Structural and Symptomatic Efficacy of Glucosamine and Chondroitin in Knee Osteoarthritis A Comprehensive Meta-analysis

1. Structural and Symptomatic Efficacy of Glucosamine and Chondroitin in Knee Osteoarthritis A Comprehensive Meta-analysisRichy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y, Reginster JY.Arch Intern Med. 2003 Jul 14; 163(13): 1514-22.    Annette L.D. Enriquez, MD, PhD University of California, San Francisco Department of Family and Community Medicine Evidence-Based Medicine Journal Club January 21, 2004

2. Clinical Scenario ID/CC: Sra. O.A. is a 57yo Mexican woman who presents to clinic with the chief complaint of “Me duelen las rodillas” HPI: She states that her knees are stiff in the morning and the pain is worse after extended periods of walking or climbing stairs. Her pain has been increasing in intensity over the last month and but is still somewhat relieved with rest and cessation of weight bearing. She has been taking acetaminophen with some relief. PE: She has a BMI of 30. There is bony enlargement of her knees bilaterally. They are tender to the touch without palpable warmth. She has limited range of motion of her bilateral lower extremities, the right side greater than the left.

3. Radiographs of Sra. O.A.’s knees

4. Buena medicina para artritis? Supplement Facts: Serving Size 2 Tablets Serving Per Container 60                                                  Amount Per Serving      %DV* Calories                                                          10 Vitamin C (as manganese ascorbate)               36 mg           60% Manganese (as manganese ascorbate)               10 mg        500% Molybdenum (as molybdenum chelate)          320 mcg        430% Glucosamine (as glucosamine sulfate)              1.5 g                + Chondroitin (as chondroitin  sulfate)                1.2 g                + ------------------------------------------------------------------ + Daily Value not established. Other Ingredients:  Stearic acid and modified cellulose gum.

5. Osteoarthritis:a major cause of morbidity and disability Osteoarthritis is widely recognized to interfere with social life, socioeconomic status, and psychological well being affecting more than 21 million Americans Virtually everyone over the age of 75 is affected in a least one joint The screening and development of new drugs has been aimed at protection and regeneration of cartilage versus broad spectrum analgesia

6. Drugs for the treatment of osteoarthritis The criterion for evaluation of drugs for the treatment of osteoarthritis symptom-modifying improvement of pain and function structure-modifying drugs prospective evaluation of radiographic changes by analysis of the joint space narrowing (JSN)

7. Previous Studies Chondroitin sulfate and glucosamine sulfate are natural compounds found in healthy cartilage and synovial fluid Symptomatic efficacy of glucosamine and chondroitin sulfate analyzed through high-quality quantitative systematic reviews Leeb et al. (2000), McAlindon et al. (2000), Towheed, et al. (2001) Since these systematic reviews were published more recent publications have assessed the structural activity of these compounds

8. Objective of this Meta-analysis Taking into account the data from more current studies the objectives of this meta-analysis were: Re-assess the symptomatic efficacy of these two compounds by subgroup analyses of the currently recommended outcomes for symptomatic efficacy based on pain and function Assess the structural efficacy of oral glucosamine sulfate and chondroitin sulfate in knee osteoarthritis through independent meta-analyses of their effects on joint space narrowing

9. Methods Analyses were based on outcomes required for the demonstration of efficacy of a drug used in the treatment of osteoarthritis Radiological evolution based on JSN Pain evaluation by visual analog scale (VAS pain) Joint mobility Lequesne Index (LI) and Western Ontario McMaster University Osteoarthritis Index (WOMAC) Validated, disease-specific, self-administered tools to assess perceived symptomatic burden of osteoarthritis Tolerance (#of adverse effects in treated and placebo) Responding-to-treatment status assessed by physicians

10. Methods Thorough search of electronic data bases, including a manual reference search, and direct contact with pharmaceutical companies Blinded review by 2 independent authors for inclusion, data extraction, and quality assessment using standardized forms Disparities resolved by third author

11. Results : Trial Flow and Study Characteristics 15 studies fulfilled inclusion criteria 1775 patients (1020 glucosamine and 755 chondroitin patients) Individual demographics similar No statistical difference observed for age, body mass index, radiologic score.

12. Results: Quantitative Data Synthesis Continuous outcomes (JSN, LI, WOMAC, VAS pain, and VAS mobility) Pooled according to a combination model accounting for outcome variability of both the placebo and treatment groups’ mean differences before and after treatment Standardized mean difference or effect size equal to: (meantx - meancontrol ) / SDpooled

13. Graphic Display of Quantitative Data Synthesis Results from each trial displayed graphically Black square representing point estimate Horizontal line representing the 95% confidence interval which would contain the true underlying effect in 95% of the occasions if the study was done repeatedly No difference Represented by dashed vertical line at 0.0 If the CI contains 0.0 (crosses the dashed vertical line), the difference in effect is not significant Results from each trial displayed graphically Black square representing point estimate Horizontal line representing the 95% confidence interval which would contain the true underlying effect in 95% of the occasions if the study was done repeatedly No difference Represented by dashed vertical line at 0.0 If the CI contains 0.0 (crosses the dashed vertical line), the difference in effect is not significant Results from each trial displayed graphically Black square representing point estimate Horizontal line representing the 95% confidence interval which would contain the true underlying effect in 95% of the occasions if the study was done repeatedly No difference Represented by dashed vertical line at 0.0 If the CI contains 0.0 (crosses the dashed vertical line), the difference in effect is not significant

14. Graphic Display of Quantitative Data Synthesis Weight of the study in the meta-analysis Represented by the area of the black square Combined Effect Size and its 95% CI Represented by a diamond Vertical line plotted through combined effect size is an measure of homogeneity between the studies

