Bone mineral density gains with a second 12-month course of romosozumab therapy following placebo or denosumab

Abstract

Romosozumab is a therapy that stimulates bone formation and reduces bone resorption. In this study of postmenopausal women with low BMD, a second course of romosozumab following a period off treatment or on denosumab increased or maintained BMD, respectively, and was well tolerated, providing insight into treatment sequence options.

Introduction: In patients with high fracture risk, therapies that stimulate bone formation provide rapid BMD gains; currently available agents, parathyroid hormone receptor agonists, are limited to a 2-year lifetime exposure and generally used for a single treatment course. However, for long-term osteoporosis management, a second treatment course may be appropriate. Romosozumab, a therapy with the dual effect of increasing bone formation and decreasing bone resorption, reduces fracture risk within 12 months. Here, we report efficacy and safety of a second romosozumab course.

Methods: In this phase 2, dose-finding study, postmenopausal women with low bone mass (T-score ≤ - 2.0 and ≥ - 3.5) received romosozumab or placebo (month 0-24) followed by placebo or denosumab (month 24-36); participants then received a year of romosozumab (month 36-48).

Results: Of 167 participants who entered the month 36-48 period, 35 had been initially randomized to romosozumab 210 mg monthly. In participants who received romosozumab 210 mg monthly followed by placebo, a second romosozumab course (n = 19) increased BMD by amounts similar to their initial treatment (month 0-12) at the lumbar spine (12.4%; 12.0%, respectively) and total hip (6.0%; 5.5%, respectively). Following denosumab, a second romosozumab course (n = 16) increased BMD at the lumbar spine (2.3%) and maintained BMD at the total hip. Safety profiles were similar between first and second romosozumab courses.

Conclusions: After 12 months off-treatment, a second romosozumab course again led to rapid and large BMD gains. Following denosumab, BMD gains with romosozumab were smaller than with initial treatment. No new safety findings were observed during the second course.

Keywords: Antiresorptive; Bone-forming agent; Clinical trial; Denosumab; Osteoporosis; Romosozumab.

Conflict of interest statement

DLK has been an investigator for Amgen, Astellas, AstraZeneca, and Eli Lilly; a speaker and consultant for Amgen, Pfizer, and Eli Lilly; and a member of a drug safety advisory board for Merck. HGB has been an investigator for Amgen, Merck, and Shire; a consultant for Amgen, Merck, Radius Health, and Shire; a speaker for Amgen, Radius Health, and Shire; and a member of a data/safety monitoring board for Grünenthal. FM has no disclosures. EG has been a speaker for Amgen and Takeda, and an advisory board member for UCB and Alexion. SP has been an investigator for Pfizer, Amgen, Gedeon Richter, and Exeltis; a speaker for Bayer Schering, Novo Nordisk, Servier, Pfizer, MSD, Gedeon Richter, ProCare Health, Shionogi, and Teva; and an advisory board member for Novo Nordisk, Gedeon Richter, ProCare Health, and Shionogi. JM and RVD are employees of and hold stock in Amgen. CY was an employee of Amgen at the time of the study and may hold stock in Amgen, and is currently an employee of Cambridge Statistics Ltd. and holds stock in Cambridge Statistics Ltd. SY was an employee of Amgen at the time of the study and may hold stock in Amgen, and is currently an employee of Atara Biotherapeutics and holds stock in Atara Biotherapeutics. CL is an employee of and holds stock in UCB Pharma. AG was an employee of Amgen at the time of the study and may hold stock in Amgen, and is currently an employee of Corcept Therapeutics and holds stock options in Corcept Therapeutics.

Figures

Fig. 1

Study schema. Participants were randomized 1:1:1:1:1:1:1:1 for 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, participants were rerandomized (1:1) within treatment groups to receive blinded placebo or denosumab 60 mg SC Q6M for 12 months, followed by a 12-month second-course period with romosozumab 210 mg QM. All participants were instructed to take calcium (≥ 1 g) and vitamin D (≥ 800 IU) daily. aParticipants randomized to alendronate switched to romosozumab 140 mg QM at month 12, were randomized to the denosumab extension period, and completed the study at month 36; these participants are not included in the present analysis (month 36 to month 48). bParticipants randomized to teriparatide completed the study at month 12 and were not included in the present analysis (month 36 to month 48). QD, every day; QM, monthly; Q3M, every 3 months; Q6M, every 6 months; QW, weekly; SC, subcutaneous

Fig. 2

Disposition for all participants randomized in the study. Participants were randomized 1:1:1:1:1:1:1:1 for 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, participants were rerandomized (1:1) within treatment groups to receive blinded placebo or denosumab 60 mg SC Q6M for 12 months, followed by a 12-month second-course period with romosozumab 210 mg QM. Of the participants initially randomized to romosozumab 210 mg QM, 19 placebo-treated and 16 denosumab-treated participants entered the second-course period. All participants were instructed to take calcium (≥ 1 g) and vitamin D (≥ 800 IU) daily. aAt month 12, participants initially randomized to receive placebo continued to receive placebo up to month 24. bAt month 12, participants initially randomized to receive a specific dose and schedule of romosozumab continued to receive their assigned treatment up to month 24. cAt month 12, participants initially randomized to receive alendronate (gray box) were switched to romosozumab 140 mg QM for 12 months, up to month 24, and were not included in the present analysis (month 36 to month 48). dParticipants initially randomized to receive teriparatide (gray box) completed the study at month 12 and were not included in the present analysis (month 36 to month 48). eCumulative number of participants who discontinued the study during the first 24 months. fNumber of participants who discontinued the study between month 24 and month 36. gOne subject was randomized to receive placebo in the initial treatment period but received romosozumab treatment. hNumber of participants who discontinued the study between month 36 and month 48. iOne participant had not undertaken the 48-month visit at the time of the analysis. PO, orally; QM, monthly; Q3M, every 3 months; Q6M, every 6 months; QW, weekly; SC, subcutaneous

Fig. 3

Percentage change from month 0 to month 48 in lumbar spine BMD (a), total hip BMD (b), P1NP (c), and β-CTX (d). Data shown are for participants who had received romosozumab 210 mg QM from month 0 to month 24 (n = 35) and had received either placebo (n = 19) or denosumab 60 mg Q6M (N = 16) from month 24 to month 36, before receiving romosozumab 210 mg QM from month 36 to month 48. Data are mean (95% CI) for BMD and median (Q1, Q3) for P1NP and β-CTX. β-CTX, β-isomer of C-terminal telopeptide of type 1 collagen; BMD, bone mineral density; CI, confidence interval; P1NP, procollagen type 1 N-terminal propeptide; Q1, Q3, first and third quartiles; QM, monthly; Q6M, every 6 months