title: Evidence on the analgesic role of bisphosphonates and denosumab in the treatment of pain due to bone metastases: A systematic review within the European Association for Palliative Care guidelines project.
abstract: Bisphosphonates and denosumab are well-established therapies to reduce the frequency and severity of skeletal-related events in patients with bone metastasis. However, the analgesic effect of these medications on bone pain is uncertain.
  
  
  
  To identify, critically appraise and synthesize existing evidence to answer the following questions: 'In adult patients with metastatic bone pain, what is the evidence that bisphosphonates and denosumab are effective and safe in controlling pain?' and 'What is the most appropriate schedule of bisphosphonate/denosumab administration to control bone pain?'. This review also updates the 2002 Cochrane review 'Bisphosphonates for the relief of pain secondary to bone metastases'.
  
  
  
  Standard systematic review and narrative synthesis.
  
  
  
  MEDLINE, EMBASE and Cochrane CENTRAL databases were searched for relevant articles published through 31 January 2014. A manual search was also performed. Study inclusion criteria were: a) conducted in adult patients; b) randomized controlled trial or meta-analisys; c) reported efficacy of bisphosphonates or denosumab on pain and/or decribed side effects versus placebo or other bisphosphonate; and d) English language.
  
  
  
  The database search yielded 1585 studies, of which 43 (enrolling 8595 and 7590 patients, respectively, in bisphosphonate and denosumab trials) met the inclusion criteria. Twenty-two (79%) of the 28 placebo-controlled trials found no analgesic benefit for bisphosphonates. None of the denosumab studies assessed direct pain relief.
  
  
  
  Evidence to support an analgesic role for bisphosphonates and denosumab is weak. Bisphosphonates and denosumab appear to be beneficial in preventing pain by delaying the onset of bone pain rather than by producing an analgesic effect per se.
authors.affiliation: 1 Palliative Care Service, Institut Català d'Oncologia, Bellvitge Biomedical Research Institute (IDIBELL), WeCare Chair: End of Life Care, Universitat Internacional de Catalunya, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Porta-Sales
authors.affiliation: 1 Palliative Care Service, Institut Català d'Oncologia, Bellvitge Biomedical Research Institute (IDIBELL), WeCare Chair: End of Life Care, Universitat Internacional de Catalunya, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Garzón-Rodríguez
authors.affiliation: 1 Palliative Care Service, Institut Català d'Oncologia, Bellvitge Biomedical Research Institute (IDIBELL), WeCare Chair: End of Life Care, Universitat Internacional de Catalunya, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Llorens-Torromé
authors.affiliation: 2 Palliative Care, Pain Therapy and Rehabilitation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.|3 European Palliative Care Research Center, Department of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Brunelli
authors.affiliation: 2 Palliative Care, Pain Therapy and Rehabilitation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pigni
authors.affiliation: 2 Palliative Care, Pain Therapy and Rehabilitation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.|3 European Palliative Care Research Center, Department of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Augusto
authors.initials: A
authors.lastname: Caraceni
mesh_terms: D000698:Analgesia / Q000379:methods; D000700:Analgesics / Q000627:therapeutic use*; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000150:complications* / Q000556:secondary*; D000072716:Cancer Pain / Q000188:drug therapy* / Q000209:etiology; D000069448:Denosumab / Q000627:therapeutic use*; D004164:Diphosphonates / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006801:Humans; D059408:Pain Management / Q000379:methods
chemical_list: D000700:Analgesics; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D000069448:Denosumab
keywords: Pain; bisphosphonates; bone metastasis; denosumab; neoplasms; palliative care