Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, United States.
Amgen Inc., Thousand Oaks, CA 91230, United States.
J Bone Miner Res. 2024 Sep 2;39(9):1268-1277. doi: 10.1093/jbmr/zjae116.
Osteoanabolic-first treatment sequences are superior to oral bisphosphonates for fracture reduction and bone mineral density (BMD) gain. However, data comparing osteoanabolic medications, with the more potent antiresorptive, denosumab (DMAb), are limited. We analyzed FRAME and FRAME Extension data to assess BMD and fracture incidence in patients treated with romosozumab (Romo) followed by DMAb (Romo/DMAb) versus DMAb (DMAb/DMAb) for 24 months. In FRAME, women aged ≥55 years (total hip [TH] or femoral neck [FN] T-score: -2.5 to -3.5) were randomized to Romo or placebo for 12 months followed by DMAb for 12 months. In FRAME Extension, both cohorts received DMAb for another 12 months. This post hoc analysis compared BMD change and fracture incidence in patients on Romo/DMAb (months 0-24) versus DMAb/DMAb (months 12-36). Patient characteristics were balanced by propensity score weighting (PSW) and sensitivity analyses were conducted using PSW with multiple imputation (PSW-MI) and propensity score matching (PSM). Unmeasured confounding was addressed using E-values. After PSW, over 24 months, compared with DMAb/DMAb, treatment with Romo/DMAb produced significantly greater BMD increases at the lumbar spine [LS], TH, and FN (mean differences: 9.3%, 4.4%, and 4.1%, respectively; all p<0.001). At month 24, in women with a baseline T-score of -3.0, the probability of achieving a T-score > -2.5 was higher with Romo/DMAb versus DMAb/DMAb (LS: 92% versus 47%; TH: 50% versus 5%). In the Romo/DMAb versus DMAb/DMAb cohorts, new vertebral fractures were significantly reduced (0.62% versus 1.26% [odds ratio = 0.45; p=0.003]) and rates of clinical, nonvertebral, and hip fractures were lower (differences not significant). Similar BMD and fracture outcomes were observed with PSW-MI and PSM sensitivity analyses. The sequence of Romo/DMAb resulted in greater BMD gains and higher probability of achieving T-scores > -2.5, significantly reduced new vertebral fracture incidence, and numerically lowered the incidence (not significant) of clinical, nonvertebral, and hip fractures versus DMAb only through 24 months.
骨合成代谢优先治疗方案在降低骨折发生率和增加骨密度（BMD）方面优于口服双膦酸盐。然而，将骨合成代谢药物与更有效的抗再吸收药物地舒单抗（DMAb）进行比较的数据有限。我们分析了 FRAME 和 FRAME 扩展数据，以评估接受罗莫佐单抗（Romo）治疗后再接受地舒单抗（Romo/DMAb）与仅接受地舒单抗（DMAb/DMAb）治疗 24 个月的患者的 BMD 和骨折发生率。在 FRAME 中，年龄≥55 岁的女性（全髋关节[TH]或股骨颈[FN]T 评分：-2.5 至-3.5）被随机分配接受 Romo 或安慰剂治疗 12 个月，然后再接受地舒单抗治疗 12 个月。在 FRAME 扩展研究中，两组患者均再接受地舒单抗治疗 12 个月。本事后分析比较了 Romo/DMAb（0-24 个月）与 DMAb/DMAb（12-36 个月）患者的 BMD 变化和骨折发生率。通过倾向评分加权（PSW）平衡患者特征，并通过 PSW 与多次插补（PSW-MI）和倾向评分匹配（PSM）进行敏感性分析。使用 E 值解决未测量的混杂因素。经过 PSW，与 DMAb/DMAb 相比，在 24 个月内，与 Romo/DMAb 治疗相比，腰椎（LS）、TH 和 FN 的 BMD 增加更为显著[LS：9.3%，TH：4.4%，FN：4.1%；所有 p<0.001]。在基线 T 评分为-3.0 的女性中，与 Romo/DMAb 相比，达到 T 评分>-2.5 的概率更高（LS：92%比 47%；TH：50%比 5%）。在 Romo/DMAb 与 DMAb/DMAb 队列中，新发椎体骨折显著减少（0.62%比 1.26%[比值比=0.45；p=0.003]），临床非椎体和髋部骨折的发生率较低（差异无统计学意义）。PSW-MI 和 PSM 敏感性分析也观察到了类似的 BMD 和骨折结果。与仅使用地舒单抗相比，Romo/DMAb 序贯治疗可显著增加 BMD 增加，提高达到 T 评分>-2.5 的概率，显著降低新发椎体骨折发生率，并在数值上降低临床、非椎体和髋部骨折的发生率（无统计学意义），直至 24 个月。
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