title: A systematic review of dosing frequency with bone-targeted agents for patients with bone metastases from breast cancer.
abstract: BACKGROUND
  Bone-targeted agents are usually administered to breast cancer patients with bone metastases every 3-4 weeks. Less frequent ('de-escalated') treatment may provide similar benefits with improved safety and reduced cost.
  
  
  METHODS
  To systematically review randomised trials comparing de-escalated treatment with bone-targeted agents (i.e. every 12-16 weeks) to standard treatment (i.e. every 3-4 weeks), a formal systematic review of the literature was performed. Two individuals independently screened citations and full text articles. Random effects meta-analyses of clinically important outcomes were planned provided homogeneous studies were identified.
  
  
  RESULTS
  Five relevant studies (n=1287 patients) were identified. Sample size ranged from 38 to 425. Information on outcomes including occurrence of SREs, bone pain, urinary N-telopeptide concentrations, serum C-telopeptide concentrations, pain medication use and safety outcomes was not consistently available. Two trials were non-inferiority studies, two dose-response evaluations and one was a pilot study. Bone-targeted agents use varied between studies, as did duration of prior therapy. Patient populations were considered heterogeneous in several ways, and thus no meta-analyses were performed. Observations from the included studies suggest there is potential that 3 month de-escalated treatment may provide similar benefits compared to 3-4 weekly treatment and that lower doses of zoledronic acid and denosumab might be equally effective.
  
  
  CONCLUSIONS
  Studies comparing standard and de-escalated treatment with bone-targeted agents in breast cancer are rare. The benefits of standard treatment compared to de-escalated therapy on important clinical outcomes remain unclear. Future pragmatic studies must be conducted to determine the merits of this approach.
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Canada; University of Ottawa, Department of Epidemiology and Community Medicine, Ottawa, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Hutton
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Canada; Ottawa Regional Cancer Centre, Ottawa, Canada.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Addison
authors.affiliation: Programs for the Assessment of Technology in Health (PATH) Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Kaitryn
authors.initials: K
authors.lastname: Campbell
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Canada; University of Ottawa, Department of Epidemiology and Community Medicine, Ottawa, Canada.
authors.forename: Dean
authors.initials: D
authors.lastname: Fergusson
authors.affiliation: Ottawa Regional Cancer Centre, Ottawa, Canada.
authors.forename: Sasha
authors.initials: S
authors.lastname: Mazarello
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Canada; Ottawa Regional Cancer Centre, Ottawa, Canada; University of Ottawa, Department of Medicine, Ottawa, Ontario Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Clemons
keywords: Bone metastasis; Breast cancer; De-escalated treatment; Systematic review