Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized, Double-Blind, Phase 2, Parallel Group Study
Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized, Double-Blind, Phase 2, Parallel Group Study
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DOI：
10.1002/jbmr.3452
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发表时间：
2018-08-01
影响因子：
6.2
通讯作者：
Grauer, Andreas
中科院分区：
文献类型：
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作者：
McClung, Michael R.;Brown, Jacques P.;Grauer, Andreas
在12个月内，romosozumab增加了骨形成并降低了骨吸收，导致低BMD绝经后女性的骨密度（BMD）增加（NCT 00896532）。在此，我们报告了研究扩展期，评估了24个月的romosozumab治疗、romosozumab停药、阿仑膦酸盐治疗后的romosozumab治疗和romosozumab治疗后的denosumab治疗。年龄在55 - 85岁之间的绝经后女性，腰椎（LS）、全髋关节（TH）或股骨颈T评分=-3.5，入选并随机分配至安慰剂组，5种romosozumab治疗方案之一（70 mg、140 mg、210 mg每月一次[QM]; 140 mg Q3 M; 210 mg Q3 M）给药24个月，或开放标签阿仑膦酸盐给药12个月，随后是romosozumab 140 mg QM给药12个月。然后，合格的受试者在原始治疗组内以1：1的比例重新随机分配至安慰剂或Denosumab 60 mg Q6 M，再治疗12个月。评价了第24个月和第36个月时BMD和骨转换标志物（BTM）较基线的百分比变化以及安全性。在最初随机分配到romosozumab，安慰剂或阿仑膦酸钠的364名参与者中，315名完成了24个月的治疗，248名完成了扩展。Romosozumab显著增加LS和TH BMD，直至第24个月，使用Romosozumab 210 mg QM观察到最大增益（LS = 15.1%; TH = 5.4%）。接受romosozumab治疗的女性在过渡至Denosumab治疗后继续增加BMD，而安慰剂治疗后BMD恢复至治疗前水平。使用romosozumab 210 mg QM，骨形成标志物P1 NP在治疗开始后最初升高，并在第12个月逐渐降低至基线以下，直至第24个月保持在基线以下;骨吸收标志物β-CTX在治疗后迅速降低，直至第24个月保持在基线以下。转换至地舒单抗进一步降低了两种BTM，而转换至安慰剂后，P1 NP恢复至基线水平，β-CTX升高至基线水平以上。至第36个月，治疗组之间的不良事件平衡。这些数据表明，romosozumab的治疗效应在停药后可逆，并通过Denosumab进一步增强。(C)2018《骨与矿物质研究作者杂志》（The Authors Journal of Bone and Mineral Research）由Wiley Periodicals，Inc.出版。
Over 12 months, romosozumab increased bone formation and decreased bone resorption, resulting in increased bone mineral density (BMD) in postmenopausal women with low BMD (NCT00896532). Herein, we report the study extension evaluating 24 months of treatment with romosozumab, discontinuation of romosozumab, alendronate followed by romosozumab, and romosozumab followed by denosumab. Postmenopausal women aged 55 to 85 years with a lumbar spine (LS), total hip (TH), or femoral neck T-score =-3.5 were enrolled and randomly assigned to placebo, one of five romosozumab regimens (70 mg, 140 mg, 210 mg monthly [QM]; 140 mg Q3M; 210 mg Q3M) for 24 months, or open-label alendronate for 12 months followed by romosozumab 140 mg QM for 12 months. Eligible participants were then rerandomized 1:1 within original treatment groups to placebo or denosumab 60 mg Q6M for an additional 12 months. Percentage change from baseline in BMD and bone turnover markers (BTMs) at months 24 and 36 and safety were evaluated. Of 364 participants initially randomized to romosozumab, placebo, or alendronate, 315 completed 24 months of treatment and 248 completed the extension. Romosozumab markedly increased LS and TH BMD through month 24, with largest gains observed with romosozumab 210 mg QM (LS = 15.1%; TH = 5.4%). Women receiving romosozumab who transitioned to denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels with placebo. With romosozumab 210 mg QM, bone formation marker P1NP initially increased after treatment initiation and gradually decreased to below baseline by month 12, remaining below baseline through month 24; bone resorption marker beta-CTX rapidly decreased after treatment, remaining below baseline through month 24. Transition to denosumab further decreased both BTMs, whereas after transition to placebo, P1NP returned to baseline and beta-CTX increased above baseline. Adverse events were balanced between treatment groups through month 36. These data suggest that treatment effects of romosozumab are reversible upon discontinuation and further augmented by denosumab. (C) 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.