A single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of romosozumab

Abstract

This phase 2 study evaluated the efficacy and safety of transitioning to zoledronate following romosozumab treatment in postmenopausal women with low bone mass. A single dose of 5 mg zoledronate generally maintained the robust BMD gains accrued with romosozumab treatment and was well tolerated.

Introduction: Follow-on therapy with an antiresorptive agent is necessary to maintain the skeletal benefits of romosozumab therapy. We evaluated the use of zoledronate following romosozumab treatment.

Methods: This phase 2, dose-finding study enrolled postmenopausal women with low bone mineral density (BMD). Subjects who received various romosozumab doses or placebo from months 0-24 were rerandomized to denosumab (60 mg SC Q6M) or placebo for 12 months, followed by open-label romosozumab (210 mg QM) for 12 months. At month 48, subjects who had received active treatment for 48 months were assigned to no further active treatment and all other subjects were assigned to zoledronate 5 mg IV. Efficacy (BMD, P1NP, and β-CTX) and safety were evaluated for 24 months, up to month 72.

Results: A total of 141 subjects entered the month 48-72 period, with 51 in the no further active treatment group and 90 in the zoledronate group. In subjects receiving no further active treatment, lumbar spine (LS) BMD decreased by 10.8% from months 48-72 but remained 4.2% above the original baseline. In subjects receiving zoledronate, LS BMD was maintained (percentage changes: - 0.8% from months 48-72; 12.8% from months 0-72). Similar patterns were observed for proximal femur BMD in both groups. With no further active treatment, P1NP and β-CTX decreased but remained above baseline at month 72. Following zoledronate, P1NP and β-CTX levels initially decreased but approached baseline by month 72. No new safety signals were observed.

Conclusion: A zoledronate follow-on regimen can maintain robust BMD gains achieved with romosozumab treatment.

Keywords: Antiresorptive; Bone mineral density; Follow-on regimen; Osteoporosis; Romosozumab.

Conflict of interest statement

MRM has received consulting fees and honoraria from Amgen and consulting fees from Myovant. MAB has received contract fees from and has been a speaker for Amgen. JPB has received research funding from Amgen, Eli Lilly, Mereo Biopharma, Radius Health, and Servier; has received consulting fees from Amgen, Eli Lilly, Orimed, and Servier; and has received lecture fees from Amgen and Eli Lilly. J-YR has received research funding from IBSA-Genevrier, Mylan, CNIEL, and Radius Health; has received lecture fees from IBSA-Genevrier, Mylan, CNIEL, and Dairy Research Council; and has received consulting fees from or participated in paid advisory boards for IBSA-Genevrier, Mylan, Radius Health, and Pierre Fabre. BLL has received research funding from Amgen and Novo Nordisk; has received consulting fees from Amgen, Eli Lilly, and UCB; and has received lecture fees from Amgen, Eli Lilly, and UCB. JM, YS, and MR are employees of and hold stock in Amgen. PDM is an employee of and holds stock in UCB Pharma. AG was an employee of Amgen at the time of the study and holds stock in Amgen.

Figures

Fig. 1

Study schema. a Subjects were randomized 1:1:1:1:1:1:1:1 to the first 24 months of treatment. Administration of placebo and the various romosozumab doses was blinded; alendronate and teriparatide were administered open-label. At month 24, subjects were rerandomized (1:1) within treatment group to placebo or denosumab (60 mg SC Q6M) for 12 months, followed by a 12-month second course of romosozumab 210 mg QM. b For subjects who reached month 48 of the study, eligibility for the month 48 to 72 zoledronate follow-on period was assessed by the investigator using a 3-step approach with no randomization. Subjects were assigned to no further active treatment if they (1) had been assigned to active treatment throughout the first 48 months (romosozumab any dose and schedule, followed by denosumab 60 mg Q6M, and then followed by romosozumab 210 mg QM); (2) had no clinical vertebral or fragility fracture between months 24 and 48; (3) had a BMD T-score > − 2.5 at the lumbar spine, total hip, or femoral neck at month 48; or (4) had any contraindication to zoledronate. All other subjects were assigned to receive a single IV dose of zoledronate 5 mg. aSubjects transitioned to romosozumab 140 mg QM at month 12, were randomized in the denosumab extension period, completed the study at month 36, and are not included in the present analysis. bSubjects completed the study at month 12 and are not included in the present analysis. cOf the subjects randomized to romosozumab 210 mg QM in the double-blind period, 12 entered the no further active treatment group and 17 entered the zoledronate group during the follow-on phase. IV intravenous, PO orally, QD every day, QM every month, Q3M every 3 months, QW every week, SC subcutaneous

Fig. 2

Percentage change in BMD at the lumbar spine, total hip, and femoral neck in all subjects who received romosozumab during months 36–48 and who were then assigned to no further active treatment (n = 51; a–c) or zoledronate (n = 90; d–f) from months 48 to 72. Data are mean (95% CI). BMD bone mineral density, CI confidence interval, DMAb denosumab, QM every month, Q6M every 6 months

Fig. 3

Percentage change in P1NP and β-CTX in all subjects who received romosozumab during months 36–48 and who were then assigned to no further active treatment (n = 51; a, b) or zoledronate (n = 90; c, d) from months 48 to 72. Data are median (Q1, Q3). β-CTX β-isomer of the C-terminal telopeptide of type I collagen, DMAb denosumab, IV intravenous, P1NP procollagen type I N-terminal propeptide, Q1 quartile 1, Q3 quartile 3, QM every month, Q6M every 6 months