Long-term impact of bone-modifying agents for the treatment of bone metastases: a systematic review



Bone-modifying agents (BMAs) for bone metastases are commonly prescribed for many years even though randomized clinical trials are only 1–2 years in duration. A systematic review on the risk-benefit of BMA use for > 2 years in breast cancer or castrate-resistant prostate cancer was conducted.


MEDLINE, Embase, and Cochrane databases were searched (1970–February 2019) for randomized and observational studies, and case series reporting on BMA efficacy (skeletal-related events and quality of life) and toxicity (osteonecrosis of the jaw, renal impairment, hypocalcemia, and atypical femoral fractures) beyond 2 years.


Of 2107 citations, 64 studies were identified. Three prospective and 9 retrospective studies were eligible. Data beyond 2 years was limited to subgroup analyses in all studies. Only one study (n = 181) reported skeletal-related event rates based on bisphosphonate exposure, with decreased rates from 27.6% (0–24 months) to 15.5% (> 24 months). None reported on quality of life. All 12 studies (denosumab (n = 948), zoledronate (n = 1036), pamidronate (n = 163), pamidronate-zoledronate (n = 522), ibandronate (n = 118)) reported ≥ 1 toxicity outcome. Seven bisphosphonate studies (n = 1077) and one denosumab study (n = 948) reported on osteonecrosis of the jaw. Across three studies (n = 1236), osteonecrosis of the jaw incidence ranged from 1 to 4% in the first 2 years to 3.8–18% after 2 years. Clinically significant hypocalcemia ranged from 1 to 2%. Severe renal function decline was ≤ 3%. Atypical femoral fractures were rare.


Evidence informing the use of BMA beyond 2 years is heterogeneous and based on retrospective analysis. Prospective randomized studies with greater emphasis on quality of life are needed.

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We would like to thank Ms. Risa Shorr, information specialist for designing and executing the search strategy for this systematic review.

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All supporting data is included in the manuscript and appendix. A summary of the protocol has been uploaded to PROSPERO.

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Conceptualization/methodology: T.L.N, A.A.A, M.J.C, B.H.

Data curation: T.L.N., M.M.T., M.F.K.I, B.B., S.F.M., A.S., R.F., L.V., C.S., M.S., A.J., D.S., A.A.A., M.J.C.

Formal analysis: All authors

Original draft: T.L.N.

Review and editing: All authors

Corresponding author

Correspondence to Terry L. Ng.

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Ng, T.L., Tu, M.M., Ibrahim, M.F.K. et al. Long-term impact of bone-modifying agents for the treatment of bone metastases: a systematic review. Support Care Cancer (2020). https://doi.org/10.1007/s00520-020-05556-0

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  • Bisphosphonates
  • Denosumab
  • Bone metastases
  • Skeletal-related events
  • Systematic review