Background: In a randomized controlled trial of men with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid (ZA) for reducing skeletal-related events (SRE, defined as pathological fracture, surgery or radiation to bone [including the use of radioisotopes], or spinal cord compression) (Fizazi, et al. Lancet 2011;377:813-822.). Recently, the composite endpoint of symptomatic skeletal event (SSE, defined as symptomatic fracture, surgery or radiation to bone, or spinal cord compression) was introduced as an alternative term/clinical trial endpoint to describe skeletal morbidity. Methods: Men with CRPC, ≥ 1 bone metastasis, and no prior IV bisphosphonate use received either SC denosumab 120 mg or IV ZA 4 mg (adjusted for creatinine clearance) in a blinded fashion every 4 weeks. Oral calcium and vitamin D supplements were recommended. SSEs included pathologic fractures considered symptomatic by the investigator, spinal cord compression and surgery and radiation to bone. Results: As previously reported, fewer men who received denosumab than ZA had confirmed first SREs, and experienced multiple SREs (Table). Similarly, fewer patients in the denosumab group than the ZA group had confirmed first SSE and multiple SSEs. The median (95% CI) estimate of time to first SSE (superiority analysis) for denosumab was not reached (28.8 mo, not estimable), and for ZA it was 24.2 (20.7, 30.2) mo (HR = 0.78 (0.66, 0.93) P = 0.01). Conclusions: Denosumab reduced the risk of skeletal events in men with CRPC regardless of endpoint definition as SRE or SSE. The risk of developing SSEs was reduced by up to 22% when comparing denosumab with ZA. Clinical trial information: NCT00321620.