Preclinical and clinical effects of RANK ligand inhibition
The RANK/RANK ligand (RANKL) pathway is key to promote osteoclast formation and activation, and prolong osteoclast survival. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL and prevents its interaction with RANK thereby inhibiting osteoclast formation, function and survival. In turn RANKL inhibitors, and more specifically a human monoclonal antibody against RANKL, Denosumab, have been developed to treat a variety of bone disorders, including osteoporosis and skeletal complications of malignancy.
The efficacy of RANKL inhibition to suppress bone turnover and improve bone mass, microstructure and strength has been demonstrated in a variety of animal models. In OPG transgenic rats for instance, long-term suppression of osteoclasts led to an increase in bone mass and volume, associated with increased bone strength versus their wild-type littermates. In ovariectomized (OVX) mice expressing a humanized RANKL (huRANKL mice), denosumab was superior to alendronate on improving bone mass, trabecular and cortical bone microarchitecture. Similarly, in OVX cynomologus monkeys, denosumab significantly increased BMD and reduced cortical porosity. Furthermore, in this model switching from alendronate to denosumab after 6 months led to greater reductions in BTMs and further improvement in bone mass and microarchitecture.
Randomized clinical trials (RCTs) have demonstrated that denosumab (60 mg s.c., q6m) inhibits bone resorption markedly and reversibly, and improves BMD in postmenopausal women with low bone mass. In two head-to-head studies, denosumab effects on BMD were greater than QW alendronate. Two large RCTs in osteoporotic post-menopausal women (23% prevalent vertebral fracture) and hypogonadal men on androgen-deprivation for non-metastatic prostate cancer, showed that denosumab reduces the incidence of vertebral fractures (−68 and −62% respectively), and in women of hip (−40%) and non-vertebral fractures (−20%). Active treatment was well tolerated (compliance rate >80% after 3 years), and overall serious adverse events were balanced vs placebo, including cancer and infections.