Bench to bedside: elucidation of the OPG–RANK–RANKL pathway and the development of denosumab

Key Points This Review chronicles the events that led to an increased understanding of osteoclast biology, the identification of osteoprotegerin (OPG) and the signalling pathway mediated by receptor activator of NF-κB (RANK) and RANK ligand (RANKL), as well as the development of the therapeutic RANKL-targeted antibody denosumab. OPG was identified through a genomics-based approach. Genetic experiments in mice elucidated the roles of OPG, RANK and RANKL in osteoclast development, activation, function and survival. A series of molecules that inhibit RANKL were developed and tested in vitro and in vivo for potential therapeutic application. RANKL inhibition was shown to: increase bone mass and strength in animal models of osteoporosis; reduce tumour-induced osteolysis and tumour burden in experimental models of bone metastases; and reduce serum calcium levels in models of hypocalcaemia of malignancy. Denosumab is a fully human monoclonal antibody against RANKL. In postmenopausal women with osteoporosis, subcutaneous denosumab dosed at 60 mg every 6 months significantly reduced the risk of new vertebral, hip and non-vertebral fractures, reduced bone turnover and increased bone mineral density at all measured skeletal sites. The effects of denosumab on increasing bone mineral density were significantly greater than alendronate, the most commonly prescribed treatment for osteoporosis, in head-to-head studies. In patients with breast and prostate cancer receiving hormone ablation therapy, denosumab (60 mg every 6 months) increased bone mineral density compared with placebo, and in prostate cancer patients it significantly reduced the risk of new vertebral fractures. In patients with advanced cancer and bone metastases from solid tumours, denosumab (administered at 120 mg every 4 weeks) was superior to the bisphosphonate zoledronic acid in preventing pathological fractures, radiation or surgery to bone, and spinal cord compression — collectively referred to as skeletal-related events. Denosumab is now approved in numerous regions throughout the world for the treatment of osteoporosis in postmenopausal women who are at high risk for fracture, for the treatment of bone loss in men or women receiving hormone ablation therapy for breast or prostate cancer who are at high risk for fracture, and for the prevention of skeletal-related events in patients with advanced cancer and bone metastases from solid tumours. Additional clinical studies are underway to evaluate the e