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There is a history of [[clinical research]] done on [[glycosaminoglycan]]s, especially [[glucosamine]] and [[chondroitin]], for the treatment of [[arthritis]].

Since [[glucosamine]] is a precursor for [[glycosaminoglycan]]s, and glycosaminoglycans are a major component of [[cartilage|joint cartilage]], some have hoped that supplemental glucosamine could beneficially influence cartilage structure, and alleviate [[arthritis]]. The effectiveness of glucosamine is controversial.<ref name="bestbets.org">[http://www.bestbets.org/bets/bet.php?id=979 The effects of Glucosamine Sulphate on OA of the knee joint]. BestBets.</ref><ref>{{cite journal | author = Burdett N, McNeil JD | title = Difficulties with assessing the benefit of glucosamine sulphate as a treatment for osteoarthritis. | journal = International journal of evidence-based healthcare | volume = 10 | issue = 3 | pages = 222–6 | date = Sep 2012 | pmid = 22925619 | doi = 10.1111/j.1744-1609.2012.00279.x }}</ref> Most recent reviews found it to be equal to<ref>{{cite journal | author = Wandel S, Jüni P, Tendal B, Nüesch E, Villiger PM, Welton NJ, Reichenbach S, Trelle S | title = Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. | journal = BMJ (Clinical research ed.) | volume = 341 | pages = c4675 | date = Sep 16, 2010 | pmid = 20847017 | pmc = 2941572 | doi = 10.1136/bmj.c4675 }}</ref><ref>{{cite journal | author = Wu D, Huang Y, Gu Y, Fan W | title = Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: a meta-analysis of randomised, double-blind, placebo-controlled trials. | journal = International journal of clinical practice | volume = 67 | issue = 6 | pages = 585–94 | date = Jun 2013 | pmid = 23679910 | doi = 10.1111/ijcp.12115 }}</ref> or only slight better than [[placebo]].<ref>{{cite journal | title = Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review [Internet]. | date = Oct 2011 | pmid = 22091473 | publisher = Agency for Healthcare Research and Quality (US) }}</ref><ref>{{cite journal | author = Miller KL, Clegg DO | title = Glucosamine and chondroitin sulfate | journal = Rheum. Dis. Clin. North Am. | volume = 37 | issue = 1 | pages = 103–18 | date = February 2011 | pmid = 21220090 | doi = 10.1016/j.rdc.2010.11.007 | quote = 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. }}</ref> A difference may exist between glucosamine sulfate and glucosamine hydrochloride, with glucosamine sulfate showing a benefit and glucosamine hydrochloride not.<ref>{{cite journal | author = Rovati LC, Girolami F, Persiani S | title = Crystalline glucosamine sulfate in the management of knee osteoarthritis: efficacy, safety, and pharmacokinetic properties. | journal = Therapeutic advances in musculoskeletal disease | volume = 4 | issue = 3 | pages = 167–80 | date = Jun 2012 | pmid = 22850875 | pmc = 3400104 | doi = 10.1177/1759720X12437753 }}</ref> The [[Osteoarthritis Research Society International]] recommends that glucosamine be discontinued if no effect is observed after six months<ref>{{cite journal | author = 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 | title = OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines | journal = Osteoarthr. Cartil. | volume = 16 | issue = 2 | pages = 137–62 | date = February 2008 | pmid = 18279766 | doi = 10.1016/j.joca.2007.12.013 | url = http://www.oarsi.org/pdfs/part_II_OARSI_recommendations_for_management_of_hipknee_OA_2007.pdf | author-separator = , }}</ref> and the [[National Institute of Clinical Excellence]] no longer recommends its use.<ref name=NICE/> Despite the difficulty in determining the efficacy of glucosamine, it remains a viable treatment option.<ref>{{cite journal | author = Henrotin Y, Mobasheri A, Marty M | title = Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis? | journal = Arthritis Research & Therapy | volume = 14 | issue = 1 | pages = 201 | date = Jan 30, 2012 | pmid = 22293240 | pmc = 3392795 | doi = 10.1186/ar3657 }}</ref>

Similar trials have been done with [[chondroitin]].

