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 openlabel 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 alendronateto-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.)

Background: Romosozumab 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.Methods: Participants were postmenopausal Japanese women with osteoporosis aged 55-85 years 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 210 mg) subcutaneously once monthly (QM) for 12 months. 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 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) at multiple visits.Results: This study enrolled 252 women who had a mean age of 67.7 years 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 210 mg 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 210 mg 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.Conclusions: In postmenopausal Japanese women with osteoporosis, romosozumab treatment resulted in large and significant gains in BMD from baseline and compared with placebo. Romosozumab 210 mg QM showed the largest gains in BMD and was generally well tolerated. The efficacy and safety of romosozumab 210 mg QM in this phase 2 study of postmenopausal women with osteoporosis were similar to those in an international phase 2 study. (C) 2017 The Authors. Published by Elsevier Inc.

Background Denosumab was superior to zoledronic acid (ZA) in reducing the risk of a first on-study skeletal-related event (SRE; HR, 0.82; 95% confidence interval (CI) 0.71, 0.95; p = 0.01) in patients with breast cancer and bone metastases (BMs; Stopeck et al., 2010). All patients who remained on treatment after the primary analysis were offered open-label (OL) denosumab for a pre-specified 2-year extension phase. Methods Women with BMs secondary to breast cancer (N = 2046) were randomly assigned to subcutaneous denosumab 120 mg or IV ZA 4 mg (adjusted for renal function) Q4W. Patients who completed this double-blind, double-dummy treatment phase were offered OL denosumab Q4W. Patients who did not participate in the OL phase were followed up for survival every 12 weeks for up to 2 years after their last dose of investigational drug. Findings Of the 752 patients who completed the double-blind phase, 667 (89%) chose to receive OL denosumab: 325 initially randomly assigned to denosumab (DD) and 342 to ZA (ZD). Total median (Q1, Q3) cumulative denosumab exposure in DD patients was 19.3 months (9.2, 32.2) (range 0.9–59.8 months). Adverse events (AEs) were comparable between groups (n = 283/318 [89%] for DD; n = 303/334 [91%] ZD) during the OL phase; 20 and 18 patients, respectively, reported osteonecrosis of the jaw; cumulative incidence was 4.7% in DD patients and 3.5% in ZD patients for the entire study duration of 5 years. Hypocalcaemia was comparable between groups (n = 12 DD; n = 9 ZD). Serious AEs were reported in 126 (39.6%) DD patients and 133 (39.8%) ZD patients. Overall survival was similar between the groups for the entire study: median 34.4 months (95% CI 31.5, 39.3) and 34.2 months (95% CI 31.0, 37.6), respectively. Interpretation This OL extension treatment phase confirmed the safety profile of denosumab in patients with breast cancer with BMs receiving up to 5 years of monthly denosumab therapy or switching to denosumab after up to 3 years of ZA. Funding Funding was provided by Amgen Inc. A.T. Stopeck is a consultant for Amgen and Novartis; A. Lipton is a member of the speakers' bureau, is a consultant, has received research support from Amgen and Novartis, and has provided expert testimony for Novartis; M. Martín is a consultant for Amgen; J-J. Body is a consultant for and has received lecture fees from both Amgen and Novartis; A. Paterson has received honoraria for speaking from Amgen, Roche, and Novartis; G.G. Steger has received travel grants and attended advisory boards for Amgen and Novartis; K. Tonkin has no disclosures; R.H. de Boer has no disclosures; Y. Fujiwara, Chugai Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma KK, Janssen Pharmaceutical KK, and Takeda Bio Development Center Limited; D. Yardley has no disclosures; J. Jassem has no disclosures; T. Takano is a medical consultant for Daiichi Sankyo; P. Solal-Céligny has no disclosures; and M. Fan and A. Braun are employed by Amgen and own stock. Denosumab was superior to zoledronic acid (ZA) in reducing the risk of a first on-study skeletal-related event (SRE; HR, 0.82; 95% confidence interval (CI) 0.71, 0.95; p = 0.01) in patients with breast cancer and bone metastases (BMs; Stopeck et al., 2010). All patients who remained on treatment after the primary analysis were offered open-label (OL) denosumab for a pre-specified 2-year extension phase. Women with BMs secondary to breast cancer (N = 2046) were randomly assigned to subcutaneous denosumab 120 mg or IV ZA 4 mg (adjusted for renal function) Q4W. Patients who completed this double-blind, double-dummy treatment phase were offered OL denosumab Q4W. Patients who did not participate in the OL phase were followed up for survival every 12 weeks for up to 2 years after their last dose of investigational drug. Of the 752 patients who completed the double-blind phase, 667 (89%) chose to receive OL denosumab: 325 initially randomly assigned to denosumab (DD) and 342 to ZA (ZD). Total median (Q1, Q3) cumulative denosumab exposure in DD patients was 19.3 months (9.2, 32.2) (range 0.9–59.8 months). Adverse events (AEs) were comparable between groups (n = 283/318 [89%] for DD; n = 303/334 [91%] ZD) during the OL phase; 20 and 18 patients, respectively, reported osteonecrosis of the jaw; cumulative incidence was 4.7% in DD patients and 3.5% in ZD patients for the entire study duration of 5 years. Hypocalcaemia was comparable between groups (n = 12 DD; n = 9 ZD). Serious AEs were reported in 126 (39.6%) DD patients and 133 (39.8%) ZD patients. Overall survival was similar between the groups for the entire study: median 34.4 months (95% CI 31.5, 39.3) and 34.2 months (95% CI 31.0, 37.6), respectively. This OL extension treatment phase confirmed the safety profile of denosumab in patients with breast cancer with BMs receiving up to 5 years of monthly denosumab therapy or switching to denosumab after up to 3 years of ZA. Funding was provided by Amgen Inc.

