Abstract
Purpose:
Anorexia nervosa (AN) is a psychiatric disorder characterized by low body weight, low BMD and increased risk of fracture. Although BMD is reduced and fracture risk elevated, BMD as assessed by DXA does not distinguish between individuals with versus those without prior history of fracture in AN. Despite having decreased peripheral adipose tissue stores, individuals with AN have enhanced bone marrow adipose tissue (BMAT), which is inversely associated with BMD. Whether increased BMAT is associated with fracture in AN is not known.
Methods:
We conducted a cross-sectional study in 62 premenopausal women, including 34 with AN and 28 normal-weight women of similar age. Fracture history was collected during patient interviews and BMD measured by DXA, BMAT by 1H-MRS and parameters of bone microarchitecture by HR-pQCT.
Results:
Sixteen women (47.1%) with AN reported prior history of fracture compared to 11 normal-weight women (39.3%, p=0.54). In the entire group and also the subset of women with AN, there were no significant differences in BMD or parameters of bone microarchitecture in women with prior fracture versus those without. In contrast, women with AN with prior fracture had greater BMAT at the spine and femur compared to those without (p=0.01 for both).
Conclusion:
In contrast to BMD and parameters of bone microarchitecture, BMAT is able to distinguish between women with AN with prior fracture compared to those without. Prospective studies will be necessary to understand BMAT’s potential pathophysiologic role in the increased fracture risk in AN.
Keywords: Bone marrow adipose tissue, anorexia nervosa, fracture
Mini Abstract/Summary:
Although bone mineral density (BMD) is decreased and fracture risk increased in anorexia nervosa, BMD does not predict fracture history in this disorder. We assessed BMD, bone microarchitecture and bone marrow adipose tissue (BMAT) in women with anorexia nervosa and found that only BMAT was associated with fracture history.
Introduction:
Anorexia nervosa is a primary psychiatric disorder defined by self-induced low body weight[1]. This disorder has a lifetime prevalence of up to 2.2% in women[2]. The most prevalent medical complication affecting women with anorexia nervosa is low bone mass; approximately 85% of women with anorexia nervosa have a bone mineral density (BMD) value more than 1 standard deviation lower than the mean of women of similar age[3]. Importantly, in addition to low BMD, individuals with anorexia nervosa have an increased risk of fracture[4–7] and prospective studies have demonstrated a 7-fold increased risk of non-vertebral fractures in women with anorexia nervosa[8].
Although individuals with anorexia nervosa have low BMD and an increased risk of fractures, BMD does not consistently predict fracture risk in this population. In adolescent girls and women with anorexia nervosa, BMD is not associated with either a history of fracture or incident vertebral fracture[5, 9–11]. Bone marrow adipose tissue (BMAT) is part of the bone marrow microenvironment and is negatively associated with BMD in girls and women with anorexia nervosa[12, 13] and older individuals[14, 15]. In populations of older individuals, BMAT at the lumbar spine is higher in individuals with vertebral fractures than those without[16], and greater BMAT saturation has also been associated with an increased risk of incident vertebral fractures[17]. Whether BMAT is associated with fracture history in women with anorexia nervosa is not known.
We studied a total of 62 women, including individuals with anorexia nervosa and normal-weight healthy controls. We hypothesized that BMAT would be positively associated with history of fracture in women with anorexia nervosa.
Materials and Methods:
Study participants and protocol
Study participants consisted of sixty-two women: 34 women with anorexia nervosa (median age [interquartile range]: 26.9 [24.9, 31.0] years) and 28 healthy controls of normal weight (median age [interquartile range]: 25.7 [23.4, 32.6] years). BMAT and/or bone parameters from a subset of study participants have been previously reported[18–23]. Study participants with anorexia nervosa met DSM-5 criteria for the disorder[1] and were recruited through advertisements or eating disorder providers. Healthy controls were recruited through advertisements and were normal-weight (18.5 kg/m2 < BMI < 25 kg/m2 at screening visit; BMI range: 20.8–24.7 kg/m2). Healthy controls did not have a history of an eating disorder, all had regular menstrual cycles, and none were taking any medications known to affect BMD. Study participants had normal thyroid function tests and other than anorexia nervosa, no study participant had a chronic disease which could affect BMD. None of the study participants (normal-weight controls or individuals with anorexia nervosa) were using estrogen/progesterone or oral contraceptives.
