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Aseptic loosening of total joint replacements is caused by wear debris-induced osteoclastic bone resorption, for which bisphosphonates (BPs) and RANK antagonists have been developed. Although BPs are effective in preventing metabolic bone loss, they are less effective for inflammatory bone loss. Because this difference has been attributed to the antiapoptotic inflammatory signals that protect osteoclasts from BP-induced apoptosis, but not RANK antagonists, we tested the hypothesis that osteoprotegerin (OPG) is more effective in preventing wear debris-induced osteolysis than zoledronic acid (ZA) or alendronate (Aln) in the murine calvaria model using in vivo micro-CT and traditional histology. Although micro-CT proved to be incompatible with titanium (Ti) particles, we were able to demonstrate a 3.2-fold increase in osteolytic volume over 10 days induced by polyethylene (PE) particles versus sham controls (0.49 AE 0.23mm 3 versus 0.15 AE 0.067mm 3 ; p < 0.01). Although OPG and high-dose ZA completely inhibited this PE-induced osteolysis (p < 0.001), pharmacological doses of ZA and Aln were less effective but still reached statistical significance (p < 0.05). Traditional histomorphometry of the sagital suture area of calvaria from both Ti and PE-treated mice confirmed the remarkable suppression of resorption by OPG (p < 0.001) versus the lack of effect by physiological BPs. The differences in drug effects on osteolysis were largely explained by the significant difference in osteoclast numbers observed between OPG versus BPs in both Ti-and PE-treated calvaria; and linear regression analyses that demonstrated a highly significant correlation between osteolysis volume and sagittal suture area versus osteoclast numbers (p < 0.001). Keywords: aseptic loosening; wear debris; osteolysis; osteoprotegerin (OPG); bisphosphonate (BP), 3D micro-CT Although total joint replacement (TJR) is one of the most successful surgeries in all of medicine, with more than 1 million being performed each year, 1 its long-term results are limited by periprosthetic osteolysis and subsequent aseptic loosening in approximately 20% of patients. 2 It has long been established that this process is caused by the generation of implant wear debris that stimulates an inflammatory response and osteoclastic resorption at the bone-implant interface, and the subject has recently been reviewed. 1 Thus, it has been proposed that drugs that inhibit the osteoclast should be effective in preventing aseptic loosening. 3 Two distinct classes of drugs that specifically target the osteoclast have been developed: bisphosphonates (BPs) and nuclear factor kappa B ligand (RANKL) antagonists. 4,5 Although BPs have been widely used as antiresorptive agents for various metabolic bone diseases (e.g., osteoporosis, Paget's disease, bone cancer), 6 they have not demonstrated clinical efficacy in the setting of inflammatory bone loss such as rheumatoid arthritis (RA). [7][8][9][10][11] This lack of efficacy has been attributed to inflammation-derived antiapoptotic ...

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