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Osteoporosis in Eating Disorders: A Follow-Up Study of Patients with Anorexia and Bulimia Nervosa

Departments of General Internal and Psychosomatic Medicine (S.Z., B.L., W.H.), and Endocrinology and Metabolism (M.J.S., C.K.), University of Heidelberg, 69115 Heidelberg, Germany; and Department of Psychological Medicine (P.J.B.), University of Sydney, New South Wales 2006, Australia

Address all correspondence and requests for reprints to: Stephan Zipfel, M.D., Department of General Internal and Psychosomatic Medicine, University of Heidelberg, Bergheimer Strasse 58, 69115 Heidelberg, Germany. E-mail: stefan_zipfel{at}med.uni-heidelberg.de

Abstract

This study prospectively investigated the course of bone mineral density (BMD) in patients with anorexia nervosa (AN) and bulimia nervosa (BN) over a 3.6-yr follow-up period. From an initial sample of 47 female patients with an eating disorder (T1), 38 (n = 24 AN; n = 14 BN) were reassessed at follow-up (T2) (participation rate, 80.1%). For nonrecovered AN patients at T2, prevalence rates of osteopenia (-1.0 SD T-score > -2.5 SD) and osteoporosis (T-score -2.5 SD) at the lumbar spine were 54.2 and 20.8%, respectively. Due to an annual loss of lumbar spine BMD (-3.7 ± 4.9%) in the chronic AN patients and a slight but insignificant annual increase (0.7 ± 1.7%) for those who recovered, the difference in BMD between both outcome groups was more pronounced at follow-up (0.93 ± 0.13 vs. 1.14 ± 0.13 g/cm²; P < 0.01). Nonrecovered AN patients with binge eating/purging type showed a significantly reduced BMD compared with patients with the restricting type (0.87 ± 0.13 vs. 1.02 ± 0.08 g/cm²; P = 0.02). Both at baseline and follow-up, AN patients had increased rates of bone resorption, as measured by urinary desoxypyridinoline, compared with a control group (n = 42) (11.4 ± 4.4 vs. 10.4 ± 7.8, P < 0.001, vs. 5.6 ± 2.4 and 10.4 ± 7.8 nM/mM creatinine, P < 0.05, respectively). The subtype of AN and body mass index were best predictors for BMD at the lumbar spine at follow-up (R² = 0.576). With one exception, all bulimic patients had BMD and markers of bone turnover within the normal range. These results suggest that patients with chronic AN, particularly of the binge eating/purging type, are at high risk for osteoporosis and may need additional therapy to prevent bone loss.

EATING DISORDERS HAVE become an important health concern in all industrialized countries, with a prevalence rate of 0.5% for anorexia nervosa (AN) and 2% for bulimia nervosa (BN) (1). It has been shown that the chronic course of AN is related to significant morbidity (2, 3, 4), with one of the most serious medical complications being severe osteopenia (5, 6, 7). In up to 50% of young female anorexics, spinal bone mineral density (BMD) has been reported to be more than 2 SD below normal (6, 7). Anorexic patients with an average duration of illness of 5.8 yr were found to have an annual fracture rate seven times greater than healthy women of the same age (8). Osteoporotic-related fractures were reported in 44% of chronic anorexic patients in the poor outcome group at long-term follow-up (5, 9).

BN is an eating disorder characterized by bingeing and purging behavior and is typically diagnosed in patients with a normal weight [Diagnostic and Statistical Manual of Mental Disorders, ed 4 (DSM-IV)] (10). Over the past 10 yr, several studies have investigated the risk of osteoporosis in patients with BN, and often these studies have produced conflicting results. For example, Newman and Halmi (11) found no difference in BMD between bulimic patients and controls, whereas Joyce et al. (12) found that bulimic patients had significantly lower BMD at the radial and trochanteric bone than expected in a matched normal population. Furthermore, Newton et al. (13) demonstrated that patients diagnosed with BN had a significantly lower mean BMD of lumbar spine (L2–L4) than controls.

Many questions remain regarding the etiology and course of bone loss in patients with eating disorders. Bone turnover has been shown to be influenced by several factors, including estrogen (E) deficiency, glucocorticoid excess, malnutrition, reduced body mass, and hyperactivity (14, 15). However, the course of bone loss is unknown, because most studies are cross-sectional and have focused only on patients with chronic outcome (>6 yr) or investigated heterogeneous groups with a broad range of duration of illness. Studies investigating recovery from osteoporosis have also yielded conflicting results. Some authors have concluded that recovery is possible for some patients, whereas others suggest that only partial improvement of BMD is attainable (3, 16, 17, 18).

