Romosozumab Treatment Research Articles

OR13-05 Romosozumab Treatment Lowers the Incidence of New Vertebral Fractures Across All Fracture Severity Grades Among Postmenopausal Women with Osteoporosis

Vertebral fractures (VFx) are the most common type of fracture in postmenopausal osteoporosis (PMO). VFx are generally classified using the Genant grading system as mild (grade 1), moderate (grade 2), or severe (grade 3) according to their degree of compression visualized on spinal x-rays. Regardless of their severity, VFx are associated with significant morbidity and carry the highest subsequent fracture rate of any fragility fracture. We assessed the incidence of new VFx by Genant severity grade in the romosozumab (Romo) vs placebo (Pbo) or alendronate (ALN) arms of the FRAME and ARCH studies, respectively.In FRAME, 7,180 women with PMO were randomized 1:1 to receive monthly Romo 210 mg or Pbo for 12 months followed by biannual denosumab (DMAb) 60 mg (Romo→DMAb or Pbo→DMAb) for 12 months. In ARCH, 4,093 women with PMO and ≥ 1 fracture were randomized 1:1 to receive monthly Romo 210 mg or weekly oral ALN 70 mg for 12 months followed by ALN 70 mg (Romo→ALN or ALN→ALN) for ≥ 12 months. Throughout both studies, lateral radiographs of the spine were assessed for the presence and severity (mild, moderate, or severe) of VFx using the Genant grading at baseline and after 12 and 24 months of treatment.The incidence of new VFx was significantly lower among patients who received Romo during the 12-month double-blind treatment phase in both studies. Over 12 months, the incidence of new VFx was 0.5% Romo vs 1.8% Pbo (P<0.001) in FRAME and 3.2% Romo vs 5.0% ALN (P=0.008) in ARCH. Over 24 months, the incidence of new VFx was 0.6% Romo→DMAb vs 2.5% Pbo→DMAb (P<0.001) in FRAME and 4.1% Romo→ALN vs 8.0% ALN→ALN (P<0.001) in ARCH. Fewer new VFx were observed in the Romo arm of both studies across all fracture severity grades. Specifically, in FRAME, the incidence of mild VFx was 0.2% Romo vs 0.4% Pbo over 12 months and 0.2% Romo→DMAb vs 0.6% Pbo→DMAb over 24 months; the incidence of moderate VFx was 0.1% Romo vs 0.9% Pbo over 12 months and 0.2% Romo→DMAb vs 1.4% Pbo→DMAb over 24 months; and the incidence of severe VFx was 0.2% Romo vs 0.5% Pbo over 12 months and 0.2% Romo→DMAb vs 0.6% Pbo→DMAb over 24 months. Similarly, in ARCH, the incidence of mild VFx was 0.5% Romo vs 1.0% ALN over 12 months and 0.4% Romo→ALN vs 1.4% ALN→ALN over 24 months; the incidence of moderate VFx was 1.3% Romo vs 2.1% ALN over 12 months and 1.8% Romo→ALN vs 3.4% ALN→ALN over 24 months; and the incidence of severe VFx was 1.5% Romo vs 1.9% ALN over 12 months and 1.9% Romo→ALN vs 3.3% ALN→ALN over 24 months.In conclusion, Romo administered over 12 months to women with PMO resulted in reductions in VFx across all fracture severity grades compared with Pbo and standard-of-care ALN. The treatment effect of Romo continued after patients transitioned to an antiresorptive agent. These data will help to foster treatment decisions in postmenopausal women at high risk for VFx.

The Effect of 1 Year of Romosozumab on the Incidence of Clinical Vertebral Fractures in Postmenopausal Women With Osteoporosis: Results From the FRAME Study.

