RANKL inhibition as a targeted approach in the management of osteoporosis

Abstract

Cortical and trabecular bone undergo a continuous and balanced remodeling process, consisting of an osteoclast-mediated boneresorption phase and an osteoblast-mediated bone-formation phase. An imbalance in this process, which favours bone resorption, results in bone loss and in damage to the skeletal microarchitecture, as seen in clinical conditions such as osteoporosis, rheumatoid arthritis and bone metastases. Currently, treatments are available for preventing or reversing excessive bone resorption through osteoclast inhibition. Among anti-resorptive treatments, nitrogen-containing bisphosphonates bind to hydroxyapatite with high affinity, are internalized by osteoclasts during the resorptionphase and inhibit osteoclast function, suppressing the mevalonate pathway. A more targeted anti-resorptive approach might be achieved through inhibition of RANK ligand (RANKL), which is one of the primary mediators of osteoclast activity, essential for osteoclast differentiation, function and survival. RANKL exerts direct catabolic effects on cortical and trabecular bone, leading to decreases in bone volume, mineral density and strength. Understanding the role of RANKL in the pathogenesis of bone disease has led to investigation of RANKL inhibition in conditions characterized by excessive bone resorption. In many preclinical models of postmenopausal osteoporosis, RANKL inhibition has prevented bone loss and microarchitecture damage, and has been associated with increased vertebral and femoral bone strength. A variety of innovative therapeutic approaches targeting RANKL inhibition are currently under investigation in humans. In randomized, controlled clinical trials, 6monthly subcutaneous administration of an experimental, fully human, monoclonal antibody against RANKL to womenwith osteopenia or postmenopausal osteoporosis significantly increased bone mineral density (BMD) at all skeletal sites (including the lumbar spine, femoral neck and distal radius) and decreased markers of bone turnover in a rapid, pronounced and sustained manner. Moreover, in two clinical studies, this therapeutic approach produced significantly greater increases in BMD than alendronate at all measured skeletal sites after 12 months of treatment. RANKL inhibition with this monoclonal antibody has recently been demonstrated to significantly reduce the risk of vertebral, non-vertebral and hip fractures inwomen with postmenopausal osteoporosis after 3 years of treatment. The frequency and pattern of reported adverse events have been similar to placebo or bisphosphonate treatment, suggesting a good tolerability profile. These data suggest that RANKL inhibition offers an additional and innovative therapeutic approach for the treatment of postmenopausal osteoporosis and, on the basis of comparative BMD results, may provide an incremental clinical benefit compared with currently available antiresorptive treatments.