==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 [[Intention to treat analysis|analysis of drop-outs]], and unclear procedures for [[double-blind|blinding]].<ref>{{cite journal | author = Adams ME | title = Hype about glucosamine | journal = [[The Lancet|Lancet]] | volume = 354 | issue = 9176 | pages = 353–4 | date = July 1999 | pmid = 10437858 | doi = 10.1016/S0140-6736(99)90040-5 | url = }}</ref><ref>{{cite journal | author = McAlindon TE, LaValley MP, Gulin JP, Felson DT | title = Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis | journal = [[Journal of the American Medical Association]] | volume = 283 | issue = 11 | pages = 1469–75 | date = March 2000 | pmid = 10732937 | doi = 10.1001/jama.283.11.1469 | url = }}</ref> At the same time, several independent studies did not detect any benefit of glucosamine supplementation on osteoarthritis.<ref>{{cite journal | author = Hughes R, Carr A | title = A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee | journal = [[Rheumatology (Oxford, England)]] | volume = 41 | issue = 3 | pages = 279–84 | date = March 2002 | pmid = 11934964 | doi = 10.1093/rheumatology/41.3.279 | url = }}</ref><ref>{{cite journal | author = Cibere J, Kopec JA, Thorne A, Singer J, Canvin J, Robinson DB, Pope J, Hong P, Grant E, Esdaile JM | title = Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis | journal = [[Arthritis and Rheumatism]] | volume = 51 | issue = 5 | pages = 738–45 | date = October 2004 | pmid = 15478160 | doi = 10.1002/art.20697 | author-separator = , }}</ref>

A [[Cochrane Collaboration|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.<ref name="pmid15846645">{{cite journal|last1=Towheed|first1=TE|last2=Maxwell|first2=L|last3=Anastassiades|first3=TP|last4=Shea|first4=B|last5=Houpt|first5=J|last6=Robinson|first6=V|last7=Hochberg|first7=MC|last8=Wells|first8=G|title=Glucosamine therapy for treating osteoarthritis.|journal=The Cochrane database of systematic reviews|date=18 April 2005|issue=2|pages=CD002946|pmid=15846645}}</ref> 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.<ref name=AFP2008>{{cite journal | author = Dahmer S, Schiller RM | title = Glucosamine | journal = American Family Physician | volume = 78 | issue = 4 | pages = 471–6 | date = August 2008 | pmid = 18756654 | url = http://www.aafp.org/afp/20080815/471.html }}</ref> 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.″<ref>{{cite journal | author = Poolsup N, Suthisisang C, Channark P, Kittikulsuth W | title = Glucosamine long-term treatment and the progression of knee osteoarthritis: Systematic review of randomized controlled trials | journal = Annals of Pharmacotherapy | volume = 39 | issue = 6 | pages = 1080–7 | year = 2005 | pmid = 15855241 | doi = 10.1345/aph.1E576 }}</ref>

A systematic review in 2007 found that effect sizes from glucosamine supplementation were highest in industry-funded studies and lowest in independent studies.
<ref>{{cite journal | author = Vlad SC, LaValley MP, McAlindon TE, Felson DT | title = Glucosamine for pain in osteoarthritis; why do trial results differ? | journal = Arthritis & Rheumatism | volume = 56 | issue = 7 | pages = 2267–77 | year = 2007 | pmid = 17599746 | doi = 10.1002/art.22728 }}</ref> 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.<ref>{{cite journal | author = Bruyere O, Reginster JY | title = Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis | journal = Drugs & aging | volume = 24 | issue = 7 | pages = 573–80 | year = 2007 | pmid = 17658908 | doi = 10.2165/00002512-200724070-00005 }}</ref> 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.<ref>{{cite journal | author = Wu D, Huang Y, Gu Y, Fan W | title = Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: A meta-analysis of randomised, double-blind, placebo-controlled trials | journal = International Journal of Clinical Practice | volume = 67 | issue = 6 | pages = 585–94 | year = 2013 | pmid = 23679910 | doi = 10.1111/ijcp.12115 }}</ref>

In 2006, the [[U.S. National Institutes of Health]] (NIH) funded a 24 week, 12.5 million-dollar [[multicenter trial|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).<ref>{{ClinicalTrialsGov|NCT00032890|Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)}}</ref> When the data from both groups were pooled and analyzed, there was no [[statistical significance|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.<ref>{{cite journal | title = The NIH Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) | journal = Journal of pain & palliative care pharmacotherapy | volume = 22 | issue = 1 | pages = 39–43 | year = 2008 | pmid = 19062354 }}</ref> 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.<ref>{{cite journal | author = 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 | title = 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 | journal = Annals of the Rheumatic Diseases | volume = 69 | issue = 8 | pages = 1459–64 | year = 2010 | pmid = 20525840 | pmc = 3086604 | doi = 10.1136/ard.2009.120469 }}</ref>