All participants presented to the Translational and Clinical Research Center at the Massachusetts General Hospital for a study visit during which a medical history and physical examination was performed. Fracture history was collected during the patient interview. The study participants self-reported whether they had sustained any fractures and if known, type of fracture (ie whether the fracture was sustained during trauma or whether it was classified as a stress fracture). We measured height as the average of three readings on a single stadiometer and we assessed body weight on an electronic scale while study participants were wearing a hospital gown. We calculated BMI using the formula [weight (kilograms)/ height (meters)2].
The Partners Institutional Review Board approved the study and it complied with the Health Insurance Portability and Accountability Act guidelines. We obtained written consent from all study participants.
Radiologic Imaging
Dual-energy X-ray absorptiometry
DXA was used to assess areal BMD of the posterior-anterior (PA) lumbar spine (L1-L4), lateral spine (L2-L4), left total hip, left femoral neck, distal 1/3 radius and total body with a Hologic Discovery A densitometer (Hologic Inc., Bedford, MA). The coefficients of variation for BMD as assessed by DXA have been reported as < 2.2%[24].
High resolution peripheral quantitative computed tomography (HR-pQCT)
As previously described, we performed HR-pQCT (isotropic voxel size of 82 μm3) in the non-dominant distal radius and tibia (Xtreme CT; Scanco Medical AG, Bruttisellen, Switzerland)[25, 26]. We estimated the biomechanical properties of the distal radius and distal tibia under uniaxial compression loading using linear microfinite element analysis of HR-pQCT images, as previously described[27, 28].
1H-Magnetic Resonance Spectroscopy (1H-MRS)
The Nutrition and Obesity Research Center at Harvard performed 1H-Magnetic Resonance Spectroscopy (1H-MRS)[12]. Using 1H-MRS (Siemens Trio, 3T, Siemens Medical Systems, Erlangen, Germany), the lipid content of the lumbar vertebra (L4), femoral epiphysis, metaphysis and mid-diaphysis. Single-voxel 1H-MRS data were obtained by positioning a 15 × 15 × 15 mm (3.4 mL) voxel in the L4 vertebral body and with spatially localized spectroscopy (PRESS) pulse sequence without water suppression (with the following parameters: TE of 30 ms, TR of 3,000 ms, 8 acquisitions, 1024 data points, and receiver bandwidth of 2000 Hz). Using a 12 × 12 × 12 mm voxel, 1H-MRS data were obtained with the same non-water suppressed PRESS pulse sequence from the femoral epiphysis, mid-diaphysis and also the femoral metaphysis (inter-trochanteric region). Using automated procedures, gradient shimming and transmit and receive gain were optimized. We have previously reported the coefficient of variation for quantification of marrow fat in this population as 3%[29].
1H-MRS data were fitted using LCModel software (version 6.1-4A) (Stephen Provencher, Oakville, ON, Canada). Metabolite quantification was obtained using eddy current correction and water scaling after transferring the data to a Linux workstation. A fitting algorithm customized for the analysis of bone marrow provided estimates for all lipid signals combined (0.9, 1.3, and 2.3 ppm). Lipid estimates using LCModel software were scaled automatically to an unsuppressed water peak (4.7 ppm) and we expressed the results as a lipid to water ratio.
Statistical Analysis
Statistical analyses were performed using JMP Pro 15.0 (SAS Institute, Carry, NC). We used the Student’s t-test to compare means and standard error of the mean (SEM) unless the data were non-normally distributed, in which case we compared medians [interquartile range] using the Wilcoxon rank sum test. We used the Chi-Square test to compare categorical data. Univariate associations were assessed using Pearson correlation coefficients (R), or Spearman’s coefficients (rho) if data were not normally distributed. Logistic regression was used to control for potential confounding variables. A two-sided p-value < 0.05 was used to indicate significance.
