Clinical trials on glucosamine and chondroitin

There is a history of clinical research done on glycosaminoglycans, especially glucosamine and chondroitin, for the treatment of arthritis.

Since glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are a major component of joint cartilage, some have hoped that supplemental glucosamine could beneficially influence cartilage structure, and alleviate arthritis. The effectiveness of glucosamine is controversial.[1][2] Most recent reviews found it to be equal to[3][4] or only slight better than placebo.[5][6] A difference may exist between glucosamine sulfate and glucosamine hydrochloride, with glucosamine sulfate showing a benefit and glucosamine hydrochloride not.[7] The Osteoarthritis Research Society International recommends that glucosamine be discontinued if no effect is observed after six months[8] and the National Institute of Clinical Excellence no longer recommends its use.[9] Despite the difficulty in determining the efficacy of glucosamine, it remains a viable treatment option.[10]

Similar trials have been done with chondroitin.[11]

History of trials

In general, the clinical trials of the mid-1990s that furnished positive results showing glucosamine efficacy were later deemed to be of poor quality due to shortcomings in their methods, including small size, short duration, poor analysis of drop-outs, and unclear procedures for blinding.[12][13] At the same time, several independent studies did not detect any benefit of glucosamine supplementation on osteoarthritis.[14][15]

A Cochrane 2005 meta-analysis of glucosamine therapy for osteoarthritis found that only the Rotta brand of glucosamine appeared to be superior to placebo in the treatment of pain and functional impairment resulting from symptomatic osteoarthritis.[16] However, when the low quality and older studies were discounted and only those using the highest-quality design were considered, there was no difference from placebo treatment.[17] A second 2005 review of glucosamine clinical trials reached a different conclusion. Published in the Annals of Pharmacotherapy, the authors of this review concluded that ″The available evidence suggests that glucosamine sulfate may be effective and safe in delaying the progression and improving the symptoms of knee OA.″[18]

A systematic review in 2007 found that effect sizes from glucosamine supplementation were highest in industry-funded studies and lowest in independent studies. [19] which may lead one to believe that bias is responsible for the heterogeneity of the clinical study findings regarding the efficacy of glucosamine. An alternative explanation may be that the two commonly available forms, sulfate and hydrochloride, while used interchangeably by the general public and even the medical community, appear to have different pharmacologic effects in vivo. Another 2007 review of the available research concluded that there was ″compelling evidence″ that glucosamine sulfate (but not hydrochloride) slowed the progression of knee and hip osteoarthritis.[20] This finding was confirmed by a 2013 meta-analysis of 19 glucosamine trials which concluded that while neither form of glucosamine appeared significantly more effective than placebo at symptom improvement, glucosamine sulfate alone showed efficacy in improving physical function in knee OA as measured by the Lequesne Index in trials lasting more than 24 months.[21]

In 2006, the U.S. National Institutes of Health (NIH) funded a 24 week, 12.5 million-dollar multicenter clinical trial (the GAIT trial) to study the effect of chondroitin sulfate, glucosamine hydrochloride, chondroitin/glucosamine in combination, and celecoxib as a treatment for knee-pain in two groups of patients with osteoarthritis of the knee: Patients with mild pain (n=1229), and patients with moderate to severe pain (n=354).[22] When the data from both groups were pooled and analyzed, there was no statistically significant difference between groups taking glucosamine HCl, chondroitin sulfate, glucosamine/chondroitin; and those taking an inactive placebo or the positive control, the prescription analgesic celecoxib. The authors of the study analyzed the moderate-to-severe pain group and found that in this group, the combination of glucosamine and chondroitin was more effective at providing pain relief than the positive control with 79% of the glucosamine group reporting at least a 20% reduction in pain compared to 70% for celecoxib and only 54% reporting a similar reduction in the placebo group. However, the researchers caution that given the small size of the sub-group, these findings should be confirmed with further studies.[23] Despite its size and design, the GAIT trial may have also had some important limitations, however. When considering the entire cohort, none of the treatments studied performed significantly better (or worse) than placebo in improving patient WOMAC pain and function scores. In other words, because of the inclusion of both a placebo and a positive control, and the fact that roughly 60% of each treatment group achieved the same level of improvement, it is difficult to conclude anything about the efficacy or non-efficacy of glucosamine in the treatment of knee OA from this study.[24]

