title: Potential mechanism of alendronate inhibition of osteophyte formation in the rat model of post-traumatic osteoarthritis: evaluation of elemental strontium as a molecular tracer of bone formation.
abstract: OBJECTIVE
  To employ elemental Strontium as a tracer of bone turnover, in the presence (or absence) of the bisphosphonate drug Alendronate, in order to spatially map osteophytogenesis and other bone turnover in rats developing post-traumatic secondary osteoarthritis (PTOA).
  
  
  METHODS
  PTOA was induced in rats by medial meniscectomy surgery. We utilized in-vivo microfocal computed tomography (CT) to follow bony adaptations in groups for 8 weeks after surgery, either with or without alendronate treatment. Electron probe microanalysis (EPMA) was used to detect Strontium incorporation in mineralizing tissues. Histologic studies were conducted on the same samples using Safranin-O/fast green and Tetrachrome staining of decalcified sections to examine articular cartilage health and osteophyte formation at the sites of elemental Strontium deposition.
  
  
  RESULTS
  EPMA revealed uniform incorporation of Strontium over actively remodeling trabecular surfaces in normal control rats. That pattern was significantly altered after meniscectomy surgery resulting in greater Strontium signal at the developing osteophyte margins. Alendronate treatment inhibited osteophyte development by 40% and 51% quantified by micro-CT volumetric measurements at 4 and 8 weeks after surgery, respectively. Osteophytes in the alendronate group were more cartilaginous in composition [i.e., lower bone mineral density (BMD)] compared to the untreated group. Histological analysis confirmed the osteophyte inhibitory effect of alendronate, and also verified reduced degeneration of the articular cartilage compared to untreated rats.
  
  
  CONCLUSIONS
  Our study confirmed that alendronate administration will reduce osteophyte formation in a rat model of post-traumatic osteoarthritis, partially through the inhibition of secondary remodeling of osteophytes. Our study is the first to employ elemental Strontium as a tracer of bone turnover in the pathogenesis of osteoarthritis and to assess the efficacy of bisphosphonate antiresorptive drug interventions on osteophytogenesis.
authors.affiliation: Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada. a.panahifar@ualberta.ca
authors.forename: A
authors.initials: A
authors.lastname: Panahifar
authors.forename: W P
authors.initials: WP
authors.lastname: Maksymowych
authors.forename: M R
authors.initials: MR
authors.lastname: Doschak
mesh_terms: D019386:Alendronate / Q000627:therapeutic use*; D000818:Animals; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004577:Electron Probe Microanalysis / Q000379:methods; D005260:Female; D009942:Organometallic Compounds; D010003:Osteoarthritis / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D010012:Osteogenesis / Q000187:drug effects; D054850:Osteophyte / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes; D000070600:Tibial Meniscus Injuries; D055114:X-Ray Microtomography / Q000379:methods
chemical_list: D050071:Bone Density Conservation Agents; D009942:Organometallic Compounds; D013876:Thiophenes; C081587:strontium ranelate; D019386:Alendronate