Adjuvant bisphosphonates or RANK-ligand inhibitors for patients with breast cancer and bone metastases: A systematic review and network meta-analysis

Crit Rev Oncol Hematol. 2019 May;137:1-8. doi: 10.1016/j.critrevonc.2019.02.004. Epub 2019 Feb 19.


Bone-modifying agents like bisphosphonates and receptor activator of nuclear factor kappaβ ligand (RANK-L) inhibitors are used as supportive treatments in breast cancer patients with bone metastases to prevent skeletal-related events (SREs). Due to missing head-to-head comparisons, a network meta-analysis was performed to provide a hierarchy of these therapeutic options. Through a systematic literature search, 21 randomized controlled trials (RCTs) that fulfilled the inclusion criteria were identified. To prevent SREs, the ranking through P-scores showed denosumab (RR: 0.62; 95%CI: 0.50-0.76), zoledronic acid (RR: 0.72; 95%CI: 0.61-0.84) and pamidronate (RR: 0.76; 95%CI: 0.67-0.85) to be significantly superior to placebo. Due to insufficient or heterogeneous data, overall survival, quality of life, pain response and adverse events were not able to be analyzed within the network. Although data were sparse on adverse events, the risk of significant adverse events appeared low. The results of this review can therefore be used to formulate clinical studies more precisely in order to standardise and focus on patient-relevant outcomes.

Keywords: Bisphosphonates; RANK-L inhibitors; RCTs; SREs.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Adjuvants, Immunologic / administration & dosage
  • Bone Density Conservation Agents / administration & dosage*
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / secondary*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Diphosphonates / administration & dosage*
  • Female
  • Humans
  • Network Meta-Analysis
  • Quality of Life
  • Randomized Controlled Trials as Topic
  • Receptor Activator of Nuclear Factor-kappa B / antagonists & inhibitors*


  • Adjuvants, Immunologic
  • Bone Density Conservation Agents
  • Diphosphonates
  • Receptor Activator of Nuclear Factor-kappa B
  • TNFRSF11A protein, human