title: Efficacy of zoledronic acid in treatment of teoarthritis is dependent on the disease progression stage in rat medial meniscal tear model.
abstract: OBJECTIVE
  To investigate whether the stage of osteoarthritis (OA) progression influenced the efficacy of the third-generation bisphosphonate zoledronic acid in a rat medial meniscal tear model.
  
  
  METHODS
  Medial meniscal tear (MMT) was surgically induced in adult male Sprague Dawley rats. Zoledronic acid (ZOL, 100 μg/kg, sc, twice a week) was administered starting immediately, early (from 4 weeks) or late (from 8 weeks) after OA induction. The degeneration of articular cartilage was evaluated with toluidine blue O staining. Subchondral bone remodeling was evaluated with X-ray micro-CT scanning. Joint pain was measured with respect to weight-bearing asymmetry. Calcitonin gene-related peptide (CGRP) expression in dorsal root ganglia (DRGs) was examined using immunofluorescence analysis. The afferent neurons in DRGs innervating the joint were identified by retrograde labeling with fluorogold.
  
  
  RESULTS
  Progressive cartilage loss was observed during 12 weeks after OA induction. Subchondral bone remodeling manifested as increased bone resorption at early stage (4 weeks), but as increased bone accretion at advanced stages (8 weeks). Immediately and early ZOL administration significantly improved subchondral microstructural parameters, attenuated cartilage degeneration, reduced weight-bearing asymmetry and CGRP expression, whereas the late ZOL administration had no significant effects.
  
  
  CONCLUSIONS
  The stage of OA progression influences the efficacy of ZOL in treating joint degeneration and pain. To obtain the maximum efficacy, bisphosphonate treatment should be initiated in rat with early stages of OA pathogenesis.
authors.affiliation: Department of Orthopedics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, China.
authors.forename: De-gang
authors.initials: DG
authors.lastname: Yu
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
authors.forename: Yuan-qing
authors.initials: YQ
authors.lastname: Mao
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Xiao-qing
authors.initials: XQ
authors.lastname: Wang
authors.forename: Hui-feng
authors.initials: HF
authors.lastname: Ding
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.forename: Guang-wang
authors.initials: GW
authors.lastname: Liu
authors.forename: Shao-bo
authors.initials: SB
authors.lastname: Nie
authors.forename: Shen
authors.initials: S
authors.lastname: Liu
authors.forename: Zhen-an
authors.initials: ZA
authors.lastname: Zhu
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D016723:Bone Remodeling / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics; D002358:Cartilage, Articular / Q000187:drug effects* / Q000473:pathology*; D004164:Diphosphonates / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000473:pathology*; D010146:Pain / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D015740:Calcitonin Gene-Related Peptide