Comparative Effectiveness of Denosumab Versus Bisphosphonates for Hypercalcemia of Malignancy: A Real-World Cohort Study.

Abstract

Context: The 2023 Endocrine Society guideline conditionally favors denosumab over intravenous bisphosphonates for hypercalcemia of malignancy (HCM), but direct comparative evidence is scarce.

Objective: To compare effectiveness of denosumab versus bisphosphonates for the treatment of HCM.

Design and setting: Observational cohort study of adults hospitalized with HCM between January 2016 and January 2026 at a large academic safety-net hospital system in the Bronx, NY.

Patients: Adults aged ≥18 years with serum calcium >10.5 mg/dL, active or prior malignancy, and treated with bisphosphonates or denosumab as inpatient. Patients with eGFR <15 mL/min/1.73 m2 or recent antiresorptive exposure were excluded.

Interventions: Intravenous bisphosphonate (zoledronic acid or pamidronate) versus denosumab.

Main outcome measures: Primary outcome was time to serum calcium normalization (≤10.5 mg/dL). Secondary outcomes included hypocalcemia, hypercalcemia recurrence, and 90-day all-cause mortality. Propensity score overlap weighting balanced baseline covariates.

Results: Among 836 patients (mean age 67.0 years; 50.1% female; 44.9% non-Hispanic Black, 29.9% Hispanic) contributing 869 admissions, 814 (93.7%) received bisphosphonates and 55 (6.3%) denosumab. Time to normalization was similar (median 1.62 vs 1.58 days; HR 0.80; 95% CI, 0.57-1.12). Hypocalcemia (HR 0.86; 95% CI, 0.58-1.26) and 90-day recurrence (HR 0.97; 95% CI, 0.54-1.74) did not differ. Ninety-day mortality was lower with denosumab (HR 0.51; 95% CI, 0.30-0.88).

Conclusions: Denosumab and bisphosphonates were associated with similar calcium normalization, hypocalcemia, and recurrence rates in this real-world observational cohort. The lower 90-day mortality observed with denosumab warrants prospective investigation given the limitations of observational research.