Efficacy of etanercept for wear debris-induced osteolysis

A major limitation of total joint arthroplasty is that up to 20% of patient s require revision surgery to correct prosthetic loosening. Aseptic looseni ng is believed to result from the phagocytosis of wear debris particles by macrophages, which secrete proinflammatory cytokines that stimulate osteoly sis. Tumor necrosis factor alpha, (TNF-alpha) has been shown to be one of t he prominent cytokines in this cascade and to be involved critically in the generation of particle-induced osteolysis. Etanercept is a soluble inhibit or of TNF-alpha, which is widely used for the treatment of rheumatoid arthr itis. Here, we show this agent's ability to prevent wear debris-induced ost eolysis. In vitro we show that Etanercept can inhibit directly osteoclastic bone resorption in a bone wafer pit assay, as well as cytokine production from titanium (Ti)-stimulated macrophages. Using a quantitative in vivo mod el of wear debris-induced osteolysis, we show that Etanercept prevents bone resorption and osteoclastogenesis. In mice treated with Etanercept at the time of osteolysis induction, bone resorption and osteoclast numbers were r educed to background levels in both normal and human TNF-alpha (hTNF-alpha) transgenic mice. In an effort to evaluate its effect on established osteol ysis, Etanercept was administered 5 days after Ti implantation, and we obse rved that further osteolysis was prevented. These data support the concept that TNF-alpha is involved critically in osteoclastogenesis and bone resorp tion during periprosthetic osteolysis and suggest that soluble TNF-alpha in hibitors may be useful as therapeutic agents for the treatment of prostheti c loosening in humans.