Increased bone mineral density for 1 year of romosozumab, vs placebo, followed by 2 years of denosumab in the Japanese subgroup of the pivotal FRAME trial and extension

Abstract

Romosozumab, which binds sclerostin, rebuilds the skeletal foundation before transitioning to antiresorptive treatment. This subgroup analysis of an international, randomized, double-blind study in postmenopausal women with osteoporosis showed efficacy and safety outcomes for romosozumab followed by denosumab in Japanese women were generally consistent with those for the overall population.

Purpose: In the international, randomized, double-blind, phase 3 FRActure study, in postmenopausal woMen with ostEoporosis (FRAME; NCT01575834), romosozumab followed by denosumab significantly improved bone mineral density (BMD) and reduced fracture risk. This report evaluates Japanese women in FRAME.

Methods: Postmenopausal women with osteoporosis (T-score - 3.5 to - 2.5 at total hip or femoral neck) received romosozumab 210 mg or placebo subcutaneously monthly for 12 months, then each group received denosumab 60 mg subcutaneously every 6 months for 24 months. The key endpoint for Japanese women was BMD change. Other endpoints included new vertebral, clinical, and nonvertebral fracture; the subgroup analysis did not have adequate power to demonstrate statistically significant reductions.

Results: Of 7180 enrolled subjects, 492 (6.9%) were Japanese (247 romosozumab, 245 placebo). BMD increases from baseline were greater (P < 0.001) for romosozumab-to-denosumab than placebo-to-denosumab at the lumbar spine (36 months, 12.7%), total hip (4.2%), and femoral neck (4.1%). Fracture risk was lower through 36 months for romosozumab-to-denosumab vs placebo-to-denosumab for new vertebral (1.7% vs 4.5%; relative risk reduction (RRR) 63%, P = 0.070), clinical (3.2% vs 7.3%; RRR 53%, P = 0.072), nonvertebral (2.8% vs 6.1%; RRR 50%, P = 0.12), and all other fracture types evaluated. Rates of adverse events and positively adjudicated serious cardiovascular events were generally balanced between groups.

Conclusions: Efficacy and safety for romosozumab-to-denosumab were similar between Japanese women and the overall population. The sequence of romosozumab to rebuild the skeletal foundation before transitioning to antiresorptive treatment with denosumab is a promising regimen for Japanese postmenopausal women with osteoporosis at high risk of fracture.

Keywords: Bone mineral density; Denosumab; Fracture; Japanese; Romosozumab.

Conflict of interest statement

A Miyauchi received a research grant from Amgen Inc.; R Dinavahi, W Yang, and J Maddox are employees and shareholders of Amgen Inc.; DB Crittenden and A Grauer were employees and shareholders of Amgen Inc. at the time this study was conducted; E Hamaya is an employee of Amgen Astellas Biopharma KK and a shareholder of Amgen Inc.; Y Nakamura is an employee of Amgen Astellas Biopharma K.K. and shareholder of Astellas Pharma Inc.; J Shimauchi is an employee of Amgen Astellas Biopharma KK; and C Libanati is an employee and shareholder of UCB Pharma.

Figures

Fig. 1

Subject disposition flowchart. QM once monthly, Q6M every 6 months

Fig. 2

Percentage change from baseline in bone mineral density (BMD): effect of romosozumab (Romo) treatment for 12 months followed by denosumab (Dmab) treatment for 24 months. Least squares mean percentage changes at a lumbar spine, b total hip, and c femoral neck. n number of subjects with evaluable data at the time point, N number of subjects randomized, Pla placebo, QM once monthly, Q6M every 6 months. *Nominal P < 0.001 between treatment groups based on analysis of covariance model adjusting for treatment, age, prevalent vertebral fracture stratification variables, baseline value, machine type, and baseline value-by-machine type interaction

Fig. 3

Responder analysis of percentage change from baseline to 12 months in bone mineral density (BMD) for individual subjects. a Lumbar spine. b Total hip. The x axis represents each individual subject. Horizontal lines reflect 3%, 6%, and 10% responses relative to baseline. Arrowheads and values represent the percentage of subjects with the indicated percentage changes in BMD. N number of subjects with a baseline BMD assessment and at least one postbaseline BMD assessment at or before 12 months

Fig. 4

Fracture risk in Japanese postmenopausal women: effect of romosozumab or placebo for 12 months, followed by denosumab treatment in all subjects for 24 months. a Subject incidence and relative risk reduction (RRR), based on relative risks, for new vertebral fracture by study visit in the analysis set for vertebral fractures. b Subject incidence and RRR, based on hazard ratios, for key fracture endpoints in the full analysis set through 36 months. The last observation was carried forward for missing data. n number of subjects with fracture, N number of subjects analyzed, NE not evaluable