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Bone metastasis: mechanisms and therapeutic opportunities

Nature Reviews Endocrinology volume 7, pages 208–218 (2011)Cite this article

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Abstract

The skeleton is one of the most common sites for metastatic cancer, and tumors arising from the breast or prostate possess an increased propensity to spread to this site. The growth of disseminated tumor cells in the skeleton requires tumor cells to inhabit the bone marrow, from which they stimulate local bone cell activity. Crosstalk between tumor cells and resident bone and bone marrow cells disrupts normal bone homeostasis, which leads to tumor growth in bone. The metastatic tumor cells have the ability to elicit responses that stimulate bone resorption, bone formation or both. The net result of these activities is profound skeletal destruction that can have dire consequences for patients. The molecular mechanisms that underlie these painful and often incurable consequences of tumor metastasis to bone are beginning to be recognized, and they represent promising new molecular targets for therapy.

Key Points

  • Bone is a common site of metastasis for many tumors, such as breast, lung and prostate cancer

  • A continuum of bone metastasis exists that extends from primarily osteolytic lesions with limited osteoblast activity to bone metastases that are predominantly osteoblastic, with limited osteoclast activity

  • The complex interactions between circulating tumor cells, circulating host cells, platelets and cell-derived factors are critical for tumor establishment at metastatic sites

  • Tumor activation of bone resorption is complex and involves both receptor activator of nuclear factor κB ligand (RANKL)-dependent and RANKL-independent mechanisms

  • Targeting bone resorption with bisphosphonates reduces osteolytic bone resorption and improves disease-free survival

  • All steps in the metastatic process and the interaction with host cells are valid therapeutic targets for the treatment of bone metastasis and tumor progression

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Figure 1: Steps involved in tumor cell metastasis from a primary site to the skeleton.
Figure 2: Biochemical markers of bone turnover are released during bone remodeling.
Figure 3: The stimulation of bone cell activity by tumors in the bone marrow.

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Acknowledgements

The authors dedicate this manuscript to the memory of Dr. Gregory R. Mundy. A fellow ex-patriot Australian, Greg's boundless energy, determination and drive virtually single-handedly motivated all of us to acknowledge and appreciate the intricacies of the bone–tumor microenvironment. His presence, unique perspective and intellect are sorely missed. Work into the mechanisms of cancer progression and bone metastases described in this Review was supported by NIH 5R01CA107160 (R. J. Griffin) and the Carl L. Nelson endowed Chair in Orthopedic Creativity (L. J. Suva).

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Authors and Affiliations

  1. Department of Orthopedic Surgery, Center for Orthopedic Research, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, 72205, AR, USA

    Larry J. Suva, Charity Washam & Richard W. Nicholas

  2. Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, 72205, AR, USA

    Robert J. Griffin

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  1. Larry J. Suva
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  2. Charity Washam
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  3. Richard W. Nicholas
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  4. Robert J. Griffin
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Contributions

L. J. Suva and C. Washam researched the data for the article. L. J. Suva and R. W. Nicholas provided substantial contributions to discussions of the content. L. J. Suva and R. J. Griffin contributed equally to writing the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Larry J. Suva.

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Suva, L., Washam, C., Nicholas, R. et al. Bone metastasis: mechanisms and therapeutic opportunities. Nat Rev Endocrinol 7, 208–218 (2011). https://doi.org/10.1038/nrendo.2010.227

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