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.<ref name=GAIT2008>{{cite journal | author = 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 | title = The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial | journal = Arthritis and Rheumatism | volume = 58 | issue = 10 | pages = 3183–91 | date = October 2008 | pmid = 18821708 | pmc = 2836125 | doi = 10.1002/art.23973 | first2 = H | last3 = Finco | last2 = Shi | first3 = MF }}</ref> 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 (0.013mm) as the placebo group (0.166mm), none of the groups experienced joint space narrowing to the degree the researchers expected (0.4mm) 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<ref>{{cite press release|url=http://nccam.nih.gov/news/2008/092908.htm |title=Dietary Supplements Glucosamine and/or Chondroitin Fare No Better than Placebo in Slowing Structural Damage of Knee Osteoarthritis |publisher=National Center for Complementary and Alternative Medicine (NCCAM) |date=2008-09-29 |accessdate=2014-05-20}}</ref> 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.<ref name=GAIT2010>{{cite journal | author = 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 | title = 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 | journal = Arthritis and Rheumatism | volume = 69 | issue = 8 | pages = 1459–64 | date = August 2010 | pmid = 20525840 | pmc = 3086604 | doi = 10.1136/ard.2009.120469 | first2 = H | last3 = Finco | last2 = Shi | first3 = MF }}</ref>

==Using meta-analyses to sort conflicting results==
==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 glucosamne.<ref>{{cite journal | author = Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y, Reginster JY | title = Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a meta-analysis | journal = [[Archives of Internal Medicine]] | volume = 163 | issue = 13 | pages = 1514–22 | date = July 2003 | pmid = 12860572 | doi = 10.1001/archinte.163.13.1514 | url = }}</ref> A 2009 review found little evidence that glucosamine was better than placebo at reversing or restoring degenerative changes to articular cartilage.<ref>{{cite journal | author = Kirkham SG, Samarasinghe RK | title = Review article: Glucosamine | journal = Journal of orthopaedic surgery (Hong Kong) | volume = 17 | issue = 1 | pages = 72–6 | year = 2009 | pmid = 19398798 }}</ref> One published in 2010 in the ''[[British Medical Journal]]'' arrived at the following conclusions:<blockquote>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.<ref>{{cite journal | author = Wandel S, Jüni P, Tendal B, Nüesch E, Villiger PM, Welton NJ, Reichenbach S, Trelle S | title = Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis | journal = British Medical Journal | volume = 341 | issue = sep16 2 | pages = c4675 | year = 2010 | pmid = 20847017 | pmc = 2941572 | doi = 10.1136/bmj.c4675 | quote = Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space }}</ref></blockquote>
Due to the controversy engendered by these results, additional meta-analyses have been undertaken in an attempt to evaluate glucosamne.<ref>{{cite journal | author = Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y, Reginster JY | title = Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a meta-analysis | journal = [[Archives of Internal Medicine]] | volume = 163 | issue = 13 | pages = 1514–22 | date = July 2003 | pmid = 12860572 | doi = 10.1001/archinte.163.13.1514 | url = }}</ref> A 2009 review found little evidence that glucosamine was better than placebo at reversing or restoring degenerative changes to articular cartilage.<ref>{{cite journal | author = Kirkham SG, Samarasinghe RK | title = Review article: Glucosamine | journal = Journal of orthopaedic surgery (Hong Kong) | volume = 17 | issue = 1 | pages = 72–6 | year = 2009 | pmid = 19398798 }}</ref> One published in 2010 in the ''[[British Medical Journal]]'' arrived at the following conclusions:<blockquote>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.<ref>{{cite journal | author = Wandel S, Jüni P, Tendal B, Nüesch E, Villiger PM, Welton NJ, Reichenbach S, Trelle S | title = Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis | journal = British Medical Journal | volume = 341 | issue = sep16 2 | pages = c4675 | year = 2010 | pmid = 20847017 | pmc = 2941572 | doi = 10.1136/bmj.c4675 | quote = Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space }}</ref></blockquote>