Purpose: Denosumab was shown to be superior to zoledronic acid in preventing skeletal related events (SRE) in patients with breast cancer and bone metastases in a randomized, double-blind phase III study. We evaluated further results from this study related to skeletal complications and health-related quality of life (HRQoL). Experimental Design: Patients were randomized 1:1 to receive subcutaneous denosumab 120 mg (n = 1,026) and intravenous placebo, or intravenous zoledronic acid 4 mg (n = 1,020) and subcutaneous placebo every 4 weeks. Analyses reported here include the proportion of patients with one or multiple on-study SREs, time to first radiation to bone, time to first SRE or hypercalcemia of malignancy, and change in HRQoL (functional assessment of cancer therapy–general). Results: Fewer patients receiving denosumab than zoledronic acid had an on-study SRE (31% vs. 36%, P = 0.006). The incidence of first radiation to bone was 12% (n = 123) with denosumab versus 16% (n = 162) with zoledronic acid. Denosumab prolonged the time to first radiation to bone by 26% versus zoledronic acid (HR, 0.74; 95% confidence interval [CI], 0.59–0.94, P = 0.012) and prolonged the time to first SRE or hypercalcemia of malignancy by 18% (HR, 0.82; 95% CI, 0.70–0.95; P = 0.007). Ten percent more patients had a clinically meaningful improvement in HRQoL with denosumab relative to zoledronic acid, regardless of baseline pain levels. Conclusions: Denosumab was superior to zoledronic acid in reducing bone-related complications of metastatic breast cancer and maintained HRQoL, providing an efficacious, well-tolerated treatment option for patients with bone metastases from breast cancer. Clin Cancer Res; 18(17); 4841–9. ©2012 AACR.

