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。在过去，它已经探索了甲状旁腺相关蛋白（PTHrP）的人体生理学。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。先前版本中的数据已经证明PTHrP在人体中至少与目前用于骨质疏松症合成代谢治疗的金标准一样有效：甲状旁腺激素或PTH（1 - 34）。此外，在上一轮资助中，我们定义了健康年轻人和绝经后女性的PTHrP（1 - 36）的完整治疗窗口：这些研究表明，高于之前使用的PTHrP剂量似乎是安全的。以及有效的。这些发现表明，更高剂量的PTHrP可能比先前研究的更有效。此外，除了潜在的上级功效之外，PTHrP似乎具有上级安全性和耐受性特征，在治疗剂量下没有高钙血症、恶心、肌肉痉挛或其它不良反应。最后，与作为混合合成代谢和分解代谢剂的PTH相反，PTHrP似乎是纯合成代谢剂。总的来说，这些研究要求进行一项PTH（1 - 34）与PTHrP（1 - 36）治疗绝经后骨质疏松症的确定性头对头比较试验。这是本研究的唯一具体目的：进行一项直接、头对头、直接对照、随机、对照临床试验，比较PTHrP（1 - 36）与PTH（1 - 34）治疗绝经后骨质疏松症，包括安全性/耐受性和疗效终点。 公共卫生相关性：骨质疏松症是绝经后妇女、老年男性和糖皮质激素治疗患者的骨折、疼痛、残疾和其他发病率以及死亡率的主要原因。抗吸收疗法部分有效，合成代谢疗法甚至更有效。目前的黄金标准合成代谢剂是PTH（1 - 34），但其安全性和有效性受到恶心，肌肉痉挛，高钙血症和其他不良反应的限制。该基金早期版本的报告表明，PTHrP可能具有上级安全性和耐受性，也可能具有优于PTH的疗效优势。本项目的目的是首次在疗效和安全性/耐受性研究中直接比较PTH和PTHrP。

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.