweight/ obese women (.0001). Fractures Of subjects with fracture data available, prevalence of any prior fracture was 43% among AN, 46% among lean controls, and 28% among overweight/obese women ( NS). revalence of prior fragility fracture was 33% in AN, 32% in lean controls, and 19% in overweight/obese women ( NS). As expected, there were few reported hip fractures in this young, premenopausal population. There was one atraumatic hip fracture among AN subjects and none among lean or overweight/obese women. Across groups, the mean attenuated was higher in women with a history of fragility fracture compared with those without a history of fragility fracture (.036).

5 4668 Neubecker Bachmann et al Hip Geometry, Strength, Fracture Risk J Clin Endocrinol Metab, December 2014, 99(12): Table 2. Associations of HSA-Derived arameters BMI, kg/m 2 Total Lean Mass, kg Amenorrhea Duration, mo Femoral Neck BMD, g/cm 2 All groups CSA, NN CSA, IT CSA, FS CSMI, NN CSMI, IT CSMI, FS Z, NN Z, IT Z, FS Cortical thickness, NN Cortical thickness, IT Cortical thickness, FS Subperiosteal width, NN NS NS Subperiosteal width, IT NS Subperiosteal width, FS Endocortical width, NN NS NS NS Endocortical width, IT NS NS NS NS Endocortical width, FS NS NS BR, NN BR, IT BR, FS AN group CSA, NN CSA, IT CSA, FS CSMI, NN CSMI, IT CSMI, FS Z, NN Z, IT Z, FS Cortical thickness, NN Cortical thickness, IT Cortical thickness, FS Subperiosteal width, NN 0.10 NS NS NS NS NS NS Subperiosteal width, IT NS NS NS NS Subperiosteal width, FS NS NS NS NS NS Endocortical width, NN NS NS NS NS Endocortical width, IT NS NS NS NS Endocortical width, FS NS NS NS NS NS BR, NN NS BR, IT NS BR, FS NS NS Lean controls group CSA, NN NS NS NS CSA, IT NS NS CSA, FS NS NS CSMI, NN NS NS CSMI, IT NS NS CSMI, FS NS NS Z, NN NS NS NS Z, IT NS NS NS Z, FS NS NS Cortical thickness, NN NS NS NS NS NS NS Cortical thickness, IT NS NS NS NS NS NS Cortical thickness, FS NS NS NS NS NS Subperiosteal width, NN NS NS NS NS NS NS Subperiosteal width, IT NS NS NS NS NS Subperiosteal width, FS NS NS NS NS NS NS Endocortical width, NN NS NS NS NS NS Endocortical width, IT NS NS NS NS NS Endocortical width, FS NS NS NS NS NS NS BR, NN NS NS NS NS BR, IT NS NS NS NS BR, FS NS NS NS NS Overweight/obese group CSA, NN NS CSA, IT NS CSA, FS NS NS (Continued)

6 doi: /jc jcem.endojournals.org 4669 Table 2. Continued BMI, kg/m 2 Total Lean Mass, kg Amenorrhea Duration, mo Femoral Neck BMD, g/cm 2 CSMI, NN NS NS CSMI, IT NS NS NS NS CSMI, FS NS NS NS Z, NN NS NS Z, IT NS NS NS Z, FS NS NS NS Cortical thickness, NN NS Cortical thickness, IT NS NS Cortical thickness, FS NS NS NS NS Subperiosteal width, NN NS NS NS NS NS NS Subperiosteal width, IT NS NS NS NS NS Subperiosteal width, FS NS NS NS NS Endocortical width, NN NS NS NS NS NS NS Endocortical width, IT NS NS NS NS Endocortical width, FS NS NS NS NS NS NS BR, NN NS NS NS BR, IT NS NS NS BR, FS NS NS NS NS NS Abbreviation: AN, anorexia nervosa; CSA, cross-sectional area; CMSI, cross-sectional moment of inertia; NN, narrow neck; IT, introchanteric; FS, femoral shaft; NS, not significant (.10); Z, section modulus; value corrected denotes values corrected for multiple comparisons. Among overweight/obese women, the mean attenuated and peak were higher in those with prior fragility fracture (.03) and any prior fracture (.008) than in women who had not experienced such fractures. Among lean controls, the mean attenuated was higher in women with prior fragility fracture than in those without prior fragility fracture (.026). Among AN women, the mean peak and attenuated did not differ by fracture history. However, the mean peak force and attenuated force (the numerators of peak and attenuated, respectively) were higher in women with AN with any prior fracture (.05), and mean attenuated force was also higher in AN subjects with prior fragility fracture (.024) compared with AN subjects who had not experienced such fractures. The mean FN BMD did not differ by history of fracture or fragility fracture across groups. The mean FN BMD was lower in overweight/obese subjects with prior fracture (.052) and prior fragility fracture (.10) Table 3. Associations of Factor of Risk compared with those without such fractures. Contrary to expectations, FN BMD was higher