title: The role of diet and exercise and of glucosamine sulfate in the prevention of knee osteoarthritis: Further results from the PRevention of knee Osteoarthritis in Overweight Females (PROOF) study.
abstract: OBJECTIVE
  The PRevention of knee Osteoarthritis in Overweight Females (PROOF) study (ISRCTN 42823086) described a trend for a decrease in the incidence of knee osteoarthritis (OA) by a tailored diet and exercise program (DEP) or by oral glucosamine sulfate in women at risk for the disease, using a composite clinical and/or radiological outcome. The aim of this updated post-hoc analysis was to re-assess the results according to more precise techniques and take advantage of the 2×2 factorial design.
  
  
  METHODS
  A total of 407 overweight (BMI ≥ 27kg/m(2)) women of 50-60 years of age with no diagnosis of knee OA were randomized to: (1) no DEP + placebo (Control, N = 102), (2) DEP + placebo (DEP, N = 101), (3) glucosamine sulfate + no DEP (GS, N = 102), and (4) DEP + glucosamine sulfate (DEP + GS, N =102) and followed for 2.5 years, with standardized postero-anterior, semiflexed (MTP) view knee radiographs at baseline and end of the study. DEP consisted of a tailored low fat and/or low caloric diet and easy to implement physical activities. Glucosamine was given as oral crystalline glucosamine sulfate 1500mg once daily, double-blinded vs. placebo. Incident knee OA was defined as radiographic progression of ≥1mm minimum joint space narrowing (mJSN) in the medial tibiofemoral compartment, as previously assessed by the visual (manual) technique and by a new semi-automated method. Logistic regression analysis was used to calculate the odds ratio for the effect of the interventions.
  
  
  RESULTS
  After 2.5 years, 11.8% of control subjects developed knee OA. This incidence was decreased with glucosamine sulfate, either alone or in combination with the DEP, but not by the DEP alone. Since there was no statistical interaction between treatments, the 2×2 factorial design allowed analysis of patients receiving glucosamine sulfate (N = 204) vs. those not receiving it (N = 203), similarly for those on the DEP (N = 203) or not (N = 204). Glucosamine sulfate significantly decreased the risk of developing knee OA: odds ratio (OR) = 0.41 (95% CI: 0.20-0.85, P = 0.02) by the manual JSN assessment method and OR = 0.42 (95% CI: 0.20-0.92, P = 0.03) by the semi-automated technique. Conversely, there was no decrease in risk with the DEP.
  
  
  CONCLUSIONS
  Glucosamine sulfate decreased the risk of developing radiographic knee OA over 2.5 years in overweight, middle-aged women at risk, as determined by medial mJSN progression. Conversely a tailored diet and exercise program exerted no preventive effect, possibly because of the lower than expected effect on weight loss.
authors.affiliation: Department of General Practice, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: j.runhaar@erasmusmc.nl.
authors.forename: Jos
authors.initials: J
authors.lastname: Runhaar
authors.affiliation: Department of Public Health, Epidemiology and Health Economics, University of Liège, Belgium.
authors.forename: Rita
authors.initials: R
authors.lastname: Deroisy
authors.affiliation: Department of General Practice, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Marienke
authors.initials: M
authors.lastname: van Middelkoop
authors.affiliation: University of Milano-Bicocca, School of Medicine, Milano, Italy; Department of Clinical Research, Rottapharm Biotech, Monza, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Barretta
authors.affiliation: Department of Clinical Research, Rottapharm Biotech, Monza, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Barbetta
authors.affiliation: Department of Radiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Oei
authors.affiliation: Department of Radiology, Maastad Hospital, Rotterdam, The Netherlands.
authors.forename: Dammis
authors.initials: D
authors.lastname: Vroegindeweij
authors.affiliation: Department of Clinical Research, Rottapharm Biotech, Monza, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Giacovelli
authors.affiliation: Department of Public Health, Epidemiology and Health Economics, University of Liège, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bruyère
authors.affiliation: Department of Clinical Research, Rottapharm Biotech, Monza, Italy.
authors.forename: Lucio C
authors.initials: LC
authors.lastname: Rovati
authors.affiliation: Department of Public Health, Epidemiology and Health Economics, University of Liège, Belgium.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Reginster
authors.affiliation: Department of General Practice, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Orthopaedics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Sita M A
authors.initials: SM
authors.lastname: Bierma-Zeinstra
mesh_terms: D003131:Combined Modality Therapy; D004038:Diet, Reducing; D005081:Exercise Therapy; D005260:Female; D005500:Follow-Up Studies; D005944:Glucosamine / Q000627:therapeutic use*; D006801:Humans; D007719:Knee Joint / Q000000981:diagnostic imaging / Q000473:pathology*; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000000981:diagnostic imaging / Q000517:prevention & control / Q000628:therapy*; D050177:Overweight / Q000178:diet therapy*
chemical_list: D005944:Glucosamine
keywords: Glucosamine sulfate; Knee osteoarthritis; Overweight; Prevention; Randomized controlled trial; Weight loss