In a phase 3 study of patients with high-risk, non-metastatic, castration-resistant prostate cancer, RANKL blockade using denosumab significantly improved bone metastasis-free survival by 4.2 months compared with placebo (HR = 0.85; p = 0.028), illustrating how manipulation of the RANKL pathway may affect disease progression [46]. This evidence concerns the gene TNFSF11 and bone metastasis.