ABSTRACTRadiographic vertebral fractures (VFxs) are the most common fractures in osteoporosis and are associated with increased morbidity, mortality, and costs. A subset of VFxs manifest clinically, usually with a sudden onset of severe back pain. Romosozumab is a monoclonal antibody that binds and inhibits sclerostin, increasing bone formation and decreasing bone resorption, leading to rapid and large increases in bone density and strength and reduction in fracture risk. The FRAME (Fracture Study in Postmenopausal Women with Osteoporosis) study of postmenopausal women with osteoporosis demonstrated a significant reduction in new VFxs with romosozumab versus placebo. Here, we report the effect of romosozumab versus placebo on clinical VFx incidence over 12 months in women reporting back pain suggestive of VFxs. FRAME enrolled 7180 postmenopausal women with osteoporosis, mean age 70.9 years (hip T‐score −2.5 to −3.5). In the first year of the study, women received monthly romosozumab 210 mg (n = 3589) or placebo (n = 3591). At regular monthly visits, women reporting back pain suggestive of a clinical VFx had a confirmatory spine X‐ray. Clinical VFx risk in the romosozumab group versus the placebo group was calculated by Cox‐proportional hazards model. Of 119 women in FRAME with back pain suggestive of a clinical VFx over 12 months, 20 were confirmed to have experienced a new/worsening VFx. Three women receiving romosozumab had a clinical VFx (<0.1% of 3589 women) versus 17 (0.5% of 3591 women) receiving placebo resulting in a reduction in clinical VFx risk of 83% in the romosozumab group versus placebo through 12 months (HR 0.17; 95% CI, 0.05 to 0.58; p = 0.001). In the three romosozumab‐treated women, clinical VFxs occurred within the first 2 months of the study with no further clinical VFxs throughout the year. Romosozumab treatment for 12 months was associated with rapid and large reductions in clinical VFx risk versus placebo. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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

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.

The clinical potential of romosozumab for the prevention of fractures in postmenopausal women with osteoporosis.

The glycoprotein sclerostin inhibits activation of the canonical Wnt pathway and thereby suppresses bone formation by inhibiting the osteoblasts. Additionally, sclerostin increases bone resorption by stimulating the production of receptor activator of nuclear factor kappa-β-ligand (RANKL). Romosozumab (ROMO) is a monoclonal antibody against sclerostin. Phase III clinical trials in postmenopausal women with osteoporosis have shown that ROMO increases bone mineral density at the lumbar spine and hip and reduces the risk of vertebral and clinical fractures in comparison with placebo. In women with severe osteoporosis, ROMO reduces the risk of vertebral, nonvertebral and clinical fractures in comparison with alendronate. ROMO is the first treatment for osteoporosis with dual action, and may become a valuable tool for improving the treatment of osteoporosis. At present, the approval of ROMO by the authorities is awaiting further investigations of a potential increased risk of cardiovascular events associated with ROMO treatment.

Romosozumab treatment in postmenopausal women with osteoporosis: a meta-analysis of randomized controlled trials

Aim: To conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the safety and efficacy of romosozumab in the treatment of postmenopausal osteoporosis. Method: A comprehensive literature review was performed of PubMed, EMBASE, Cochrane Controlled Trials Registry, and Web of Science for RCTs. Outcome measures were changes in lumbar spine, total hip and femoral neck bone mineral density (BMD), incidence of fractures and adverse events. Six trials were finally included. Results: Romosozumab resulted in a significantly lower risk of new vertebral fracture (relative risk (RR) 0.37, 95% confidence interval (CI) 0.18–0.77, p = 0.005, n = 5371), non-vertebral fracture (RR 0.78, 95% CI 0.66–0.92, p < 0.0001, n = 5635) and hip fracture (RR 0.59, 95% CI 0.44–0.79, p = 0.0004, n = 5635) compared with other therapies. The BMD was significantly increased at the lumbar spine (weighted mean difference (WMD) 13.33, 95% CI 11.41–15.25, p < 0.00001, n = 198), total hip (WMD 5.09, 95% CI 3.81–6.38, p < 0.00001, n = 184) and femoral neck (WMD 4.70, 95% CI 3.50–5.90, p < 0.00001, n = 175) compared with placebo. There was no significant difference in the incidence of adverse events in patients with romosozumab compared to other therapies (RR 1.00, 95% CI 0.98–1.02). Conclusion: In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment resulted in a significantly lower risk of fracture. Romosozumab 210 mg monthly showed the largest gains in BMD, and was generally well tolerated.

Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis

BackgroundRomosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption.MethodsWe enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1:1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open-label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in ≥330 patients). Secondary end points included the incidences of nonvertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated.ResultsOver a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2046 patients]) than in the alendronate-to-alendronate group (11.9% [243 of 2047 patients]) (P<0.001). Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of 2047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (P<0.001). The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [10.6%]; P=0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients [2.5%] vs. 38 of 2014 patients [1.9%]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed.ConclusionsIn postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. (Funded by Amgen and others; ARCH ClinicalTrials.gov number, NCT01631214.)

Romosozumab increases bone mineral density in postmenopausal Japanese women with osteoporosis: A phase 2 study

BackgroundRomosozumab is a monoclonal antibody that inhibits sclerostin and rapidly increases bone mineral density (BMD) through a dual effect on bone by increasing bone formation and decreasing bone resorption, as shown in a global phase 2 study in postmenopausal women with low bone mass. Here, we report the key results of a phase 2, double-blind, placebo-controlled, dose-ranging study to assess the efficacy and safety of romosozumab in postmenopausal Japanese women with osteoporosis. MethodsParticipants were postmenopausal Japanese women with osteoporosis aged 55–85years with a lumbar spine, total hip, or femoral neck dual-energy X-ray absorptiometry T-score≤−2.5. Women were randomized to receive placebo or romosozumab (70, 140, or 210mg) subcutaneously once monthly (QM) for 12months. The primary efficacy endpoint was the percentage change from baseline in lumbar spine BMD at month 12. Secondary efficacy endpoints included the percentage change from baseline in lumbar spine BMD at month 6, total hip and femoral neck BMD at months 6 and 12, and serum bone turnover markers procollagen type 1N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) at multiple visits. ResultsThis study enrolled 252 women who had a mean age of 67.7years and mean T-scores of −2.7, −1.9, and −2.3 at the lumbar spine, total hip, and femoral neck, respectively. All romosozumab doses significantly increased BMD at month 12 compared with placebo (p<0.01), with the largest mean gains from baseline observed with romosozumab 210mg QM (lumbar spine=16.9%, total hip=4.7%, and femoral neck=3.8%). All doses of romosozumab significantly increased the levels of bone-formation marker P1NP and reduced the levels of bone-resorption marker CTX by week 1 (p<0.001 vs placebo). In the 210mg QM group, P1NP levels peaked at month 1 and fell below placebo levels by month 12; CTX levels were lowest at week 1 and remained below placebo through month 12. The patient incidences of adverse events and serious adverse events were generally comparable between treatment groups. ConclusionsIn postmenopausal Japanese women with osteoporosis, romosozumab treatment resulted in large and significant gains in BMD from baseline and compared with placebo. Romosozumab 210mg QM showed the largest gains in BMD and was generally well tolerated. The efficacy and safety of romosozumab 210mg QM in this phase 2 study of postmenopausal women with osteoporosis were similar to those in an international phase 2 study.

Kinetic reconstruction reveals time-dependent effects of romosozumab on bone formation and osteoblast function in vertebral cancellous and cortical bone in cynomolgus monkeys

