title: Pre-emptive, early, and delayed alendronate treatment in a rat model of knee osteoarthritis: effect on subchondral trabecular bone microarchitecture and cartilage degradation of the tibia, bone/cartilage turnover, and joint discomfort.
abstract: OBJECTIVE
  Bisphosphonates are considered potential disease modifying osteoarthritis (OA) agents. The present study investigated the efficacy of pre-emptive, early, and delayed alendronate (ALN) treatment initiation on subchondral trabecular bone and cartilage in low-dose monosodium iodoacetate (MIA)-induced knee OA in rats.
  
  
  METHODS
  Male rats received pre-emptive (n = 12, day 0-end of week 2), early (n = 12, end of week 2-end of week 6), or delayed (n = 12, end of week 6-end of week 10) ALN treatment (30 μg/kg/week). Pre-emptive ALN-treated rats were scanned using in vivo micro-computed tomography (micro-CT) after 2 weeks and then sacrificed, early ALN-treated rats were scanned after 2 and 6 weeks and sacrificed, and the delayed ALN-treated rats were scanned after 2, 6, and 10 weeks of OA induction and sacrificed. After sacrifice, bone histomorphometry and histology of the tibia and biomarker analyses were undertaken. Changes in hind limb weight-bearing were assessed from day -1 until day 14.
  
  
  RESULTS
  MIA-induced pathological features similar to progressive human OA in the cartilage and subchondral bone. Pre-emptive ALN treatment preserved subchondral trabecular bone microarchitecture, prevented bone loss, decreased bone turnover and joint discomfort. Pre-emptive ALN treatment had moderate effects on cartilage degradation. Early and delayed ALN treatments prevented loss of trabeculae and decreased bone turnover, but had no significant effect on cartilage degradation.
  
  
  CONCLUSIONS
  ALN prevented increased bone turnover and preserved the structural integrity of subchondral bone in experimental OA. The time point of treatment initiation is crucial for treating OA. Treating both the subchondral bone and cartilage in OA would be clinically more beneficial.
authors.affiliation: Bone and Joint Research Laboratory, Directorate of Surgical Pathology, SA Pathology and Hanson Institute, Frome Road, Adelaide, SA 5000, Australia; Discipline of Anatomy and Pathology, School of Medical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia. Electronic address: geetha.mohan@alumni.adelaide.edu.au.
authors.forename: G
authors.initials: G
authors.lastname: Mohan
authors.forename: E
authors.initials: E
authors.lastname: Perilli
authors.forename: I H
authors.initials: IH
authors.lastname: Parkinson
authors.forename: J M
authors.initials: JM
authors.lastname: Humphries
authors.forename: N L
authors.initials: NL
authors.lastname: Fazzalari
authors.forename: J S
authors.initials: JS
authors.lastname: Kuliwaba
mesh_terms: D019386:Alendronate / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D064236:Cartilage Oligomeric Matrix Protein / Q000097:blood; D002358:Cartilage, Articular / Q000187:drug effects* / Q000473:pathology; D024042:Collagen Type I / Q000097:blood; D024043:Collagen Type II / Q000652:urine; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008297:Male; D020370:Osteoarthritis, Knee / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000652:urine; D010455:Peptides / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D055114:X-Ray Microtomography
chemical_list: D050071:Bone Density Conservation Agents; C577538:COMP protein, rat; D064236:Cartilage Oligomeric Matrix Protein; D024042:Collagen Type I; D024043:Collagen Type II; D010446:Peptide Fragments; D010455:Peptides; C543437:collagen II C-telopeptide; C052929:collagen type I trimeric cross-linked peptide; D019386:Alendronate
keywords: Alendronate; Animal model; In vivo micro-CT; Monosodium iodoacetate; Osteoarthritis; Subchondral trabecular bone