David B. Herzog

Osteoporosis in women with anorexia nervosa.

Because estrogen deficiency predisposes to osteoporosis, we assessed the skeletal mass of women with anorexia nervosa, using direct photon absorptiometry to measure radial bone density in 18 anorectic women and 28 normal controls. The patients with anorexia had significantly reduced mean bone density as compared with the controls (0.64 +/- 0.06 vs. 0.72 +/- 0.04 g per square centimeter, P less than 0.001). Vertebral compression fractures developed in two patients, and bone biopsy in one of them demonstrated osteoporosis. Bone density in the patients was not related to the estradiol level (r = 0.02). Levels of parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were normal despite low calcium intakes. The patients with anorexia who reported a high physical activity level had a greater bone density than the patients who were less active (P less than 0.001); this difference could not be accounted for by differences in age, relative weight, duration of illness, or serum estradiol levels. The bone density of physically active patients did not differ from that of active or sedentary controls. We conclude that women with anorexia nervosa have a reduced bone mass due to osteoporosis, but that a high level of physical activity may protect their skeletons.

Recovery and Relapse in Anorexia and Bulimia Nervosa: A 7.5-Year Follow-up Study

OBJECTIVE To assess the course and outcome of anorexia nervosa (AN) and bulimia nervosa (BN) at a median of 90 months of follow-up in a large cohort of women with eating disorders. METHOD A prospective, naturalistic, longitudinal design was used to map the course of AN and BN in 246 women. Follow-up data are presented in terms of full and partial recovery, predictors of time to recovery, and rates and predictors of relapse. RESULTS The full recovery rate of women with BN was significantly higher than that of women with AN, with 74% of those with BN and 33% of those with AN achieving full recovery by a median of 90 months of follow-up. Intake diagnosis of AN was the strongest predictor of worse outcome. No predictors of recovery emerged among bulimic subjects. Eighty-three percent of women with AN and 99% of those with BN achieved partial recovery. Approximately one third of both women with AN and women with BN relapsed after full recovery. No predictors of relapse emerged. CONCLUSIONS The findings suggest that the course of AN is characterized by high rates of partial recovery and low rates of full recovery, while the course of BN is characterized by higher rates of both partial and full recovery.

Prevalence and predictive factors for regional osteopenia in women with anorexia nervosa.