Results:
Clinical characteristics
Table 1 lists the clinical characteristics of the study participants. Duration of anorexia nervosa was a mean of 12.2 ± 1.1 years (range: 2–29 years) in women with anorexia nervosa and duration of amenorrhea was a median of 42 [24.5, 93] months. Sixteen subjects with anorexia nervosa (47.1%) reported a history of fracture compared to 11 normal-weight subjects (39.3%) which was not a statistically significant difference (p=0.54). Eight study participants with anorexia nervosa, or 50% of those with a history of fracture, reported sustaining more than one fracture whereas only two of the normal-weight control subjects (18.2%) had a history of more than one fracture (p=0.08). Of the 16 subjects with anorexia nervosa with a history of fracture, nine (56%) reported a fracture occurring after the initiation of the eating disorder and an additional three subjects (19%) reported a history of fracture within the same year as their diagnosis. The median time between onset of anorexia nervosa and most recent fracture was 14 years with a range of 3–20 years for those reporting a fracture after diagnosis. The remaining four subjects (25%) sustained their fractures before onset of anorexia nervosa. Duration of anorexia nervosa was significantly longer in subjects who reported a fracture after onset of their disorder (median duration of 18 [13.5, 20] years) as compared to those who had a history of fracture prior to their diagnosis (median duration of 6 years [5.25, 11.25]; p=0.017).
Table 1:
Clinical characteristics of study participants
| Anorexia nervosa (n=34) | Normal-weight controls (n=28) | p-value | |
|---|---|---|---|
| Age (years)* | 26.9 [24.9, 31.0] | 25.7 [23.4, 32.6] | 0.72 |
| BMI (kg/m2)* | 17.4 [15.2, 18.3] | 22.3 [21.5, 23] | <0.0001 |
| % Ideal body weight | 75.9 ± 1.5 | 100.5 ± 1.1 | <0.0001 |
| Duration of anorexia nervosa (years) | 12.2 ± 1.1 | ----------- | |
| Duration of amenorrhea (months)* | 42 [24.5, 93] | ----------- | |
| Self-reported aerobic exercise/week (hours) | 2.5 [0, 6.6] (range: 0–14) | 3 [1.1, 4.5] (range: 0–8) | 0.64 |
| History of any fracture % (n) | 47.1 (16) | 39.3 (11) | 0.54 |
| History of more than one fracture % (n) | 50 (8) | 18.2 (2) | 0.08 |
| Type of Fracture (if known) | |||
| Stress fracture (n) | 7 | 2 | 0.12 |
| Fragility fracture (n) | 1 | 0 | 0.38 |
| Fracture due to trauma (n) | 3 | 1 | 0.84 |
| Bone mineral density (BMD) | |||
| Lumbar spine BMD (g/cm2)* | 0.799 [0.712, 0.901] | 0.945 [0.893, 1.042] | <0.0001 |
| Lateral spine BMD (g/cm2) | 0.606 ± 0.016 | 0.784 ± 0.012 | <0.0001 |
| Total Hip BMD (g/cm2) | 0.763 ± 0.018 | 0.947 ± 0.019 | <0.0001 |
| Femoral neck BMD (g/cm2) | 0.661 ± 0.016 | 0.813 ± 0.021 | <0.0001 |
| Distal 1/3 radius (g/cm2) | 0.684 ± 0.009 | 0.700 ± 0.008 | 0.18 |
| Total body BMD (g/cm2)* | 0.940 [0.888, 0.977] | 1.044 [0.996, 1.085] | <0.0001 |
Data are reported as mean ± SEM unless not normally distributed, in which case median [interquartile range] is reported and denoted by an asterisk (*)
Study participants with anorexia nervosa reported a total of 27 fractures and normal-weight subjects reported a total history of 14 fractures. For the anorexia nervosa subjects, 12 of the 27 fractures were lower extremity fractures (including stress or traumatic), four were pelvic/sacral fractures, three were wrist/forearm fractures, two were clavicular/non-humeral shoulder fractures, one was a facial fracture, and the remaining five fractures were digital (hand) fractures. In the normal-weight subjects, three of the 14 fractures were lower extremity fractures, two were clavicular/non-humeral shoulder fractures, seven were wrist/forearm fractures and the remaining two were digital (hand) fractures. Only two subjects, one with anorexia nervosa and one normal-weight subject, reported only sustaining a single digital (hand) fracture; the remaining digital (hand) fractures were sustained in participants who also reported additional non-digital fractures. Subjects with anorexia nervosa had significantly lower BMD at the spine and hip compared to normal-weight subjects (p < 0.0001 at all sites).
BMAT (Table 2) was significantly greater in participants with anorexia nervosa (0.96 ± 0.08 lipid/water) compared to normal-weight participants (0.51 ± 0.03 lipid/water) at the L4 vertebra (p<0.0001) and the femoral metaphysis (anorexia nervosa: 4.83 [3.65, 7.08] lipid/water versus normal-weight: 2.84 [2.15, 4.62] lipid/water; p=0.001). With respect to parameters of bone microarchitecture (Table 2), cortical thickness and trabecular bone volume fraction (BV/TV) were significantly lower at both the radius and tibia in women with anorexia nervosa as compared to normal-weight subjects (p ≤ 0.01 for all analyses). Estimates of bone strength (stiffness and failure load) were similarly lower in subjects with anorexia nervosa as compared to normal-weight subjects at the radius and tibia (p<0.001 for all analyses).
