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Effects of Recombinant Human IGF-I and Oral Contraceptive Administration on Bone Density in Anorexia Nervosa

Neuroendocrine Unit (S.G., L.T., K.M., A.K.), and the Adolescent Eating Disorders Unit (D.H.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Steven Grinspoon, M.D., Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: . sgrinspoon{at}partners.org

Abstract

Over 90% of women with anorexia nervosa demonstrate osteopenia, and almost 40% demonstrate osteoporosis at one or more skeletal sites. In addition to estrogen deficiency causing an increase in bone resorption, nutritional effects on the GH–IGI-I axis may contribute to the severe bone loss in this population by decreasing bone formation. We tested the hypothesis that recombinant human IGF-I (rhIGF-I) would increase bone density in women with anorexia nervosa and furthermore assessed the effects of combined rhIGF-I and oral contraceptive administration (OCP) in this population. Sixty osteopenic women with Diagnosis and Statistical Manual of Mental Disorders IV Revised confirmed anorexia nervosa [age (25.2 ± 0.7 yr, range 18–38 yr), body mass index (17.8 ± 0.3 kg/m² ), spinal bone mineral density T score (-2.1 ± 0.1 SD) were randomized to one of four treatment groups [rhIGF-I (30 µg/kg sc twice daily) and a daily oral contraceptive (Ovcon 35, 35 µg ethinyl estradiol and 0.4 mg norethindrone], rhIGF-I alone (30 µg/kg sc twice daily), oral contraceptive alone, or neither treatment for 9 months. All subjects received calcium 1500 mg/d and a standard multivitamin containing 400 IU of vitamin D. Administration of rhIGF-I was placebo controlled and blinded to subjects. The rhIGF-I was titrated to maintain IGF-I levels within the age-adjusted normal range for each patient and was well tolerated. The effects of rhIGF-I and OCP were analyzed simultaneously among all subjects in a factorial analysis and in an analysis of the four individual treatment groups. Anteroposterior spinal bone density increased significantly in response to rhIGF-I (1.1% ± 0.5% vs. -0.6% ± 0.8%, P = 0.05, all rhIGF-I vs. all placebo treated, respectively, by analysis of covariance). In contrast, OCP did not result in increased bone density (0.8% ± 0.6% vs. -0.4% ± 0.8%, P = 0.21, all OCP vs. all non-OCP treated, respectively, by analysis of covariance). However, bone density increased to the greatest extent in the combined treatment group (rhIGF-I and OCP), compared with control patients receiving no active therapy (1.8% ± 0.8% vs. 0.3% ± 0.6% vs. -0.2% ± 0.8% vs. -1.0% ± 1.3%, rhIGF-I and OCP vs. rhIGF-I alone vs. OCP alone vs. no active therapy, P < 0.05 for rhIGF-I and OCP vs. no active therapy). These data demonstrate that osteopenic women with anorexia nervosa treated with rhIGF-I showed more beneficial changes in bone density, compared with patients not treated with rhIGF-I. Antiresorptive therapy with OCP is not sufficient to improve bone density in undernourished patients, but such therapy may augment the effects of rhIGF-I in a combined treatment strategy. Further long-term studies are needed to investigate the effects of rhIGF-I and combined anabolic/antiresorptive strategies on bone in women with anorexia nervosa.

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