Pathophysiology of PTH-related Protein (1-36) in Humans

描述（由申请人提供）：这是R-01DK51081的竞争性延续申请。过去对甲状旁腺激素相关蛋白（PTHrP）在人体生理中的作用进行了探讨。在最近的周期中，它还专注于探索PTHrP作为治疗骨质疏松症的合成代谢骨骼剂的治疗潜力。先前版本的数据表明，PTHrP至少与目前用于骨质疏松症合成代谢治疗的金标准：甲状旁腺激素或PTH一样有效（1-34）。此外，在前一轮融资中，我们已经确定了PTHrP在健康年轻人和绝经后妇女中的完整治疗窗口（1-36）：这些研究表明，比以前使用的剂量更高的PTHrP似乎既安全又有效。这些发现表明，高剂量的PTHrP可能比先前的研究更有效。此外，除了潜在的优越疗效外，PTHrP似乎具有优越的安全性和耐受性，在治疗剂量下没有高钙血症、恶心、肌肉痉挛或其他不良反应。最后，与甲状旁腺激素是一种混合合成代谢和分解代谢剂相比，甲状旁腺激素似乎是一种纯合成代谢剂。总的来说，这些研究要求对PTH（1-34）与PTHrP（1-36）治疗绝经后骨质疏松症进行明确的头对头比较试验。这是本研究的单一特定目的：进行PTHrP（1-36）与PTH（1-34）治疗绝经后骨质疏松症的直接、直接比较、随机对照临床试验，同时具有安全性/耐受性和有效性终点。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.