The purpose of the present study was to prospectively determine the course of BMD and bone turnover in patients with AN and BN across a 3.6-yr follow-up period. We attempted to answer the following questions: 1) What is the course of BMD in patients with AN and BN 3.6 yr after initial inpatient treatment, and does subgroup classification and outcome of the eating disorder have an impact on BMD? 2) Are these differences related to bone turnover and its hormonal regulation? 3) Which parameters are the best predictors of BMD at the lumbar spine at follow-up?

Materials and Methods

Study population

From an initial sample of 51 patients with a history of an eating disorder consecutively admitted to the eating disorder unit at the University Hospital at Heidelberg, Germany, for inpatient or outpatient treatment between 1993 and 1996, 47 patients were included at baseline (T1). Four patients had to be excluded due to an additional illness or treatment known to affect bone status (two patients with inflammatory bowel disease; one with severe renal insufficiency, treated with glucocorticoids; and one comorbid diabetes mellitus type I). After a mean follow-up period of 3.6 ± 1.5 yr (T2), patients were reassessed at the eating disorder unit. A complete set of data (T1 and T2) could be gathered for 38 patients (participation rate 80.8%). At admission, consent for participation in the follow-up study was obtained from the entire sample.

At baseline, patients were diagnosed according to the DSM-IV criteria (10) with either AN (16 restricting type and 8 binge-eating/purging type) or BN (9 purging type and 5 nonpurging type). According to the DSM-IV, the restricting subtype describes presentations in which weight loss is accomplished primarily through dieting or fasting. In contrast, the binge-eating/purging subtype is used when the individual has regularly engaged in binge eating or purging (or both). Purging behavior is characterized by vomiting or the misuse of laxatives, diuretics, or enemas. None of the BN patients had a history of AN. According to Ward et al. (18), the recovery criteria for follow-up (T2) were a body mass index (BMI) of more than 18.5 kg/m² and the resumption of menses for at least 6 months. Nine former anorexic patients showed a recovery, whereas 15 patients still met the full criteria for AN (7 restricting, 8 binge-eating/purging type). In the BN group, five patients had fully recovered from their eating disorder, four patients were still bulimic, and five were classified as eating disorder not otherwise specified. The patient group meeting diagnostic criteria of bulimia or eating disorder not otherwise specified was classified as bulimic and compared with the fully recovered BN (Rec_BN) patients. All patients were evaluated using a structured interview, which specifically assessed risk factors for osteoporosis. A detailed history regarding the course of the illness was also taken. Relative E exposure was defined as the actual time of E exposure divided by the expected total time of E exposure. Total time of E exposure equals time of regular menstruation, pregnancy, or use of contraceptives; expected time of E exposure equals age minus age at menarche. A potential effect of AN on age at menarche was neglected, because the average age at the beginning of the disease was almost 18 yr (5).

In addition, an age-matched group of healthy female controls (n = 42) was assessed for skeletal status and bone turnover. A careful history was taken to ensure that the control subjects had neither a history of an eating disorder nor other medical illnesses known to affect bone health. The study was approved by the Ethics Committee of the University of Heidelberg, and written consent was obtained from all participants before participation.

Measurement of BMD

Body composition and BMD at the lumbar spine (L2–L4) were measured by dual energy x-ray absorptiometry (DXA) (DPX-L; Lunar Corp., Madison, WI) equipped with software for an adult population (version 1.3z). Values were compared with previously published age- and sex-matched control samples, measured with the same protocol using the same device (19). The coefficient of variation (CV = SD/mean) was 0.79% for the lumbar spine (L2–L4) BMD, as determined by daily cross calibration by phantom measurement, using the manufacturer’s device-specific phantom. DXA scans for the determination of lumbar spine were conducted on the same Lunar Corp. DPX-L at baseline (T1) and follow-up (T2). At the lumbar spine, patients were categorized as having normal BMD (T-score > -1.0 SD), osteopenia (-1.0 SD T-score > -2.5 SD), or osteoporosis (T-score -2.5 SD), according to World Health Organization criteria.