in AN subjects with any prior fracture (.046) and trended toward being higher in the AN subjects with prior fragility fracture (.084) than in those without such fractures. Consistent with the BMD findings above, mean HSAderived parameters did not differ by fracture history. Determinants of HSA-derived femoral geometry BMI was associated with favorable HSA-derived variables across groups and within AN (Table 2; ,.05) but not within lean control or overweight/obese groups after controlling for multiple comparisons (Table 2). LBM was associated with superior values of all HSA-derived parameters (CSA, CSMI, section modulus, cortical thickness, subperiosteal width, endocortical width, and BR) across groups and most HSA-derived parameters BMI, kg/m 2 Total Lean Mass, kg IGF-1, ng/ml Amenorrhea Duration, mo All groups Factor of risk, peak NS NS NS NS Factor of risk, attenuated NS NS AN group Factor of risk, peak NS NS NS NS NS Factor of risk, attenuated NS NS NS Lean controls group Factor of risk, peak NS NS NS NS NS NS Factor of risk, attenuated NS NS NS NS NS NS Overweight/obese group Factor of risk, peak NS NS NS NS Factor of risk, attenuated NS NS NS NS Abbreviation: AN, anorexia nervosa; NS, not significant (.10); denotes values corrected for multiple comparisons.

7 4670 Neubecker Bachmann et al Hip Geometry, Strength, Fracture Risk J Clin Endocrinol Metab, December 2014, 99(12): Figure 1. Women with AN have impaired hip geometry and strength at all hip sites compared with lean controls and overweight/obese women, as assessed by CSA (panel A), CSMI (panel B), section modulus, Z (panel C), cortical thickness (panel D), subperiosteal width (panel E), and BR (panel G). Overweight/obese women have superior hip geometry and strength compared with lean controls and AN subjects, as assessed by CSA (panel A), CSMI (panel B), Z (panel C), and cortical thickness (panel D) at all sites, and by BR (panel G) at the IT region and FS. *,.031. AN, anorexia nervosa; NN, narrow neck; IT, intertrochanteric; FS, femoral shaft. within AN group (Table 2; ,.05). LBM was associated positively with CSA, CSMI, and section modulus among overweight/obese women (Table 2; ,.03). Duration of amenorrhea (Table 2; ,.05) and duration of anorexia nervosa ( ,.05) were associated with impaired CSA, CSMI, section modulus, cortical thickness, and BR. In a subset with IGF-1 levels available, IGF-1 correlated with superior cortical thickness, CSA, and section modulus at NN across groups ( ,.01). FN BMD was associated with favorable values of CSA, CSMI, section modulus, and BR across and within groups ( ,.04) but not consistently with subperiosteal width, endocortical width, or cortical thickness within groups (Table 2). On multivariate analysis, after controlling for FN BMD, LBM remained a significant predictor of CSA, CSMI, section modulus, subperiosteal width, and endocortical width at all sites across groups and in AN, and of cortical thickness at IT and FS across groups. LBM explained more of the variability than did FN BMD for subperiosteal width at all sites, CSMI at all sites, and section modulus at FS across groups and within AN. When duration of amenorrhea was added to the model, LBM and duration of amenorrhea were significant independent determinants of most HSA-derived parameters (positively and negatively, respectively) in the group as a whole and within AN. Determinants of factor-of-risk () The peak and attenuated (Table 3) were positively associated with the duration of amenorrhea across groups and within AN (Table 3; ,.011) and with duration of AN ( ,.0004). The attenuated was associated negatively with LBM across groups ( 0.47 to 0.49,.0002). The peak was associated negatively with IGF-1 across groups ( 0.28,.018) and among overweight/obese women ( 0.53,.007). Discussion We demonstrated that women with AN have impaired hip geometry, and in contrast, overweight/obese women have superior hip geometry, as assessed by HSA-derived parameters compared with lean controls. Overweight/obese women had higher BMD, but they also had higher peak