Anorexia nervosa is highly prevalent among U.S. women (1, 2) and is associated with substantial bone loss (3-6). Bone loss in women with this disorder is multifactorial; is related in part to estrogen deficiency and to direct effects of undernutrition (3, 4, 7); and is rapid, often occurring within 6 months of disease onset (4) and persisting to some degree after weight recovery (8). It is important to determine the prevalence of regional bone loss at different skeletal sites because it may predict site-specific fracture rates (9). We therefore measured bone mineral density (BMD) at several skeletal sites to determine the prevalence rates and predictive factors of regional osteopenia and osteoporosis in a large community-based sample of women with anorexia nervosa. Methods We studied 130 women with anorexia nervosa recruited through community advertisements and community physician referral. Telephone screening interviews were used to exclude patients who reported normal weight and menses; use of bisphosphonates, calcitonin, or glucocorticoids; or medical conditions other than anorexia nervosa that are known to affect BMD. Women who had regular uterine withdrawal bleeding while receiving estrogen therapy and women with concomitant bulimia nervosa were permitted to participate. Eligible patients underwent a 3-hour outpatient visit at the General Clinical Research Center of the Massachusetts General Hospital in Boston. Height, weight, age at menarche, time since last menstrual period, previous and current estrogen use, fracture history, and frame size were determined. Calcium and vitamin D intake were determined by diet history in a subset of 60 patients. The diagnosis of anorexia nervosa, according to criteria specified in Diagnostic and Statistical Manual of Mental Disorders, fourth edition, was confirmed in all patients (10). All patients gave written consent, as required by the Subcommittee on Human Studies. Bone mineral density at the anteriorposterior lumbar spine (L1L4), lateral spine, left total hip, femoral neck, and greater trochanter was determined with dual-energy x-ray absorptiometry using a Hologic 4500 densitometer (Hologic, Inc., Waltham, Massachusetts) (lumbar spine SD, 0.01 g/cm2) (11). At each skeletal site, 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. Data on BMD in a subset of 30 patients were published previously (7). Wrist and frame size were determined (12, 13), and body mass index and percentage of ideal body weight were calculated (14). Age at menarche and time since last menstrual period were assessed for all patients. Whenever possible, total duration of amenorrhea since menarche was determined (n =78). Current and previous lifetime estrogen use, including type of estrogen, was quantified and categorized for each patient. We used the MantelHaenszel test to compare BMD at the anteriorposterior and lateral spine, stratifying on patients. Standard least-squares multivariate regression models were constructed for each skeletal site by using age, age at menarche, time since last menstrual period, weight, height, wrist size, and fracture history as covariates. Covariates were chosen in advance as important clinical variables affecting BMD. Adjusted regression coefficients and confidence intervals were determined for each covariate. Data are expressed as the mean SE. The funding source had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Clinical data and data on BMD are shown in Table 1. Ninety-eight percent of patients were white and 2% were Asian. Mean T-scores were 1.4 0.1 SD for the anteriorposterior spine, 1.8 0.1 SD for the lateral spine, and 1.4 0.1 SD for the total hip. Twenty-six percent of patients (n =34) reported a history of fracture (foot or ankle [n =6], hand or wrist [n =7], leg [n =1], arm or elbow [n =4], stress fracture [n =5], and other fracture [n =11]). Table 1. Clinical Characteristics of Study Patients and Comparison by Estrogen Use and Menstrual History Osteopenia and osteoporosis, respectively, were seen at the anteriorposterior spine in 50% and 13% of patients, at the lateral spine in 57% and 24% of patients, and at the total hip in 47% and 16% of patients. Normal BMD was seen at the anteriorposterior spine in only 37% of patients, at the lateral spine in 19% of patients, and at the total hip in 37% of patients. Results of lateral and anteriorposterior spinal tests of BMD were discordant in 36 patients, of whom 31 had normal BMD at the anteriorposterior spine (T-score>1.0) but low BMD at the lateral spine (T-score 1.0) (P<0.001). Bone mineral density was reduced by at least 1.0 SD at one or more skeletal sites in 92% of patients and by at least 2.5 SD in 38% of patients. No differences in BMD were observed between patients with anorexia nervosa alone and patients with anorexia nervosa and concomitant bulimia nervosa (P>0.05 at all sites; data not