Biochemical parameters

Biochemical markers of bone turnover and hormonal parameters were measured in all patients at T1 and T2, and in controls at follow-up (T2). All specimens were collected between 0800 and 1000 h, after an overnight fast. Serum and urine samples were processed and frozen within 2 h of collection. Serum calcium, phosphorous, and total alkaline phosphatase (TAP Pharmaceuticals, Inc., Lake Forest, IL) were measured using an automated colorimetric assay (BM Hitachi System 704 analyzer, Roche Molecular Biochemicals, Mannheim, Germany). Intraassay and interassay variations were less than 5% for all assays. Human intact serum osteocalcin (OC) was detected with a competitive luminescence immunoassay (LUMItest osteocalcin, Brahms Diagnostica, Berlin, Germany). CVs were less than 10% for intraassay variance and less than 15% for interassay variance. Urinary immunoreactive free desoxypyridinoline (DPD) was determined by a specific ELISA (Pyrilin KS-D, Metra Biosystems, Mountain View, CA) as described earlier (20, 21, 22, 23). CVs were below 10% for intraassay variance and 12–15% for interassay variance. Values were corrected for urinary creatinine, measured in a Beckmann II creatinine analyzer using the Jaffe Rate technique with alkaline picrate (nM DPD/mM creatinine). LH in serum was measured with the Chiron Corp. (Emeryville, CA) Diagnostics ACS:180 Automated Chemiluminescence System (normal range, 1–10 U/liter; CV 6.0%). FSH in serum (FSH) was also measured by the Chiron Diagnostics ACS:180 (Chiron Corp., Emeryville, CA) (normal range, 1–11 U/liter). Expected results of the serum samples taken from 524 healthy individuals were as follows: 1) follicular phase, median, 5.6; range, 2.5–10.2; 2) midcycle peak, median, 9.0; range, 3.4–33.4; and 3) luteal phase, median, 2.9; range, 1.5–9.1. Intraassay total CV was 4.6%. Serum cortisol was measured using the 100T kit of the Nichols Institute Diagnostics (0800 h, 50–250 µ/liter). Sensitivity is 0.8 µg/liter, intraassay CV is 4.0%, and interassay CV is 8.0%.

Statistical analysis

The data were evaluated using SPSS for Windows (Release 10.0) (SPSS, Inc., Chicago, IL). Unless otherwise noted, descriptive parameters are expressed as mean ± SD. To compare group differences, t tests were performed. In case of skew distribution or inhomogeneous variance, Wilcoxon 2-sample tests were computed. Rank correlations (Spearman correlation coefficient) were used to determine the degree of relationship between BMD and clinical parameters at follow-up (T2). Multiple stepwise regression analyses were performed using clinical data from AN patients to identify predictors of BMD at the lumbar spine (L2–L4). A stepwise forward algorithm was used, with the inclusion or exclusion P value set at 0.05. All group comparisons were conducted as explorative analysis, meaning no adjustment of P values was made.

Results

Baseline characteristics (T1)

There were no significant differences between age at onset (17.8 ± 3.7 vs. 17.6 ± 4.1 yr) and age at first admission (21.0 ± 4.2 vs. 21.8 ± 2.9 yr) between the 24 patients diagnosed with AN and the 14 patients diagnosed with BN. Mean duration of illness for AN and BN before inpatient treatment (T1) was 3.2 ± 0.5 and 4.2 ± 1.2 yr, respectively. Weight and BMI at baseline were 39.6 ± 6.8 kg and 13.7 ± 1.7 kg/m² for the AN patients and 52.4 ± 9.4 kg and 20.0 ± 2.1 kg/m² for the BN group, respectively. The menstrual history of AN and BN patients revealed a period of secondary amenorrhea of 2.9 ± 2.6 vs. 0.6 ± 0.6 yr, respectively. Baseline BMD (T1) at the lumbar spine was reduced (T-score, -1.08 ± 1.51 SD) for the AN patients and in the normal range (T-score, 0.05 ± 0.93 SD) for the BN group.

Body composition and BMD in the outcome groups

At follow-up (T2), there were no age differences between the different outcome groups and the control group (F = 1.04; P = 0.39). At baseline and follow-up, weight and body composition of Rec_AN patients differed significantly compared with the nonrecovered group (Table 1). Mean BMI at follow-up for the nonrecovered AN group was 14.5 ± 2.0 kg/m², indicating that these patients were still markedly underweight. This finding is also reflected by a low fat mass (4.9 ± 3.1 kg) and a mean percentage of body fat of 11.8 ± 6.4%, as measured by DXA.

