Romosozumab and antiresorptive treatment: the importance of treatment sequence

Abstract

To evaluate whether treatment sequence affects romosozumab response, this analysis reviewed studies where romosozumab was administered before or following an antiresorptive (alendronate or denosumab). Initial treatment with romosozumab followed by an antiresorptive resulted in larger increases in bone mineral density of both hip and spine compared with the reverse sequence.

Introduction: Teriparatide followed by an antiresorptive increases bone mineral density (BMD) more than using an antiresorptive first. To evaluate whether treatment sequence affects romosozumab response, we reviewed randomized clinical trials where romosozumab was administered before (ARCH, FRAME) or following (STRUCTURE, Phase 2 extension) an antiresorptive (alendronate or denosumab, respectively).

Methods: We evaluated BMD percentage change for total hip (TH) and lumbar spine (LS) and response rates (BMD gains ≥ 3% and ≥ 6%) at years 1 and 2 (except STRUCTURE with only 1-year data available).

Results: With 1-year romosozumab initial therapy in ARCH and FRAME, TH BMD increased 6.2% and 6.0%, and LS BMD increased 13.7% and 13.1%, respectively. When romosozumab was administered for 1 year after alendronate (STRUCTURE) or denosumab (Phase 2 extension), TH BMD increased 2.9% and 0.9%, respectively, and LS BMD increased 9.8% and 5.3%, respectively. Over 2 years, TH and LS BMD increased 7.1% and 15.2% with romosozumab/alendronate, 8.5% and 16.6% with romosozumab/denosumab, and 3.8% and 11.5% with denosumab/romosozumab, respectively. A greater proportion of patients achieved BMD gains ≥ 6% when romosozumab was used first, particularly for TH, versus the reverse sequence (69% after romosozumab/denosumab; 15% after denosumab/romosozumab).

Conclusion: In this study, larger mean BMD increases and greater BMD responder rates were achieved when romosozumab was used before, versus after, an antiresorptive agent. Since BMD on treatment is a strong surrogate for bone strength and fracture risk, this analysis supports the thesis that initial treatment with romosozumab followed by an antiresorptive will result in greater efficacy versus the reverse sequence.

Keywords: Anabolic; Antiresorptive; Romosozumab; Teriparatide; Treatment sequence.

Fig. 1

Study designs for ARCH (a), FRAME (b), STRUCTURE (c), and Phase 2 extension (d). For each study, the gray box depicts the study arm that was not included in this analysis. N = number of patients in the study. n = number of patients in each study arm. ^aPatients received alendronate in the 1 year immediately before screening. ^bOf the 52 women initially randomized to placebo from months 0–24, 18 were rerandomized to denosumab and 34 to other treatments or discontinued study. Q6M every 6 months, QD daily, QMmonthly, QW weekly, SC subcutaneous

Fig. 2

Mean percentage change from baseline in total hip BMD (a, b) and lumbar spine (c, d) at 1 year with romosozumab and cumulative 2 years after sequential treatment. Data analyzed were from four studies: ARCH (NCT01631214), FRAME (NCT01575834), STRUCTURE (NCT01796301), and the Phase 2 extension (NCT00896532). n = number of patients who received romosozumab and had total hip or lumbar spine BMD measurements at baseline and at specified timepoints. Percentage changes from baseline were assessed by an ANCOVA model adjusted for baseline covariates in FRAME, a repeated measures model adjusted for baseline covariates in ARCH and STRUCTURE, and as summary statistics in the Phase 2 extension. Least squares means and 95% CI are shown for ARCH, FRAME, and STRUCTURE, and means and 95% CI based on summary statistics are shown for the Phase 2 extension. ^aPatients had received oral bisphosphonate for ≥ 3 years before screening and alendronate (70 mg QW) for ≥ 1 year immediately before screening; BMD was not measured in the 1 year of alendronate before romosozumab. ^bPatients received placebo during months 0–24, denosumab during months 24–36, and romosozumab during months 36–48; cumulative gains are relative to the month 24 baseline. ALN alendronate; ANCOVA, analysis of covariance; BMD, bone mineral density; CI, confidence interval; DMAb, denosumab; M, month; N/A, not applicable;  Ph 2 Ext, Phase 2 Extension; QW, weekly; ROMO, romosozumab

Fig. 3

Median absolute changes in serum PINP and β-CTX in women treated with romosozumab prior to antiresorptive therapy (a, b) and in women treated with romosozumab after alendronate (c) or denosumab (d). Data analyzed were from ARCH (NCT01631214), FRAME (NCT01575834), STRUCTURE (NCT01796301), and the Phase 2 extension (NCT00896532) using descriptive statistics. For the Phase 2 extension, baseline (month 0) is at month 36 of the study when patients transitioned from denosumab to romosozumab. n = number of patients who received romosozumab in each study and had PINP and β-CTX assessments at baseline and specified timepoints. β-CTX, β-isomer of the C-terminal telopeptide of type I collagen; PINP, procollagen type 1 N-terminal propeptide; Q1, Q3, first and third quartiles; Q6M, every 6 months; QM, monthly; QW, weekly