San Francisco Coordinating Center, CPMC Research Institute, San Francisco, CA, USA.
Geneva University Hospital, Geneva, Switzerland.
J Bone Miner Res. 2018 Feb;33(2):190-198. doi: 10.1002/jbmr.3337. Epub 2017 Nov 22.
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. Clinicaltrails.gov: NCT00089791 (FREEDOM) and NCT00523341 (Extension). © 2017 American Society for Bone and Mineral Research.
地舒单抗可减少骨吸收和椎体及非椎体骨折风险。在预定剂量漏用后 3 个月，地舒单抗停药会增加骨转换标志物，6 个月时达到高于基线水平，12 个月时骨密度（BMD）降至基线水平。我们分析了 FREEDOM 研究或其扩展研究中停药的参与者发生新的或恶化的椎体骨折（尤其是多发椎体骨折）的风险。参与者接受每 6 个月一次的地舒单抗或安慰剂 Q6M 治疗，停止治疗，末次剂量后至少 7 个月留在研究中。在 FREEDOM 或扩展研究中停药的 1001 名参与者中，椎体骨折发生率从治疗期间的每 100 名参与者-年 1.2 例增加到 7.1 例，与接受并随后停药安慰剂的参与者相似（n=470；每 100 名参与者-年 8.5 例）。在有≥1 例停药后椎体骨折的参与者中，停药组中多发（>1 例）的比例（60.7%）高于安慰剂组（38.7%；p=0.049），分别对应多发椎体骨折的风险为 3.4%和 2.2%。在有既往椎体骨折的患者中，停药后患多发椎体骨折的比值比（95%置信区间）分别为无既往椎体骨折患者的 3.9（2.1-7.2）倍，且停药后每多 1 年随访比值比为 1.6（1.3-1.9）倍；在有可获得的停药后总髋部（TH）BMD 测量值的参与者中，每 1%年化 TH BMD 丢失的比值比为 1.2（1.1-1.3）倍。在停药期间非椎体骨折的发生率相似（2.8，地舒单抗；3.8，安慰剂）。停药后，椎体骨折率增加至未治疗参与者的水平。在停药后发生椎体骨折的大多数患者有多发椎体骨折，既往椎体骨折患者风险最大。因此，停止用地舒单抗治疗的患者应迅速转为其他抗吸收治疗。Clinicaltrails.gov：NCT00089791（FREEDOM）和 NCT00523341（Extension）。 © 2017 年美国骨与矿物研究协会。
