This is a competing continuation application of R-01DK51081. In the past, it has explored the human physiology of parathyroid hormone-related protein (PTHrP). In its most recent cycles, it has also focused on exploring the therapeutic potential of PTHrP as an anabolic skeletal agent for the treatment of osteoporosis. Data in the prior versions have demonstrated that PTHrP is at least as efficacious in humans as the current gold standard for the anabolic treatment of osteoporosis: parathyroid hormone or PTH(1-34). In addition, in the prior round of funding, we have defined the complete therapeutic window of PTHrP(1-36) in healthy young adults as well as in postmenopausal women: these studies demonstrate that doses of PTHrP higher than those previously employed appear safe as well as effective. These findings suggest that higher doses of PTHrP may be even more efficacious than those prior studied. Further, in addition to potential superior efficacy, PTHrP appears to have a superior safety and tolerability profile, with no hypercalcemia, nausea, muscle cramps or other adverse effects at therapeutic doses. Finally, in contrast to PTH which is a mixed anabolic and catabolic agent, PTHrP appears to be a pure anabolic agent. Collectively, these studies mandate a definitive head-to-head comparator trial of PTH(1-34) vs. PTHrP(1-36) in the treatment of postmenopausal osteoporosis. This is the single Specific Aim of this study: To perform a direct, head-to-head, direct comparator, randomized, controlled clinical trial of PTHrP(1-36) vs. PTH(1-34) for the treatment of postmenopausal osteoporosis, with both safety/tolerability and efficacy endpoints.
Osteoporosis is a major cause of fracture, pain, disability, and other morbidities as well as mortality in postmenopausal women, aging men, and patients treated with glucocorticoids. Anti-resorptive therapies are partially effective, and anabolic therapies are even more effective. The current gold standard anabolic agent is PTH(1-34), but its safety and efficacy is limited by nausea, muscle cramps, hypercalcemia and other adverse effects. Reports published from earlier versions of this grant suggest that PTHrP may have superior safety and tolerability, and also may confer efficacy advantages over PTH. The purpose of this project is to directly compare, for the first time, PTH and PTHrP in an efficacy and safety/tolerability study.
|Wesseling-Perry, Katherine; Wang, Hejing; Elashoff, Robert et al. (2014) Lack of FGF23 response to acute changes in serum calcium and PTH in humans. J Clin Endocrinol Metab 99:E1951-6|
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|Zaritsky, Joshua; Rastogi, Anjay; Fischmann, George et al. (2014) Short daily hemodialysis is associated with lower plasma FGF23 levels when compared with conventional hemodialysis. Nephrol Dial Transplant 29:437-41|
|Wesseling-Perry, Katherine; Salusky, Isidro B (2013) Phosphate binders, vitamin D and calcimimetics in the management of chronic kidney disease-mineral bone disorders (CKD-MBD) in children. Pediatr Nephrol 28:617-25|
|Wesseling-Perry, Katherine; Pereira, Renata C; Tsai, Eileen et al. (2013) FGF23 and mineral metabolism in the early post-renal transplantation period. Pediatr Nephrol 28:2207-15|
|Bacchetta, Justine; Wesseling-Perry, Katherine; Kuizon, Beatriz et al. (2013) The skeletal consequences of growth hormone therapy in dialyzed children: a randomized trial. Clin J Am Soc Nephrol 8:824-32|
|Augustine, Marilyn; Horwitz, Mara J (2013) Parathyroid hormone and parathyroid hormone-related protein analogs as therapies for osteoporosis. Curr Osteoporos Rep 11:400-6|
|Wesseling-Perry, Katherine; Salusky, Isidro B (2013) Chronic kidney disease: mineral and bone disorder in children. Semin Nephrol 33:169-79|
|Horwitz, Mara J; Augustine, Marilyn; Khan, Leila et al. (2013) A comparison of parathyroid hormone-related protein (1-36) and parathyroid hormone (1-34) on markers of bone turnover and bone density in postmenopausal women: the PrOP study. J Bone Miner Res 28:2266-76|
|Carneiro, Raquel M; Prebehalla, Linda; Tedesco, Mary Beth et al. (2013) Evaluation of markers of bone turnover during lactation in African-Americans: a comparison with Caucasian lactation. J Clin Endocrinol Metab 98:523-32|
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