title: Urinary TIINE concentrations in a randomized controlled trial of doxycycline in knee osteoarthritis: implications of the lack of association between TIINE levels and joint space narrowing.
abstract: OBJECTIVE
  To use the collagenase cleavage site neoepitope, TIINE, a marker of type II collagen breakdown in cartilage, to analyze the mechanism underlying the slowing of joint space narrowing (JSN) in patients with knee osteoarthritis treated with doxycycline.
  
  
  METHODS
  The creatinine-adjusted urinary TIINE concentration was determined at baseline and every 6 months thereafter in a subset of patients who completed a 30-month randomized, placebo-controlled study of the effect of doxycycline on radiographic progression of JSN. The subset was selected a priori to permit comparison of 60 radiographic progressors with 60 radiographic nonprogressors. JSN was determined in highly standardized, semiflexed anteroposterior images.
  
  
  RESULTS
  The coefficient of variation of TIINE concentrations over the 5 study visits was 30%. At the 5 semiannual followup visits, the mean TIINE concentration for doxycycline-treated patients was higher than that for the placebo group. In both treatment groups, the correlation between TIINE levels and JSN in the index knee was weak (for doxycycline, r(2) = 0.06, P = 0.08; for placebo, r(2) = 0.06, P = 0.05).
  
  
  CONCLUSIONS
  High variability from visit to visit limits the sensitivity of the TIINE assay for detecting changes in individual patients and restricts its utility to group comparisons. The increase in TIINE concentration with treatment indicates that inhibition of collagenase-mediated breakdown of type II collagen in articular cartilage is unlikely to have accounted for the observed reduction of JSN in the index knees of patients in the doxycycline treatment group.
authors.affiliation: School of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA. IGO@Otterness.net
authors.forename: Ivan G
authors.initials: IG
authors.lastname: Otterness
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Brandt
authors.forename: Marie-Pierre Hellio
authors.initials: MP
authors.lastname: Le Graverand
authors.forename: Steven A
authors.initials: SA
authors.lastname: Mazzuca
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000652:urine; D024043:Collagen Type II / Q000652:urine*; D004318:Doxycycline / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007719:Knee Joint / Q000000981:diagnostic imaging; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000652:urine*; D011859:Radiography
chemical_list: D000900:Anti-Bacterial Agents; D015415:Biomarkers; D024043:Collagen Type II; D061965:Matrix Metalloproteinase Inhibitors; D004318:Doxycycline