[Anti-RANKL antibody for the management of bone metastasis]

Bone metastasis is relatively common in patients with breast, prostate, and lung cancer, and may cause severe bone pain, pathological fractures, hypercalcemia and other bone-related complications that drastically undermine quality of life. The currently-available treatments for bone metastasis are unsatisfactory in their effectiveness and outcome. Bone continuously undergoes remodeling through a repeated cycle of osteoclastic bone resorption and osteoblastic bone formation. When cancer cells metastasize to the bone, their growth is promoted under the influence of a variety of growth factors that are supplied from the bone as a consequence of osteoclastic bone resorption. This, in turn, causes an increased production of osteoclast- and osteoblast-stimulating cytokines in these cancer cells, leading to a further increase in bone remodeling. This vicious cycle between bone and metastatic cancer cells supports the development and progression of bone metastases. Accumulating evidence shows that RANKL, a cytokine expressed in osteoblasts/bone marrow stromal cells, plays an important role in the formation, activation, and survival of osteoclasts, which are key players in bone remodeling. RANKL is thus expected to inhibit bone metastasis by disrupting this vicious cycle, and is considered a rational new therapeutic intervention for bone metastasis. In animal models, inhibition with RANKL has been shown to prevent the development of bone metastases. Based on the promising results from these preclinical studies, a fully human monoclonal anti-RANKL antibody, denosumab, has been developed. In three phase III clinical trials of denosumab versus zoledronic acid(ZA)in advanced cancer patients with bone metastases, denosumab was superior or equal to ZA in delaying the time to the first on-study skeletal-related events(SRE). In conclusion, denosumab, a fully human monoclonal anti-RANKL antibody with a targeted mechanism of action, enables us to more easily and effectively treat bone metastases and manage cancer patients with bone metastases.