Summary <p>Denosumab-associated hypocalcemia is common in real-world settings. In this Saudi cohort, 21.1% developed hypocalcemia, with diuretic use and vitamin D deficiency as key predictors. Findings highlight that individualized risk assessment and monitoring may enhance the safety of osteoporosis treatment.</p> Background <p>Denosumab, a widely used antiresorptive agent for osteoporosis, has demonstrated significant benefits in reducing fracture risk. However, hypocalcemia is a recognized adverse effect, with real-world data suggesting higher incidence rates than those reported in clinical trials. This study explores the incidence, severity, and predictors of denosumab-associated hypocalcemia in a Saudi cohort.</p> Methods <p>A retrospective analysis was conducted at a tertiary care hospital, involving 303 Saudi adults with osteoporosis who received denosumab. The study evaluated changes in calcium levels, incidence of hypocalcemia, and potential risk factors, including vitamin D status, renal function, and medication use. Multivariate logistic regression identified predictors of hypocalcemia.</p> Results <p>Hypocalcemia occurred in 21.1% of patients, with 71.9% experiencing mild (grade 1) hypocalcemia. Most cases were asymptomatic (73.4%), with tingling and muscle aches reported in a minority of patients. Diuretic use emerged as a significant predictor (aOR 3.44, <i>p</i> = 0.008). Vitamin D deficiency was strongly associated with severe hypocalcemia (grade 3). Despite adherence to standard calcium and vitamin D supplementation, a substantial proportion of patients developed hypocalcemia, underscoring the need for individualized monitoring.</p> Conclusion <p>Hypocalcemia following denosumab is common in real-world practice, particularly in patients on diuretics or with low vitamin D levels. Clinicians should consider comprehensive pre-treatment risk assessment and tailored monitoring strategies to mitigate adverse outcomes in osteoporosis management.</p>