Denosumab for treatment of hypercalcemia of malignancy

J Clin Endocrinol Metab. 2014 Sep;99(9):3144-52. doi: 10.1210/jc.2014-1001. Epub 2014 Jun 10.

Abstract

Context: Hypercalcemia of malignancy (HCM) in patients with advanced cancer is often caused by excessive osteoclast-mediated bone resorption. Patients may not respond to or may relapse after iv bisphosphonate therapy.

Objective: We investigated whether denosumab, a potent inhibitor of osteoclast-mediated bone resorption, reduces serum calcium in patients with bisphosphonate-refractory HCM.

Design, setting, and participants: In this single-arm international study, participants had serum calcium levels corrected for albumin (CSC) >12.5 mg/dL (3.1 mmol/L) despite bisphosphonates given >7 and ≤30 days before screening.

Intervention: Patients received 120 mg sc denosumab on days 1, 8, 15, and 29 and then every 4 weeks.

Main outcome measures: The primary endpoint was the proportion of patients with CSC ≤11.5 mg/dL (2.9 mmol/L) (response) by day 10. Secondary endpoints included response by visit, duration of response, and the proportion of patients with a complete response (CSC ≤10.8 mg/dL [2.7 mmol/L]) by day 10 and during the study.

Results: Patients (N = 33) had solid tumors or hematologic malignancies. By day 10, 21 patients (64%) reached CSC ≤11.5 mg/dL, and 12 patients (33%) reached CSC ≤10.8 mg/dL. During the study, 23 patients (70%) reached CSC ≤11.5 mg/dL, and 21 patients (64%) reached CSC ≤10.8 mg/dL. Estimated median response duration was 104 days. The most common serious adverse events were hypercalcemia worsening (5 patients, 15%) and dyspnea (3 patients, 9%).

Conclusions: In patients with HCM despite recent iv bisphosphonate treatment, denosumab lowered serum calcium in 64% of patients within 10 days, inducing durable responses. Denosumab may offer a new treatment option for HCM.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Bone Density Conservation Agents / administration & dosage
  • Bone Resorption / drug therapy
  • Bone Resorption / etiology
  • Denosumab
  • Diphosphonates / administration & dosage
  • Female
  • Gastrointestinal Diseases / chemically induced
  • Humans
  • Hypercalcemia / drug therapy*
  • Hypercalcemia / etiology*
  • Hypophosphatemia / chemically induced
  • Internationality
  • Male
  • Middle Aged
  • Neoplasms / complications*
  • RANK Ligand / antagonists & inhibitors*
  • Serum Albumin / metabolism
  • Therapeutics
  • Young Adult

Substances

  • Antibodies, Monoclonal, Humanized
  • Bone Density Conservation Agents
  • Diphosphonates
  • RANK Ligand
  • Serum Albumin
  • TNFSF11 protein, human
  • Denosumab