LAM KID

[Inhibition of receptor activator of nuclear kappa-B ligand: pathophysiology and preclinical data]

LAKATOS Péter, NÁDASI Edit

OCTOBER 20, 2011

LAM KID - 2011;1(02)

[Bone remodeling is a lifelong process, in which the balanced functions of osteoclasts and osteoblasts have a key role. In certain conditions, for example during the dramatical hormonal changes in the postmenopausal period, the upset of this balance leads to a pathologically increased bone loss. Such conditions lead to an increased bone loss, which results in an increased risk of fractures. Bone resorption is primarily regulated by a member of the tumor necrosis factor family, receptor activator of nuclear factor κB ligand, which plays a central role in the development, function and survival of osteoclasts. Catabolic effects of this ligand is inhibited by another member of the tumor necrosis factor family, osteoprotegerin, which binds to the ligand and prevents its interaction with its receptor, the receptor activator of nuclear factor κB. Osteoclast activity is at least partly dependent on the relative balance of the ligand and osteoprotegerin. It has been shown in a number of animal models that inhibition of the ligand markedly decreases bone resorption and increases cortical and cancellous bone volume, density and strength, without having any significant effect on other organs. On the basis of these findings, inhibition of receptor activator of nuclear κB ligand is a promising therapy of conditions characterised by increased bone loss. In phase 3 clinical trials, denosumab therapy significantly increased bone mineral density at various regions of the skeleton and significantly decreased the levels of bone turnover markers compared with placebo and alendronate therapy, and significantly decreased the incidence of new vertebral, total hip and nonvertebral fractures compared with placebo. On the basis of these findings, denosumab therapy offers a novel, revolutionary solution for the treatment of postmenopausal osteoporosis.]

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