View larger version (14K): [in this window] [in a new window]   Figure 1. BMD at the lumbar spine (L2–L4) in AN and Rec_AN patients, as well as BN and Rec_BN patients at follow-up. The subgroup of AN patients still suffering had a significantly lower (*, P < 0.01) lumbar spine BMD compared with the Rec_AN patients. The box-length represents the range from the first to the third quartile, including the median. The whiskers extend to the smallest and largest observation, and circles represent outlying values more than 1.5 box-lengths from the 75th percentile.

View larger version (16K): [in this window] [in a new window]   Figure 2. Shown are percentages of annual change of lumbar spine BMD plotted against the BMI at follow-up in both patient groups. Values of the AN patients are indicated by circles, and values of the BN patients are indicated by triangles.

A stepwise multivariate regression analysis was performed to evaluate the contribution of clinical parameters to BMD at the lumbar spine at follow-up. The following variables were entered in the model: age at onset, duration of illness, E exposure, duration of ERT, AN subtype, BMI at T2, and minimal BMI since onset of illness. For anorexic patients, lumbar spine BMD (g/cm²) was best predicted by the subtype of AN (binge eating/purging type vs. restricting type), which explained 39.6% (F = 13.5; P = 0.002) followed by the BMI at follow-up, which explained an additional 18.0% of the variance in lumbar spine BMD (F = 13.9; P < 0.001). Thus, the total model explained 57.6% of the variance of BMD (g/cm²) at the lumbar spine for the anorexic group. In anorexic patients, neither the duration of ERT nor E exposure were independent predictors for BMD at follow-up. Due to the relatively small number of BN patients demonstrating only marginal variations in lumbar spine BMD, no regression analysis was conducted.

Biochemical parameters

The biochemical parameters for the different AN outcome groups are summarized in Table 2. In AN patients at baseline and follow-up, serum calcium, phosphorous, albumin, PTH, as well as DPD levels were significantly elevated, whereas OC levels were within the normal range. Rec_AN patients revealed the lowest levels in bone formation and bone resorption markers. Mean group differences in biochemical parameters in the BN group were less marked (Table 3). Compared with controls, BN patients at baseline and follow-up had significantly higher serum calcium and serum creatinine levels, whereas only at baseline were DPD levels significantly elevated.

As shown in Table 4, in the group of AN patients, body weight and body composition, duration of secondary amenorrhea, as well as binge eating/purging were associated with lumbar spine BMD (g/cm²) at follow-up. Additional correlations were found between markers of bone turnover, 25OH vitamin D, and serum total alkaline phosphate. Purging behavior was significantly associated with OC (r = 0.47; P = 0.027) and DPD levels (r = 0.53; P = 0.011). OC and DPD levels showed a high intercorrelation (r = 0.82; P < 0.001). For the bulimic group, only lean body mass, relative E exposure, and serum total alkaline phosphate were associated with lumbar spine BMD at follow-up.

In a further step, both subgroups of AN patients still suffering (binge eating/purging type and restricting type) were directly compared with respect to their bone status. Patients with a binge eating/purging type had a significantly lower lumbar spine BMD at follow-up (Fig. 3), compared with the subgroup with restricting type (0.87 ± 0.13 vs. 1.02 ± 0.08 g/cm²; P = 0.02). This difference was independent of initial lumbar spine BMD (P = 0.23), the actual BMI at T2 (P = 0.34) and baseline (P = 0.61), lean body mass (P = 0.85), age at onset (P = 0.80), and duration of illness (P = 0.46). Although both groups had a similar duration of illness, patients with the binge eating/purging type had a significantly longer duration of amenorrhea (P = 0.01), compared with the restricting type patients. Consequently, the binge-eating/purging subgroup showed an elevated bone turnover with higher levels of DPD (12.8 vs. 4.8; P = 0.04) and a tendency for OC levels in the same direction (11.9 vs. 5.5; P = 0.08). Serum phosphorous levels were significantly associated with OC and DPD levels (r = 0.66, P = 0.001 vs. r = 6.7, P = 0.001, respectively).

View larger version (14K): [in this window] [in a new window]   Figure 3. Shown are the significantly different BMD values (*, P = 0.02) at the lumbar spine (L2–L4) between the subgroup of restricting (n = 7) vs. binge eating/purging (n = 8) anorexic patients at follow-up. The whiskers extend to the smallest and largest observation, and circles represent outlying values more than 1.5 box-lengths from the 75th percentile.

