J Mater Sci: Mater Med (2006) 17:667–673 DOI 10.1007/s10856-006-9230-x Effect of bisphosphonates on the stimulation of macrophages by alumina ceramic particles: A comparison with ultra-high-molecular-weight polyethylene Alain Petit · Fackson Mwale · John Antoniou · David J. Zukor · Olga L. Huk Received: 3 January 2004 / Accepted: 21 October 2005 C  Springer Science + Business Media, LLC 2006 Abstract Wear particle-induced osteolysis and loosening is a critical process that limits the longevity of total hip arthroplasty. Despite their potential value in the manage- ment of aseptic loosening, little is known about the cel- lular 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-α re- lease 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 parti- cles in combination with pamidronate or clodronate. Re- sults showed that pamidronate and clodronate can in- hibit UHMWPE particle-induced TNF-α release while they had no effect on Al 2 O 3 -stimulated TNF-α 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 fragmen- tation. 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. Interest- ingly, the number of macrophages co-incubated with parti- A. Petit · F. Mwale · J. Antoniou · D. J. Zukor · O. L. Huk () Division of Orthopaedic Surgery, McGill University, Lady Davis Institute for Medical Research, The Sir Mortimer B. Davis—Jewish General Hospital, 3755 Chemin de la Cote Ste-Catherine, Montreal, QC H3 T 1 E2, Canada e-mail: ohuk@ldi.jgh.mcgill.ca cles 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. Introduction Implant wear producing particulate debris leading to oste- olysis and subsequent loosening is a critical process that limits the longevity of total hip arthroplasty. Indeed, wear particles initiate an inflammatory response characterized by macrophage phagocytosis of the particles, leading to the re- lease of mediators that induce bone resorption [1, 2]. Results from our laboratory suggest that bisphosphonates (BPs) can reduce human periprosthetic osteolysis [3]. Others have also shown that alendronate can inhibit wear debris mediated os- teolysis in a canine model [4]. BPs are a class of synthetic compounds that are powerful inhibitors of bone resorption both in vitro and in vivo. They are well tolerated and ef- fective in the treatment of various metabolic bone diseases and skeletal disorders [5, 6]. Despite their potential value in the management of aseptic loosening, little is known about the macrophage response to BPs in the presence of par- ticulate debris. Using a co-culture macrophage/osteoblast model, Horowitz and Gonzales showed that pamidronate was effective in inhibiting resorption stimulated by con- ditioned medium from macrophages exposed to polyethy- lene particles [7]. Ibandronate also inhibited UHMWPE- stimulated human macrophage TNF-α release in vitro [8]. We demonstrated that the induction of macrophage apop- tosis by pamidronate is implicated in the inhibitory effect of this BP on UHMWPE-stimulated TNF-α release [9]. To better understand the interaction between wear particles and BPs, the present study compares the effect of pamidronate Springer