IGF-I AND BONE LOSS IN WOMEN WITH ANOREXIA NERVOSA

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION (Adapted from the Applicant's Abstract): Anorexia nervosa is an increasingly common disorder among young women, characterized by self-imposed restrictive nutritional practices, which occurs in 0.5 to 1.0% of college age women in the United States. This psychiatric disorder results in significant medical complications, which cause morbidity and increased mortality. One of the most prevalent and predictable co-morbid conditions is osteopenia. Bone loss is a severe, frequent and often permanent co-morbid medical complication of anorexia nervosa, resulting in crush fractures. The majority of young women have evidence of bone loss and 50% of women have bone density measurements greater than 2SD below normal and below the fracture threshold. The extreme rapidity of bone loss in anorexia nervosa is well-documented. Of importance, bone loss can occur in less than one year. Reduced bone mass is often permanent, despite recovery, and such young women will have a permanent increased risk of fractures throughout life. Anorexia nervosa is a unique state of imbalanced bone turnover, with decreased bone formation and increased resorption. In contrast to other states of bone loss associated with estrogen deficiency, estrogen therapy is ineffective in stabilizing or improving bone mass. Therefore, it is suggested that the bone loss seen in anorexia nervosa is unique in terms of severity and pathogenesis. Given the complex medical and compliance issues in patients with this disorder, approaches to the prevention and treatment of osteoporosis differ from other populations. Effective therapy of bone loss during acute illness would reduce fracture risk throughout life. Of importance, a therapeutic intervention may only need to be used for a relatively short period of time while the disease is still active in many patients. Because there are currently no treatments for this serious medical sequela of anorexia nervosa, it is critical to develop efficacious treatment strategies to prevent the significant morbidity associated with osteopenia in this population. Insulin-like growth factor-I is a nutritionally regulated hormone with potent autocrine/paracrine effects on bone growth and remodeling. Anorexia nervosa leads directly to pathologic state of IGF-I deficiency. It is hypothesized that IGF-I administration plays a critical role in normalizing bone turnover and, long-term, will improve bone density and prevent the progressive debilitating osteopenia in young women with anorexia nervosa. The applicants have now demonstrated a dose-dependent effect of short-term rhIGF-I administration to increase markers of bone formation and/or resorption. They note that these are the first data to show that IGF-I can increase bone turnover and, more specifically, bone formation in patients with anorexia nervosa. Because of its effects on bone formation, rhIGF-I may represent a novel approach to treating the severe osteoporosis resulting from anorexia nervosa in young women. In the current proposal, they will investigate the physiology of the effects of acute administration of rhIGF-I to reverse the IGF-I deficiency state. They will investigate the time course of effects on bone turnover and whether rhIGF-I administration has prolonged effects on bone formation. They will determine whether chronic administration of rhIGF-I increases bone mass, and the interaction of IGF-I and gonadal steroids to both increases bone formation and decreases resorption.