Anorexia nervosa is an increasingly common disorder among young women, characterized by self-imposed restrictive nutritional practices, which occurs in 0.5 to 1% of college-age women in the United States. This psychiatric disorder results in significant medical complications, which cause morbidity and increased mortality. 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 2 SD 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, the bone loss seen in anorexia nervosa is unique in terms of severity and pathogenesis. Given the complex medical 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 sequelae of anorexia nervosa, it is critical to develop efficacious treatment strategies to prevent the significant morbidity associated with osteopenia in this population. Testosterone is a nutritionally regulated endogenous anabolic hormone which stimulates bone formation and has anti-resorptive effects. Anorexia nervosa leads directly to testosterone deficiency. We hypothesize that testosterone plays a critical role in bone turnover and long-term, it's administration will improve bone density and prevent the progressive debilitating osteopenia in young women with anorexia nervosa. We have now demonstrated an effect of short-term testosterone administration to increase markers of bone formation and/or resorption. Because of its effects on bone formation, testosterone may represent a novel approach to treating the severe osteoporosis resulting from anorexia nervosa in young women. We now have preliminary data demonstrating that Actonel, a bisphosphonate, can decrease bone resorption and increase bone mass in these women. In the current proposal we will investigate the physiology of the effects of testosterone administration of rhlGF-I to reverse the androgen deficiency state. We will investigate the effects of testosterone on bone turnover and whether it has prolonged effects on bone density. We will determine whether a combined anabolic and anti-resorptive strategy using testosterone and Actonel will increase bone formation, decrease resorption and increase bone density.
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