Bone metastases are a hallmark of castration-resistant prostate cancer (CRPC), occurring in approximately 84% of patients. These metastases result in severe skeletal-related events (SREs), such as pathological fractures, spinal cord compression, and the need for radiation therapy or surgery. This meta-analysis evaluates the impact of bisphosphonates (zoledronic acid [ZA]) and receptor activator of nuclear factor-κB ligand-inhibitors (denosumab) as adjunctive therapies for patients with prostate cancer who have developed bone metastases. A systematic and rigorous methodology was followed by adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines to ensure transparency and reliability. A comprehensive search was conducted across medical databases and relevant publications to identify studies comparing denosumab and ZA in managing skeletal complications in patients with CRPC. Inclusion criteria required studies to report outcomes such as SREs, symptomatic skeletal events (SSEs), bone metastasis-free survival (BMFS), progression-free survival (PFS), adverse events, and cost implications. Data extraction was performed using standardized templates to collect demographic, clinical, and economic data. The meta-analysis demonstrated that denosumab was superior to ZA in reducing SREs and SSEs in patients with CRPC. The total incidence of SREs was significantly lower with denosumab (40.7%) compared to ZA (59.3%, p=0.009). Similarly, the incidence of SSEs was reduced to 47.2% with denosumab, compared to 52.8% with ZA (p=0.029). In addition, denosumab extended BMFS by 4.2 months (33.2 vs. 29.5 months, p=0.031) and PFS by 2.4 months (21.7 vs. 19.3 months, p=0.027). However, overall survival was comparable between the two treatments. Adverse events were slightly more frequent with denosumab (93.1% vs. 91.4%), as well as higher rates of hypocalcemia (2.2% vs. 1.46%) and osteonecrosis of the jaw (ONJ) (2.8% vs. 2.41%). This meta-analysis demonstrates that denosumab is superior to ZA in reducing the incidence and delaying the onset of SREs and SSEs in patients with CRPC and bone metastases. Denosumab also extends BMFS, providing an additional clinical advantage. However, these benefits come with a higher risk of adverse events such as hypocalcemia and ONJ, as well as significantly increased costs. While ZA remains an effective treatment, denosumab may be the preferred option for patients at higher risk of SREs or those who can tolerate its adverse effects and cost.