In this study, a rat calvaria/macrophage co-culture model was used to study the effects of various agents upon bone resorption induced by macrophage exposure to bone cement particles. The experimental group consisted of calvaria bone disks set in tissue culture medium on stainless-steel platforms into wells with macrophages adherent to the bottom which are exposed to the particles. Tumor necrosis factor alpha (TNF-alpha), prostaglandin E2 (PGE2), and calcium 45 (Ca45 were released in significant amounts in this system. Interleukin 1 alpha (IL-1 alpha) was not detected. Indomethacin inhibited the production of PGE2, but did not affect TNF release or inhibit the release of Ca45. Anti-TNF antibody neutralized the presence of TNF to undetectable levels, but did not affect PGE2 release or inhibit Ca45 release. The addition of calcitonin did not inhibit Ca45 release by calvaria. In contrast, the addition of disodium pamidronate, a member of the bisphosphonate family, was effective in inhibiting the release of Ca45 even after 96 h of incubation. In prior studies, incubation of calvaria in conditioned medium from macrophages exposed to cement particles led to resorption through a mechanism which is dependent upon TNF production by macrophages, and PGE2 production by cells in bone. In this two-way system, in which macrophages and cells in bone are allowed to interact, this dependency was no longer evident. Pamidronate was the only agent tested which suppressed the increase in bone resorption associated with macrophage exposure to bone cement particles to levels which were not significantly different from unexposed calvaria. By delaying or preventing bone resorption associated with macrophage exposure to bone cement particles, bisphosphonates may have a clinical role in cemented joint arthroplasty by decreasing the rate or incidence of aseptic loosening and prolonging implant longevity.