DESCRIPTION (provided by applicant): Anorexia Nervosa (AN) affects 0.5-1% of college-aged women in the US and is characterized by extreme, self- induced starvation. Of the many medical co-morbidities associated with AN, severe bone loss is the most common and often persists despite weight recovery. Importantly, this bone loss is associated with an increased risk of fracture; a prospective study demonstrated that women with AN have a 7-fold increased risk of fracture compared to age-matched controls. Therefore, a treatment to prevent the severe bone loss associated with AN is critical, but there are currently no approved treatments for AN-associated bone loss. Amenorrhea and resultant hypoestrogenemia, which are characteristic findings in women with AN, are significant contributors to the loss of bone mass in this disease. This is supported by the fact that duration of amenorrhea is inversely associated with bone mineral density (BMD) in women with AN. Yet, despite this association, initial studies investigating the effects of oral estrogen in women with AN did not demonstrate a benefit. This is likely due to the fact that oral estrogen suppresses production of IGF-I - an important mediator of bone formation. Importantly, IGF-I is a nutritionally-mediated hormone and levels are already low in women with AN and these low levels are an important contributing factor to the low bone mass. Therefore further suppression of IGF-I by oral estrogen can exacerbate the loss of bone mass. Unlike oral estrogen, transdermal estrogen does not have the same IGF-I-suppressing effects and in healthy, postmenopausal women transdermal estrogen increases IGF-I levels. Transdermal estrogen increases BMD in adolescent girls with AN but because bone turnover is quite different in women with AN compared to adolescents, whether transdermal estrogen will improve BMD in older, premenopausal women with AN is currently unknown. Dr. Fazeli is an Assistant Professor of Medicine at Harvard Medical School and Assistant in Medicine at Massachusetts General Hospital (MGH). She is on staff in the Neuroendocrine Unit at MGH and devotes the majority of her time to clinical research. She is well-supported by MGH and has full access to the Neuroendocrine Unit, Clinical Research Center and Harvard Catalyst CTSC resources. Her co-mentors, Drs. Anne Klibanski and Mary Bouxsein, are well-funded and invested in the direction of Dr. Fazeli's research. During the course of her K23 award, Dr. Fazeli has already obtained critical training in biostatistics and research design at the Harvard School of Public Health, from which she earned a Master of Public Health degree. She has also published a first-author paper demonstrating the effects of teriparatide on BMD in women with AN (Specific Aim 1 of her K23 award). If awarded, this grant will support Dr. Fazeli in obtaining critical preliminary data for an R01 application investigating the effects of teriparatide and transdermal estrogen replacement on bone mineral density in older, premenopausal women with AN.

PUBLIC HEALTH RELEVANCE: Anorexia nervosa, a disorder that predominantly affects women, is characterized by extreme, self-induced weight loss and is associated with many medical complications including significant bone loss and an increased risk of fracture. Although the majority of these women have low estrogen levels -- which may be an important contributor to the bone loss - oral estrogen does not increase bone mineral density in adult women with anorexia nervosa. Recently, treatment with transdermal estrogen was found to improve bone mineral density in adolescent girls with anorexia nervosa but because bone turnover is different in adult women with anorexia nervosa as compared to adolescents with the disease, whether transdermal estrogen replacement will improve bone mineral density in adult women with anorexia nervosa is unknown and the focus of this study.