The aim of this study is to conduct a comparison study between the efficacy and safety of zoledronic acid and clodronate in malignant hypercalcemia secondary to bone metastases in Egyptian adult patients. This is a prospective observational study conducted 80 patients (40 in each group), who were assigned to receive either zoledronic acid (4 mg over a 30 min infusion) every 3-4 weeks or clodronate (a single dose of 1,500 mg over a 4 h infusion) monthly for 3 months. The primary efficacy analysis was the proportion of patients with at least one skeletal-related event. The safety was assessed based on the frequencies of the reported adverse effects as nausea, vomiting, anemia, etc. The calcium level significantly decreased in both groups. At least one skeletal-related event occurred in 15 (37.5%) patients receiving zoledronic acid and 32 (80%) patients receiving clodronate. Radiotherapy and fractures represented the highest event observed in both groups. At least one adverse event was experienced by 20 (50%) patients treated with zoledronic acid, while 26 (65%) patients on clodronate recorded one or more adverse event. Pyrexia was the most commonly reported side effect and flare phenomena. Both treatment groups were comparable regarding the reported adverse events. Both medications did not show any significant nephrotoxicity detected by elevation in the creatinine level. Zoledronic acid and clodronate have demonstrated clinical utility in the treatment of hypercalcaemia in cancer patients. Zoledronic acid provides a more effective and convenient treatment than clodronate, while both maintaining a similar safety profile.