Hypocalcaemia in patients with metastatic bone disease treated with denosumab

Eur J Cancer. 2015 Sep;51(13):1812-21. doi: 10.1016/j.ejca.2015.05.016. Epub 2015 Jun 17.


Background: This analysis was performed to further characterise treatment-emergent hypocalcaemia in patients with bone metastases receiving denosumab.

Methods: Laboratory abnormalities and adverse events of hypocalcaemia in patients with metastatic bone disease were analysed using data from three identically designed phase 3 trials of subcutaneous denosumab 120 mg (n = 2841) versus intravenous zoledronic acid 4 mg (n = 2836).

Results: The overall incidence of laboratory events of hypocalcaemia grade ⩾ 2 was higher with denosumab (12.4%) than with zoledronic acid (5.3%). Hypocalcaemia events were primarily grade 2 in severity and usually occurred within the first 6 months of treatment. Patients who reported taking calcium and/or vitamin D supplements had a lower incidence of hypocalcaemia. Prostate cancer or small-cell lung cancer, reduced creatinine clearance and higher baseline bone turnover markers of urinary N-telopeptide of type I collagen (uNTx; > 50 versus ⩽ 50 nmol/mmol) and bone-specific alkaline phosphatase (BSAP; > 20.77 μg/L [median] versus ⩽ 20.77 μg/L) values were important risk factors for developing hypocalcaemia. The risk associated with increased baseline BSAP levels was greater among patients who had > 2 bone metastases at baseline versus those with ⩽ 2 bone metastases at baseline.

Conclusion: Hypocalcaemia was more frequent with denosumab versus zoledronic acid, consistent with denosumab's greater antiresorptive effect. Low serum calcium levels and potential vitamin D deficiency should be corrected before initiating treatment with a potent osteoclast inhibitor, and corrected serum calcium levels should be monitored during treatment. Adequate calcium and vitamin D intake appears to substantially reduce the risk of hypocalcaemia.

Trial registration: ClinicalTrials.gov NCT00321464 NCT00321620 NCT00330759.

Keywords: Bone metastasis; Denosumab; Hypocalcaemia; Risk factors; Zoledronic acid.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / adverse effects*
  • Biomarkers / blood
  • Bone Density Conservation Agents / adverse effects*
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / secondary*
  • Calcium / blood*
  • Clinical Trials, Phase III as Topic
  • Denosumab / adverse effects*
  • Diphosphonates / adverse effects
  • Humans
  • Hypocalcemia / blood
  • Hypocalcemia / chemically induced*
  • Hypocalcemia / diagnosis
  • Hypocalcemia / epidemiology
  • Hypocalcemia / prevention & control
  • Imidazoles / adverse effects
  • Incidence
  • Retrospective Studies
  • Risk Assessment
  • Risk Factors
  • Severity of Illness Index
  • Time Factors
  • Treatment Outcome
  • Vitamin D Deficiency / complications
  • Vitamin D Deficiency / diagnosis
  • Zoledronic Acid


  • Antineoplastic Agents
  • Biomarkers
  • Bone Density Conservation Agents
  • Diphosphonates
  • Imidazoles
  • Denosumab
  • Zoledronic Acid
  • Calcium

Associated data

  • ClinicalTrials.gov/NCT00321464
  • ClinicalTrials.gov/NCT00321620
  • ClinicalTrials.gov/NCT00330759