For anorexic patients, this study found high prevalence rates of osteopenia (34.8 vs. 54.2%) and osteoporosis (13.0 vs. 20.8%) at the lumbar spine at a mean duration of illness of 3 (T1) and 7 yr (T2). These rates are in agreement with current data from a large community-based study examining a sample of women with AN (24). In our prospective study, significant differences were found between the subgroup with a chronic course and those who had achieved recovery at follow-up. In addition to an average increase of more than five BMI points, with similar improvements in fat mass and percentage of body fat, significant differences in BMD at the lumbar spine were found between the outcome groups. With an annual loss in BMD at the lumbar spine of 3.7%, thus representing a group of fast-losers, the nonrecovered patients reached a mean T-score of -1.7 SD. This fast loss of bone mass is comparable to findings from an earlier study that found an annual bone loss among anorexic patients of about 3% after conducting serial CT investigations at the lumbar spine (25). In contrast, the subgroups of recovered patients already had a more favorable course of illness at baseline with respect to weight, duration of illness, secondary amenorrhea, and lumbar spine BMD, and demonstrated a slight but insignificant annual increase in bone mass (0.7%) during the follow-up period. This finding is partly consistent with a study by Klibanski et al. (26), which demonstrated that a subgroup of fully recovered patients, all of whom had an initial percentage ideal body weight of greater than 70%, had a total increase of 19.3% of BMD at the lumbar spine. Although these results are partly promising, some disagreement still exists as to whether full recovery is possible, particularly for those anorexic patients with a long and serious course. For example, one recent cross-sectional study demonstrated an unexpectedly high rate of persistent osteopenia (78%) following recovery from AN (18). Another study, (17) examining 19 recovered anorexic women at 21 yr postrecovery, while showing reduced BMD at the femoral neck, found that patient BMD at the lumbar spine was not significantly different from that of controls. Our data indicate that weight gain in particular plays a crucial role in the process of normalization of bone mass at the lumbar spine. This finding is in accordance with Hotta et al. (27) who demonstrated that markers of bone metabolism were normal in a subsample of patients whose BMI reached at least 16.5 kg/m². The result of the regression analysis to predict bone mass at follow-up revealed a similar finding. Besides the subtype of AN, weight at follow-up was the best predictor of BMD at the lumbar spine in the anorexic group. However, it should be noted that there is an increasing body of literature investigating the potential influence of body composition on the accuracy of BMD measurement by DXA (28). A recent large-scale cross-sectional study (29) investigated the association between bone size and volumetric density in women with AN. Karlsson et al. (29) reported that a substantial proportion of the deficit in bone mass in anorexic patients was due to smaller bone size. Recovery from illness was associated with near-normal bone size and volumetric BMD. However, incomplete recovery of lean and fat mass may account for part of the remaining deficit in bone size, but not volumetric BMD.

Although weight was a strong predictor of lumbar spine BMD in our intermediate-term follow-up study, the variance of lumbar spine BMD in patients with similar weight indicates that more factors are involved [e.g. genetic predisposition (30)]. With the identification of the subtype of AN, we were able to identify an additional illness-related predictor for lumbar spine BMD. In keeping with an overall long-term poor general outcome (31), our intermediate term results indicate that AN patients of the binge eating/purging subtype are at an increased risk of developing osteoporosis. This result was independent of initial bone mass, weight history, and duration of illness. However, the purging patients did experience significantly lower E exposure, which may explain the development of bone loss in this particular group. A similar result was found in a study by Baker et al. (32) that showed the value of the frequency of vomiting in predicting lumbar spine BMD. The exact underlying mechanisms need to be further investigated.

