KF, MC, MS, RD, JB, LK, PM, NS, and MR enrolled sufferers. study is signed up with ClinicalTrials.gov, amount PPIA “type”:”clinical-trial”,”attrs”:”text”:”NCT00321620″,”term_id”:”NCT00321620″NCT00321620, and continues to be completed. Results 1904 patients had been randomised, of whom 950 designated to denosumab and 951 designated to get zoledronic acidity were qualified to receive the efficacy evaluation. Median duration on research at primary evaluation cutoff time was 122 a few months (IQR 59C185) for sufferers on denosumab and 112 a few months (IQR 56C174) for all those on zoledronic acidity. Median time for you to SCH772984 initial on-study skeletal-related event was 207 a few months (95% CI 188C249) with denosumab weighed against 171 a few months (150C194) with zoledronic acidity (hazard proportion 082, 95% CI 071C095; p=00002 for non-inferiority; p=0008 for superiority). Undesirable occasions were documented in 916 sufferers (97%) on denosumab and 918 sufferers (97%) on zoledronic acidity, and serious undesirable events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. SCH772984 More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p 00001). Osteonecrosis of the jaw occurred infrequently (22 [2%] 12 [1%]; p=009). Interpretation Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a SCH772984 novel treatment option in men with bone metastases from castration-resistant prostate malignancy. Funding Amgen. Introduction In western countries, prostate malignancy is the most common non-dermatological malignant disease in men. An estimated 217 730 new cases will have been diagnosed in 2010 2010 in the USA1 and 382 250 cases were diagnosed in 2008 in Europe2 accounting for 28% and 22% of new non-cutaneous malignancy diagnoses, respectively. Bone metastases often develop in SCH772984 patients with advanced prostate malignancy; the associated complications present a substantial disease and economic burden.3 Since the late 1990s, the assessment of bone-targeted brokers for treatment of bone metastases has been based on the endpoint of skeletal-related events, a composite of local skeletal complications consisting of pathological fracture, spinal cord compression, and radiotherapy or surgery to bone. This composite endpoint was the primary endpoint in a phase 3 study in which intravenous zoledronic acid was better than placebo for prevention of skeletal-related events in patients with bone metastases from castration-resistant prostate malignancy.4,5 Although bone metastases from prostate cancer have a predominantly osteoblastic appearance, histological findings6 and analysis of bone turnover markers7,8 support the view that excess osteoclastic activity induces bone destruction in these metastases.9 RANKL is the main driver of osteoclast formation, function, and survival.10 In-vitro co-culture of prostate cancer cells with osteoblasts produced upregulation of RANKL and downregulation of the endogenous RANKL inhibitor OPG.11 In-vivo inhibition of RANKL in an osteoblastic prostate cancer model also decreased SCH772984 sclerotic changes in the bone.12 Denosumab is a human monoclonal antibody against RANKL; it inhibits osteoclast-mediated bone destruction and is being investigated in clinical studies in men with advanced prostate malignancy,13 including for prevention of bone metastases. We undertook a phase 3 study to compare the efficacy and security of denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate malignancy. Methods Patients In this phase 3 study undertaken between May, 2006, and October, 2009, men aged 18 years or older were enrolled from 342 centres in 39 countries worldwide. Eligible patients experienced histologically confirmed prostate malignancy, existing or previous radiographic evidence of at least one bone metastasis, and documented failure of at least one hormonal therapy, indicated by a rising prostate-specific antigen concentration, with a final concentration of 04 g/L or.