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

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

PROSPERO registration number

CRD42019126813

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Acknowledgments

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

Availability of data and material

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

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Medicine, University of Ottawa, Ottawa, ON, K1H 8L6, Canada

    Terry L. Ng, Sharon F. McGee, Amirrtha Srikanthan, Arif A. Awan & Mark J. Clemons

  2. Ottawa Hospital Research Institute, Ottawa, ON, Canada

    Terry L. Ng, Megan M. Tu, Sharon F. McGee, Amirrtha Srikanthan, Lisa Vandermeer, Carol Stober, Marta Sienkiewicz, Ahwon Jeong, Deanna Saunders, Arif A. Awan, Brian Hutton & Mark J. Clemons

  3. Division of Medical Oncology, The Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada

    Terry L. Ng, Sharon F. McGee, Amirrtha Srikanthan, Arif A. Awan & Mark J. Clemons

  4. Division of Clinical Sciences, Medical Oncology, Northern Ontario School of Medicine, Thunder Bay, ON, P7B 5E1, Canada

    Mohammed F. K. Ibrahim

  5. Comprehensive Cancer Center -Medical Oncology, King Fahad Medical City, Riyadh, Saudi Arabia

    Bassam Basulaiman

  6. Division of Medical Oncology, London Regional Cancer Program, London Health Sciences Centre, University of Western Ontario, London, ON, Canada

    Ricardo Fernandes

  7. School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada

    Brian Hutton

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  1. Terry L. Ng
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Contributions

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 29, 925–943 (2021). https://doi.org/10.1007/s00520-020-05556-0

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