To date, few studies have longitudinally evaluated bone turnover in patients suffering from AN and BN, and these studies have yielded mostly conflicting results (33, 34, 35, 36, 37). For patients with AN, some authors have reported high resorption rates and normal to low bone formation rates (25, 37), whereas others have found no change in bone metabolism (35). Grinspoon et al. (7) demonstrated significantly increased rates of bone resorption with decreased rates of bone formation in a pretreatment group of AN patients. In our study, the anorexic patients at baseline and the subgroup of nonrecovered anorexic patients at follow-up both showed an elevated bone resorption but normal bone formation. Similar findings of an uncoupling of bone turnover processes were recently described by Stefanis et al. (36). Over longer periods of time, such an uncoupling of bone formation and resorption is likely to cause a net loss of bone mass. Again, the subgroup of AN patients with binge eating/purging type in our study showed the highest bone resorption. However, the recovered patients showing mainly an unchanged lumbar spine BMD at follow-up had a pattern of low bone turnover with both decreased bone resorption and bone formation activity. Despite the resumption of menses in the recovered patients, this group continued to have comparably low E, FSH, and LH levels. This finding may be important in explaining the reduced state of bone formation in this particular group. In chronic anorexic patients, the mean FSH level was found to be more than twice the mean LH level, a finding consistent with hypothalamic amenorrhea (8, 38, 39, 40). In our study, E exposure was associated with BMD at the lumbar spine, but was not an independent predictor. This finding partly confirms earlier cross-sectional studies that found duration of E deficiency associated with BMD at the lumbar spine (5, 26, 39, 40). However, Grinspoon et al. (41) reported that the severity of osteopenia was greater in anorexic patients when compared with an age-matched sample of patients with hypothalamic amenorrhea without a history of an eating disorder. Karlsson et al. (29) showed that women with AN who were treated with ERT had higher volumetric BMD values and bone size relative to untreated AN patients.

At follow-up, both bulimic patient outcome groups (recovered and nonrecovered) had mean BMD values at the lumbar spine within the normal range, with only one bulimic patient in the range of osteopenia. This finding is consistent with other cross-sectional studies that have also failed to demonstrate a significant bone loss in normal weight bulimic patients without a history of AN (13, 14, 42). However, an earlier cross-sectional study involving 20 bulimic patients showed that bulimic patients with a history of AN, a persistently low BMI, and prolonged secondary amenorrhea were at risk for osteoporosis (11). Our study confirms that normal weight bulimic patients without a history of AN are not at risk for osteoporosis. This finding is also supported by the pattern of bone turnover at follow-up, with only an insignificantly increased level of the bone resorption marker.

In conclusion, the nonrecovered AN patients demonstrated an increased bone resorption as well as a marked loss of bone mass at the lumbar spine. The subtypes of AN and BMI at follow-up were the best predictors of BMD at the lumbar spine. AN patients with binge eating/purging type had the worst outcome with respect to bone status. Our data indicate that binge eating/purging behavior, in our sample mostly vomiting, is not only a risk factor for poor general outcome (31), but also for the development of osteoporosis. Patients with BN did not show an elevated risk for osteoporosis. Although weight restoration and normalization of eating patterns are recommended as the first line of defense in preventing osteoporosis in patients with eating disorders, further research should investigate the use of osteotropic agents that increase bone formation in anorexic patients at high risk for the development of osteoporosis.

Footnotes

This research was supported by grants from the Medical Faculty, University of Heidelberg (Project No. 161/1997).

Abbreviations: AN, Anorexia nervosa; BMD, bone mineral density; BMI, body mass index; BN, bulimia nervosa; CV, coefficient of variation; DPD, desoxypyridinoline; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, ed 4; DXA, dual energy x-ray absorptiometry; E, estrogen; ERT, E replacement therapy; OC, osteocalcin; Rec_AN, recovered AN; Rec_BN, recovered BN; TAP, total alkaline phosphatase.

Received November 8, 2000.

Accepted August 7, 2001.

