title: Should de-escalation of bone-targeting agents be standard of care for patients with bone metastases from breast cancer? A systematic review and meta-analysis.
abstract: BACKGROUND
  De-escalation of bone-targeted agents, such as bisphosphonates and denosumab, from 4- to 12-weekly dosing is an increasingly used strategy in patients with bone metastases from breast cancer. It is unclear whether there is sufficient evidence to support de-escalation as a standard of care.
  
  
  METHODS
  A systematic review of randomized trials comparing standard 4-weekly administration of bone-targeted agents with de-escalated (Q12-weekly) dosing in breast cancer patients was carried out. Medline, PubMed and the Cochrane Register of Controlled Trials were searched from inception until November 2014 for relevant studies. Outcomes of interest included skeletal-related event (SRE) rates, bone pain, adverse events (AEs) and bone turnover biomarkers. Random-effects meta-analyses were carried out.
  
  
  RESULTS
  A total of nine citations representing seven unique studies were eligible. One study is ongoing with no reported data. Six studies reported data for at least one outcome of interest. Data were available comparing standard versus de-escalated therapy for pamidronate (1 study, 38 patients), zoledronate (3 studies, 1117 patients) and denosumab (2 studies, 284 patients). Meta-analysis of five trials reporting data for on-study SRE rates between standard (61/443 patients) and de-escalated (49/392 patients) arms produced a summary risk ratio of 0.90 (95% confidence interval 0.63-1.29). Meta-analyses of data for AEs and bone turnover biomarkers also showed no statistically significant differences between standard and de-escalated arms, though only limited numbers of patients and events were present for most analyses.
  
  
  CONCLUSIONS
  In this systematic review of studies of bisphosphonates and denosumab, there appears to be no difference in SREs or pain with de-escalated therapy. While a large, hopefully definitive study is ongoing, the data presented so far are consistent with de-escalation of bone-targeting agents becoming a standard of care for patients with bone metastases from breast cancer.
authors.affiliation: Department of Medicine and Division of Medical Oncology, The Ottawa Hospital.
authors.forename: M F K
authors.initials: MF
authors.lastname: Ibrahim
authors.affiliation: Ottawa Hospital Research Institute and Department of Medicine, University of Ottawa.
authors.forename: S
authors.initials: S
authors.lastname: Mazzarello
authors.affiliation: The Ottawa General Hospital, Ottawa, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Shorr
authors.affiliation: Ottawa Hospital Research Institute and Department of Medicine, University of Ottawa.
authors.forename: L
authors.initials: L
authors.lastname: Vandermeer
authors.affiliation: Department of Medicine and Division of Medical Oncology, The Ottawa Hospital.
authors.forename: C
authors.initials: C
authors.lastname: Jacobs
authors.affiliation: Department of Medicine and Division of Medical Oncology, The Ottawa Hospital Ottawa Hospital Research Institute and Department of Medicine, University of Ottawa.
authors.forename: J
authors.initials: J
authors.lastname: Hilton
authors.affiliation: Ottawa Hospital Research Institute and Department of Medicine, University of Ottawa.
authors.forename: B
authors.initials: B
authors.lastname: Hutton
authors.affiliation: Department of Medicine and Division of Medical Oncology, The Ottawa Hospital Ottawa Hospital Research Institute and Department of Medicine, University of Ottawa mclemons@toh.on.ca.
authors.forename: M
authors.initials: M
authors.lastname: Clemons
mesh_terms: D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000556:secondary*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy; D002986:Clinical Trials as Topic / Q000379:methods; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D059039:Standard of Care / Q000592:standards
chemical_list: D050071:Bone Density Conservation Agents
keywords: biomarker; bisphosphonate; bone metastasis; breast cancer; de-escalated treatment; skeletal-related event