shown). Twenty-three percent of patients were current estrogen users (mean duration, 25.3 5.4 months) and 58% were previous estrogen users (mean duration, 23.9 3.1 months). Bone mineral density did not differ at any site according to current or previous estrogen use (Table 1). Age, body mass index, and age at menarche were similar in the subgroup comparisons according to estrogen status. Oral contraceptives were used in all but 3 of the current estrogen users (10%) and all but 7 of the ever-estrogen users (10%); these 10 women received conjugated estrogen. Similar results were obtained in a subanalysis limited to the patients receiving oral contraceptives (data not shown). Total duration of estrogen use was not correlated with BMD at the anteriorposterior spine, lateral spine, femoral neck, total hip, trochanter, or total body (P>0.10 for all comparisons). Patients with primary amenorrhea (n =7) weighed less and had lower BMD at all sites than patients with secondary amenorrhea (n =123) (Table 1), although sample size was small in the primary amenorrhea group. Total calcium intake was not correlated with BMD at any site (P>0.1 for all sites). Fifty-seven percent of patients were receiving calcium supplements, 53% were receiving a multivitamin containing 400 IU of vitamin D, and 43% were receiving both. Bone mineral density did not differ in patients receiving nutritional supplements (data not shown). Weight was a significant independent predictor of BMD at all skeletal sites (Table 2). Patients with normal BMD, osteopenia, and osteoporosis at the total hip weighed 48.7 0.8 kg, 45.9 0.8 kg, and 39.0 0.7 kg, respectively. Similar trends were seen at other skeletal sites (data not shown). Age at menarche was a significant independent predictor of BMD measured by anteriorposterior spinal densitometry. Time since last menstrual period was a significant predictor of BMD at the anteriorposterior and lateral spine. Our results were similar when we used multivariate regression models with total duration of amenorrhea instead of last menstrual period in patients for whom this information was available (n =78) (data not shown). Table 2. Univariate and Multivariate Regression Analyses Discussion Our data demonstrate the high prevalence and profound degree of site-specific bone loss in women with anorexia nervosa. Our study design had advantages: Patients were recruited from the community and were not preselected for bone loss, and we evaluated bone loss at several skeletal sites. Although weight was highly significant as a predictor of bone loss at all sites, time since last menstrual period and age at menarche were significant predictive factors for BMD at the anteriorposterior spine, suggesting a greater relative influence of estrogen deficiency at this site. Other mechanisms may also contribute to reduced BMD in patients with anorexia nervosa, such as failure to achieve peak BMD, hypercortisolemia, and reduced vitamin D intake (4). However, we did not see any association between calcium or vitamin D intake and BMD. Increased risk for fracture is the major clinical implication of bone loss in women with anorexia nervosa. Fracture risk doubles with each decrease of 1 SD in BMD (9). Our data therefore suggest that patients with anorexia are at a markedly increased risk for fracture at many skeletal sites. A relatively high percentage of patients reported a previous history of fracture, but because radiologic confirmation was not obtained, relative risk for fracture was not determined. Bone mineral density was reduced by at least 1.0 SD at one or more skeletal sites in 97% of women with fractures, but fracture site was not correlated with the location of osteopenia. Although our study was not designed to prospectively investigate the efficacy of estrogen use in women with anorexia nervosa, no effect of previous or current estrogen use on BMD was demonstrated at any skeletal sites. These retrospective data stand in partial contrast to cross-sectional data from a previous study, which suggested an effect of estrogen exposure at the lumbar spine but not at other sites (15). The minimal effect of estrogen exposure on BMD in our study is consistent with that seen in a previous randomized study, which showed no effect of estrogenprogestin replacement therapy on BMD in patients with anorexia nervosa (16). The effectiveness of estrogen in increasing or preserving BMD in women with anorexia nervosa may be mitigated by continued undernutrition, which may act to uncouple bone formation and resorption. We have previously shown that women with anorexia nervosa exhibit low bone formation rates and increased resorption rates (3). Hotta and colleagues (17) have shown that low rates of bone formation in patients with anorexia nervosa increase with feeding, suggesting a mechanism whereby bone formation is reduced by undernutrition and