8 doi: /jc jcem.endojournals.org 4671 Figure 2. peak (panel A) was higher in overweight/obese than lean controls and trended toward being higher in overweight/obese than AN; peak did not differ between AN and lean controls. attenuated (panel B) was highest in AN, followed by lean controls, and lowest in overweight/obese (OW). *,.007. White squares, AN; gray squares, lean controls (C); black squares, overweight/obese (OW). force due to higher body mass, leading to higher peak factor of risk. However, after taking into account the cushioning effects from trochanteric soft tissue, attenuated factor of risk was highest in the AN and lowest in the overweight/obese women. Our findings suggest that trochanteric soft tissue may protect obese women against hip fracture and that lack of trochanteric soft tissue may increase risk of hip fracture in women with AN. Importantly, a history of fragility fracture was not associated with BMD across groups but was associated with attenuated factor of risk in the group as a whole, among obese, and among lean controls. Histories of any fracture and fragility fracture were associated with attenuated force in AN. These results suggest that soft tissue padding may help explain variations in fracture risk not explained by BMD. Fracture risk cannot be accounted for by BMD alone. rior studies have demonstrated that low BMI is a risk factor for hip fracture, even after adjustment for BMD (2), and that most postmenopausal obese women with lowtrauma fractures have normal BMD at the hip and spine (5). Limitations of traditional BMD to fully predict fracture risk has led to the development of tools to estimate bone structure, which may help explain fracture risk. HSA provides information about the geometry of the proximal femur. In our study, even after adjusting for BMD, lean mass and amenorrhea remained significant predictors of most HSA-derived parameters, implying that HSA may provide additional information to help us understand factors that influence bone strength. Furthermore, our results suggest that attenuated factor of risk, which accounts for soft tissue padding, may lend additional insight beyond BMD into fracture risk in AN and obese populations. Lack of trochanteric soft tissue padding in low BMI and AN populations may contribute to increased hip fracture risk independent of BMI. Conversely, in obesity, peak factor of risk was higher in overweight/obese women, but when attenuated for trochanteric soft tissue thickness, was lowest in overweight/obese women. This may help explain the reported site-specific fracture risk differences in obesity not explained by BMD; obese women tend to fracture less at skeletal sites with more soft tissue padding, including the hip, and tend to fracture more frequently at sites with less soft tissue padding, such as the humerus. rior studies have shown that lean mass is an important determinant of BMD in AN, more so than BMI or fat mass (31). In the present study, we demonstrated that lean mass was a significant positive predictor of most HSA-derived parameters across groups and in AN, even after controlling for femoral neck BMD, and was negatively associated with attenuated (which accounts for BMD), suggesting that lean mass may be associated with greater hip strength and decreased fracture risk at the hip independent of BMD. The duration of amenorrhea remained an independent predictor of most HSA-estimated parameters within the AN group after controlling for FN BMD and lean mass; this could be because the duration of amenorrhea reflects the duration of estrogen deficiency or is a proxy for the severity of nutritional deprivation, which is associated with low IGF-1 levels. Despite the fact that we had only IGF-1 levels in a subset of subjects, IGF-1 was positively associated with most HSA-derived factors across groups, which could reflect the anabolic effects of IGF-1 on bone. Many AN subjects were diagnosed during adolescence, so failure of pubertal skeletal development may have contributed to their impaired hip geometry. Malnutrition can interfere with achieving optimal peak bone mass, and protein-calorie malnutrition may be mediated in part by IGF-1 (29). Limitations of our study arise from its cross-sectional and retrospective nature. Factor of risk for hip fracture has been validated in older populations (15), but we are unable to validate our estimates of fracture risk due to the lack of prospective fracture data and the low prevalence