Abstract Background Primary results from a phase 3, randomized, double-blind double-dummy trial showed that compared with zoledronic acid (ZA), denosumab reduced the risk of developing a first on-study SRE by 18% (hazard ratio, 0.82; 95% CI 0.71 to 0.95; P = 0.01), and the risk of multiple SREs by 23% (rate ratio, 0.77; 95% CI 0.66 to 0.89; P = 0.001) in patients with breast cancer and bone metastases. Based on superior efficacy and favorable safety data from the study's primary analysis (Stopeck et al, 2010), all patients who remained on treatment were offered open-label denosumab in a prespecified 2-year extension treatment phase. Materials and Methods: A total of 2046 patients with breast cancer and bone metastasis were randomized to receive either subcutaneous (SC) denosumab 120 mg and intravenous (IV) placebo or IV ZA 4 mg (adjusted for renal function) and SC placebo Q4W in the double-blinded treatment phase. Patients who completed the double-blinded treatment phase were offered open-label denosumab Q4W for up to 2 years from the start of the open-label treatment phase. Patients who did not participate in the open-label treatment were followed for survival every 12 weeks for up to 2 years after their last dose of investigational product in the double-blinded treatment phase. Results: Of the 752 patients who completed the double-blinded treatment phase, 667 (89%) patients entered the open-label treatment phase: 325 (48.7%) initially randomized to the denosumab group (DD) and 342 (51.3%) to the ZA group in the double-blinded treatment phase (ZD). Demographics were comparable between groups. The total median (Q1, Q3) cumulative denosumab exposure (including double-blinded and open-label treatment phases) for DD patients was 19.3 months (9.2, 32.2) (range 0.9−59.8 months). Adverse events (AEs) were comparable between groups (n = 283/318 [89%] for DD patients; n = 303/334 [91%] ZD patients). An additional 20 patients in the DD group and 18 patients in the ZD group reported osteonecrosis of the jaw, resulting in a cumulative incidence of 4.7% for DD patients and 3.5% for ZD patients for the entire study duration of 5 years. Hypocalcemia AEs during the open-label treatment phase were comparable between groups (n = 12 DD; n = 9 ZD). The most common AEs were nausea, fatigue, and back pain. Serious AEs were reported in 126 (39.6%) DD patients and 133 (39.8%) ZD patients. Overall survival was similar between groups over the entire study: median 34.4 months (95% CI 31.5 to 39.3) for DD patients, 34.2 months (95% CI 31.0 to 37.6) for ZD patients. Conclusion: A two-year open-label extension treatment phase confirmed the long-term safety profile of denosumab in these breast cancer patients with bone metastases who continued receiving denosumab for up to 5 years or who switched from ZA to denosumab. No new safety signals were observed with up to 5 years of monthly denosumab therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-07.

We compared the activity of denosumab with zoledronic acid for delaying or preventing hypercalcaemia of malignancy (HCM) in patients with advanced cancer and bone metastases or with multiple myeloma.Patient-level data were combined from two identically designed, randomised, double-blind, active-controlled, phase III trials of advanced cancer patients with breast cancer and other solid tumours (excluding breast or prostate cancer) or multiple myeloma. End-points included time to first on-study HCM, time to first and subsequent on-study HCM, proportion of patients experiencing HCM and proportion of patients experiencing recurrent HCM.Denosumab significantly delayed the time to first on-study HCM, representing a 37% reduction in the hazard ratio (HR) compared with zoledronic acid (HR, 0.63; 95% confidence interval (CI): 0.41–0.98; P = 0.042) and reduced the risk of developing recurrent HCM (time to first and subsequent on-study HCM) by 52% (rate ratio, 0.48; 95% CI: 0.29–0.81; P = 0.006). The median time on study was 12.9 months. Fewer patients receiving denosumab compared with zoledronic acid experienced an HCM event (1.7% versus 2.7%; P = 0.028). Of the 84 patients experiencing an HCM event, 40% of those receiving zoledronic acid experienced >1 event of HCM compared with 31% of those receiving denosumab.Denosumab treatment was more efficacious than treatment with zoledronic acid in delaying or preventing HCM in advanced cancer patients with breast cancer, other solid tumours or multiple myeloma.

The intensity of bone remodeling is a critical determinant of the decay of cortical and trabecular microstructure after menopause. Denosumab suppresses remodeling more than alendronate, leading to greater gains in areal bone mineral density (aBMD). These greater gains may reflect differing effects of each drug on bone microarchitecture and strength. In a phase 2 double-blind pilot study, 247 postmenopausal women were randomized to denosumab (60 mg subcutaneous 6 monthly), alendronate (70 mg oral weekly), or placebo for 12 months. All received daily calcium and vitamin D. Morphologic changes were assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and distal tibia and QCT at the distal radius. Denosumab decreased serum C-telopeptide more rapidly and markedly than alendronate. In the placebo arm, total, cortical, and trabecular BMD and cortical thickness decreased (-2.1% to -0.8%) at the distal radius after 12 months. Alendronate prevented the decline (-0.6% to 2.4%, p = .051 to <.001 versus placebo), whereas denosumab prevented the decline or improved these variables (0.3% to 3.4%, p < .001 versus placebo). Changes in total and cortical BMD were greater with denosumab than with alendronate (p <= .024). Similar changes in these parameters were observed at the tibia. The polar moment of inertia also increased more in the denosumab than alendronate or placebo groups (p < .001). Adverse events did not differ by group. These data suggest that structural decay owing to bone remodeling and progression of bone fragility may be prevented more effectively with denosumab. (c) 2010 American Society for Bone and Mineral Research.

