Profound osteopenia is a frequent and often irreversible complication of anorexia nervosa (AN). Adolescents with AN often have a reduced peak bone mass and are at increased risk for early osteoporosis and fractures. These young women have subnormal serum levels of gonadal steroids and the adrenal androgen dehydroepiandrosterone (DHEA) that may be associated with their low bone mineral density (BMD). Low DHEA levels are accompanied by decreased levels of insulin-like growth factor I (IGF-I), estrogen, and testosterone. Previous data from our group indicate that oral DHEA therapy in young women with AN: increases lean body mass, serum levels of bone formation markers and IGF-I, and decreases urinary markers of bone resorption. We also found that standard hormonal replacement therapy (HRT) significantly decreased bone resorption markers. Information on the effects of these therapies on bone strength and ultimate fracture risk is lacking. In this project, we will test the hypothesis that combined therapy with DHEA and estrogen/progestin will enhance bone mass in patients with AN through anabolic and antiosteolytic mechanisms. We will test the hypothesis that 18 months of DHEA + HRT will increase BMD and markers of bone formation, while decreasing bone resorption markers in these patients. The proposed study will examine whether restoring normal levels of DHEA and estrogen in these young women will increase bone mass during a critical period for bone accretion. The study will also examine whether DHEA's anabolic effects on bone are mediated through the skeletal IGF-I regulatory system. Using cross-sectional analyses of dual energy x-ray absorptiometry (DXA) data, we will also measure indices of bone structural geometry to determine if mechanical strength is compromised in these young women, and if strength is restored in response to combined anabolic/antiresorptive therapy. To gain new information on the mechanisms underlying bone loss and fracture risk in young women with AN, our research goals are:
Specific Aim 1 : Through a randomized controlled trial, to measure the effects of an 18-month course of DHEA + HRT on bone mass, markers of bone turnover, and serum levels of IGF-I compared to placebo.
Specific Aim 2 : To determine whether combined therapy with adrenal and gonadal steroid replacement changes bone structure to increase strength compared to placebo, as assessed through cross-sectional geometric analysis of DXA data.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Winer, Karen
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Children's Hospital Boston
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DiVasta, Amy D; Feldman, Henry A; Beck, Thomas J et al. (2014) Does hormone replacement normalize bone geometry in adolescents with anorexia nervosa? J Bone Miner Res 29:151-7
Divasta, Amy D; Feldman, Henry A; Gordon, Catherine M (2014) Vertebral fracture assessment in adolescents and young women with anorexia nervosa: a case series. J Clin Densitom 17:207-11
Pitts, Sarah; Blood, Emily; Divasta, Amy et al. (2014) Percentage body fat by dual-energy X-ray absorptiometry is associated with menstrual recovery in adolescents with anorexia nervosa. J Adolesc Health 54:739-41
Divasta, Amy D; Feldman, Henry A; Giancaterino, Courtney et al. (2012) The effect of gonadal and adrenal steroid therapy on skeletal health in adolescents and young women with anorexia nervosa. Metabolism 61:1010-20
Divasta, Amy D; Feldman, Henry A; Brown, Julia N et al. (2011) Bioavailability of vitamin D in malnourished adolescents with anorexia nervosa. J Clin Endocrinol Metab 96:2575-80
DiVasta, Amy D; Walls, Courtney E; Feldman, Henry A et al. (2010) Malnutrition and hemodynamic status in adolescents hospitalized for anorexia nervosa. Arch Pediatr Adolesc Med 164:706-13
Divasta, Amy D; Gordon, Catherine M (2010) Hormone replacement therapy and the adolescent. Curr Opin Obstet Gynecol 22:363-8
Ecklund, Kirsten; Vajapeyam, Sridhar; Feldman, Henry A et al. (2010) Bone marrow changes in adolescent girls with anorexia nervosa. J Bone Miner Res 25:298-304
DiVasta, Amy D; Feldman, Henry A; Quach, Ashley E et al. (2009) The effect of bed rest on bone turnover in young women hospitalized for anorexia nervosa: a pilot study. J Clin Endocrinol Metab 94:1650-5
Haagensen, A L; Feldman, H A; Ringelheim, J et al. (2008) Low prevalence of vitamin D deficiency among adolescents with anorexia nervosa. Osteoporos Int 19:289-94

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