Psychiatric Comorbidity in Treatment-Seeking Anorexics and Bulimics

Current and lifetime psychiatric diagnoses were compared in 229 female patients seeking treatment for current episodes of anorexia nervosa (N = 41), bulimia nervosa (N = 98) and mixed anorexia nervosa and Schizophrenia-Lifetime Version, which was modified to include a section for DSM-III-R eating disorders, the Longitudinal Interval Follow-up Evaluation, and the Structured Interview for DSM-III Personality Disorders. Seventy-three percent of the anorexia nervosa subjects, 60% of the bulimia nervosa subjects, and 82% of the mixed anorexia nervosa and bulimia nervosa subjects had a current comorbid Axis I diagnosis. Major depression was the most commonly diagnosed comorbid disorder. Low rates of alcohol and substances abuse disorder were diagnosed, and personality disorder occurred in a minority of the sample. The subjects with mixed disorder manifested a higher lifetime prevalence of kleptomania than either the anorexics or the bulimics. High levels of comorbidity were noted across the eating disorder samples. Mixed disorder subjects manifested the most comorbid psychopathology and especially warrant further study.

Mortality in eating disorders: a descriptive study.

OBJECTIVE We report rates and causes of death for a cohort of 246 eating-disordered women and provide descriptive information on their eating disorder and comorbid diagnoses. METHOD Data on mortality were collected as part of a longitudinal study of anorexia nervosa and bulimia nervosa, now in its 11th year. Other data sources included death certificates, autopsy reports, relative interviews, and a National Death Index search. RESULTS Seven deaths have occurred during the study, all among anorexic subjects with a history of binging and purging and with comorbid Axis I disorders. The crude mortality rate was 5.1%. The standardized mortality ratios for death (9.6) and suicide (58.1) were significantly elevated (p <. 001). CONCLUSIONS Anorexia nervosa is associated with a substantial risk of death and suicide. Features correlated with fatal outcome are longer duration of illness, binging and purging, comorbid substance abuse, and comorbid affective disorders.

Effects of anorexia nervosa on clinical, hematologic, biochemical, and bone density parameters in community-dwelling adolescent girls

Objective. Anorexia nervosa (AN) is an eating disorder that leads to a number of medical sequelae in adult women and has a mortality rate of 5.6% per decade; known complications include effects on hematologic, biochemical, bone density, and body composition parameters. Few data regarding medical and developmental consequences of AN are available for adolescents, in particular for an outpatient community-dwelling population of girls who have this disorder. The prevalence of AN is increasing in adolescents, and it is the third most common chronic disease in adolescent girls. Therefore, it is important to determine the medical effects of this disorder in this young population. Methods. We examined clinical characteristics and performed hematologic, biochemical, hormonal, and bone density evaluations in 60 adolescent girls with AN (mean age: 15.8 ± 1.6 years) and 58 healthy adolescent girls (mean age: 15.2 ± 1.8 years) of comparable maturity. Nutritional and pubertal status; vital signs; a complete blood count; potassium levels; hormonal profiles; bone density at the lumbar and lateral spine; total body, hip, and femoral neck (by dual-energy x-ray absorptiometry) and body composition (by dual-energy x-ray absorptiometry) were determined. Results. All measures of nutritional status such as weight, percentage of ideal body weight, body mass index, lean body mass, fat mass, and percentage of fat mass were significantly lower in girls with AN than in control subjects. Girls with AN had significantly lower heart rates, lower systolic blood pressure, and lower body temperature compared with control subjects. Total red cell and white cell counts were lower in AN than in control subjects. Among girls with AN, 22% were anemic and 22% were leukopenic. None were hypokalemic. Mean age at menarche did not differ between the groups. However, the proportion of girls who had AN and were premenarchal was significantly higher compared with healthy control subjects who were premenarchal, despite comparable maturity as determined by bone age. Ninety-four percent of premenarchal girls with AN versus 28% of premenarchal control subjects were above the mean age at menarche for white girls, and 35% of premenarchal AN girls versus 0% of healthy adolescents were delayed >2 SD above the mean. The ratio of bone age to chronological age, a measure of delayed maturity, was significantly lower in girls with AN versus control subjects and correlated positively with duration of illness and markers of nutritional status. Serum estradiol values were lower in girls with AN than in control subjects, and luteinizing hormone values trended lower in AN. Levels of insulin-like growth factor-I were also significantly lower in girls with AN. Estradiol values correlated positively with insulin-like growth factor-I, a measure of nutritional status essential for growth (r = 0.28). All measures of bone mineral density (z scores) were lower in girls with AN than in control subjects, with lean body mass, body mass index, and age at menarche emerging as the most important predictors of bone density. Bone density z scores of <−1 at any one site were noted in 41% of girls with AN, and an additional 11% had bone density z scores of <−2. Conclusions. A high prevalence of hemodynamic, hematologic, endocrine, and bone density abnormalities are reported in this large group of community-dwelling adolescent girls with AN. Although a number of these consequences of AN are known to occur in hospitalized adolescents, the occurrence of these findings, including significant bradycardia, low blood pressure, and pubertal delay, in girls who are treated for AN on an outpatient basis is of concern and suggests the need for vigilant clinical monitoring, including that of endocrine and bone density parameters.

