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Denosumab in patients with cancer—a surgical strike against the osteoclast

Nature Reviews Clinical Oncology volume 9, pages 110–118 (2012)Cite this article

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Abstract

Elucidation of the molecular pathways underlying bone turnover has revealed potential therapeutic targets, including receptor activator of nuclear factor-κB ligand (RANKL), which is a mediator of osteoclast formation, function and survival. Denosumab is a fully human monoclonal antibody that binds to and inhibits RANKL. This agent has been developed for use in patients with early-stage and advanced-stage cancer, as well as for the treatment of osteoporosis, and can prevent bone loss and reduce fragility fractures in both types of disease. In the bone metastasis setting, several large phase III studies have shown that denosumab is more effective than bisphosphonates, namely zoledronic acid, in reducing skeletal morbidity arising from a wide range of tumors. In addition, a remarkable activity of denosumab has been demonstrated in giant-cell tumors of the bone. Subsequent studies of denosumab have demonstrated that it can delay bone metastasis in patients with castration-resistant prostate cancer; adjuvant studies in patients with breast cancer are in progress. This Review critically explores the emerging role of denosumab in maintaining bone health in the oncology setting, and discusses the factors that are likely to influence the choice between bisphosphonates and denosumab in clinical practice.

Key Points

  • Denosumab, a human monoclonal antibody, inhibits receptor activator of nuclear factor-κB ligand (RANKL), which mediates the increased bone resorption resulting from bone metastasis and cancer treatment

  • Phase III trials in patients with bone metastases of breast cancer, prostate cancer and other solid tumors demonstrated the superiority of denosumab over zoledronic acid in reducing skeletal morbidity

  • A strong antitumor response has been observed in phase II studies of denosumab in giant-cell tumors of bone

  • Denosumab is less likely than zoledronic acid to induce renal toxic effects and acute-phase reactions, but both drugs are associated with similar incidence of osteonecrosis of the jaw

  • Depending on the cost, denosumab could become widely used in the management of bone health in oncology

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Figure 1: The role of RANKL in the vicious cycle of bone metastases.
Figure 2: A Fisher plot demonstrating the superiority of denosumab over zoledronic acid in delaying SREs in phase III trials.
Figure 3: Imaging and histological findings in a patient with a giant-cell tumor of the sacrum before and after denosumab treatment.

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Acknowledgements

J. E. Brown has been awarded a Clinician Scientist Fellowship by Cancer Research UK.

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Authors and Affiliations

  1. Cancer Research UK Center, St. James's Hospital, Leeds, LS9 7TF, UK

    Janet E. Brown

  2. Sheffield Cancer Research Center, Weston Park Hospital, Whitham Road, Sheffield, S10 2SJ, UK

    Robert E. Coleman

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Both authors contributed to all aspects of the article, including researching data, discussion of content, and writing, reviewing and editing the manuscript before submission.

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Correspondence to Robert E. Coleman.

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Competing interests

J. E. Brown declares that she is a consultant for and has received honoraria from Amgen. She has also received honoraria and grant funding from Novartis. R. E. Coleman declares that he is a consultant for and has received honoraria and grant funding from Novartis. He has also received honoraria from Amgen.

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Brown, J., Coleman, R. Denosumab in patients with cancer—a surgical strike against the osteoclast. Nat Rev Clin Oncol 9, 110–118 (2012). https://doi.org/10.1038/nrclinonc.2011.197

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