References

1. Hsu LK 1996 Epidemiology of the eating disorders. Psychiatr Clin North Am 19:681–700[CrossRef][Medline]
2. Becker AE, Grinspoon SK, Klibanski A, Herzog DB 1999 Eating disorders. N Engl J Med 340:1092–1098[Free Full Text]
3. Beumont PJV, Russell JD, Touyz SW 1993 Treatment of anorexia nervosa. Lancet 341:1635–1640[CrossRef][Medline]
4. Zipfel S, Specht T, Herzog W 1998 Medical complications in eating disorders. In: Hoeck H, Treasure J, Katzman M, eds. The integration of neurobiology in the treatment of eating disorders. New York: Wiley and Sons; 457–484
5. Herzog W, Minne H, Deter C, Leidig G, Schellberg D, Wuster C, Gronwald R, Sarembe E, Kroger F, Bergmann G, Petzold E, Hahn P, Schepank H, Ziegler R 1993 Outcome of bone mineral density in anorexia nervosa patients 11.7 years after first admission. J Bone Miner Res 8:597–605[Medline]
6. Zipfel S, Beumont PJ, Russell J, Herzog W 2000 Osteoporosis in eating disorders. Eur Eat Disorders Rev 8:108–116[CrossRef]
7. Grinspoon S, Baum H, Lee K, Anderson E, Herzog D, Klibanski A 1996 Effects of short-term recombinant human insulin-like growth factor I administration on bone turnover in osteopenic women with anorexia nervosa. J Clin Endocrinol Metab 81:3864–3870[Abstract/Free Full Text]
8. Biller BM, Saxe V, Herzog DB, Rosenthal DI, Holzman S, Klibanski A 1989 Mechanisms of osteoporosis in adult and adolescent women with anorexia nervosa. J Clin Endocrinol Metab 68:548–554[Abstract]
9. Herzog W, Deter HC, Fiehn W, Petzold E 1997 Medical findings and predictors of long-term physical outcome in anorexia nervosa: a prospective, 12-year follow-up study. Psychol Med 27:269–279[CrossRef][Medline]
10. American Psychiatric Association 1994 Diagnostic and statistical manual of mental disorders (DSM-IV), ed 4. Washington, DC: American Psychiatric Association
11. Newman MM, Halmi KA 1989 Relationship of bone density to estradiol and cortisol in anorexia nervosa and bulimia. Psychiatry Res 29:105–112[CrossRef][Medline]
12. Joyce JM, Warren DL, Humphries LL, Smith AJ, Coon JS 1990 Osteoporosis in women with eating disorders: comparison of physical parameters, exercise, and menstrual status with SPA and DPA evaluation. J Nucl Med 31:325–331[Abstract/Free Full Text]
13. Newton JR, Freeman CP, Hannan WJ, Cowen S 1993 Osteoporosis and normal weight bulimia nervosa: which patients are at risk? J Psychosom Res 37:239–247[CrossRef][Medline]
14. Sundgot BJ, Bahr R, Falch JA, Schneider LS 1998 Normal bone mass in bulimic women. J Clin Endocrinol Metab 83:3144–3149[Abstract/Free Full Text]
15. Andersen AE, Woodward PJ, LaFrance N 1995 Bone mineral density of eating disorder subgroups. Int J Eat Disord 18:335–342[Medline]
16. Bachrach LK, Katzman D, Litt IF, Guido D, Marcus R 1991 Recovery from osteopenia in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab 72:602–606[Abstract]
17. Hartman D, Crisp A, Rooney B, Rackow C, Atkinson R, Patel S 2000 Bone density of women who have recovered from anorexia nervosa. Int J Eat Disord 28:107–112[CrossRef][Medline]
18. Ward A, Brown N, Treasure J 1997 Persistent osteopenia after recovery from anorexia nervosa. Int J Eat Disord 22:71–75[CrossRef][Medline]
19. Butz S, Wuster C, Scheidt-Nave C, Gotz M, Ziegler R 1994 Forearm BMD as measured by peripheral quantitative computed tomography (pQCT) in a German reference population. Osteoporos Int 4:179–184[CrossRef][Medline]
20. Robins SP, Woitge H, Hesley R, Ju J, Seyedin S, Seibel MJ 1994 Direct, enzyme-linked immunoassay for urinary deoxypyridinoline as a specific marker for measuring bone resorption. J Bone Miner Res 9:1643–1649[Medline]
21. Robins SP, Black D, Paterson C, Reid D, Duncan A, Seibel MJ 1991 Evaluation of urinary hydroxypyridinium crosslink measurement as resorption markers in metabolic bone disease. Eur J Clin Invest 21:310–315[Medline]
22. Seibel MJ, Baylink DJ, Farley JR, Epstein S, Yamauchi M, Eastell R, Pols HA, Raisz LG, Gundberg CM 1997 Basic science and clinical utility of biochemical markers of bone turnover–a Congress report. Exp Clin Endocrinol Diabetes 105:125–133[Medline]
