title: Denosumab for treatment of hypercalcemia of malignancy.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Patients received 120 mg sc denosumab on days 1, 8, 15, and 29 and then every 4 weeks.
  
  
  METHODS
  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.
authors.affiliation: University of Texas, MD Anderson Cancer Center (M.I.H.), Houston, Texas 77030; Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College (I.G.G.), New York, New York 10065; Institut Gustave Roussy (S.L.), Villejuif, France; Yale School of Medicine (K.I.), New Haven, Connecticut 06510; Montefiore Medical Center-Bronx (R.G.), New York, New York 10467; Endocrinology Department, Medical Center for Postgraduate Education (W.M.), Warsaw, Poland; Lee Moffitt Cancer Center and Research Institute (B.Y.), Tampa, Florida 33607; Peninsula Regional Medical Center (P.Z.), Salisbury, Maryland 21801; Institut Régional du Cancer de Montpellier-Val d'Aurelle (D.T.), Montpellier, France; California Cancer Associates for Research and Excellence (A.B.), Encinitas, California 92024; Centre Hospitalier Universitaire de Limoges-Hôpital Dupuytren (A.J.), Limoges, France; Policlinico Universitario Campus Bio-Medico (G.T.), Rome, Italy; and Amgen Inc (W.Y., A.B., R.K.J.), Thousand Oaks, California 91320.
authors.forename: Mimi I
authors.initials: MI
authors.lastname: Hu
authors.forename: Ilya G
authors.initials: IG
authors.lastname: Glezerman
authors.forename: Sophie
authors.initials: S
authors.lastname: Leboulleux
authors.forename: Karl
authors.initials: K
authors.lastname: Insogna
authors.forename: Rasim
authors.initials: R
authors.lastname: Gucalp
authors.forename: Waldemar
authors.initials: W
authors.lastname: Misiorowski
authors.forename: Bennett
authors.initials: B
authors.lastname: Yu
authors.forename: Paul
authors.initials: P
authors.lastname: Zorsky
authors.forename: Diego
authors.initials: D
authors.lastname: Tosi
authors.forename: Alberto
authors.initials: A
authors.lastname: Bessudo
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jaccard
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tonini
authors.forename: Wendy
authors.initials: W
authors.lastname: Ying
authors.forename: Ada
authors.initials: A
authors.lastname: Braun
authors.forename: Rajul K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage; D001862:Bone Resorption / Q000188:drug therapy / Q000209:etiology; D000069448:Denosumab; D004164:Diphosphonates / Q000008:administration & dosage; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D006934:Hypercalcemia / Q000188:drug therapy* / Q000209:etiology*; D017674:Hypophosphatemia / Q000139:chemically induced; D038622:Internationality; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications*; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D012709:Serum Albumin / Q000378:metabolism; D013812:Therapeutics; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D053245:RANK Ligand; D012709:Serum Albumin; C505688:TNFSF11 protein, human; D000069448:Denosumab