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.<ref>{{cite journal | author = Giacovelli G, Rovati LC | title = Glucosamine and osteoarthritis. Conclusions not supported by methods and results | journal = BMJ (Clinical research ed.) | volume = 341 | pages = c6338 | year = 2010 | pmid = 21062886 | doi = 10.1136/bmj.c6338 }}</ref> 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".<ref>{{cite web|url=http://www.bmj.com/rapid-response/2011/11/03/report-bmj-post-publication-review-meeting|title=Report from BMJ post publication review meeting|author=Groves T|year=2010|accessdate=17 Feb 2015}}</ref>
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.<ref>{{cite journal | author = Giacovelli G, Rovati LC | title = Glucosamine and osteoarthritis. Conclusions not supported by methods and results | journal = BMJ (Clinical research ed.) | volume = 341 | pages = c6338 | year = 2010 | pmid = 21062886 | doi = 10.1136/bmj.c6338 }}</ref> The methodological problems with the paper eventually led the editors of the ''BMJ'' to withdraw their support for the conclusions and recommendations of Wandel and colleagues.<ref>{{cite web|url=http://newhope360.com/blog/meta-analysis-claims-its-latest-victim-glucosamine|title=Meta-analysis claims its latest victim: glucosamine|author=MacKay D|publisher=New Hope 360, Penton Media Inc.|website=http://newhope360.com|year=2011|accessdate=14 May 2014}}</ref>


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.<ref name="FDA2004">{{cite web|url=http://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm073400.htm|title=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)|author=Hubbard WK, Associate Commissioner of Policy and Planning|year=2004; update 2012|publisher=United States Department of Health and Human Services, Food and Drug Administration|accessdate=14 May 2014}}</ref>
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.<ref name="FDA2004">{{cite web|url=http://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm073400.htm|title=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)|author=Hubbard WK, Associate Commissioner of Policy and Planning|year=2004; update 2012|publisher=United States Department of Health and Human Services, Food and Drug Administration|accessdate=14 May 2014}}</ref>
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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.<ref>{{cite pmid|24905534}}</ref>
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.<ref>{{cite pmid|24905534}}</ref>

==Summary of results==
Many [[randomized controlled trial]]s have been conducted with mixed results. These trials have been summarized:
* In 2007, Reichenbach ''et al.''<ref name="pmid17438317">{{cite journal | author = Reichenbach S, Sterchi R, Scherer M, Trelle S, Bürgi E, Bürgi U, Dieppe PA, Jüni P | title = Meta-analysis: chondroitin for osteoarthritis of the knee or hip | journal = Ann Intern Med | volume = 146 | issue = 8 | pages = 580–90 | year = 2007 | pmid = 17438317 | pmc = | doi = 10.7326/0003-4819-146-8-200704170-00009}}</ref><ref name="pmid17764135">{{cite journal | author = Lane N | title = Review: based on evidence from higher-quality trials, chondroitin does not reduce pain in knee or hip osteoarthritis | journal = ACP J. Club | volume = 147 | issue = 2 | pages = 44 | year = 2007 | pmid = 17764135 | doi = | url = }}</ref> used explicit methods to conduct and report<ref name="pmid10584742">{{cite journal | author = Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF | title = Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses | journal = Lancet | volume = 354 | issue = 9193 | pages = 1896–900 | year = 1999 | pmid = 10584742 | pmc = | doi = 10.1016/S0140-6736(99)04149-5 }}</ref> a [[systematic review]] of 20 trials and concluded "large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent. Use of chondroitin in routine clinical practice should therefore be discouraged."
* Also in 2007, Bruyere ''et al.''<ref name="pmid17658908">{{cite journal | author = Bruyere O, Reginster JY | title = Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis | journal = Drugs Aging | volume = 24 | issue = 7 | pages = 573–80 | year = 2007 | pmid = 17658908 | pmc = | doi = 10.2165/00002512-200724070-00005 }}</ref> without using explicit methodology for reviewing trials concluded "there is compelling evidence that glucosamine sulfate and chondroitin sulfate may interfere with progression of OA."