In a follow-up study in 2008, 572 patients from the GAIT trial continued their supplementation for 2 years. After 2 years of supplementation with glucosamine and chondroitin sulfate, alone or in combination, there was no benefit in slowing the loss of cartilage, in terms of joint space width, when compared to a placebo or celecoxib.[25] As in the original GAIT study, this follow up study was confounded by unexpected results that made if difficult to conclude anything definitive about the effect of glucosamine on slowing the progression of OA. Despite the fact that the glucosamine group showed less than one-tenth the joint narrowing (0.013 mm) as the placebo group (0.166 mm), none of the groups experienced joint space narrowing to the degree the researchers expected (0.4 mm) over the two year period based on earlier studies of OA disease progression. Thus, while the researchers rightly concluded that no treatment in this study was found to produce a ″a clinically important reduction″ in joint space width loss[26] none of the participants experienced clinically important progression of their disease during the study period either. In another 2-year follow-up study involving 662 patients from the GAIT trial, published in 2010, there was neither significant pain reduction nor improved function when comparing glucosamine and/or chondroitin to a placebo although the positive control also failed to perform significantly better that the placebo in this study.[27]

Using meta-analyses to sort conflicting results

Due to the controversy engendered by these results, additional meta-analyses have been undertaken in an attempt to evaluate glucosamine.[28] A 2009 review found little evidence that glucosamine was better than placebo at reversing or restoring degenerative changes to articular cartilage.[29] One published in 2010 in the British Medical Journal arrived at the following conclusions:

Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space. Health authorities and health insurers should not cover the costs of these preparations, and new prescriptions to patients who have not received treatment should be discouraged.[30]

These conclusions, however, are not shared by all researchers in the field. Specifically, the authors of the 2010 BMJ meta-analysis have been criticized for poor methodology by including too many dissimilar studies in their analysis.[31] In a subsequent discussion the editors of the BMJ concluded that, while they still supported the overall results of the study, they no longer accepted the specific conclusions that glucosamine and chondroitin should not be recommended by health authorities or covered by health insurers, stating that these claims "were not directly supported by [the authors'] data".[32]

Nevertheless in 2012, the U.S. Food and Drug Administration (FDA) maintained its position (first published in a comprehensive 2004 letter) that there is no credible scientific evidence to support the proposed health claims regarding consumption of glucosamine and chondroitin sulfate and reduced risk of osteoarthritis, joint degeneration, and cartilage deterioration.[33]

Also in 2012, a review highlighted the ongoing conflicting clinical data regarding the efficacy of glucosamine concluding both that 1) "...glucosamine sulfate shows an effect size superior to (or at least equal to) the commonly used analgesic or nonsteroidal anti-inflammatory drugs but has no rare or adverse effects" and 2) the majority of clinical trials assessing glucosamine reported a significant number of subjects who failed to respond to treatment, thereby questioning the benefit of glucosamine.[34]

A 2014 review and analysis conducted by the La Universidad del Zulia located in Maracaibo, Venezuela and funded by the Venezuelan government's Technological, Humanistic, and Scientific Development Council concluded that the preponderance of the available evidence indicates that glucosamine, specifically the sulfate form, has disease-modifying effects and provides symptomatic relief for at least some individuals suffering from OA. The report classified glucosamine as a Symptomatic Slow Acting Drugs for Osteoarthritis (SYSADOA) and states:

Although further research is required...glucosamine supplements have been more than sufficiently proven to display overtly beneficial risk-to-reward profiles, and they should remain fundamental components of OA therapy.[35]

A further meta-analysis published in December 2014 by the Parker Institute (Copenhagen, Denmark) sponsored by the Oak Foundation concluded that glucosamine sulfate, but not glucosamine HCl, did have a significant effect on osteoarthritis pain but only when one particular brand was used. Once this effect size was corrected for bias and heterogeneity, the effect size became clinically unimportant.[36]