Table 2:
Bone marrow adipose tissue, parameters of bone microarchitecture and estimates of bone strength of study participants
| Anorexia nervosa (n=34) | Normal-weight controls (n=28) | p-value | |
|---|---|---|---|
| Bone marrow adipose tissue | |||
| L4 vertebra (lipid/water) | 0.96 ± 0.08 | 0.51 ± 0.03 | <0.0001 |
| Femoral epiphysis (lipid/water) | 7.33 ± 0.50 | 7.66 ± 0.50 | 0.64 |
| Femoral diaphysis (lipid/water) | 6.60 ± 0.60 | 5.55 ± 0.49 | 0.18 |
| Femoral metaphysis (lipid/water)* | 4.83 [3.65, 7.08] | 2.84 [2.15, 4.62] | 0.001 |
| Microarchitecture parameters at radius | |||
| Trabecular BV/TV (%) | 0.111 ± 0.005 | 0.133 ± 0.005 | 0.003 |
| Trabecular number (1/mm)* | 1.75 [1.62, 1.94] | 1.93 [1.81, 2.06] | 0.007 |
| Trabecular thickness (mm)* | 0.063 [0.056, 0.069] | 0.066 [0.061, 0.077] | 0.12 |
| Trabecular separation (mm)* | 0.516 [0.446, 0.547] | 0.455 [0.416, 0.477] | 0.005 |
| Cortical thickness (mm) | 0.67 ± 0.03 | 0.78 ± 0.03 | 0.01 |
| Estimates of bone strength at radius | |||
| Stiffness (kN/mm) | 60.9 ± 2.5 | 72.6 ± 2.3 | <0.0001 |
| Failure load (kN) | 3.1 ± 0.1 | 3.7 ± 0.1 | <0.0001 |
| Microarchitecture parameters at tibia | |||
| Trabecular BV/TV (%) | 0.120 ± 0.006 | 0.147 ± 0.005 | 0.001 |
| Trabecular number (1/mm)* | 1.65 [1.30, 1.92] | 1.80 [1.64, 1.95] | 0.057 |
| Trabecular thickness (mm) | 0.074 ± 0.002 | 0.081 ± 0.002 | 0.03 |
| Trabecular separation (mm)* | 0.523 [0.451, 0.695] | 0.472 [0.437, 0.540] | 0.04 |
| Cortical thickness (mm)* | 0.96 [0.88, 1.06] | 1.19 [1.11, 1.23] | 0.0001 |
| Estimates of bone strength at tibia | |||
| Stiffness (kN/mm) | 168.1 ± 6.9 | 206.6 ± 5.6 | <0.0001 |
| Failure load (kN) | 8.5 ± 0.3 | 10.4 ± 0.3 | <0.0001 |
Data are reported as mean ± SEM unless not normally distributed, in which case median [interquartile range] is reported and denoted by an asterisk (*)
Association between BMD and parameters of bone microarchitecture and fractures
In the group as a whole (n=62), 27 participants reported a history of fracture. There were no significant differences in BMD at any site when comparing subjects with a history of fracture to those without a history of fracture (Table 3). Similarly, in the group of participants with anorexia nervosa (Table 3), there were no significant differences in BMD at any site in study participants with a history of fracture compared to those without (p ≥ 0.27 at all sites). There were also no significant differences in BMD at any site in the group of normal-weight participants when comparing those with versus those without a history of fracture (p ≥ 0.16 at all sites).
