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Bone-targeted agents (BTAs), such as zoledronic acid and denosumab, delay the occurrence of skeletal-related events (SREs) in metastatic prostate cancer (PCa) patients. Recently, several agents, such as abiraterone acetate, enzalutamide and radium-223, were approved for the treatment of metastatic castration-resistant PCa (mCRPC). These agents resulted in improved overall survival (OS), pain control and had positive effects on bone health. Combining BTAs to the newly approved agents demonstrates additional benefits that warrant a review of available evidence looking at appropriate combination therapies and timing of BTAs for optimizing the management of advanced and metastatic PCa.Post-hoc analyses of randomized trials demonstrated some benefits from combination therapy, such as increased OS when denosumab was used concurrently with radium-223 and when BTAs were used with abiraterone acetate. BTAs were not beneficial for the prevention of bone metastases.There is a suggestion of synergy or additive effects between BTAs and new agents approved for the treatment of metastatic PCa, resulting in potential clinical benefits. Therefore, prospective randomized studies evaluating the safety and benefits of combination therapies to address gaps in the literature are needed to optimize treatment of mCRPC.