Summary of results

Many randomized controlled trials have been conducted with mixed results. These trials have been summarized:

The effectiveness of glucosamine is controversial.[1][41] Most recent reviews found it to be equal to[42][43] or only slightly better than placebo.[44][45] A difference may exist between glucosamine sulfate and glucosamine hydrochloride, with glucosamine sulfate showing a benefit and glucosamine hydrochloride not.[46] The Osteoarthritis Research Society International recommends that glucosamine be discontinued if no effect is observed after six months[47] and the National Institute of Clinical Excellence no longer recommends its use[9] although the Arthritis Foundation compares the effectiveness of glucosamine to traditional NSAID therapy.[48] Despite the difficulty in determining the efficacy of glucosamine, it remains a viable treatment option according to some experts.[49]

Chondroitin is not recommended as a treatment for osteoarthritis.[37]

GAIT trial

The major trial included in the two reviews above was the Glucosamine/Chondroitin Arthritis Intervention, or GAIT Trial.[11][50][51] GAIT was funded by the National Institutes of Health to test the effects of chondroitin and glucosamine on osteoarthritis of the knee. This multicenter, placebo-controlled, double-blind, six-month-long trial found that glucosamine plus chondroitin had no statistically significant effect on symptoms of osteoarthritis in the osteoarthritis patients studied. The study, in addition to an inactive placebo, also included an active control, the FDA-approved prescription analgesic drug celecoxib. The researchers found that those taking the active control drug fared no better or worse than those taking glucosamine, glucosamine and chondroitin combined or the inactive placebo.[52]

However, in the moderate-to-severe pain subgroup, the combination of chondroitin and glucosamine was found to be clinically more effective (in 25% of the patients) in treating pain than celecoxib or chondroitin and glucosamine taken individually. Due to small sample sizes in the sub-group (roughly 250 people), the researchers concluded that this needs further validation. The study also found chondroitin sulfate to have no significant effect in reducing joint swelling, effusion, or both. These results indicate that glucosamine and chondroitin do not effectively relieve pain in the overall group of osteoarthritis patients, though it may be an effective treatment for those suffering from moderate-to-severe pain.[53]

In a follow-up study, 572 patients from the GAIT Trial continued the supplementation for two years. After two years of supplementation with glucosamine and chondroitin sulfate, alone or in combination, there was no benefit in slowing the loss of cartilage, in terms of joint space width, when compared to a placebo.[25] However, no patient group, placebo or glucosamine alone, or in combination, experienced joint space width loss at even half the rate expected during this study, making it difficult to assess the clinical effectiveness of any treatment on the progression of OA.[54]

In another two-year follow-up study, there was no significant pain reduction or improved function when compared to either inactive placebo or celecoxib [27][52] Some of the researchers' ties to Pfizer (which makes celecoxib) have brought into question the validity of the study.[55]

The lead author of the GAIT Trial, Allen D. Sawitzke, MD, expressed his disappointment with unexpectedly equivocal findings of the trial, noting in an interview with the Arthritis Foundation, that because of significant limitations, like a small sample size, the GAIT Trial likely didn’t have enough power to determine whether glucosamine and chondroitin are effective treatments for knee osteoarthritis or not.[56]

The LEGS study

The Long-term Evaluation of Glucosamine Sulfate (LEGS) study was to determine whether glucosamine sulfate, chondroitin sulfate or a combination of both are effective treatments for chronic knee pain due to osteoarthritis. 502 patients (from 605 enrolled) were followed for two years.[57] The main outcomes were disease progression, as measured by joint space narrowing (JSN) and knee pain (VAS). The combination treatment did result in a small but statistically significant (0.1mm) decrease in 2-year JSN compared with placebo but there was no difference in JSN between this group and the other treatment groups and no differences between any group for changes in knee pain. in summary, there was no significant symptomatic benefit detected for these dietary supplements, and a longer study would be required to test the efficacy of both supplements combined.[58]

