Title

 

Authors

L. Sinigaglia

Rheumatology Unit, “G. Pini” Hospital, Milan (Italy)

 

Abstract

Cortical and trabecular bone undergo a continuous and balanced remodeling process, consisting of an osteoclast-mediated bone resorption phase and an osteoblast-mediated bone formation phase. An imbalance in this process, with an excessive bone resorption activity, results in accelerated bone loss and in skeletal microarchitecture deterioration, leading to a reduction of bone strength and an increased risk of fracture. RANK Ligand (RANKL), a protein expressed by osteoblasts, plays a key role in osteoclasts formation, function and survival through the interaction with its receptor, RANK, expressed on the surface of osteoclasts. In postmenopausal women, reduced levels of estrogen lead to an increased expression of RANKL, which exerts direct catabolic effects on cortical and trabecular bone, leading to an increased bone loss and a reduction of bone density and strength. Understanding the role of RANKL in the pathogenesis of osteoporosis has led to the investigation of RANKL inhibition as a new targeted anti-resorptive approach. In many preclinical models of postmenopausal osteoporosis, RANKL inhibition has prevented bone loss and microarchitecture deterioration, 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, 6-monthly subcutaneous administration of a fully human, monoclonal antibody against RANKL to women with osteopenia or postmenopausal osteoporosis significantly and continuously increased bone mineral density (BMD) over time at all trabecular and cortical 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 (lumbar spine, femoral neck and distal radius) after 12 months of treatment. RANKL inhibition with this monoclonal antibody has finally been demonstrated to significantly reduce the risk of vertebral (68%), non-vertebral (20%) and hip (40%) fractures in women with postmenopausal osteoporosis after 3 years of treatment. The frequency and pattern of reported adverse events has been similar to placebo or bisphosphonate treatment, suggesting a good tolerability profile. Recently, continuous exposure to this treatment up to 6 years has confirmed its efficacy in significantly increasing BMD and reducing markers of bone turnover, with a maintained good safety 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 bisphosphonate treatments.