Original studies
The Effect of Estrogen-Progestin Treatment on Bone Mineral Density in Anorexia Nervosa

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Abstract

Introduction: Osteopenia is a serious complication of anorexia nervosa (AN). Although in other states of estrogen deficiency, estrogen replacement therapy increases bone mass, its role in AN remains unresolved.

Study Objective: To study the effect of estrogen-progestin administration on bone mass in AN.

Design, Setting, and Participants: A prospective observational study of 50 adolescents with AN (mean age 16.8 ± 2.3 yrs) was conducted in a tertiary referral center.

Main Outcome Measures: Bone mineral density (BMD) of the lumbar spine and left hip were prospectively measured using dual-energy x-ray absorptiometry at baseline and annually.

Interventions: Twenty-two subjects received estrogen-progestin and 28 standard treatment (Rx) alone. Estrogen-progestin was administered daily as an oral contraceptive containing 20–35 mcg ethinyl estradiol. All subjects received calcium supplementation and the same medical, psychological, and nutritional intervention (standard Rx). Mean length of follow-up was 23.1 ± 11.4 months.

Results: At presentation, patients were malnourished (79.5% ± 7.6% IBW), hypoestrogenemic (estradiol 24.7 ± 10.7 pg/mL), and had reduced bone mass (lumbar spine BMD −2.01 ± 0.69 SD below the young adult reference mean). Ninety-two percent of subjects were osteopenic and 26% met WHO criteria for osteoporosis. Body weight, and no treatment group, was the major determinant of BMD. At one-year follow-up, there were no significant differences in absolute values or in net change of lumbar spine or femoral neck BMD between those who received estrogen-progestin and those who received standard Rx (80% power of finding a 3% difference in BMD at 1 yr). In those followed for 2–3 yrs, osteopenia was persistent and in some cases progressive.

Conclusion: In our study population, estrogen-progestin did not significantly increase BMD compared with standard Rx. These results question the common practice of prescribing hormone replacement therapy to increase bone mass in AN.

Introduction

Osteoporosis affects an estimated 25 to 30 million American adults, primarily postmenopausal women.1 The development of osteoporosis and fractures in later life depends not only on the rate of bone loss in adulthood, but also on the amount of bone present at skeletal maturity.2 Peak bone mass is achieved during the late stages of pubertal development,3, 4, 5, 6, 7 and in females, very little net gain in bone mineral density occurs following 2 years postmenarche.4, 6 Anorexia nervosa is a disease of adolescence that affects 1 in 200 adolescent females and is associated with profound osteopenia and increased fracture risk.8 The degree of osteopenia depends on the age of onset and duration of amenorrhea and is due, in part, to estrogen deficiency.9

In other states of estrogen deficiency, estrogen replacement therapy prevents further bone loss. In both postmenopausal women and women who have undergone oophorectomy, maximal effect is obtained when estrogen replacement is begun within two years of natural or surgical menopause.10 Progesterone alone, in the form of cyclic medroxyprogesterone, has also been found to increase bone density in young active women with amenorrhea and other menstrual disturbances.11 The oral contraceptive pill contains both estrogen and progestin and is simpler to take than the sequential estrogen-followed-by-progestin regimen commonly used in postmenopausal women. Furthermore, low-dose oral contraceptive pills contain approximately three times the equivalent dose of estrogen compared with the standard postmenopausal regimen. Low-dose oral contraceptive pills have been widely used in adolescents with few side effects.12

The efficacy of either estrogen alone or combination estrogen-progestin in the treatment of osteopenia of anorexia nervosa remains unresolved. In a retrospective study, Seeman et al showed that adult women with anorexia nervosa who had been on oral contraceptives, had higher bone density at the lumbar spine than those with no contraceptive exposure.13 Seeman suggested that the use of oral contraceptives should be given serious consideration as part of the treatment of anorexia nervosa, and in clinical practice, oral contraceptives are widely prescribed for this purpose. In the only prospective randomized placebo-controlled trial published to date, Klibanski et al found that in adults with anorexia nervosa, estrogen replacement therapy did not significantly increase bone mineral density when compared with placebo.14

Adolescence is a crucial time for the development of peak bone mass and data from studies in adults cannot necessarily be applied to adolescents. To our knowledge, there have been no published prospective trials that have demonstrated the efficacy of either estrogen replacement therapy or combination estrogen-progestin for osteopenia in anorexia nervosa in the adolescent age group. Our objective was to evaluate whether combination estrogen-progestin treatment increased bone mineral density in adolescents with anorexia nervosa. We hypothesized that at one-year follow-up, adolescents treated with estrogen-progestin would have greater net increases in lumbar vertebral and femoral neck bone mineral densities than those who received standard treatment.

Section snippets

Subjects

Fifty subjects were enrolled from patients with anorexia nervosa who were being treated at the Eating Disorders Center of Schneider Children's Hospital of Long Island Jewish Medical Center. Eligible subjects were adolescent females between 13 and 21 yr who met DSM-IV criteria for anorexia nervosa.15 All subjects had either primary amenorrhea or secondary amenorrhea of greater than 6 months duration.

Subjects were excluded from participation if they were already receiving hormonal therapy (such

Results

Baseline clinical and demographic data of the 50 subjects enrolled in the study are shown in Table 1. Both caloric and calcium intake were low and energy expenditure was high. Mean length of amenorrhea in those who had previously menstruated was 16.0 ± 8.8 months. As expected, on presentation, patients were malnourished, hypoestrogenemic, and osteopenic. On initial evaluation, 46 patients (92%) had a lumbar spine bone mineral density more than 1.0 SD below the young adult reference range

Discussion

The major finding of our study is that contrary to our hypothesis, in our population of adolescents with anorexia nervosa, estrogen-progestin did not significantly increase bone mineral density when compared with standard treatment. Despite weight gain and supplementation of calcium and vitamin D, bone mineral density did not increase significantly in either of the treatment groups.

Our results are in agreement with those of Klibanski et al, who studied adults (mean age 23.7 yr) and found that

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