Development of guidelines based on these results

Clinical practice guidelines based on trials prior to publication of the negative review by Reichenbach[37] and the equivocal GAIT trial[11] recommended the use of chondroitin. The OARSI (OsteoArthritis Research Society International) recommended chondroitin sulfate as the second-most-effective treatment for moderate cases of osteoarthritis (although the guidelines were published in 2008, the developers closed their search date in January 2006 – prior to the GAIT trial).[47] In 2003, the European League Against Rheumatism (EULAR) supported the usefulness of chondroitin sulfate in the management of knee osteoarthritis and granted the highest level of evidence, 1A, and strength of the recommendation, A, to this product.[59]

References

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  2. ↑ Burdett N, McNeil JD (Sep 2012). "Difficulties with assessing the benefit of glucosamine sulphate as a treatment for osteoarthritis.". International journal of evidence-based healthcare 10 (3): 222–6. doi:10.1111/j.1744-1609.2012.00279.x. PMID 22925619.
  3. ↑ Wandel S, Jüni P, Tendal B, Nüesch E, Villiger PM, Welton NJ, Reichenbach S, Trelle S (Sep 16, 2010). "Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis". BMJ (Clinical research ed.) 341: c4675. doi:10.1136/bmj.c4675. PMC 2941572. PMID 20847017.
  4. ↑ Wu D, Huang Y, Gu Y, Fan W (Jun 2013). "Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: a meta-analysis of randomised, double-blind, placebo-controlled trials.". International journal of clinical practice 67 (6): 585–94. doi:10.1111/ijcp.12115. PMID 23679910.
  5. ↑ "Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review [Internet].". Agency for Healthcare Research and Quality (US). Oct 2011. PMID 22091473.
  6. ↑ Miller KL, Clegg DO (February 2011). "Glucosamine and chondroitin sulfate". Rheum. Dis. Clin. North Am. 37 (1): 103–18. doi:10.1016/j.rdc.2010.11.007. PMID 21220090. The best current evidence suggests that the effect of these supplements, alone or in combination, on OA pain, function, and radiographic change is marginal at best.
  7. ↑ Rovati LC, Girolami F, Persiani S (Jun 2012). "Crystalline glucosamine sulfate in the management of knee osteoarthritis: efficacy, safety, and pharmacokinetic properties.". Therapeutic advances in musculoskeletal disease 4 (3): 167–80. doi:10.1177/1759720X12437753. PMC 3400104. PMID 22850875.
  8. ↑ Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, Bierma-Zeinstra S, Brandt KD, Croft P, Doherty M, Dougados M, Hochberg M, Hunter DJ, Kwoh K, Lohmander LS, Tugwell P (February 2008). "OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines" (PDF). Osteoarthr. Cartil. 16 (2): 137–62. doi:10.1016/j.joca.2007.12.013. PMID 18279766.
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  21. ↑ Wu D, Huang Y, Gu Y, Fan W (2013). "Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: A meta-analysis of randomised, double-blind, placebo-controlled trials". International Journal of Clinical Practice 67 (6): 585–94. doi:10.1111/ijcp.12115. PMID 23679910.
  22. ↑ Clinical trial number NCT00032890 for "Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)" at ClinicalTrials.gov
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  24. ↑ Sawitzke AD, Shi H, Finco MF, Dunlop DD, Harris CL, Singer NG, Bradley JD, Silver D, Jackson CG, Lane NE, Oddis CV, Wolfe F, Lisse J, Furst DE, Bingham CO, Reda DJ, Moskowitz RW, Williams HJ, Clegg DO (2010). "Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT". Annals of the Rheumatic Diseases 69 (8): 1459–64. doi:10.1136/ard.2009.120469. PMC 3086604. PMID 20525840.