of hip fracture in our young population. Although hip fractures are uncommon in young populations, the hip is a valuable skeletal site to study because hip BMD (32) and hip geometry (12, 33) are predictive of overall fracture risk in previously studied populations. Our retrospective data suggest this to be the case in women with AN and obesity, despite the fact that we found that trochanteric soft tissue cushioning appears to be an important determinant of fracture risk, and most other fracture sites have less soft tissue padding than the hip. We cannot explain this, and we acknowledge that the fracture prediction models presented and our understanding of the determinants of frac-

9 4672 Neubecker Bachmann et al Hip Geometry, Strength, Fracture Risk J Clin Endocrinol Metab, December 2014, 99(12): ture risk are imperfect and incomplete. Nevertheless, the facts that we observed positive correlations between attenuated and prior fracture prevalence over all skeletal sites and that attenuated was found to predict future fractures in a large prospective study (15) suggest that attenuated is a valid, if not perfect, predictor of overall fractures. Other limitations of our study include lack of complete fracture history (including skeletal site and circumstances) in all individuals and incomplete IGF-1 data. Also, subject selection was limited to individuals with hip DXAs available from prior studies, which led to variability in the number of subjects between groups. In conclusion, this is the first report to demonstrate that women with anorexia nervosa have impaired hip geometry and strength by HSA and elevated attenuated factor of risk and that overweight/obese women have superior hip geometry and strength by HSA and decreased attenuated factor of risk. These data suggest a higher possible risk of hip fracture in AN and lower possible risk in obesity. revalence of fragility fracture was not associated with BMD across groups but was associated with attenuated factor of risk across groups, in obese, and in lean controls and with attenuated force in AN. Our findings suggest that soft tissue padding, which can attenuate the force applied to the bone during a fall, may help explain site-specific fracture risk in the AN and obese populations not captured by BMD. Lean mass was positively associated with most HSA-derived parameters and negatively with attenuated, whereas durations of amenorrhea and AN were associated negatively with several HSA-derived variables and with higher peak and attenuated, suggesting that these factors may play important roles in hip strength and fracture risk. Furthermore, we demonstrated that after controlling for FN BMD, lean mass and amenorrhea duration were independent predictors (positively and negatively, respectively) of most HSA-derived parameters, suggesting that these parameters provide information about hip structure not fully explained by BMD alone. Longitudinal studies are needed to evaluate the ability of HSA and factor of risk to predict fracture in AN and obesity. Future studies are indicated to evaluate the role of soft tissue padding, particularly in obesity in which there are skeletal site-specific differences in fracture risk not explained by BMD. Acknowledgments Address all correspondence and requests for reprints to: Karen K. Miller, MD, Massachusetts General Hospital, 55 Fruit Street, Bulfinch 457B, Boston, MA kkmiller@mgh.harvard.edu. This work was supported by National Institutes of Health Grants R01 HL , K24 HL092902, R01 DK052625, R24 DK092759, K23 DK094820, K23 MH092560, K23 RR-23090, T32 DK , UL1 RR025758, and K12 HD Disclosure Summary: The authors have nothing to disclose. References 1. Compston JE, Flahive J, Hosmer DW, et al. Relationship of weight, height, and body mass index with fracture risk at different sites in postmenopausal women: the Global Longitudinal Study of Osteoporosis in Women (GLOW). J Bone Miner Res. 2014;29: Johansson H, Kanis JA, Oden A, et al. A meta-analysis of the association of fracture risk and body mass index in women. J Bone Miner Res. 2014;29: Lucas AR, Melton LJ 3rd, Crowson CS, O Fallon WM. Long-term fracture risk among women with anorexia nervosa: a populationbased cohort study. 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