title: Effect of antiresorptive and anabolic bone therapy on development of osteoarthritis in a posttraumatic rat model of OA.
abstract: BACKGROUND
  Osteoarthritis (OA) is a leading cause of disability, but despite the high unmet clinical need and extensive research seeking dependable therapeutic interventions, no proven disease-modifying treatment for OA is currently available. Due to the close interaction and interplay between the articular cartilage and the subchondral bone plate, it has been hypothesized that antiresorptive drugs can also reduce cartilage degradation, inhibit excessive turnover of the subchondral bone plate, prevent osteophyte formation, and/or that bone anabolic drugs might also stimulate cartilage synthesis by chondrocytes and preserve cartilage integrity. The benefit of intensive zoledronate (Zol) and parathyroid hormone (PTH) therapy for bone and cartilage metabolism was evaluated in a rat model of OA.
  
  
  METHODS
  Medial meniscectomy (MM) was used to induce OA in male Lewis rats. Therapy with Zol and human PTH was initiated immediately after surgery. A dynamic weight-bearing (DWB) system was deployed to evaluate the weight-bearing capacity of the front and hind legs. At the end of the 10-week study, the rats were euthanized and the cartilage pathology was evaluated by contrast (Hexabrix)-enhanced μCT imaging and traditional histology. Bone tissue was evaluated at the tibial metaphysis and epiphysis, including the subchondral bone. Histological techniques and dynamic histomorphometry were used to evaluate cartilage morphology and bone mineralization.
  
  
  RESULTS
  The results of this study highlight the complex changes in bone metabolism in different bone compartments influenced by local factors, including inflammation, pain and mechanical loads. Surgery caused severe and extensive deterioration of the articular cartilage at the medial tibial plateau, as evidenced by contrast-enhanced μCT and histology. The study results showed the negative impact of MM surgery on the weight-bearing capacity of the operated limb, which was not corrected by treatment. Although both Zol and PTH improved subchondral bone mass and Zol reduced serum CTX-II level, both treatments failed to prevent or correct cartilage deterioration, osteophyte formation and mechanical incapacity.
  
  
  CONCLUSIONS
  The various methods utilized in this study showed that aggressive treatment with Zol and PTH did not have the capacity to prevent or correct the deterioration of the hyaline cartilage, thickening of the subchondral bone plate, osteophyte formation or the mechanical incapacity of the osteoarthritic knee.
authors.affiliation: Global Science and Technology, Pfizer Global Research and Development, Pfizer Inc., 100 Eastern Point Road, Groton, CT, 06340, USA. cedo.bagi@pfizer.com.
authors.forename: Cedo M
authors.initials: CM
authors.lastname: Bagi
authors.affiliation: Comparative Medicine, Global Science and Technology, Pfizer Global Research and Development, Pfizer Inc., 100 Eastern Point Road, Groton, CT, 06340, USA. edwin.r.berryman@pfizer.com.
authors.forename: Edwin
authors.initials: E
authors.lastname: Berryman
authors.affiliation: Comparative Medicine, Global Science and Technology, Pfizer Global Research and Development, Pfizer Inc., 100 Eastern Point Road, Groton, CT, 06340, USA. david.zakur.@pfizer.com.
authors.forename: David E
authors.initials: DE
authors.lastname: Zakur
authors.affiliation: Investigative Pathology, Drug Safety Research and Development, Pfizer Inc., 100 Eastern Point Road, Groton, CT, 06340, USA. Dean.Wilkie@pfizer.com.
authors.forename: Dean
authors.initials: D
authors.lastname: Wilkie
authors.affiliation: Comparative Medicine, Global Science and Technology, Pfizer Global Research and Development, Pfizer Inc., 100 Eastern Point Road, Groton, CT, 06340, USA. catharine.j.andresen@pfizer.com.
authors.forename: Catharine J
authors.initials: CJ
authors.lastname: Andresen
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002358:Cartilage, Articular / Q000000981:diagnostic imaging / Q000473:pathology; D019902:Chondrocytes / Q000187:drug effects / Q000473:pathology; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D010003:Osteoarthritis / Q000000981:diagnostic imaging* / Q000473:pathology; D010281:Parathyroid Hormone / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D010281:Parathyroid Hormone; D000077211:Zoledronic Acid