  25. 1 2 Sawitzke AD, Shi H, Finco MF, Dunlop DD, Bingham CO, Harris CL, Singer NG, Bradley JD, Silver D, Jackson CG, Lane NE, Oddis CV, Wolfe F, Lisse J, Furst DE, Reda DJ, Moskowitz RW, Williams HJ, Clegg DO; Shi, H; Finco, MF (October 2008). "The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial". Arthritis and Rheumatism 58 (10): 3183–91. doi:10.1002/art.23973. PMC 2836125. PMID 18821708.
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  27. 1 2 Sawitzke AD, Shi H, Finco MF, Dunlop DD, Harris CL, Singer NG, Bradley JD, Silver D, Jackson CG, Lane NE, Oddis CV, Wolfe F, Lisse J, Furst DE, Bingham CO, Reda DJ, Moskowitz RW, Williams HJ, Clegg DO; Shi, H; Finco, MF (August 2010). "Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT". Arthritis and Rheumatism 69 (8): 1459–64. doi:10.1136/ard.2009.120469. PMC 3086604. PMID 20525840.
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  30. ↑ Wandel S, Jüni P, Tendal B, Nüesch E, Villiger PM, Welton NJ, Reichenbach S, Trelle S (2010). "Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis". British Medical Journal 341 (sep16 2): c4675. doi:10.1136/bmj.c4675. PMC 2941572. PMID 20847017. Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space
  31. ↑ Giacovelli G, Rovati LC (2010). "Glucosamine and osteoarthritis. Conclusions not supported by methods and results". BMJ (Clinical research ed.) 341: c6338. doi:10.1136/bmj.c6338. PMID 21062886.
  32. ↑ Groves T (2010). "Report from BMJ post publication review meeting". Retrieved 17 Feb 2015.
  33. ↑ Hubbard WK, Associate Commissioner of Policy and Planning (October 7, 2004). "Letter Regarding the Relationship Between the Consumption of Glucosamine and/or Chondroitin Sulfate and a Reduced Risk of: Osteoarthritis; Osteoarthritis-related Joint Pain, Joint Tenderness, and Joint Swelling; Joint Degeneration; and Cartilage Deterioration(Docket No. 2004P-0059)". United States Department of Health and Human Services, Food and Drug Administration. Retrieved 14 May 2014. (Updated 2012.)
  34. ↑ Henrotin Y, Mobasheri A, Marty M (2012). "Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis?". Arthritis Research & Therapy 14 (1): 201. doi:10.1186/ar3657. PMC 3392795. PMID 22293240./
  35. ↑ Salazar J, Bello L, Chávez M, Añez R, Rojas J, Bermúdez V (2014). "Glucosamine for Osteoarthritis: Biological Effects, Clinical Efficacy, and Safety on Glucose Metabolism". Arthritis 2014: 432463. doi:10.1155/2014/432463. PMC 3941227. PMID 24678419.
  36. ↑ Eriksen, P; Bartels, E. M.; Altman, R. D.; Bliddal, H; Juhl, C; Christensen, R (2014). "Risk of bias and brand explain the observed inconsistency in trials on glucosamine for symptomatic relief of osteoarthritis: A meta-analysis of placebo-controlled trials". Arthritis Care & Research 66 (12): 1844–55. doi:10.1002/acr.22376. PMID 24905534.
  37. 1 2 3 Reichenbach S, Sterchi R, Scherer M, Trelle S, Bürgi E, Bürgi U, Dieppe PA, Jüni P (2007). "Meta-analysis: chondroitin for osteoarthritis of the knee or hip". Ann Intern Med 146 (8): 580–90. doi:10.7326/0003-4819-146-8-200704170-00009. PMID 17438317.
  38. ↑ Lane N (2007). "Review: based on evidence from higher-quality trials, chondroitin does not reduce pain in knee or hip osteoarthritis". ACP J. Club 147 (2): 44. PMID 17764135.
  39. ↑ Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF (1999). "Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses". Lancet 354 (9193): 1896–900. doi:10.1016/S0140-6736(99)04149-5. PMID 10584742.
