Parathyroid Hormone-Related Protein for the Treatment of Postmenopausal Osteoporosis: Defining the Maximal Tolerable Dose
Parathyroid Hormone-Related Protein for the Treatment of Postmenopausal Osteoporosis: Defining the Maximal Tolerable Dose
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DOI：
10.1210/jc.2009-0233
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发表时间：
2010-03-01
影响因子：
5.8
通讯作者：
Stewart, Andrew F.
中科院分区：
文献类型：
--
作者：
Horwitz, Mara J.;Tedesco, Mary Beth;Stewart, Andrew F.
背景：甲状旁腺激素是唯一被批准用于治疗人类骨质疏松症的骨骼合成代谢药物。PTH是一种混合合成代谢和分解代谢剂，PTHrP与PTH不同，间歇性给药时PTHrP表现出可能是一种纯合成代谢剂的特征。PTHrP的全部剂量范围尚不清楚。目的：本研究的主要目的是确定PTHrP的完全治疗窗口期和剂量限制性毒性。次要目的是确定PTHrP是否在最高可用剂量下保持纯合成代谢谱。设计：这是一项单盲、两部分、剂量递增的临床试验。环境：本研究在大学学术环境中进行。患者或其他参与者：参与者包括41名年龄在45岁至75岁之间的健康绝经后妇女。干预措施：干预措施包括PTHrP（1-36）或安慰剂，剂量递增设计，为期3周。主要观察指标：测量了安全性指标（高钙血症、恶心、呕吐、血流动力学、潮红、杂项）和骨转换指标。结果：在接受500和625 μ g/d治疗3周的受试者中，间歇性PTHrP是安全的，未发生严重不良事件。服用750 μ g/d的受试者出现轻度高钙血症。骨转换标记表明，即使在最高剂量下，每日sc PTHrP可能不会激活骨吸收，即可能纯粹是合成代谢。有趣的是，当发生高钙血症时，它可能不是由骨吸收引起的，而是由1,25二羟基维生素d激活肠道钙吸收引起的。结论：与甲状肾上腺素相比，在高达750 μ g/d的剂量下，间歇性给药的PTHrP似乎是一种纯骨骼合成代谢剂。令人惊讶的是，高剂量的PTHrP可以激活1,25二羟基维生素D的产生。本文获得的剂量信息可用于设计PTHrP与PTH的长期头对头比较疗效试验。[J] .中华内分泌杂志，2005,22(5):379 - 387。
Context: PTH is the only approved skeletal anabolic agent for the treatment of human osteoporosis. Unlike PTH, which is a mixed anabolic and catabolic agent, PTHrP displays features suggesting that it may be a pure anabolic agent when intermittently administered. The full dose range of PTHrP is unknown.Objectives: The primary objective of the study was to define the complete therapeutic window and dose-limiting toxicities of PTHrP. The secondary objective was to determine whether PTHrP retains a pure anabolic profile at the highest usable doses.Design: This was a single-blinded, two-part, dose-escalating clinical trial.Setting: The study was conducted in a university academic setting.Patients or Other Participants: Participants included 41 healthy postmenopausal women between the ages of 45 and 75 yr.Intervention: Interventions included PTHrP(1-36) or placebo in a dose-escalating design for 3 wk.Main Outcome Measures: Safety measures (hypercalcemia, nausea, vomiting, hemodynamics, flushing, miscellaneous) and bone turnover markers were measured.Results: Intermittent PTHrP was administered safely and without serious adverse events in subjects receiving 500 and 625 mu g/d for 3 wk. Subjects receiving 750 mu g/d developed mild hypercalcemia. Bone turnover markers suggested that even at the highest doses, daily sc PTHrP may not activate bone resorption, i.e. may be purely anabolic. Interestingly, when hypercalcemia occurred, it may have resulted not from bone resorption but from activation of intestinal calcium absorption by 1,25 dihydroxyvitamin D.Conclusions: In doses as high as 750 mu g/d, in contrast to PTH, intermittently administered PTHrP appears to act as a pure skeletal anabolic agent. Surprisingly, PTHrP in the high doses studied activates 1,25 dihydroxyvitamin D production. Dosing information obtained herein can be used to design a longer term head-to-head comparative efficacy trial of PTHrP vs. PTH. (J Clin Endocrinol Metab 95: 1279-1287, 2010)