Abstract

Cortical and trabecular bone undergo a continuous and balanced remodelingprocess, which consists of a phase of resorption, mediated by osteoclasts, anda phase of neoformation mediated by osteoblasts. The activity of both, osteoblastsand osteoclasts, is regulated by the osteocytes, which are the most abundantcells in bone tissue. An imbalance of this process with an excessive resorptionactivity causes a loss of bone mass and microarchitectural deterioration ofthe skeleton, with consequent reduction of bone strength and increased riskof fractures. The ligand for the “Receptor Activator of Nuclear Factor Kappa-B” (RANK-L), a protein expressed by osteoblasts, plays a fundamental role inthe formation, activation and survival of osteoclasts, through interaction withits receptor RANK, expressed on the surface of osteoclasts. The discovery ofthe role of RANK-L in the pathogenesis of osteoporosis has led to study theeffects of its inhibition as a new approach and specific antiresorptive therapy.In several preclinical models of postmenopausal osteoporosis, the inhibitionof RANK-L has prevented the loss of bone mass and deterioration of bone microarchitectureand has been associated with increased bone strength at bothvertebral and femoral skeletal sites. In humans, subcutaneous administration,every 6 months, of a fully human monoclonal antibody directed specificallyagainst RANK-L (denosumab) has determined, in the course of randomizedcontrolled clinical trials, significant and continuous increases in bone mineraldensity (BMD) over time at all skeletal sites – trabecular and cortical – examined(lumbar spine, femoral neck and distal radius), and rapid, marked andprolonged reductions in markers of bone turnover in women with osteopeniaor postmenopausal osteoporosis. Inhibition of RANK-L with this monoclonalantibody has been shown to significantly reduce the risk of vertebral (-68%),non-vertebral (-20%), and femoral (-40%) fractures, after 3 years of treatmentin postmenopausal women with osteoporosis. The extension of these studiesto five years has confirmed the effects of treatment with denosumab on BMD,on the inhibition of bone remodeling and on fracture risk. The frequency andtype of adverse events reported were similar to that of placebo or treatmentwith bisphosphonates, indicating a good tolerability profile. These data suggestthat the specific inhibition of RANK-L represents an innovative therapeuticapproach for reducing the risk of fragility fractures.
Original languageItalian
Pages (from-to)38-49
Number of pages12
JournalGIORNALE DI GERONTOLOGIA
Volume61
Publication statusPublished - 2013

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