Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension
Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension
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DOI：
10.1002/jbmr.3337
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发表时间：
2018-02-01
影响因子：
6.2
通讯作者：
Brown, Jacques P.
中科院分区：
文献类型：
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作者：
Cummings, Steven R.;Ferrari, Serge;Brown, Jacques P.
地舒单抗可降低骨吸收以及椎骨和非椎骨骨折风险。在省略计划剂量后3个月，Denosumab停药可增加骨转换标志物，6个月时达到高于基线水平，12个月时骨矿物质密度（BMD）降低至基线水平。我们分析了在FREEDOM研究或其扩展期间停用地舒单抗的受试者新发或恶化椎骨骨折（尤其是多发性椎骨骨折）的风险。受试者接受2剂地舒单抗或安慰剂Q6 M，停止治疗，并在末次给药后7个月继续参加研究。在FREEDOM或扩展期停用地舒单抗的1001例受试者中，椎体骨折发生率从治疗期间的1.2/100受试者-年增加至7.1，与接受安慰剂后停用的受试者相似（n=470; 8.5/100受试者-年）。在有1处停止治疗椎骨骨折的参与者中，停用地舒单抗的参与者中有多处（>1）骨折的比例（60.7%）高于安慰剂（38.7%; p=0.049），对应的多处椎骨骨折风险分别为3.4%和2.2%。停用地舒单抗后发生多发性椎体骨折的几率（95%置信区间）为3.9（2.1-7. 2)在治疗前或治疗过程中，既往有椎体骨折的患者比无椎体骨折的患者高1.6倍，并且每增加一年的停药随访，该比值高1.6（1.3-1.9）倍;在有可用的停药全髋关节（TH）BMD测量结果的参与者中，每1%的年TH BMD损失，该比值高1.2（1.1-1.3）倍。停药期间非椎骨骨折的发生率（每100参与者-年）相似（地舒单抗组2.8;安慰剂组3.8）。地舒单抗停药后，椎骨骨折发生率增加至未治疗受试者中观察到的水平。在停用地舒单抗后发生椎骨骨折的大多数受试者发生多处椎骨骨折，既往发生椎骨骨折的受试者风险最大。因此，停用地舒单抗的患者应迅速转换为替代抗骨吸收治疗。：NCT 00089791（FREEDOM）和NCT 00523341（扩展）。(c)2017年美国骨与矿物质研究学会。
Denosumab reduces bone resorption and vertebral and nonvertebral fracture risk. Denosumab discontinuation increases bone turnover markers 3 months after a scheduled dose is omitted, reaching above-baseline levels by 6 months, and decreases bone mineral density (BMD) to baseline levels by 12 months. We analyzed the risk of new or worsening vertebral fractures, especially multiple vertebral fractures, in participants who discontinued denosumab during the FREEDOM study or its Extension. Participants received 2 doses of denosumab or placebo Q6M, discontinued treatment, and stayed in the study 7 months after the last dose. Of 1001 participants who discontinued denosumab during FREEDOM or Extension, the vertebral fracture rate increased from 1.2 per 100 participant-years during the on-treatment period to 7.1, similar to participants who received and then discontinued placebo (n=470; 8.5 per 100 participant-years). Among participants with 1 off-treatment vertebral fracture, the proportion with multiple (>1) was larger among those who discontinued denosumab (60.7%) than placebo (38.7%; p=0.049), corresponding to a 3.4% and 2.2% risk of multiple vertebral fractures, respectively. The odds (95% confidence interval) of developing multiple vertebral fractures after stopping denosumab were 3.9 (2.1-7. 2) times higher in those with prior vertebral fractures, sustained before or during treatment, than those without, and 1.6 (1.3-1.9) times higher with each additional year of off-treatment follow-up; among participants with available off-treatment total hip (TH) BMD measurements, the odds were 1.2 (1.1-1.3) times higher per 1% annualized TH BMD loss. The rates (per 100 participant-years) of nonvertebral fractures during the off-treatment period were similar (2.8, denosumab; 3.8, placebo). The vertebral fracture rate increased upon denosumab discontinuation to the level observed in untreated participants. A majority of participants who sustained a vertebral fracture after discontinuing denosumab had multiple vertebral fractures, with greatest risk in participants with a prior vertebral fracture. Therefore, patients who discontinue denosumab should rapidly transition to an alternative antiresorptive treatment. : NCT00089791 (FREEDOM) and NCT00523341 (Extension). (c) 2017 American Society for Bone and Mineral Research.