Denosumab and bisphosphonates: rivals or potential "partners"? A "hybrid" molecule hypothesis

Bisphosphonates are well established as the treatment of choice for disorders of excessive bone resorption, including osteoporosis. They bind bone mineral with high affinity and through internalization by the resorbing osteoclasts, affect their function and survival. Receptor activator of nuclear factor-κB ligand (RANKL) is a cytokine essential for osteoclast differentiation, activation, and survival. Denosumab, a human monoclonal antibody that neutralizes RANKL, constitutes a promising antiresorptive agent for osteoporosis treatment. However, its presumable interaction with the immune system could adversely affect immune response resulting in increased risk of infections. We hypothesize that bisphosphonates could serve as a vehicle for the delivery of denosumab selectively to the skeleton. Thus, the effect on the immune system could be minimized, along with a potential increase in the antiresorptive efficacy, as a result of the combined action of denosumab and the bisphosphonate on the earlier and later stages of osteoclast life, respectively.