Mechanisms underlying the long-term and withdrawal effects of denosumab therapy on bone

Denosumab, a human monoclonal antibody against receptor activator of nuclear factor-kappa B ligand (RANKL), is a potent inhibitor of osteoclast differentiation and activity. As the first biologic drug used to treat osteoporosis, denosumab has shown potent anti-resorptive properties and anti-fracture efficacy. The effects of this drug are also unique compared with the effects of bisphosphonates: namely, long-term treatment with this drug results in a continuous gain of bone mineral density, whereas withdrawal of the drug results in a transient overshoot in bone turnover and rapid bone loss. Although the mechanisms for these specific effects remain incompletely understood, emerging experimental and clinical data have started to highlight potential biological and pharmacological mechanisms by which denosumab might affect osteoclasts, as well as osteoblasts, and cause both sustained bone gain and bone loss upon treatment cessation. This Perspective discusses those potential mechanisms and the future studies and clinical implications that might ensue from these findings. Long-term treatment with the anti-resorptive drug denosumab results in a continuous gain in bone mineral density, whereas denosumab withdrawal results in a transient overshoot in bone turnover, with rapid bone loss. This Perspective explores the potential mechanisms underlying these effects.

Automated summary

Denosumab, a human monoclonal antibody against RANKL, inhibits osteoclast differentiation and activity, leading to anti-resorptive properties and anti-fracture efficacy. Compared with bisphosphonates, denosumab results in continuous bone mineral density gain during long-term treatment and rapid bone loss upon withdrawal. The underlying mechanisms for these effects are not fully understood, but emerging data suggest that denosumab may affect both osteoclasts and osteoblasts, causing sustained bone gain and bone loss. Future studies and clinical implications are discussed in this Perspective.