IL RANK LIGANDO QUALE TARGET TERAPEUTICO NEL TRATTAMENTO DELLE PAZIENTI ANZIANE CON OSTEOPOROSI

Cortical and trabecular bone undergo a continuous and balanced remodeling process, which consists of a phase of resorption, mediated by osteoclasts, and a phase of neoformation mediated by osteoblasts. The activity of both, osteoblasts and osteoclasts, is regulated by the osteocytes, which are the most abundant cells in bone tissue. An imbalance of this process with an excessive resorption activity causes a loss of bone mass and microarchitectural deterioration of the skeleton, with consequent reduction of bone strength and increased risk of fractures. The ligand for the “Receptor Activator of Nuclear Factor Kappa- B” (RANK-L), a protein expressed by osteoblasts, plays a fundamental role in the formation, activation and survival of osteoclasts, through interaction with its receptor RANK, expressed on the surface of osteoclasts. The discovery of the role of RANK-L in the pathogenesis of osteoporosis has led to study the effects of its inhibition as a new approach and specific antiresorptive therapy. In several preclinical models of postmenopausal osteoporosis, the inhibition of RANK-L has prevented the loss of bone mass and deterioration of bone microarchitecture and has been associated with increased bone strength at both vertebral and femoral skeletal sites. In humans, subcutaneous administration, every 6 months, of a fully human monoclonal antibody directed specifically against RANK-L (denosumab) has determined, in the course of randomized controlled clinical trials, significant and continuous increases in bone mineral density (BMD) over time at all skeletal sites – trabecular and cortical – examined (lumbar spine, femoral neck and distal radius), and rapid, marked and prolonged reductions in markers of bone turnover in women with osteopenia or postmenopausal osteoporosis. Inhibition of RANK-L with this monoclonal antibody has been shown to significantly reduce the risk of vertebral (-68%), non-vertebral (-20%), and femoral (-40%) fractures, after 3 years of treatment in postmenopausal women with osteoporosis. The extension of these studies to five years has confirmed the effects of treatment with denosumab on BMD, on the inhibition of bone remodeling and on fracture risk. The frequency and type of adverse events reported were similar to that of placebo or treatment with bisphosphonates, indicating a good tolerability profile. These data suggest that the specific inhibition of RANK-L represents an innovative therapeutic approach for reducing the risk of fragility fractures.