10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension
10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension
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DOI：
10.1016/s2213-8587(17)30138-9
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发表时间：
2017-07-01
影响因子：
44.5
通讯作者：
Papapoulos, Socrates
中科院分区：
文献类型：
--
作者：
Bone, Henry G.;Wagman, Rachel B.;Papapoulos, Socrates
背景骨质疏松症是一种慢性疾病，因此长期安全有效的治疗非常重要。我们的目的是评估地舒单抗的长期安全性和有效性，地舒单抗广泛用于治疗绝经后妇女的骨质疏松症。方法在多中心、随机、双盲、安慰剂对照、3期FREEDOM试验中，年龄60 - 90岁的绝经后骨质疏松症妇女在北美、欧洲、拉丁美洲和澳大拉西亚的214个中心入组，并随机分配（1：1）每6个月接受60 mg地舒单抗或安慰剂皮下注射，持续3年。所有完成FREEDOM试验且未中止治疗或缺失一剂以上试验用药物的受试者都有资格入组开放标签、7年扩展期，其中所有受试者均接受Denosumab治疗。这些数据代表了在FREEDOM中接受3年地舒单抗并在扩展期继续接受地舒单抗的女性最长10年的地舒单抗暴露（长期组），以及接受3年安慰剂并在扩展期过渡到地舒单抗的女性最长7年的暴露（交叉组）。主要结局为安全性监测，包括不良事件发生率和严重不良事件发生率的评估、安全性实验室分析物（即血清化学和血液学）的变化以及受试者地舒单抗抗体形成的发生率。次要结局包括新发椎体、髋关节和非椎体骨折以及腰椎、全髋关节、股骨颈和1/3桡骨的骨密度（BMD）。根据随机化FREEDOM治疗分配进行分析。在FREEDOM或扩展期接受至少一剂试验用药物的所有受试者均纳入合并安全性分析。入组扩展期并具有观察数据的所有受试者均纳入疗效分析。FREEDOM试验（NCT 00089791）及其扩展试验（NCT 00523341）均在ClinicalTrials.gov注册。5 928名（76%）妇女有资格参加扩展，其中4 550名（77%）在2007年8月7日至2008年6月20日期间参加（2 343名长期，2 207名交叉）。2626名女性（1343名长期; 1283名交叉）完成了扩展。在10年的过程中，所有接受Denosumab治疗的受试者的不良事件年发生率从165.3/100参与者-年降至95.9/100参与者-年。严重不良事件发生率随时间推移基本稳定，在11.5 - 14.4/100参与者-年之间变化。在伸展过程中，每组均发生1例非典型股骨骨折。长期组报告了7例颌骨骨坏死，交叉组报告了6例。扩展期内新发椎骨骨折（范围为0.90%-1.86%）和非椎骨骨折（范围为0.84%-2.55%）的年发生率保持较低水平，与FREEDOM研究前3年期间Denosumab组中观察到的发生率相似，低于虚拟长期安慰剂队列的预测发生率。在长期组中，腰椎BMD较FREEDOM基线增加21.7%，全髋增加9.2%，股骨颈增加9.0%，1/3半径增加2.7%。在交叉组中，腰椎、全髋关节、股骨颈和三分之一半径的BMD较扩展基线分别增加16.5%、7.4%、7.1%和2.3%。与原始试验期间观察到的结果相比，Denosumab治疗长达10年与不良事件发生率低、骨折发生率低以及BMD持续增加而无平台期相关。
Background Long-term safety and efficacy of osteoporosis treatment are important because of the chronic nature of the disease. We aimed to assess the long-term safety and efficacy of denosumab, which is widely used for the treatment of postmenopausal women with osteoporosis.Methods In the multicentre, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, postmenopausal women aged 60-90 years with osteoporosis were enrolled in 214 centres in North America, Europe, Latin America, and Australasia and were randomly assigned (1:1) to receive 60 mg subcutaneous denosumab or placebo every 6 months for 3 years. All participants who completed the FREEDOM trial without discontinuing treatment or missing more than one dose of investigational product were eligible to enrol in the open-label, 7-year extension, in which all participants received denosumab. The data represent up to 10 years of denosumab exposure for women who received 3 years of denosumab in FREEDOM and continued in the extension (long-term group), and up to 7 years for women who received 3 years of placebo and transitioned to denosumab in the extension (crossover group). The primary outcome was safety monitoring, comprising assessments of adverse event incidence and serious adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry and haematology), and participant incidence of denosumab antibody formation. Secondary outcomes included new vertebral, hip, and non-vertebral fractures as well as bone mineral density (BMD) at the lumbar spine, total hip, femoral neck, and one-third radius. Analyses were done according to the randomised FREEDOM treatment assignments. All participants who received at least one dose of investigational product in FREEDOM or the extension were included in the combined safety analyses. All participants who enrolled in the extension with observed data were included in the efficacy analyses. The FREEDOM trial (NCT00089791) and its extension (NCT00523341) are both registered with ClinicalTrials.gov.Findings Between Aug 3, 2004, and June 1, 2005, 7808 women were enrolled in the FREEDOM study. 5928 (76%) women were eligible for enrolment in the extension, and of these, 4550 (77%) were enrolled (2343 long-term, 2207 crossover) between Aug 7, 2007, and June 20, 2008. 2626 women (1343 long-term; 1283 crossover) completed the extension. The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165.3 to 95.9 per 100 participant-years over the course of 10 years. Serious adverse event rates were generally stable over time, varying between 11.5 and 14.4 per 100 participant-years. One atypical femoral fracture occurred in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group and six cases in the crossover group. The yearly incidence of new vertebral fractures (ranging from 0.90% to 1.86%) and non-vertebral fractures (ranging from 0.84% to 2.55%) remained low during the extension, similar to rates observed in the denosumab group during the first three years of the FREEDOM study, and lower than rates projected for a virtual long-term placebo cohort. In the long-term group, BMD increased from FREEDOM baseline by 21.7% at the lumbar spine, 9.2% at total hip, 9.0% at femoral neck, and 2.7% at the onethird radius. In the crossover group, BMD increased from extension baseline by 16.5% at the lumbar spine, 7.4% at total hip, 7.1% at femoral neck, and 2.3% at one-third radius.Interpretation Denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau.