title: Differential effects of biologic versus bisphosphonate inhibition of wear debris-induced osteolysis assessed by longitudinal micro-CT.
abstract: 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 +/- 0.23 mm(3) versus 0.15 +/- 0.067 mm(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).
authors.affiliation: The Center for Musculoskeletal Research, University of Rochester, 601 Elmwood Avenue, Box 665, Rochester, New York 14642-0001, USA.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tsutsumi
authors.forename: Colleen
authors.initials: C
authors.lastname: Hock
authors.forename: C Dustin
authors.initials: CD
authors.lastname: Bechtold
authors.forename: Steven T
authors.initials: ST
authors.lastname: Proulx
authors.forename: Susan V
authors.initials: SV
authors.lastname: Bukata
authors.forename: Hiromu
authors.initials: H
authors.lastname: Ito
authors.forename: Hani A
authors.initials: HA
authors.lastname: Awad
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Regis J
authors.initials: RJ
authors.lastname: O'Keefe
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schwarz
mesh_terms: D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D001672:Biocompatible Materials; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D007091:Image Processing, Computer-Assisted; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects* / Q000473:pathology; D010014:Osteolysis / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control*; D053244:Osteoprotegerin / Q000494:pharmacology*; D020959:Polyethylene; D011475:Prosthesis Failure; D012886:Skull / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D013499:Surface Properties; D014057:Tomography, X-Ray Computed; D000077211:Zoledronic Acid
chemical_list: D001672:Biocompatible Materials; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D053244:Osteoprotegerin; D000077211:Zoledronic Acid; D020959:Polyethylene; D019386:Alendronate