AdenosineA2a Receptor Agonists: Can they Prevent/Treat Joint Prosthesis Loosening?

Bruce Cronstein MD, Sally Frenkel PhD

We previously reported that adenosine A2A receptors suppress inflammation and that activation of these receptors with agonists can suppress inflammation in vitro and in vivo.  In preliminary studies, we observed that adenosine A2A receptors can also suppress osteoclast formation in vitro; mice lacking these receptors have increased numbers of bone osteoclasts that appear hyperactive and, when examined in vivo, have diminished bone density. 

The percentage of hip arthroplasties performed in the US in younger patients (age 45-64) continues to rise. These patients typically place a higher demand on their prostheses than elderly recipients, often reducing prosthesis longevity. Survival of joint components is dependent on biological fixation, and is undermined by prosthesis loosening. A major contributing factor to the development of aseptic prosthesis loosening is inflammation and osteoclast-mediated bone resorption in response to prosthesis-derived wear particles. We hypothesize that adenosine A2A receptor agonists may prevent osteoclast-mediated bone resorption at the site of prosthesis wear.  If so, site-specific delivery of the agonist could enhance implant survival, delaying or eliminating the need for revision arthroplastic surgery.

The proposed pilot study will examine the effect of adenosine A2A receptor agonists on bone resorption in a calvarial model of wear particle-induced bone resorption. With  positive results, we will further examine: 1.The mechanism(s) by which adenosine A2A receptor activation diminishes osteoclast formation in vitro, and 2. Development of delivery mechanisms for adenosine receptor agonists into the periprosthetic area, such as agonist-loaded prosthesis cement.