  40. ↑ Bruyere O, Reginster JY (2007). "Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis". Drugs Aging 24 (7): 573–80. doi:10.2165/00002512-200724070-00005. PMID 17658908.
  41. ↑ Burdett N, McNeil JD (September 2012). "Difficulties with assessing the benefit of glucosamine sulphate as a treatment for osteoarthritis". Int J Evid Based Healthc 10 (3): 222–6. doi:10.1111/j.1744-1609.2012.00279.x. PMID 22925619.
  42. ↑ Wandel S, Jüni P, Tendal B, Nüesch E, Villiger PM, Welton NJ, Reichenbach S, Trelle S (2010). "Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis". BMJ 341: c4675. doi:10.1136/bmj.c4675. PMC 2941572. PMID 20847017.
  43. ↑ Wu D, Huang Y, Gu Y, Fan W (June 2013). "Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: a meta-analysis of randomised, double-blind, placebo-controlled trials". Int. J. Clin. Pract. 67 (6): 585–94. doi:10.1111/ijcp.12115. PMID 23679910.
  44. ↑ Chou R, McDonagh MS, Nakamoto E, Griffin J (2011). Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review. Comparative Effectiveness Reviews. Rockville: Agency for Healthcare Research and Quality. PMID 22091473.
  45. ↑ Miller KL, Clegg DO (February 2011). "Glucosamine and chondroitin sulfate". Rheum. Dis. Clin. North Am. 37 (1): 103–18. doi:10.1016/j.rdc.2010.11.007. PMID 21220090. The best current evidence suggests that the effect of these supplements, alone or in combination, on OA pain, function, and radiographic change is marginal at best.
  46. ↑ Rovati LC, Girolami F, Persiani S (June 2012). "Crystalline glucosamine sulfate in the management of knee osteoarthritis: efficacy, safety, and pharmacokinetic properties". Ther Adv Musculoskelet Dis 4 (3): 167–80. doi:10.1177/1759720X12437753. PMC 3400104. PMID 22850875.
  47. 1 2 Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, Bierma-Zeinstra S, Brandt KD, Croft P, Doherty M, Dougados M, Hochberg M, Hunter DJ, Kwoh K, Lohmander LS, Tugwell P (February 2008). "OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines". Osteoarthr. Cartil. 16 (2): 137–62. doi:10.1016/j.joca.2007.12.013. PMID 18279766.
  48. ↑ http://www.arthritistoday.org/arthritis-treatment/natural-and-alternative-treatments/supplements-and-herbs/supplement-guide/glucosamine.php
  49. ↑ Henrotin Y, Mobasheri A, Marty M (2012). "Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis?". Arthritis Research & Therapy 14 (1): 201. doi:10.1186/ar3657. PMC 3392795. PMID 22293240.
  50. ↑ Baime MJ (2006). "Glucosamine and chondroitin sulphate did not improve pain in osteoarthritis of the knee". Evid Based Med 11 (4): 115. doi:10.1136/ebm.11.4.115. PMID 17213128.
  51. ↑ Baime MJ (2006). "Glucosamine and chondroitin sulfate did not improve pain in osteoarthritis of the knee". ACP J. Club 145 (1): 17. PMID 16813365.
  52. 1 2 Sawitzke AD, Shi H, Finco MF, Dunlop DD, Harris CL, Singer NG, Bradley JD, Silver D, Jackson CG, Lane NE, Oddis CV, Wolfe F, Lisse J, Furst DE, Bingham CO, Reda DJ, Moskowitz RW, Williams HJ, Clegg DO (2010). "Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT". Ann. Rheum. Dis. 69 (8): 1459–64. doi:10.1136/ard.2009.120469. PMC 3086604. PMID 20525840.
  53. ↑ "Questions and Answers: NIH Glucosamine/Chondroitin Arthritis Intervention Trial Primary Study". National Center for Complementary and Integrative Health (NCCIH). October 2008. Retrieved 2014-05-20.
  54. ↑ http://nccih.nih.gov/news/2008/092908.htm
  55. ↑ Jay Gordon, MD (2006-02-26). "Did You Understand the Arthritis Study? I Did". Huffingtonpost.com. Retrieved 2014-05-20.
  56. ↑ http://www.arthritistoday.org/news/glucosamine-chondroitin-ineffective.php
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