IBMS BoneKEy | Perspective

RANKL: Targeting bone and cancer to treat skeletal complications of malignancy

Margaret K Crook
Theresa A Guise

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DOI:10.1138/20090396

Abstract

The RANKL signaling pathway is a key mediator of osteoclastic bone resorption in response to stimuli from cancer cells. Bone resorption releases growth factors that then further stimulate cancer growth in a “vicious cycle”. RANKL inhibition effectively decreases solid tumor bone metastases, myeloma and hypercalcemia of malignancy in animal studies. In clinical trials, humanized RANKL antibody therapy is effective in all of these settings and in cancer treatment-related bone loss as well. Although there are theoretical concerns that inhibition of RANKL signaling could impact the immune system or increase the incidence of neoplasms, neither of these adverse outcomes have been realized clinically to date. Emerging research suggests that RANKL signaling plays additional roles in cancer cells independent of osteoclasts by increasing homing of cancer cells to bone and invasive potential. Osteoclast eradication caused by RANKL inhibition may also offer advantages in suppression of bone turnover compared to bisphosphonates. Thus, targeting RANKL in skeletal complications of malignancy potently suppresses bone turnover to improve skeletal mortality in those conditions, and may have direct antitumor effects as well.

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