Table 3:
Bone mineral density, bone microarchitecture parameters and estimates of bone strength in premenopausal women with versus those without a history of fracture and in the subset of women with anorexia nervosa with versus without a history of fracture
| Fracture (n=27) | No fracture (n=35) | p-value | Anorexia nervosa with fracture (n=16) | Anorexia nervosa without fracture (n=18) | p-value | |
|---|---|---|---|---|---|---|
| Bone mineral density (BMD) | ||||||
| Lumbar spine BMD (g/cm2) | 0.880 ± 0.031 | 0.887 ± 0.019 | 0.84 | 0.762 [0.683, 0.879] | 0.827 [0.732, 0.908] | 0.27 |
| Lateral spine BMD (g/cm2) | 0.683 ± 0.025 | 0.686 ± 0.020 | 0.92 | 0.568 [0.522, 0.672] | 0.596 [0.558, 0.638] | 0.70 |
| Total Hip BMD (g/cm2) | 0.841 ± 0.026 | 0.850 ± 0.023 | 0.81 | 0.762 ± 0.026 | 0.763 ± 0.025 | 0.98 |
| Femoral neck BMD (g/cm2) | 0.725 ± 0.025 | 0.733 ± 0.022 | 0.81 | 0.656 ± 0.025 | 0.665 ± 0.023 | 0.80 |
| Distal 1/3 radius (g/cm2) | 0.692 ± 0.009 | 0.690 ± 0.009 | 0.88 | 0.677 ± 0.012 | 0.689 ± 0.014 | 0.52 |
| Total body BMD (g/cm2) | 0.984 ± 0.018 | 0.995 ± 0.015 | 0.64 | 0.938 ± 0.023 | 0.959 ± 0.023 | 0.52 |
| Microarchitecture parameters at radius | ||||||
| Trabecular BV/TV (%) | 0.115 [0.089, 0.138] | 0.119 [0.109, 0.139] | 0.28 | 0.103 ± 0.008 | 0.118 ± 0.005 | 0.14 |
| Trabecular number (1/mm) | 1.77 [1.70, 1.98] | 1.84 [1.69, 2.05] | 0.46 | 1.73 [1.60, 1.95] | 1.79 [1.62, 1.90] | 0.69 |
| Trabecular thickness (mm) | 0.064 ± 0.002 | 0.067 ± 0.002 | 0.30 | 0.061 ± 0.002 | 0.067 ± 0.003 | 0.12 |
| Trabecular separation (mm) | 0.510 [0.440, 0.535] | 0.470 [0.426, 0.530] | 0.42 | 0.519 [0.447, 0.567] | 0.505 [0.444, 0.547] | 0.57 |
| Cortical thickness (mm) | 0.70 ± 0.04 | 0.74 ± 0.03 | 0.35 | 0.65 ± 0.05 | 0.69 ± 0.04 | 0.55 |
| Estimates of bone strength at radius | ||||||
| Stiffness (kN/mm) | 66.1 ± 2.9 | 66.1 ± 2.4 | 0.98 | 60.2 [44.4, 74.7] | 58.3 [53.9, 65.6] | 0.72 |
| Failure load (kN) | 3.4 ± 0.1 | 3.3 ± 0.1 | 0.98 | 3.1 [2.2, 3.7] | 3.0 [2.8, 3.2] | 0.62 |
| Microarchitecture parameters at tibia | ||||||
| Trabecular BV/TV (%) | 0.128 ± 0.008 | 0.135 ± 0.005 | 0.89 | 0.114 ± 0.011 | 0.124 ± 0.008 | 0.47 |
| Trabecular number (1/mm) | 1.69 [1.48, 1.91] | 1.78 [1.54, 1.94] | 0.46 | 1.55 ± 0.11 | 1.65 ± 0.08 | 0.44 |
| Trabecular thickness (mm) | 0.077 ± 0.003 | 0.078 ± 0.002 | 0.84 | 0.072 ± 0.003 | 0.076 ± 0.003 | 0.43 |
| Trabecular separation (mm) | 0.515 [0.450, 0.579] | 0.491 [0.435, 0.564] | 0.53 | 0.523 [0.452, 0.828] | 0.523 [0.446, 0.641] | 0.64 |
| Cortical thickness (mm) | 1.06 [0.93, 1.19] | 1.09 [0.91, 1.23] | 0.58 | 0.97 [0.88, 1.06] | 0.96 [0.87, 1.08] | 0.93 |
| Estimates of bone strength at tibia | ||||||
| Stiffness (kN/mm) | 188.4 ± 8.8 | 183.3 ± 6.1 | 0.63 | 173.3 ± 11.3 | 163.5 ± 8.3 | 0.49 |
| Failure load (kN) | 9.5 ± 0.4 | 9.3 ± 0.3 | 0.71 | 8.8 ± 0.6 | 8.3 ± 0.4 | 0.51 |
Data are reported as mean ± SEM unless not normally distributed, in which case median [interquartile range] is reported
In the group as whole, there were no statistically significant differences in bone microarchitecture parameters (Table 3) or estimated bone strength at the radius or tibia in participants with a history of fracture as compared to those without a history of fracture (p ≥ 0.28 for all analyses). In the subjects with anorexia nervosa (Table 3), there were also no significant differences in parameters of bone microarchitecture or estimated bone strength at the radius or tibia when comparing individuals with a history of fracture to those without a history of fracture (p ≥ 0.12 for all analyses). In the normal-weight participants, there was similarly no differences in parameters of bone microarchitecture or estimated bone strength at the radius or tibia when comparing individuals with a history of fracture to those without (p ≥ 0.34 for all analyses).
