A system was developed to expose macrophages to polyethylene in vitro. Exposure of macrophages to these particles in isolation led to the release of tumor necrosis factor alpha and prostaglandin E2. Exposure of macrophages in co-culture with osteoblasts to polyethylene particles increased the release of prostaglandin E2 and also led to the release of interleukin-6. Incubation of radiolabelled calvariae with conditioned medium from macrophages exposed to polyethylene particles alone or to particles in co-culture with osteoblasts led to bone resorption reflected by release of 45Ca. Incubation with pamidronate was effective in inhibiting resorption stimulated by conditioned medium from macrophages exposed to these particles alone or in co-culture with osteoblasts. This demonstrates that pamidronate, or other bisphosphonates, may be effective in inhibiting bone resorption at the implant/bone interface in association with the macrophage response to particulate polyethylene. Further investigation into the possible use of pamidronate or other bis-phosphonates in the treatment of aseptic loosening is warranted.