Aseptic loosening secondary to periprosthetic osteolysis remains a serious orthopaedic problem and the greatest limitation of total joint replacement. This process is caused by wear debris-induced osteoclastic bone resorption, for which effective small molecule (bisphosphonates, BPs) and biologic (RANK antagonists) drugs have been developed. While BPs have proven to be effective in preventing metabolic bone loss in non-inflammatory conditions such as osteoporosis, they do not have the same efficacy in the setting of inflammatory bone loss such as that observed in periprosthetic osteolysis. Since this difference has been attributed to the anti-apoptotic inflammatory signals that protect osteoclasts from BP-induce 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. Based on the shortcomings of previous animal studies that focused on 2D imaging and histology endpoints, and the emergence of quantitative 3D-CT, we developed in vivo micro-CT methods for the murine calvaria model to more rigorously test our hypothesis and correlate the osteolysis results with traditional histology. Although this approach proved to be incompatible with titanium (Ti) particles, due to metal artifact, we were able to demonstrate a 3.2-fold increase in osteolytic volume over 10 days induced by ultra high molecular weight polyethylene (PE) particles vs. sham controls (0.49 +/− 0.23mm3 vs. 0.15 +/− 0.067mm3; p<0.01). While 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) vs. 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 vs. 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 vs. osteoclast numbers (p<0.001). Taken together our results demonstrate the sensitivity and utility of in vivo 3D-CT to detect the effects of BPs on wear debris-induced osteolysis that could not be observed by histology alone; and that the greater suppression of bone resorption observed with OPG treatment vs. BPs is due to its ability to dramatically reduce osteoclast numbers in the presence of inflammatory signals.
Keywords: Aseptic Loosening, wear debris, osteolysis, osteoprotegerin (OPG), bisphosphonate (BP), 3D-micro-CT