De-escalation of bone-modifying agents in patients with bone metastases from breast cancer: a systematic review and meta-analysis

  • Arif Ali Awan
  • Brian Hutton
  • John Hilton
  • Sasha Mazzarello
  • Catherine Van Poznak
  • Lisa Vandermeer
  • Brianne Bota
  • Carol Stober
  • Marta Sienkiewicz
  • Dean Fergusson
  • Risa Shorr
  • Mark ClemonsEmail author



Bone-modifying agents (BMAs) such as bisphosphonates and denosumab are usually administered every 4 weeks (standard) in patients with bone metastases from breast cancer to prevent skeletal-related events (SREs). Recent randomized controlled trials suggest every 12-week (de-escalated) dosing interval may be non-inferior. The objective of this systematic review and meta-analysis was to compare the efficacy and harms of standard with de-escalated administration of BMA’s in patients with bone metastases from breast cancer.


We searched Medline, PubMed, and the Cochrane Register of Controlled Trials from 1947 to March 14, 2018 and conference abstracts from (2014–March 14, 2018) for randomized clinical trials comparing every 4-week and every 12-week dosing interval of bone-modifying agents. Using PRISMA guidelines, meta-analyses were performed using random-effects models, with findings reported as risk ratios with 95% confidence intervals (CI).


From a total of 1311 citations, we identified 8 full-text articles and 1 abstract comprising data from 5 completed randomized clinical trials (n = 1807). Zoledronate administration every 12 weeks compared to every 4 weeks produced a summary risk ratio of 1.05 (95% CI 0.88–1.25) for patients with ≥ 1 on-study SRE indicating similar efficacy. These results did not differ whether patients had received prior intravenous bisphosphonate. De-escalation was associated with a non-statistically significant lower risk of increased creatinine (summary risk ratio 0.41 [95% CI 0.15–1.16]). Currently, there are insufficient data for pamidronate and denosumab de-escalation.


These data are supportive of de-escalation of zoledronate from onset for patients with bone metastases from breast cancer.


Bisphosphonates Denosumab Breast cancer Bone metastasis Skeletal-related event De-escalated treatment 



This project received no outside funding and was supported with internal research funds.

Compliance with ethical standards

Conflict of interest

Dr. Awan reports participating in the Novartis Canada Advisory Board on the use of Ribociclib. Dr. Hutton reports personal fees from Cornerstone Research, outside the submitted work. Dr. van Poznak reports personal fees from UpToDate and institutional research funds from Bayer, outside the submitted work. The remaining authors declare that they have no conflicts of interest (Hilton, Mazzarello, Vandermeer, Bota, Stober, Sienkiewicz, Fergusson, Shorr, and Clemons).

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

Informed consent

Not applicable as this is a systematic review.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Arif Ali Awan
    • 1
  • Brian Hutton
    • 2
  • John Hilton
    • 1
  • Sasha Mazzarello
    • 3
  • Catherine Van Poznak
    • 4
  • Lisa Vandermeer
    • 3
  • Brianne Bota
    • 3
  • Carol Stober
    • 3
  • Marta Sienkiewicz
    • 3
  • Dean Fergusson
    • 2
  • Risa Shorr
    • 5
  • Mark Clemons
    • 1
    • 2
    • 3
    Email author
  1. 1.Division of Medical OncologyThe Ottawa Hospital Cancer CentreOttawaCanada
  2. 2.Department of Medicine and School of Epidemiology, Public Health and Preventive MedicineUniversity of OttawaOttawaCanada
  3. 3.Cancer Research Group, Ottawa Hospital Research InstituteOttawaCanada
  4. 4.Division of Hematology/OncologyUniversity of MichiganAnn ArborUSA
  5. 5.The Ottawa HospitalOttawaCanada

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