Anorexia nervosa (AN) is an increasingly common disorder in adolescent girls, with a prevalence of 0.2 to 1.0% in Western societies. Adolescence is a critical time for bone mineral accretion as more than 90% of peak bone mass is established during this time, and peak bone mass is a major determinant of osteoporosis and fracture risk throughout life. Factors critical to the marked increase in bone mass through puberty include rising levels of estrogen, and estrogen induced increases in growth hormone and insulin like growth factor-1 (IGF-1). Low bone density is a frequent complication of adolescents with AN, and is concerning for increased fracture risk. Mechanisms underlying the low bone density characteristic of AN include profound estrogen deficiency and very low levels of IGF-1. Thus far, there are no established therapies to maximize bone mass accrual and peak bone mass in teenagers with AN, and prevent fractures. Although AN is associated with profound IGF-1 and estrogen deficiency, both of which are critical to bone development, effects of administration of recombinant human rhIGF-1 with estrogen versus estrogen alone has not been investigated in adolescents with this disorder. In addition, the effect of AN on bone microarchitecture, a better indicator of fracture risk than bone density or bone strength, has not been prospectively examined. In the current proposal, effects of administration of rhIGF-1 and estrogen versus estrogen alone will be studied. In the first specific aim we will prospectively investigate the effect of rhIGF-1 and estrogen vs. estrogen alone on bone density and bone turnover in adolescent girls with AN and compare bone accrual to normal adolescents. In the second aim, we will investigate the effects of rhIGF-1 and estrogen on bone microarchitecture and bone strength in adolescents with AN. These studies will be essential in developing strategies to address the profound loss of bone accrual seen in this large population of adolescent girls at high fracture risk.

Public Health Relevance

Low bone density is characteristic of anorexia nervosa, a condition that is very prevalent in Adolescence. Because these years are critical to attainment of peak bone mass, an important determinant of bone health and fracture risk in later life, the onset of anorexia nervosa in the adolescent years is particularly worrisome. This proposal will examine possible therapeutic strategies to increase bone density and optimize peak bone mass in adolescents with anorexia nervosa.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062249-07
Application #
8254392
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (04))
Program Officer
Malozowski, Saul N
Project Start
2002-07-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
7
Fiscal Year
2012
Total Cost
$703,692
Indirect Cost
$249,639
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Misra, Madhusmita; Klibanski, Anne (2014) Anorexia nervosa and bone. J Endocrinol 221:R163-76
Singhal, Vibha; Misra, Madhusmita; Klibanski, Anne (2014) Endocrinology of anorexia nervosa in young people: recent insights. Curr Opin Endocrinol Diabetes Obes 21:64-70
Misra, Madhusmita; Klibanski, Anne (2014) Endocrine consequences of anorexia nervosa. Lancet Diabetes Endocrinol 2:581-92
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Ouyang, Suidong; Hsuchou, Hung; Kastin, Abba J et al. (2014) Leukocyte infiltration into spinal cord of EAE mice is attenuated by removal of endothelial leptin signaling. Brain Behav Immun 40:61-73
Faje, Alexander T; Karim, Lamya; Taylor, Alex et al. (2013) Adolescent girls with anorexia nervosa have impaired cortical and trabecular microarchitecture and lower estimated bone strength at the distal radius. J Clin Endocrinol Metab 98:1923-9
Misra, Madhusmita; Katzman, Debra K; Clarke, Hannah et al. (2013) Hip structural analysis in adolescent boys with anorexia nervosa and controls. J Clin Endocrinol Metab 98:2952-8
Misra, Madhusmita; Katzman, Debra K; Estella, Nara Mendes et al. (2013) Impact of physiologic estrogen replacement on anxiety symptoms, body shape perception, and eating attitudes in adolescent girls with anorexia nervosa: data from a randomized controlled trial. J Clin Psychiatry 74:e765-71
Faje, Alexander T; Fazeli, Pouneh K; Katzman, Debra et al. (2013) Inhibition of Pref-1 (preadipocyte factor 1) by oestradiol in adolescent girls with anorexia nervosa is associated with improvement in lumbar bone mineral density. Clin Endocrinol (Oxf) 79:326-32
Misra, Madhusmita; Klibanski, Anne (2011) Bone health in anorexia nervosa. Curr Opin Endocrinol Diabetes Obes 18:376-82

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