COMORBIDITY AND OUTCOME IN EATING DISORDERS

This article reviews the data on comorbidity, course, and outcome in anorexia nervosa and bulimia nervosa. Recovery, relapse, the process of recovery, and predictors of outcome are reviewed. Although significant differences exist among outcome studies, the data suggest that patients with anorexia and bulimia tend to improve symptomatically over time. Anorexia nervosa and bulimia nervosa are associated with substantial rates of comorbidity. The relationship between eating disorders and depression, anxiety disorders, substance abuse, and personality disorders is discussed.

Activity, inactivity, and obesity: racial, ethnic, and age differences among schoolgirls.

Physical activity, inactivity, and obesity were assessed by questionnaire among a multiethnic sample of 552 girls in grades 5 through 12. Hispanics and Asians reported lower activity levels than other racial groups. Only 36% of the entire sample and less than one fifth of either Asians or Hispanics met the year 2000 goal for strenuous physical activity. Physical activity was inversely associated with age and age-adjusted body mass index. Obesity was unrelated to inactivity.

Patterns and Predictors of Recovery in Anorexia Nervosa and Bulimia Nervosa

OBJECTIVE The purpose of this study was to assess the course and outcome of anorexia nervosa and bulimia nervosa at 1 year in a large cohort of women with eating disorders. METHOD A prospective, naturalistic, longitudinal design was used to map the course of 225 women with anorexia nervosa, bulimia nervosa, and mixed anorexia and bulimia nervosa. Structured interviews were conducted quarterly. Follow-up data are presented in terms of patterns of recovery, clinical features predictive of time to recovery, and the role of comorbid disorders as fixed predictors. RESULTS The recovery rate of bulimics was significantly better than that of anorexic or mixed subjects, yet nearly half the anorexic and mixed subjects no longer met full DSM-III-R criteria for at least 8 consecutive weeks during the first year of follow-up. Percent ideal body weight and type of eating disorder were significantly associated with outcome. CONCLUSIONS Our findings suggest that the diagnosis of anorexia nervosa has severe implications.

Physiologic Estrogen Replacement Increases Bone Density in Adolescent Girls with Anorexia Nervosa

Anorexia nervosa (AN) is prevalent in adolescents and is associated with decreased bone mineral accrual at a time critical for optimizing bone mass. Low BMD in AN is a consequence of nutritional and hormonal alterations, including hypogonadism and low estradiol levels. Effective therapeutic strategies to improve BMD in adolescents with AN have not been identified. Specifically, high estrogen doses given as an oral contraceptive do not improve BMD. The impact of physiologic estrogen doses that mimic puberty on BMD has not been examined. We enrolled 110 girls with AN and 40 normal‐weight controls 12 to 18 years of age of similar maturity. Subjects were studied for 18 months. Mature girls with AN (bone age [BA] ≥15 years, n = 96) were randomized to 100 µg of 17β‐estradiol (with cyclic progesterone) or placebo transdermally for 18 months. Immature girls with AN (BA < 15 years, n = 14) were randomized to incremental low‐dose oral ethinyl‐estradiol (3.75 µg daily from 0 to 6 months, 7.5 µg from 6 to 12 months, 11.25 µg from 12 to 18 months) to mimic pubertal estrogen increases or placebo for 18 months. All BMD measures assessed by dual‐energy X‐ray absorptiometry (DXA) were lower in girls with AN than in control girls. At baseline, girls with AN randomized to estrogen (AN E + ) did not differ from those randomized to placebo (AN E–) for age, maturity, height, BMI, amenorrhea duration, and BMD parameters. Spine and hip BMD Z‐scores increased over time in the AN E+ compared with the AN E– group, even after controlling for baseline age and weight. It is concluded that physiologic estradiol replacement increases spine and hip BMD in girls with AN.