Association between BMAT and fractures
In the group as a whole, BMAT at the L4 vertebra was significantly greater in participants with a history of fracture (0.81 [0.48, 1.27] lipid/water) than in those without a history of fracture (0.55 [0.36, 0.88] lipid/water, p=0.02) (Table 4). This difference remained significant after controlling for BMI (p=0.02) and when controlling for BMD of the lumbar spine (p=0.02). In the group as a whole, BMAT at the L4 vertebra and femoral metaphysis were inversely associated with BMD at the spine and hip (Table 5). When separating the group into those with a history of fracture (n=27) and those without (n=35), the inverse association between BMAT at the L4 vertebra and femoral metaphysis and BMD was stronger in those with a history of fracture as compared to those without. In participants with a history of fracture, the correlation coefficients for BMAT at the L4 vertebra and BMD at the spine and hip ranged from rho = −0.66 to −0.86 as compared to −0.34 to −0.45 in those without a history of fracture (Table 5).
Table 4:
Bone marrow adipose tissue at the spine and hip in premenopausal women with versus those without a history of fracture and in the subset of women with anorexia nervosa with versus without a history of fracture
| Fracture (n=27) | No fracture (n=35) | p-value | Anorexia nervosa with fracture (n=16) | Anorexia nervosa without fracture (n=18) | p-value | |
|---|---|---|---|---|---|---|
| Bone marrow adipose tissue | ||||||
| L4 vertebra (lipid/water) | 0.81 [0.48, 1.27] | 0.55 [0.36, 0.88] | 0.02 | 1.18 ± 0.12 | 0.77 ± 0.10 | 0.01 |
| Femoral epiphysis (lipid/water) | 7.99 ± 0.43 | 7.08 ± 0.52 | 0.18 | 8.21 ± 0.59 | 6.54 ± 0.75 | 0.09 |
| Femoral diaphysis (lipid/water) | 6.78 ± 0.69 | 5.62 ± 0.46 | 0.17 | 8.19 ± 0.95 | 5.18 ± 0.61 | 0.01 |
| Femoral metaphysis (lipid/water) | 3.66 [2.61, 5.81] | 4.45 [2.66, 6.24] | 0.75 | 5.65 ± 0.61 | 5.09 ± 0.55 | 0.50 |
Data are reported as mean ± SEM unless not normally distributed, in which case median [interquartile range] is reported
Table 5:
Univariate associations between bone marrow adipose tissue at the vertebra and femur and bone mineral density at the spine and hip.