Romosozumab, a humanized monoclonal sclerostin antibody under development for the treatment of osteoporosis, has a unique mechanism of action on bone—increasing bone formation and decreasing bone resorption. The effects on bone formation are transient, eliciting a rapid increase in bone formation that attenuates with continued treatment. Although bone formation attenuates, bone mineral density (BMD) continues to increase. To explore potential tissue-level mechanisms that could contribute to a progressive increase in spine BMD, we used kinetic reconstruction techniques to examine the effects of romosozumab on modeling and remodeling units in vertebral cancellous bone from adult cynomolgus monkeys administered romosozumab for 10 and 28weeks.The 10-week study duration captured a period of high modeling-based bone formation, and the 28-week study duration followed the self-regulation or attenuation of bone formation in cancellous bone that occurs with long-term treatment. Sequential fluorochrome labels applied for the kinetic reconstruction were also used to evaluate treatment effects on osteoblast function as early as 3weeks, and on bone formation and bone accrual in the vertebral cortex over 28weeks.Kinetic reconstruction of remodeling and modeling formation sites in vertebral cancellous bone revealed that romosozumab effected significant transient increases in mineral apposition rate in remodeling sites at week 3 that was not sustained with continued treatment. However, romosozumab treatment caused sustained improvement in fractional labeling of osteoid, an index of osteoblast efficiency, at remodeling formative sites at both weeks 10 and 28 that was the major contributor to significant increases in final wall thickness (W.Th) of remodeling packets. Remodeling W.Th matched the final W.Th of modeling packets at week 10. At both weeks 10 and 28, romosozumab significantly decreased eroded surface (ES/BS). At week 28, romosozumab also significantly reduced resorption period (Rs.P) and final resorption depth (Rs.De). The reduced final Rs.De combined with the increased W.Th resulted in a significant increase in bone balance (BB) at the level of the remodeling unit. Assessment of bone formation on the vertebral periosteal and endocortical surfaces following 28weeks of treatment revealed that romosozumab significantly increased bone formation on these surfaces, which had attenuated by week 28, resulting in significant increases in new periosteal and endocortical bone by week 28.These data suggest that multiple factors potentially contribute to the increase in spine BMD with romosozumab treatment. In the early period of treatment, increased modeling-based bone formation, increased W.Th at remodeling sites, a decrease in remodeling space secondary to decreased ES/BS in vertebral cancellous bone, and increased periosteal and endocortical bone formation in the vertebral cortex contribute to the early increase in spine BMD. Following the self-regulation of bone formation when modeling-based bone formation has attenuated, a decrease in remodeling space secondary to reduced ES/BS and a positive BB secondary to decreased final Rs.De and increased W.Th contribute to the progressive increase in spine BMD with long-term treatment.

Romosozumab Treatment in Postmenopausal Women with Osteoporosis

BackgroundRomosozumab, a monoclonal antibody that binds sclerostin, increases bone formation and decreases bone resorption.MethodsWe enrolled 7180 postmenopausal women who had a T score of –2.5 to –3.5 at the total hip or femoral neck. Patients were randomly assigned to receive subcutaneous injections of romosozumab (at a dose of 210 mg) or placebo monthly for 12 months; thereafter, patients in each group received denosumab for 12 months, at a dose of 60 mg, administered subcutaneously every 6 months. The coprimary end points were the cumulative incidences of new vertebral fractures at 12 months and 24 months. Secondary end points included clinical (a composite of nonvertebral and symptomatic vertebral) and nonvertebral fractures.ResultsAt 12 months, new vertebral fractures had occurred in 16 of 3321 patients (0.5%) in the romosozumab group, as compared with 59 of 3322 (1.8%) in the placebo group (representing a 73% lower risk with romosozumab; P<0.001). Clinical fractures had occurred in 58 of 3589 patients (1.6%) in the romosozumab group, as compared with 90 of 3591 (2.5%) in the placebo group (a 36% lower risk with romosozumab; P=0.008). Nonvertebral fractures had occurred in 56 of 3589 patients (1.6%) in the romosozumab group and in 75 of 3591 (2.1%) in the placebo group (P=0.10). At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3325 patients] in the romosozumab group vs. 2.5% [84 of 3327] in the placebo group, a 75% lower risk with romosozumab; P<0.001). Adverse events, including instances of hyperostosis, cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and two cases of osteonecrosis of the jaw were observed in the romosozumab group.ConclusionsIn postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months. The lower risk of clinical fracture that was seen with romosozumab was evident at 1 year. (Funded by Amgen and UCB Pharma; FRAME ClinicalTrials.gov number, NCT01575834.)

Inhibition of sclerostin in the management of osteoporosis: results of a phase 2 clinical trial meet expectations.

Inhibition of sclerostin in the management of osteoporosis: results of a phase 2 clinical trial meet expectations.