Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: A randomized blinded phase 2 clinical trial
Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: A randomized blinded phase 2 clinical trial
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DOI：
10.1016/j.bone.2008.04.007
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发表时间：
2008-08-01
期刊：
影响因子：
4.1
通讯作者：
Martin, Javier San
中科院分区：
文献类型：
--
作者：
Miller, Paul D.;Bolognese, Michael A.;Martin, Javier San
简介：Denosumab是一种全人源单克隆抗体，可抑制核因子-κ B配体（RANKL）的受体激活剂，RANKL是破骨细胞形成、功能和存活的重要介质，已证明可降低接受治疗患者的骨转换并增加骨矿物质密度（BMD）。我们评估了地舒单抗的长期疗效和安全性，以及绝经后低骨量妇女停止和重新开始地舒单抗治疗的效果。方法：腰椎T评分为-1.8至-4.0或股骨近端T评分为-1.8至-3.5的绝经后妇女随机接受地舒单抗治疗，每3个月一次（Q3M; 6、14或30 mg）或每6个月（Q6M; 14、60、100或210 mg）;安慰剂;或每周开放标签口服阿仑膦酸钠。24个月后，接受地舒单抗治疗的患者继续接受60 mg Q6M治疗额外24个月，停止治疗，或停止治疗12个月，然后重新开始地舒单抗（60 mg Q6M）治疗12个月。维持安慰剂队列。接受阿仑膦酸钠治疗的患者停用阿仑膦酸钠并接受随访。BMD和骨转换标志物（BTM）的变化以及安全性outcomes.Results：总体而言，262/412（64%）患者完成了48个月的研究。连续、长期地舒单抗治疗增加了腰椎（9.4%至11.8%）和全髋关节（4.0%至6.1%）的BMD。BTM在48个月内持续受到抑制。地舒单抗停药与治疗停药前12个月内腰椎BMD降低6.6%和全髋BMD降低5.3%相关。地舒单抗重新治疗使腰椎BMD较原始基线值增加9.0%。BTM水平在停药后升高，并在重新开始治疗后降低。治疗组之间的不良事件发生率相似。结论：在绝经后妇女低BMD，长期地舒单抗治疗导致在整个研究过程中的BMD和BTM的减少增益。对骨转换的影响在停药后完全可逆，并在随后的重新治疗后恢复。(c)2008年爱思唯尔公司All rights reserved.
Introduction: Denosumab is a fully human monoclonal antibody that inhibits receptor activator of nuclear factor-kappa B ligand (RANKL), an essential mediator of osteoclast formation, function, and survival that has been shown to decrease bone turnover and increase bone mineral density (BMD) in treated patients. We assessed the long-term efficacy and safety of denosumab, and the effects of discontinuing and restarting denosumab treatment in postmenopausal women with low bone mass.Methods: Postmenopausal women with a lumbar spine T-score of -1.8 to -4.0 or proximal femur T-score of -1.8 to -3.5 were randomized to denosumab every 3 months (Q3M; 6, 14, or 30 mg) or every 6 months (Q6M; 14, 60, 100, or 210 mg); placebo; or open-label oral alendronate weekly. After 24 months, patients receiving denosumab either continued treatment at 60 mg Q6M for an additional 24 months, discontinued therapy, or discontinued treatment for 12 months then re-initiated denosumab (60 mg Q6M) for 12 months. The placebo cohort was maintained. Alendronate-treated patients discontinued alendronate and were followed. Changes in BMD and bone turnover markers (BTM) as well as safety outcomes were evaluated.Results: Overall, 262/412 (64%) patients completed 48 months of study. Continuous, long-term denosumab treatment increased BMD at the lumbar spine (9.4% to 11.8%) and total hip (4.0% to 6.1%). BTM were consistently suppressed over 48 months. Discontinuation of denosumab was associated with a BMD decrease of 6.6% at the lumbar spine and 5.3% at the total hip within the first 12 months of treatment discontinuation. Retreatment with denosumab increased lumbar spine BMD by 9.0% from original baseline values. Levels of BTM increased upon discontinuation and decreased with retreatment. Adverse event rates were similar among treatment groups.Conclusions: In postmenopausal women with low BMD, long-term denosumab treatment led to gains in BMD and reduction of BTM throughout the course of the study. The effects on bone turnover were fully reversible with discontinuation and restored with subsequent retreatment. (c) 2008 Elsevier Inc. All rights reserved.