| All study participants (n=62) |
Participants with history of fracture (n=27) |
Participants without history of fracture (n=35) |
|
|---|---|---|---|
| Bone marrow adipose tissue at L4 vertebra | |||
| Bone mineral density at lumbar spine |
rho = −0.52
p < 0.0001 |
rho = −0.66
p = 0.0002 |
rho = −0.34
p = 0.047 |
| Bone mineral density at lateral spine |
rho = −0.58
p < 0.0001 |
rho = −0.74
p < 0.0001 |
rho = −0.45
p = 0.007 |
| Bone mineral density at total hip |
rho = −0.55
p < 0.0001 |
rho = −0.80
p < 0.0001 |
rho = −0.37
p = 0.03 |
| Bone mineral density at femoral neck |
rho = −0.52
p < 0.0001 |
rho = −0.86
p < 0.0001 |
rho = −0.30 p = 0.08 |
| Bone marrow adipose tissue at Femoral Epiphysis | |||
| Bone mineral density at lumbar spine | R = 0.05 p = 0.72 |
R = −0.12 p = 0.57 |
R = 0.19 p = 0.27 |
| Bone mineral density at lateral spine | R= −0.04 p = 0.78 |
R= −0.11 p = 0.57 |
R= 0.02 p = 0.93 |
| Bone mineral density at total hip | R = −0.02 p = 0.89 |
R = −0.22 p = 0.27 |
R = 0.10 p = 0.57 |
| Bone mineral density at femoral neck | R = −0.05 p = 0.69 |
R = −0.21 p = 0.30 |
R = 0.04 p = 0.83 |
| Bone marrow adipose tissue at Femoral Diaphysis | |||
| Bone mineral density at lumbar spine | R = −0.14 p = 0.28 |
R = −0.29 p = 0.14 |
R = 0.09 p = 0.63 |
| Bone mineral density at lateral spine | R= −0.07 p = 0.58 |
R= −0.28 p = 0.16 |
R= 0.18 p = 0.32 |
| Bone mineral density at total hip | R = −0.05 p = 0.72 |
R = −0.13 p = 0.52 |
R = 0.05 p = 0.79 |
| Bone mineral density at femoral neck | R = −0.07 p = 0.57 |
R = −0.15 p = 0.44 |
R = 0.01 p = 0.94 |
| Bone marrow adipose tissue at Femoral Metaphysis | |||
| Bone mineral density at lumbar spine |
rho = −0.35
p = 0.005 |
rho = −0.48
p = 0.01 |
R = −0.25 p = 0.16 |
| Bone mineral density at lateral spine |
rho = −0.48
p < 0.0001 |
rho = −0.59
p = 0.001 |
R = −0.34 p = 0.049 |
| Bone mineral density at total hip |
rho = −0.40
p = 0.001 |
rho = −0.47
p = 0.01 |
R = −0.27 p = 0.12 |
| Bone mineral density at femoral neck |
rho = −0.39
p = 0.002 |
rho = −0.46
p = 0.015 |
R = −0.28 p = 0.11 |
Pearson correlation coefficients (R) are reported unless data were not normally distributed, in which case Spearman’s coefficients (rho) are reported
In the participants with anorexia nervosa, BMAT was also significantly greater in subjects with a history of fracture as compared to those without at the L4 vertebra (with fracture: 1.18 ± 0.12 lipid/water versus without fracture: 0.77 ± 0.10 lipid/water, p=0.01) and at the femoral diaphysis (with fracture: 8.19 ± 0.95 lipid/water versus without fracture: 5.18 ± 0.61 lipid/water, p=0.01). These differences remained significant when controlling for BMI (p=0.03 for BMAT at the L4 vertebra and p=0.04 for BMAT at the femoral diaphysis). These results also remained significant when controlling for BMD (p= 0.02 when controlling for BMD of the lumbar spine for BMAT at the L4 vertebra and p=0.02 when controlling for BMD of the total hip for BMAT at the femoral diaphysis). When we controlled for duration of amenorrhea, the results were no longer significant at the L4 vertebra (p=0.14) but remained significant at the femoral diaphysis (p=0.01), suggesting that duration of amenorrhea may be a mediator in the association between BMAT and fracture history at the spine but not the hip. In the group of normal-weight controls, there were no significant differences in BMAT at any site in subjects with a history of fracture as compared to those without (p ≥ 0.12 at all sites).
Discussion:
Our data demonstrate that in contrast to BMD and bone microarchitecture, BMAT distinguishes women with anorexia nervosa and a history of fracture from those without. In women with anorexia nervosa, those with a history of fracture had higher BMAT at the L4 vertebra and the femoral diaphysis. Although these results remained significant after controlling for BMI and BMD, when controlling for duration of amenorrhea, women with anorexia nervosa and a history of fracture continued to have higher levels of BMAT at the femoral diaphysis but not the L4 vertebra suggesting that hypoestrogenemia may mediate the association between fractures and BMAT at the spine but not the hip.
Low BMD is a well-described characteristic of anorexia nervosa. Approximately 85% of adult women with anorexia nervosa have a BMD at least one standard deviation lower than that of women of similar age[3] and multiple studies have demonstrated that adolescent girls, women and men with anorexia nervosa also have an increased risk of fracture compared to normal-weight individuals of similar age[4–7]. Although low BMD is a predictor of fracture risk in post-menopausal women[30], studies to date have not demonstrated an association between BMD and fracture history in anorexia nervosa[5, 9]. In fact, at least two prior studies have demonstrated the opposite, that girls and women with a history of fracture are more likely to have higher BMD as compared to those without[5, 10]. We also did not find an association between BMD and fracture history in women with anorexia nervosa, supporting the fact that BMD may not be helpful in discriminating between individuals with a history of fracture compared to those without in this population.
