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

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.