Odanacatib for the treatment of postmenopausal osteoporosis: results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT Extension study
Odanacatib for the treatment of postmenopausal osteoporosis: results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT Extension study
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DOI：
10.1016/s2213-8587(19)30346-8
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发表时间：
2019-12-01
影响因子：
44.5
通讯作者：
Sabatine, Marc S.
中科院分区：
文献类型：
--
作者：
McClung, Michael R.;O'Donoghue, Michelle L.;Sabatine, Marc S.
背景 Odanacatib 是一种组织蛋白酶 K 抑制剂，可减少骨吸收，同时维持骨形成。先前的研究表明，odanacatib 可以增加骨量低的绝经后妇女的骨矿物质密度。我们的目的是研究 odanacatib 降低绝经后骨质疏松症女性骨折风险的有效性和安全性。方法 长期 Odanacatib 骨折试验 (LOFT) 是一项多中心、随机、双盲、安慰剂对照、事件驱动的研究，在 40 个国家的 388 个门诊诊所进行。符合资格的参与者是年龄至少 65 岁、绝经后 5 年或以上的女性，如果既往没有椎体骨折，则股骨颈或总髋骨矿物质密度 T 评分在 -2.5 至 -4.0 之间，如果既往有椎骨骨折，则股骨颈或总髋骨矿物质密度 T 评分在 -1.5 至 -4.0 之间。既往有髋部骨折、超过一处椎骨骨折或全髋部或股骨颈 T 评分低于 -4.0 的女性不符合资格，除非她们不能或不愿意使用经批准的骨质疏松症治疗。参与者被随机分配 (1:1) 接受口服 odanacatib（50 毫克每周一次）或匹配的安慰剂。在对既往放射学椎体骨折进行分层后，使用交互式语音识别系统进行随机化，并且对研究参与者、研究人员及其工作人员以及赞助人员隐藏治疗。如果研究在双盲治疗 5 年之前完成，同意的参与者可以参加双盲扩展研究 (LOFT Extension)，从随机分组起继续其最初的治疗分配长达 5 年。主要终点是椎体骨折的发生率，使用基线、每年 6 个月和 12 个月以及最后一次研究访视时收集的 X 光片来评估，这些参与者在基线和至少一个其他时间点可获得可评估的 X 光片图像，并根据临床病史和 X 光片评估，判定髋部和非椎骨骨折是骨质疏松症造成的。对接受至少一剂研究药物的参与者进行安全性评估。判定的心血管安全终点是心血管死亡、心肌梗死或中风以及新发心房颤动或扑动的复合终点。还评估了个体心血管终点和死亡。 LOFT和LOFT Extension已在ClinicalTrials.gov（编号NCT00529373）和欧洲临床试验数据库（EudraCT编号2007-002693-66）注册。结果在2007年9月14日至2009年11月17日期间，我们随机分配了16 071名可评估患者接受治疗：8043名患者接受奥达那卡替布治疗，8043名患者接受奥达那卡替布治疗。 8028 改为安慰剂。中位随访 36.5 个月（IQR 34.43-40.15）后，4297 名分配至 odanacatib 的女性和 3960 名分配至安慰剂的女性参加了 LOFT Extension（总中位随访 47.6 个月，IQR 35.45-60.06）。在 LOFT 中，奥达那卡替布与安慰剂的主要结局累积发生率分别为：放射学椎体骨折 3.7% (251/6770) 对比 7.8% (542/6910)，风险比 (HR) 0.46，95% CI 0.40-0.53；髋部骨折 0.8% (65/8043) 对比 1.6% (125/8028)、0.53、0.39-0.71；非椎骨骨折 5.1% (412/8043) vs 6.7% (541/8028)、0.77、0.68-0.87；所有p
Background Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis.Methods The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between -2.5 and -4.0 if no previous radiographic vertebral fracture, or between -1.5 and -4.0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than -4.0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66).Findings Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36.5 months (IQR 34.43-40.15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47.6 months, IQR 35.45-60.06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3.7% (251/6770) versus 7.8% (542/6910), hazard ratio (HR) 0.46, 95% CI 0.40-0.53; hip fractures 0.8% (65/8043) versus 1.6% (125/8028), 0.53, 0.39-0.71; non-vertebral fractures 5.1% (412/8043) versus 6.7% (541/8028), 0.77, 0.68-0.87; all p