We also did not find an association between bone microarchitecture parameters and fracture history in women with anorexia nervosa. Although a prior study demonstrated deficient trabecular microstructure in women with a history of fracture compared to those without, the study included individuals with anorexia nervosa as well as normal-weight women and obese women[22]. Whether bone microarchitecture parameters are able to discriminate between those with a history of fracture versus those without in the population of women with anorexia nervosa alone was not evaluated. In adolescents with anorexia nervosa, trabecular bone score -- a method of estimating bone texture using DXA images of the lumbar spine – has also not been useful in distinguishing between those with a history of fracture compared to those without[31]. Therefore, data to date do not suggest that bone microarchitecture parameters are able to discriminate between those with and without a history of fracture in the population of girls and women with anorexia nervosa, though sample sizes are generally relatively small.
In contrast, we show that BMAT was able to discriminate between women with anorexia nervosa with a prior history of fracture compared to those without. Importantly, given the fact that the fractures occurred prior to our measurement of BMAT, we are not able to discern whether the increased BMAT in this population occurs as a response to the fracture, or is a predisposing factor which increases the risk of fracture. In studies inclusive of postmenopausal women and aging individuals, BMAT has been associated with an increased risk of prevalent vertebral fractures[15, 16]. Differences in BMAT composition have also been associated with incident and prevalent fractures; higher saturated lipid content is associated with fragility fractures, vertebral fractures and in men with a mean age 82.6 years, increased saturated lipid content is also associated with an increased risk of clinical fracture[17, 32]. Importantly, in these populations of postmenopausal and older individuals, and in contrast to girls and women with anorexia nervosa, lower BMD is also associated with an increased risk of fracture[30, 33]. Therefore, associations that are observed in postmenopausal and older-aged populations cannot be extrapolated to premenopausal women with anorexia nervosa.
Interestingly, when controlling for duration of amenorrhea, we found that the association between BMAT at the spine and fracture history was no longer significant as compared to the association between femoral BMAT and fracture history, which remained significant even after controlling for amenorrhea. In postmenopausal women, treatment with estradiol is associated with a decrease in marrow adipocyte volume fraction obtained from transiliac bone biopsies[34] and in premenopausal women with anorexia nervosa, treatment with estradiol leads to a significant decrease in BMAT at the spine but not the femur[35]. Therefore, the potential association between BMAT and bone fragility may be influenced by estrogen-status and may play a more significant role in the spine than in the hip in premenopausal populations.
Limitations of our study include the cross-sectional study design and the assessment of BMAT after the occurrence of self-reported fractures. The fact that we were able to discern an association between BMAT and fracture history in a relatively small population though suggests that a strong association exists between BMAT and fracture history. Our normal-weight control population also had a relatively high fracture-history rate (and one that was not significantly different from the women with anorexia nervosa); therefore, it’s possible that this control group was more similar to the anorexia nervosa group than we had anticipated and may explain why although BMAT at the femoral diaphysis – a site that discriminated between those with a history of fracture and those without in anorexia nervosa – was higher in women with anorexia nervosa as compared to the normal-weight group, the difference was not statistically significant. The fact that we were able to detect a significant association between BMAT and fracture history in this more homogenous group provides further support for these findings. It is important to note though that prospective studies have not yet been performed looking at the utility of bone microarchitecture or BMAT in predicting fractures in individuals with anorexia nervosa. Future prospective studies will be necessary to better understand the pathophysiologic role of BMAT in the low bone mass characteristic of anorexia nervosa and to identify modalities to predict fractures in this population.
Acknowledgements:
We would like to thank the nurses and bionutritionists of the MGH Translational and Clinical Research Center for their expert care. The project described was supported by grants UL 1TR002541 (The Harvard Clinical and Translational Science Center, National Center for Advancing Translational Sciences), UL1 RR025758 (Harvard Clinical and Translational Science Center), 1S10RR023405 (National Center for Research Resources) and NIH grants R24 DK084970, P30 DK040561, K24DK109940 and R01 HD099139. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Footnotes
Disclosures: PKF is a consultant for Regeneron and Strongbridge Biopharma. Tran Dang, Alexander Faje, Erinne Meenaghan, Miriam Bredella, Mary Bouxsein and Anne Klibanski declare they have no conflict of interest.
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