One Year of Romosozumab Followed by Two Years of Denosumab Maintains Fracture Risk Reductions: Results of the FRAME Extension Study

Abstract

Romosozumab, a humanized monoclonal antibody that binds and inhibits sclerostin, has the dual effect of increasing bone formation and decreasing bone resorption. As previously reported in the pivotal FRActure study in postmenopausal woMen with ostEoporosis (FRAME), women with a T‐score of ≤ –2.5 at the total hip or femoral neck received subcutaneous placebo or romosozumab once monthly for 12 months, followed by open‐label subcutaneous denosumab every 6 months for an additional 12 months. Upon completion of the 24‐month primary analysis period, eligible women entered the extension phase and received denosumab for an additional 12 months. Here, we report the final analysis results through 36 months, including efficacy assessments of new vertebral, clinical, and nonvertebral fracture; bone mineral density (BMD); and safety assessments. Of 7180 women enrolled, 5743 (80%) completed the 36‐month study (2851 romosozumab‐to‐denosumab; 2892 placebo‐to‐denosumab). Through 36 months, fracture risk was reduced in subjects receiving romosozumab versus placebo for 12 months followed by 24 months of denosumab for both groups: new vertebral fracture (relative risk reduction [RRR], 66%; incidence, 1.0% versus 2.8%; p < 0.001), clinical fracture (RRR, 27%; incidence, 4.0% versus 5.5%; p = 0.004), and nonvertebral fracture (RRR, 21%; incidence, 3.9% versus 4.9%; p = 0.039). BMD continued to increase for the 2 years with denosumab treatment in both arms. The substantial difference in BMD achieved through 12 months of romosozumab treatment versus placebo was maintained through the follow‐up period when both treatment arms received denosumab. Subject incidence of adverse events, including positively adjudicated serious cardiovascular adverse events, were overall balanced between groups. In conclusion, in postmenopausal women with osteoporosis, 12 months of romosozumab led to persistent fracture reduction benefit and ongoing BMD gains when followed by 24 months of denosumab. The sequence of romosozumab followed by denosumab may be a promising regimen for the treatment of osteoporosis. © 2018 American Society for Bone and Mineral Research.

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

“…In this subgroup analysis of Japanese postmenopausal women with osteoporosis in the phase 3 FRAME trial, the outcomes for BMD, fracture risk, and safety through 36 months were consistent with those for the overall FRAME population [ 28 , 29 ]. In both populations, subjects in the romosozumab-to-denosumab group showed significantly higher increases in BMD at the spine, total hip, and femoral neck at 12, 24, and 36 months than the subjects in the placebo-to-denosumab group, and the romosozumab-to-denosumab group had consistently lower fracture incidences for all fracture types evaluated.…”

“…At 12 months, women in each treatment group transitioned to open-label treatment with the antiresorptive agent denosumab, administered every 6 months for an additional 24 months, including an open-label period (months 12–24) and an extension period (months 24–36). Significant improvements in BMD and fracture risk in the romosozumab-to-denosumab group persisted through 36 months in FRAME, supporting the benefit of rebuilding the skeletal foundation with romosozumab before transitioning to antiresorptive treatment with denosumab [ 29 ]. This subgroup analysis of FRAME examined cumulative results for BMD and fracture risk through 36 months among Japanese postmenopausal women with osteoporosis.…”

Senile Osteoporosis: The Involvement of Differentiation and Senescence of Bone Marrow Stromal Cells

“…Therefore, in order to treat senile osteoporosis, it is required to use the strategies in what BMSCs can be stimulated either to differentiate into more osteoblasts than adipocytes or be eliminated their senescence. To date, numerous molecules including parathyroid hormone (PTH 1-84) or only its N-terminal fragment teriparatide (PTH 1-34), bisphosphonates, tetracycline, cationic peptides and antibodies like denosumab and romosozumab have been used in the treatment of senile osteoporosis [15][16][17][18][19]. However, most of them are limited either, due to their severe side effects or inhibition of just bone resorption without decreasing bone regeneration.…”

“…Therefore, both abnormal differentiation and senescence of BMSCs lead to the reduced number of osteoblasts in old ages, which result in decreased bone formation, thus, cause senile osteoporosis. To date, numerous medicines have been used to treat senile osteoporosis, but there are still some limitations, due to their side effects [15][16][17][18][19]. Therefore, in order to find out proper treatments, it is the focus of new era cell-based therapy research to uncover the molecular mechanisms behind the differentiation and senescence of BMSCs.…”

Improved in vivo Experimental Screening Identifies an Anabolic Analog of 1,25 Dihydroxyvitamin D3 With Minimal Bone Resorption Activity

“…The currently approved anabolic therapies, teriparatide, abaloparatide, and romosozumab, are available in injectable formulations only. Because the recommended duration of treatment is limited to 2 years for the parathyroid hormone and parathyroid hormone–related peptide analogs and 1 year for the anti‐sclerostin antibody, strategies are being developed to inhibit bone loss after therapy discontinuation because, in the absence of antiresorptive treatment, gains in bone density are progressively lost . In addition, romosozumab was found to be associated with increased cardiovascular risks in the phase 3 trial, and was approved only for high‐risk osteoporosis.…”