23. Seibel MJ, Woitge HW, Farahmand I, Oberwittler H, Ziegler R 1998 Automated and manual assays for urinary crosslinks of collagen: which assay to use? Exp Clin Endocrinol Diabetes 106:143–148[Medline]
24. Grinspoon S, Thomas E, Pitts S, Gross E, Mickley D, Miller K, Herzog D, Klibanski A 2000 Prevalence and predictive factors for regional osteopenia in women with anorexia nervosa. Ann Intern Med 133:790–794[Abstract/Free Full Text]
25. Ruegsegger P, Muller A, Dambacher MA, Ittner J, Willi J, Kopp HG 1988 Bone loss in female patients with anorexia nervosa. Schweiz Med Wochenschr 118:233–238[Medline]
26. Klibanski A, Biller BM, Schoenfeld DA, Herzog DB, Saxe VC 1995 The effect of estrogen administration on trabecular bone loss in young women with anorexia nervosa. J Clin Endocrinol Metab 80:898–904[Abstract]
27. Hotta M, Shibasaki T, Sato K, Demura H 1998 The importance of body weight history in the occurrence and recovery of osteoporosis in patients with anorexia nervosa: evaluation by dual x-ray absorptiometry and bone metabolic markers. Eur J Endocrinol 139:276–283[Abstract]
28. Bolotin HH, Sievänen H 2001 Inaccuracies inherent in dual-energy x-ray absorptiometry in vivo bone mineral density can seriously mislead diagnostic/prognostic interpretations of patient-specific bone fragility. J Bone Miner Res 16:799–805[CrossRef][Medline]
29. Karlsson MK, Weigall SJ, Duan Y, Seeman E 2000 Bone size and volumetric density in women with anorexia nervosa receiving estrogen replacement therapy and in women recovered from anorexia nervosa. J Clin Endocrionol Metab 85:3177–3182[Abstract/Free Full Text]
30. Eisman JA 1999 Genetics of osteoporosis. Endocr Rev 20:788–804[Abstract/Free Full Text]
31. Zipfel S, Lowe B, Reas DL, Deter HC, Herzog W 2000 Long-term prognosis in anorexia nervosa: lessons from a 21-year follow-up study. Lancet 355:721–722[CrossRef][Medline]
32. Baker D, Roberts R, Towell T 2000 Factors predictive of bone mineral density in eating-disordered women: a longitudinal study. Int J Eat Disord 27:29–35[CrossRef][Medline]
33. Fonseca VA, D’Souza V, Houlder S, Thomas M, Wakeling A, Dandona P 1988 Vitamin D deficiency and low osteocalcin concentrations in anorexia nervosa. J Clin Pathol 41:195–197[Abstract/Free Full Text]
34. Carmichael KA, Carmichael DH 1995 Bone metabolism and osteopenia in eating disorders. Medicine (Baltimore) 74:254–267[CrossRef][Medline]
35. Abrams S, Silber T, Esteban N 1993 Mineral balance and bone turnover in adolescents with anorexia nervosa. J Pediatr 123:326–331[CrossRef][Medline]
36. Stefanis N, Mackintosh C, Abraha HD, Treasure J, Moniz C 1998 Dissociation of bone turnover in anorexia nervosa. Ann Clin Biochem 35:709–716
37. Calero JA, Munoz MT, Argente J, Traba ML, Mendez-Davila C, Garcia-Moreno C, de la Piedra C 1999 A variation in bone alkaline phosphatase levels that correlates positively with bone loss and normal levels of aminoterminal propeptide of collagen I in girls with anorexia nervosa. Clin Chim Acta 285:121–129[CrossRef][Medline]
38. Miller KK, Klibanski A 1999 Clinical review: amenorrheic bone loss. J Clin Endocrinol Metab 84:1775–1783[Free Full Text]
39. Seeman E, Szmukler GI, Formica C, Tsalamandris C, Mestrovic R 1992 Osteoporosis in anorexia nervosa: the influence of peak bone density, bone loss, oral contraceptive use, and exercise. J Bone Miner Res 7:1467–1474[Medline]
40. Iketani T, Kiriike N, Nakanishi S, Nakasuji T 1995 Effects of weight gain and resumption of menses on reduced bone density in patients with anorexia nervosa. Biol Psychiatry 37:521–527[CrossRef][Medline]
41. Grinspoon S, Miller K, Coyle C, Krempin J, Armstrong C, Pitts S, Herzog D, Klibanski A 1999 Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea. J Clin Endocrinol Metab 84:2049–2055[Abstract/Free Full Text]
42. Goebel G, Schweiger U, Kruger R, Fichter MM 1999 Predictors of bone mineral density in patients with eating disorders. Int J Eat Disord 25:143–150[CrossRef][Medline]

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