Background: Zoledronic Acid is a bisphosphonate used in a 4-week schedule for the treatment of bone metastases. Some randomized trials supported its role also when administered every 12 weeks. Methods: we performed a systematic review and a meta-analysis in order to evaluate the two different schedules in terms of skeletal morbidity rate (SMR), skeletal related events (SRE) and adverse events (AEs). Results: our results showed a clinical difference favouring the 12-week schedule in terms of AEs (RR 1.17, 95% CI 1.06–1.29). No signifcant differences were found for SMR (RR 0.97, 95% CI 0.84–1.13) and SRE (RR 1.02, 95% CI 0.89–1.16). Conclusions: Our findings support in clinical practice the 12-week schedule an alternative to the standard 4-week schedule in advanced breast and prostate cancer, in particular when the clinical comorbidities of the patients suggest a higher risk of renal failure or hypocalcaemia.