Adolescent girls with anorexia nervosa (AN) exhibit hormonal abnormalities that predispose to alterations in bone turnover, accrual, and modeling that can ultimately lead to irreversible skeletal deficits. The current investigators have a longtime interest in how hormonal alterations in this disease lead to changes in bone marrow composition and skeletal losses. The proposed project builds on a recent double-blind, placebo- controlled trial of dehydroepiandrosterone (DHEA) and estrogen replacement therapy (ERT) in adolescents with AN. The current investigators have shown that this combined anabolic + antiresorptive regimen mitigated bone loss of the axial skeleton as evidenced by dual-energy x-ray absorptiometry (DXA) measures of the spine and whole body. There is interest in whether this therapeutic regimen also affects the appendicular skeleton, a question of high clinical importance as young adolescents fracture extremities much more commonly than the axial skeleton. Preliminary data from the current group have also shown that adolescents with AN exhibit shifts from red to yellow (fatty) marrow with progression of disease and develop increased marrow fat. These young women, who paradoxically have depleted subcutaneous fat, have increased fat within bone marrow, with potential adverse long-term consequences for bone formation, bone accretion during adolescence, and ultimately, lifetime skeletal health. Further research is needed to determine whether this conversion of red to yellow marrow in adolescents mirrors findings in adults indicating an associated decreased bone density and increased fracture risk. This proposal seeks to investigate this question through a novel clinical trial of combined therapy with DHEA+ERT on bone mineral density (BMD) and bone marrow composition, examining the role of hormonal factors in the conversion of red to yellow marrow and relation of findings to appendicular BMD. Over the one-year trial, state-of-the-art imaging techniques will be employed, including peripheral quantitative computed tomography (pQCT), visual assessments of magnetic resonance imaging (MRI) data, MR relaxometry and magnetic resonance spectroscopy to measure bone mineral density and evaluate bone marrow composition, respectively. We also seek to understand hormonal mediators of the changes observed in both bone density and bone marrow composition, including adrenal and gonadal steroids, insulin-like growth factors, growth hormone, and ghrelin, adiponectin, and leptin. The proposed project will test hypotheses raised by the pilot imaging data, in particular whether hormonal abnormalities in girls with AN influence mesenchymal stem cells to differentiate preferentially into adipocytes over osteoblasts. Enhancing understanding of the mechanisms underlying skeletal losses in this young patient population has the potential to fill critical knowledge gaps that will improve the care of adolescents with AN. Knowledge gained from this study may also have application to other diseases across the age spectrum that are associated with bone loss and involve alterations in bone marrow composition.

Public Health Relevance

This project seeks to understand the mechanisms behind a promising new therapy, a combined regimen of dehydroepiandrosterone + estrogen replacement therapy, for adolescents with anorexia nervosa, through a randomized controlled trial. The proposal will explore effects of this combined regimen on both bone density of the peripheral skeleton and bone marrow composition, and will examine how hormonal factors mediate skeletal losses and alter marrow composition in this disease. Enhancing understanding of the mechanisms underlying skeletal losses in this young patient population will fill critical knowledge gaps that will potentially improve the care of adolescents with anorexia nervosa.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Chen, Faye H
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Children's Hospital Boston
United States
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Vajapeyam, Sridhar; Ecklund, Kirsten; Mulkern, Robert V et al. (2018) Magnetic resonance imaging and spectroscopy evidence of efficacy for adrenal and gonadal hormone replacement therapy in anorexia nervosa. Bone 110:335-342
DiVasta, Amy D; Feldman, Henry A; O'Donnell, Jennifer M et al. (2017) Effect of Exercise and Antidepressants on Skeletal Outcomes in Adolescent Girls With Anorexia Nervosa. J Adolesc Health 60:229-232
Ecklund, Kirsten; Vajapeyam, Sridhar; Mulkern, Robert V et al. (2017) Bone marrow fat content in 70 adolescent girls with anorexia nervosa: Magnetic resonance imaging and magnetic resonance spectroscopy assessment. Pediatr Radiol 47:952-962
DiVasta, A D; Feldman, H A; O'Donnell, J M et al. (2016) Skeletal outcomes by peripheral quantitative computed tomography and dual-energy X-ray absorptiometry in adolescent girls with anorexia nervosa. Osteoporos Int 27:3549-3558
Donaldson, Abigail A; Feldman, Henry A; O'Donnell, Jennifer M et al. (2015) Spinal Bone Texture Assessed by Trabecular Bone Score in Adolescent Girls With Anorexia Nervosa. J Clin Endocrinol Metab 100:3436-42
Donaldson, Abigail A; Gordon, Catherine M (2015) Skeletal complications of eating disorders. Metabolism 64:943-51
DiVasta, Amy D; Mulkern, Robert V; Gordon, Catherine M et al. (2015) MR Imaging in a case of severe anorexia nervosa: the 'flip-flop' effect. Pediatr Radiol 45:617-20
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
Bialo, Shara R; Gordon, Catherine M (2014) Underweight, overweight, and pediatric bone fragility: impact and management. Curr Osteoporos Rep 12:319-28

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