The goal of this application is to support my personal development as a clinical investigator and to help me train future clinical investigators. My clinical research program has 4 major areas of investigation: 1) the roles of androgens and estrogens in bone metabolism in men, 2) effects of the menopause transition on bone metabolism (The SWAN Study), 3) anabolic effects of PTH on bone metabolism in men and women, and 4) effects of dietary phosphate on the regulation of FGF23. The first area encompasses many completed, ongoing, and planned studies. We have previously reported the effects of hypogonadism and sex steroid replacement on bone mineral density (BMD) in GnRH-deficient men, men with histories of delayed puberty, and men with adult-onset hypogonadism. We have also reported novel ways to prevent hypogonadism-induced bone loss in men with prostate cancer and have examined the physiological roles of androgens and estrogens in male bone metabolism. In this proposal we plan to determine the specific dose-response relationships between androgens and estrogens and bone metabolism in men. The Study of Women's Health Across the Nation (SWAN) is a large multicenter, multi-ethnic study investigating a wide range of physiologic, endocrinologic, epidemiologic, and psychosocial issues as women transition through the menopause. In SWAN we recently described novel ethnic patterns of BMD and bone turnover and are now focusing on longitudinal changes in BMD. My primary goals in SWAN are to assess the roles of chronological and ovarian aging in bone loss during the menopause transition and to identify factors associated with varying rates of bone loss. Our group has a long interest in anabolic effects of PTH. We published the first randomized, controlled trial using PTH therapy in humans and recently reported that alendronate reduces the anabolic actions of PTH. In this proposal we will examine the changes in BMD after stopping PTH, the effects of PTH re-treatment on bone metabolism, and effects of graded increases in PTH dosing. The fourth area of investigation is to explore the physiological regulation of FGF23, a putative newly described phosphaturic hormone, by dietary phosphate. If I am successful in obtaining this award, I will be able to continue t o devote the most of my time to my clinical research studies and mentoring. I currently mentor 3 trainees (2 with K23 Awards and 1 with an NRSA) and several additional trainees are interested in joining our group. The current K24 has been extremely successful in allowing me to pursue my own clinical research career goals and to train a group of promising young investigators. Without continued K24 support, I will need to increase my clinical activities, reduce my research time, and forego training of new clinical investigators.
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