title: Hypocalcaemia in patients with metastatic bone disease treated with denosumab.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, CHU Brugmann, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: jean-jacques.body@chu-brugmann.be.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Body
authors.affiliation: Michigan Bone and Mineral Clinic, Detroit, MI, USA. Electronic address: hgbone.md@att.net.
authors.forename: Henry G
authors.initials: HG
authors.lastname: Bone
authors.affiliation: Department of Medical Oncology, Royal Melbourne Hospital, Melbourne, VIC, Australia. Electronic address: richard.deboer@wh.org.au.
authors.forename: Richard H
authors.initials: RH
authors.lastname: de Boer
authors.affiliation: Stony Brook Cancer Center, Stony Brook, NY, USA. Electronic address: Alison.Stopeck@stonybrookmedicine.edu.
authors.forename: Alison
authors.initials: A
authors.lastname: Stopeck
authors.affiliation: Department of Medical Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA. Electronic address: cvanpoz@med.umich.edu.
authors.forename: Catherine
authors.initials: C
authors.lastname: Van Poznak
authors.affiliation: Department of Urology, Hospital Universitario Pedro Ernesto, Rio de Janeiro, Brazil. Electronic address: damiao@email.com.
authors.forename: Ronaldo
authors.initials: R
authors.lastname: Damião
authors.affiliation: Department of Medical Oncology, Institut Gustave Roussy, University of Paris Sud, Villejuif, France. Electronic address: Karim.FIZAZI@igr.fr.
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.affiliation: Department of Medicine, Joan Karnell Cancer Center at Pennsylvania Hospital, Philadelphia, PA, USA. Electronic address: dhhenry@juno.com.
authors.forename: David H
authors.initials: DH
authors.lastname: Henry
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS-Osteoncology and Rare Tumors Center, Meldola, Italy. Electronic address: toni.ibrahim@irst.emr.it.
authors.forename: Toni
authors.initials: T
authors.lastname: Ibrahim
authors.affiliation: Division of Oncology, Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, PA, USA. Electronic address: alipton@hmc.psu.edu.
authors.forename: Allan
authors.initials: A
authors.lastname: Lipton
authors.affiliation: Department of Surgery, University of Montreal Hospital Center, Montreal, QC, Canada. Electronic address: fredsaad@videotron.ca.
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.affiliation: Department of Urology, Carolina Urologic Research Center, Myrtle Beach, SC, USA. Electronic address: nshore@gsuro.com.
authors.forename: Neal
authors.initials: N
authors.lastname: Shore
authors.affiliation: Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan. Electronic address: takano@toranomon.gr.jp.
authors.forename: Toshimi
authors.initials: T
authors.lastname: Takano
authors.affiliation: Department of Hematology/Oncology, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: ashaywitz@gmail.com.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Shaywitz
authors.affiliation: Department of Hematology/Oncology, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: hueiw@amgen.com.
authors.forename: Huei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Hematology/Oncology, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: ozzie.bracco@gmail.com.
authors.forename: Oswaldo L
authors.initials: OL
authors.lastname: Bracco
authors.affiliation: Department of Hematology/Oncology, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: adahbraun@yahoo.de.
authors.forename: Ada
authors.initials: A
authors.lastname: Braun
authors.affiliation: Department of Hematology/Oncology, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: PKost@roadrunner.com.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kostenuik
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D015415:Biomarkers / Q000097:blood; D050071:Bone Density Conservation Agents / Q000009:adverse effects*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D002118:Calcium / Q000097:blood*; D017326:Clinical Trials, Phase III as Topic; D000069448:Denosumab / Q000009:adverse effects*; D004164:Diphosphonates / Q000009:adverse effects; D006801:Humans; D006996:Hypocalcemia / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology / Q000517:prevention & control; D007093:Imidazoles / Q000009:adverse effects; D015994:Incidence; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D014808:Vitamin D Deficiency / Q000150:complications / Q000175:diagnosis; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000069448:Denosumab; D000077211:Zoledronic Acid; D002118:Calcium
keywords: Bone metastasis; Denosumab; Hypocalcaemia; Risk factors; Zoledronic acid