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Title: Romosozumab followed by denosumab versus denosumab only: a post hoc analysis of FRAME and FRAME extension.
Author: Cosman F, Oates M, Betah D, Timoshanko J, Wang Z, Ferrari S, McClung MR.
Journal: J Bone Miner Res; 2024 Sep 02; 39(9):1268-1277. PubMed ID: 39041711.
Abstract:
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. In patients with very high fracture risk, a treatment sequence with a bone-forming agent, followed by a bisphosphonate (one type of antiresorptive that reduces bone loss) is more effective in increasing bone mineral density (BMD) and reducing fracture risk compared to treatment with bisphosphonates alone. Here, we utilized patient data from the FRAME and FRAME Extension clinical trials to compare changes in BMD and fracture incidence in postmenopausal women with osteoporosis treated with the bone-forming agent, romosozumab (Romo), for 12 months followed by the most potent antiresorptive, denosumab (DMAb), for 12 months (Romo/DMAb) versus patients treated with DMAb alone for 24 months. Propensity score weighting was used to balance the patient characteristics between the two groups. We found that BMD gains were significantly higher in patients treated with the Romo/DMAb sequence versus DMAb alone; these patients also had a higher probability of achieving a T-score above the osteoporosis range (>–2.5). In addition, new vertebral fractures were significantly lower and rates of clinical, nonvertebral, and hip fractures trended lower in patients treated with the Romo/DMAb sequence versus DMAb alone. Thus, a 24-months treatment sequence of Romo/DMAb compared with DMAb alone, resulted in higher BMD gains and lower fracture risk.

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