title: Toxicities following treatment with bisphosphonates and receptor activator of nuclear factor-κB ligand inhibitors in patients with advanced prostate cancer.
abstract: BACKGROUND
  Advanced prostate cancer (PCa) is associated with skeletal complications, both as a result of bone metastases and because of fractures associated with fragility due to androgen-deprivation therapy (ADT). Osteoclast inhibitors are commonly used to reduce skeletal complications but are associated with a number of potential adverse events.
  
  
  OBJECTIVE
  To review clinical trials of osteoclast inhibitors in advanced PCa, to discuss the adverse event profile of these agents, and to discuss strategies to address specific adverse events.
  
  
  METHODS
  PubMed was searched for reports of clinical trials of osteoclast inhibitors in advanced PCa. As zoledronic acid and denosumab are used most commonly in this disease, these trials were the focus. The literature was reviewed to identify key publications addressing the prevention and management of adverse events associated with these drugs.
  
  
  RESULTS
  The major findings of the trials and the adverse events are discussed. Prevention and management of common adverse events are addressed.
  
  
  CONCLUSIONS
  Zoledronic acid prevents loss of bone mineral density associated with ADT and delays skeletal-related events in metastatic castration-resistant PCa (mCRPC). Denosumab reduces the incidence of fragility fractures associated with ADT, delays the onset of bone metastases in nonmetastatic castration-resistant disease, and is superior to zoledronic acid in the prevention of skeletal complications in mCRPC. Adverse events associated with both agents include osteonecrosis of the jaw and hypocalcemia. Hypocalcemia is more common with denosumab. Zoledronic acid requires dose modifications for renal insufficiency, is contraindicated in severe renal insufficiency, and has been associated with deterioration of renal function. Appropriate patient selection with close attention to dental health, supplementation with calcium and vitamin D, and monitoring of laboratory values are effective strategies to minimize the impact of adverse events associated with osteoclast inhibitors in advanced PCa.
authors.affiliation: Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address: bgartrel@montefiore.org.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Gartrell
authors.affiliation: Academic Unit of Clinical Oncology, Weston Park Hospital, CR-UK/YCR Sheffield Cancer Research Centre, Sheffield, UK.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Coleman
authors.affiliation: Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.affiliation: Department of Urology, University Hospital Charité, Berlin, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Miller
authors.affiliation: Division of Urology, Centre Hospitalier de l'Université de Montréal, CRCHUM, Montréal, QC, Canada.
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.affiliation: Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy.
authors.forename: Cora N
authors.initials: CN
authors.lastname: Sternberg
authors.affiliation: Tisch Cancer Center Institute, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galsky
mesh_terms: D000726:Androgen Antagonists / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000209:etiology; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000009:adverse effects*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D000069448:Denosumab; D004164:Diphosphonates / Q000009:adverse effects*; D050723:Fractures, Bone / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D006996:Hypocalcemia / Q000139:chemically induced; D007093:Imidazoles / Q000009:adverse effects*; D008297:Male; D058990:Molecular Targeted Therapy / Q000009:adverse effects; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018579:Patient Selection; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012307:Risk Factors; D016896:Treatment Outcome; D000077211:Zoledronic Acid
chemical_list: D000726:Androgen Antagonists; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D000069448:Denosumab; D000077211:Zoledronic Acid
keywords: Adverse events; Bisphosphonates; Bone-targeted agents; Denosumab; Prostate cancer; Systematic review