ORF34-07 - Comparing Bisphosphonates and Denosumab for Hypercalcemia Treatment : A Propensity-Matched Cohort Study

Introduction and

Methods: IV bisphosphonates are traditionally considered first line treatment of hypercalcemia, with denosumab as an emerging alternative, especially for hypercalcemia of malignancy. Existing studies are largely restricted to small cohorts, single-center experiences, or select oncologic populations, leaving uncertainty regarding optimal first-line therapy and the magnitude of hypocalcemia risk across diverse patient groups. We conducted a retrospective cohort study using the TriNetX Global Collaborative Network (169 healthcare organizations, January 2014-December 2024).
Adults (≥18 years) with documented hypercalcemia (≥2 serum calcium measurements ≥12.0 mg/dL) who received bisphosphonates (zoledronic acid, pamidronate, or ibandronate) or denosumab within 7 days of hypercalcemia diagnosis were included. Patients receiving both medications within 3 months were excluded. We performed 1:1 propensity score matching, adjusting for demographics, comorbidities (chronic kidney disease, malignancies, hyperparathyroidism), and baseline calcium and albumin levels. Primary outcomes were time to normocalcemia (calcium ≤10.5 mg/dL), hypocalcemia (≤8.5 mg/dL), and severe hypocalcemia (≤7.0 mg/dL) within 30 days. Kaplan-Meier survival analysis and Cox proportional hazards regression were used for time-to-event analyses.

Results: After matching, 866 patients in each cohort were analyzed (mean age and comorbidities balanced). Bisphosphonates achieved normocalcemia more frequently (83.5% vs 76.6%, p< 0.001) and more rapidly (median 3 vs 5 days, HR 1.40, 95% CI 1.26-1.56, p< 0.001). Overall hypocalcemia rates were similar between groups (46.5% vs 46.7%, p=0.962). However, severe hypocalcemia occurred significantly more frequently with denosumab (19.9% vs 12.8%, p< 0.001; HR 0.66, 95% CI 0.52-0.84, p=0.001), representing a 55% increased risk compared to bisphosphonates.

Conclusion: Bisphosphonates demonstrated superior effectiveness in achieving normocalcemia compared to denosumab, with faster calcium correction and higher response rates. While both agents had similar overall hypocalcemia rates, denosumab was associated with a significantly higher risk of severe hypocalcemia. These findings support bisphosphonates as first-line therapy for hypercalcemia, with careful monitoring for severe hypocalcemia when denosumab is used.