Wear particle-induced osteolysis and loosening is a critical process that limits the longevity of total hip arthroplasty. Despite their potential value in the management of aseptic loosening, little is known about the cellular response to bisphosphonates (BPs) in the presence of particulate debris. In the present study, we compared the effect of pamidronate and clodronate, two structurally different bisphosphonates, on the induction of TNF-alpha release by alumina ceramic (Al(2)O(3)) and ultra-high-molecular-weight-polyethylene (UHMWPE) particles. We also looked, by Trypan blue exclusion, at the viability of J774 mouse macrophages incubated with Al(2)O(3) and UHMWPE particles in combination with pamidronate or clodronate. Results showed that pamidronate and clodronate can inhibit UHMWPE particle-induced TNF-alpha release while they had no effect on Al(2)O(3)-stimulated TNF-alpha release. The co-incubation of pamidronate or clodronate and Al(2)O(3) had no effect on the induction by Al(2)O(3) of poly(ADP-ribose)polymerase (PARP) proteolysis and DNA fragmentation. On the other hand, UHMWPE particles had no effect on these apoptotic markers. However, the co-incubation of pamidronate or clodronate with UHMWPE particles led to the appearance of these markers of apoptosis. Al(2)O(3) and UHMWPE particles had no effect on macrophage cell death or the number of macrophages at the end of experiments. Co-incubation of UHMWPE particles with pamidronate and clodronate led to a significant increase in cell death. Interestingly, the number of macrophages co-incubated with particles and pamidronate or clodronate significantly decreased. In conclusion, our results suggest that the effect of BPs on particle-stimulated macrophages is, at least in part, particle composition dependent.