PURPOSEThis randomized study compared denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor κ B (RANK) ligand, with zoledronic acid in delaying or preventing skeletal-related events (SREs) in patients with breast cancer with bone metastases.PATIENTS AND METHODSPatients were randomly assigned to receive either subcutaneous denosumab 120 mg and intravenous placebo (n = 1,026) or intravenous zoledronic acid 4 mg adjusted for creatinine clearance and subcutaneous placebo (n = 1,020) every 4 weeks. All patients were strongly recommended to take daily calcium and vitamin D supplements. The primary end point was time to first on-study SRE (defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression).RESULTSDenosumab was superior to zoledronic acid in delaying time to first on-study SRE (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .01 superiority) and time to first and subsequent (multiple) on-study SREs (rate ratio, 0.77; 95% CI, 0.66 to 0.89; P = .001). Reduction in bone turnover markers was greater with denosumab. Overall survival, disease progression, and rates of adverse events (AEs) and serious AEs were similar between groups. An excess of renal AEs and acute-phase reactions occurred with zoledronic acid; hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred infrequently (2.0%, denosumab; 1.4%, zoledronic acid; P = .39).CONCLUSIONDenosumab was superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer metastatic to bone and was generally well tolerated. With the convenience of a subcutaneous injection and no requirement for renal monitoring, denosumab represents a potential treatment option for patients with bone metastases.

Abstract Background: Intravenous (IV) bisphosphonates (BP) are currently used to treat bone metastases and prevent skeletal-related events (SRE) in patients with advanced breast cancer. In a phase 3 study, denosumab, a fully human monoclonal antibody against RANKL, was shown to be superior to zoledronic acid (ZA) in delaying or preventing SREs in patients with breast cancer and bone metastases. This prespecified analysis compares ZA and denosumab for the incidence of acute-phase reactions (flu-like syndrome including pyrexia, chills, flushing, bone pain, arthralgias, and myalgias) during the first 3 days after initial treatment in that study. Methods: Eligible patients were randomized in a double-blind, double-dummy fashion to receive IV ZA 4 mg (adjusted for creatinine clearance as specified by the Zometa label) or subcutaneous denosumab 120 mg every 4 weeks. Most patients (99%) were women; mean (SD) age was 57 (12) years, and baseline characteristics were balanced between groups. Safety analyses were conducted in patients who received ≥1 dose of denosumab (N=1020) or ZA (N=1013). Patient records were searched for adverse events (AEs) and serious AEs that occurred during the first 3 days after the first administration of study drug, using 37 prespecified MedDRA 12.0 preferred terms potentially indicating acute-phase reactions. Per study protocol, AEs were considered serious if they were fatal, life-threatening, required or prolonged in-patient hospitalization, resulted in a persistent or significant disability, or were considered to present a significant medical hazard. Results: AEs associated with acute-phase reactions in the first 3 days after treatment occurred in fewer patients in the denosumab group (10.4%) than in the ZA group (27.3%; P<0.0001), and no events were attributed to denosumab. The most common acute-phase reaction AEs included pyrexia (0.9% denosumab, 11.5% ZA), fatigue (2.4% denosumab, 4.0% ZA), bone pain (1.3% denosumab, 3.6% ZA), chills (0.3% denosumab, 3.6% ZA), and arthralgia (1.5% denosumab, 3.2% ZA). No patients (0%) in the denosumab group and 10 patients (1%) in the ZA group reported serious AEs associated with acute-phase reactions during the first 3 days. These events included pyrexia (n=7); bone pain (n=2); and asthenia, back pain, chest pain, chills, headache, and malaise (n=1 each). For 6 of the 10 patients, events of pyrexia, chest pain, chills, and bone pain were resolved within 4 days. Three patients with serious acute-phase reaction AEs discontinued ZA treatment after the first dose. Conclusion: Patients treated with denosumab experienced no serious AEs of acute-phase reaction and significantly fewer overall AEs of acute-phase reaction than patients receiving ZA. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-09.