15. Joint Space Narrowing

16. Results: Quantitative Data Synthesis Structural efficacy of glucosamine on JSN Data provide highly significant (P<.001) evidence of structural efficacy on minimum JSN Global effect size found was 0.41 (95% CI, 0.21-0.60) Results for two large studies being consistent (P for heterogeneity=.95) Activity rated as low to medium based on effect size scale Effect size converted to natural unit Potential minimum JSN difference between placebo and active drug groups would be 0.27mm (95% CI, 0.13-0.41mm) after 3 years of daily administration of 1500mg of glucosamine sulfate 2 chondroitin studies produced comparable results but high-quality, detailed articles were missing and this analysis was withdrawn2 chondroitin studies produced comparable results but high-quality, detailed articles were missing and this analysis was withdrawn

17. Symptomatic Outcomes

18. Results: Quantitative Data Synthesis Symptomatic changes compared with baseline observed in the treated groups were significant Glucosamine only WOMAC (P for association <.002) Glucosamine and Chondroitin Lequesne Index (P for association <.001) VAS pain (P for association <.001) VAS mobility (P for association <.001) No placebo group showed significant improvement

19. Results: Quantitative Data Synthesis Dichotomous outcomes (responder to treatment, experiencing adverse events) Pooled according to additive and multiplicative combination models Calculated individual relative risks for each study and global relative risks Graphically, relative risk of 1.0 or no difference represented by dashed vertical line

20. Responder to Treatment

21. Results: Responder Responding-to-treatment status was assessed by physicians Relative risk of being a responder when allocated to glucosamine or chondroitin or placebo was 1.60 (95%CI, 1.38-1.82) The associated absolute risk difference when an additive combination model was used for meta-analysis was 20% (95% CI, 15%-26%) and the number needed to treat was 4.9

22. Adverse Events

23. Results:Adverse Effects Overall safety of the two treatments has been evaluated by comparing the number of adverse events in glucosamine or chondroitin or placebo groups in all studies Global relative risk (random effects) from presenting an adverse reaction when allocated to either treatment group versus placebo was 0.80 (95% CI, 0.59-1.08; P for association <.15) Confirms the safety profile of glucosamine and chondroitin to be excellent

24. Results: Quantitative Data Synthesis Confirmed symptomatic efficacy of glucosamine and chondroitin sulfate on all six outcomes currently recommended to assess symptomatic efficacy based on pain and function Minimal time for onset of significant action was 2 weeks for either treatment group

25. Conclusions 7 individual outcome-oriented meta-analyses of randomized clinical trials were performed The data demonstrate efficacy for glucosamine on JSN and WOMAC The data demonstrate comparable efficacy for glucosamine and chondroitin on LI, VAS pain, and VAS mobility Both compounds were well tolerated Further long-term studies are needed to evaluate the structural efficacy of chondroitin Further studies on the relationship between structural and symptomatic changes, osteoarthritis stage and possible use in prevention

26. Evaluating Meta-analyses Focused clinical question? Appropriate selection criteria for inclusion of articles? Important, relevant articles missed? Validity/quality of included studies appraised? Data abstraction reproducible? Results from different studies homogeneous?

27. Analysis of Publication Bias

28. Evaluation for Publication Bias Funnel-plot graph to assess for publication bias showed a light asymmetry on the right side of the graph More small sample studies associated with high effect sizes than small sample studies showing small effects Asymmetry significant at P = .08 Robustness analyses performed to evaluate the potential effect of a publication bias Based on robustness of results, conservative approach, and data from unselected studies, global estimators show substantial beneficial benefits on symptoms of glucosamine and chondroitin therapy compared with placebo

29. Comments The estimated minimal LI pain difference between the chondroitin or glucosamine group and the placebo group is 2.08 points (95% CI, 1.51-2.65 points) after 90 days of treatment The estimated minimal VAS pain difference between the chondroitin or glucosamine group and the placebo group is 1.26 cm (95% CI, 0.94-1.58 cm) after 90 days of treatment Global relative risk for being a responder to treatment depending on the allocation to glucosamine or chondroitin or placebo, is 1.6 (95% CI, 1.38-1.82; P for association <.001) Absolute risk difference for being a responder to treatment depending on the allocation to glucosamine or chondroitin or placebo, is 20% and the associated number needed to treat is 4.87

30. The Bottom Line : Major Points and Relevance to Patient Care Are the results valid? Confirmed symptomatic efficacy of glucosamine sulfate and chondroitin sulfate Possible long-term efficacy of the two compounds based on observed structural changes in two studies Was meta-analysis of only two studies with similar results necessary?

31. The Bottom Line : Major Points and Relevance to Patient Care Are outcomes important to my patients? Decreased symptoms important Significance of joint space narrowing unclear

32. The Bottom Line : Major Points and Relevance to Patient Care Would results change my practice if valid? Recommend glucosamine sulfate 1500mg/d and chondroitin sulfate 1200mg/d Take medications for at least 2 weeks to see a reduction of symptoms Expect one out of every five patients to respond

33. Unanswered Questions What dosage and dosage form is most effective? Glucosamine sulfate versus hydrochloride? Tablet versus liquid? Glucosamine versus chondroitin sulfate?

34. National Institutes of Health (NIH) Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) Multi-center clinical trial in the United States test the effects of glucosamine and chondroitin for treatment of knee osteoarthritis, used separately or in combination effect on reducing pain and improving functional ability in patients with knee osteoarthritis assess whether glucosamine and chondroitin can reduce or halt the progression of knee osteoarthritis