The effectiveness of [[glucosamine]] is controversial.<ref name="bestbets.org"/><ref name="pmid22925619">{{cite journal | author = Burdett N, McNeil JD | title = Difficulties with assessing the benefit of glucosamine sulphate as a treatment for osteoarthritis | journal = Int J Evid Based Healthc | volume = 10 | issue = 3 | pages = 222–6 | date = September 2012 | pmid = 22925619 | doi = 10.1111/j.1744-1609.2012.00279.x }}</ref> Most recent reviews found it to be equal to<ref name="pmid20847017">{{cite journal | author = Wandel S, Jüni P, Tendal B, Nüesch E, Villiger PM, Welton NJ, Reichenbach S, Trelle S | title = Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis | journal = BMJ | volume = 341 | issue = | pages = c4675 | year = 2010 | pmid = 20847017 | pmc = 2941572 | doi = 10.1136/bmj.c4675 }}</ref><ref name="pmid23679910">{{cite journal | author = Wu D, Huang Y, Gu Y, Fan W | title = Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: a meta-analysis of randomised, double-blind, placebo-controlled trials | journal = Int. J. Clin. Pract. | volume = 67 | issue = 6 | pages = 585–94 | date = June 2013 | pmid = 23679910 | doi = 10.1111/ijcp.12115 }}</ref> or only slightly better than [[placebo]].<ref name="pmid22091473">{{cite book |author=Chou R, McDonagh MS, Nakamoto E, Griffin J |year=2011 |title=Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review |series=Comparative Effectiveness Reviews |location=Rockville |publisher=[[Agency for Healthcare Research and Quality]] |url=https://www.ncbi.nlm.nih.gov/books/NBK65646/ |pmid=22091473}}{{page needed|date=October 2013}}</ref><ref name="pmid21220090">{{cite journal | author = Miller KL, Clegg DO | title = Glucosamine and chondroitin sulfate | journal = Rheum. Dis. Clin. North Am. | volume = 37 | issue = 1 | pages = 103–18 | date = February 2011 | pmid = 21220090 | doi = 10.1016/j.rdc.2010.11.007 | quote = 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. }}</ref> A difference may exist between glucosamine sulfate and glucosamine hydrochloride, with glucosamine sulfate showing a benefit and glucosamine hydrochloride not.<ref name="pmid22850875">{{cite journal | author = Rovati LC, Girolami F, Persiani S | title = Crystalline glucosamine sulfate in the management of knee osteoarthritis: efficacy, safety, and pharmacokinetic properties | journal = Ther Adv Musculoskelet Dis | volume = 4 | issue = 3 | pages = 167–80 | date = June 2012 | pmid = 22850875 | pmc = 3400104 | doi = 10.1177/1759720X12437753 }}</ref> The [[Osteoarthritis Research Society International]] recommends that glucosamine be discontinued if no effect is observed after six months<ref name="pmid18279766">{{cite journal | author = 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 | title = OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines | journal = Osteoarthr. Cartil. | volume = 16 | issue = 2 | pages = 137–62 | date = February 2008 | pmid = 18279766 | doi = 10.1016/j.joca.2007.12.013 }}</ref> and the [[National Institute of Clinical Excellence]] no longer recommends its use<ref name=NICE>{{cite web | author = Conaghan P | title = Osteoarthritis — National clinical guideline for care and management in adults | url=http://www.nice.org.uk/nicemedia/pdf/CG059FullGuideline.pdf | format = PDF| accessdate = 2008-04-29 }}</ref> although the Arthritis Foundation compares the effectiveness of glucosamine to traditional NSAID therapy.<ref>http://www.arthritistoday.org/arthritis-treatment/natural-and-alternative-treatments/supplements-and-herbs/supplement-guide/glucosamine.php</ref> Despite the difficulty in determining the efficacy of glucosamine, it remains a viable treatment option according to some experts.<ref name="pmid22293240">{{cite journal | author = Henrotin Y, Mobasheri A, Marty M | title = Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis? | journal = Arthritis Res. Ther. | volume = 14 | issue = 1 | page = 201 | year = 2012 | pmid = 22293240 | pmc = 3392795 | doi = 10.1186/ar3657 }}</ref>

[[Chondroitin sulfate|Chondroitin]] is not recommended as a treatment for [[osteoarthritis]].<ref name="pmid17438317">{{cite journal | author = Reichenbach S, Sterchi R, Scherer M, Trelle S, Bürgi E, Bürgi U, Dieppe PA, Jüni P | title = Meta-analysis: chondroitin for osteoarthritis of the knee or hip | journal = Annals of Internal Medicine | volume = 146 | issue = 8 | pages = 580–90 | date = April 2007 | pmid = 17438317 | doi = 10.7326/0003-4819-146-8-200704170-00009 }}</ref>

==GAIT trial==
The major trial included in the two reviews above was the Glucosamine/Chondroitin Arthritis Intervention, or GAIT Trial.<ref name="pmid16495392">{{cite journal | author = Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, Bradley JD, Bingham CO, Weisman MH, Jackson CG, Lane NE, Cush JJ, Moreland LW, Schumacher HR, Oddis CV, Wolfe F, Molitor JA, Yocum DE, Schnitzer TJ, Furst DE, Sawitzke AD, Shi H, Brandt KD, Moskowitz RW, Williams HJ | title = Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis | journal = N Engl J Med | volume = 354 | issue = 8 | pages = 795–808 | year = 2006 | pmid = 16495392 | pmc = | doi = 10.1056/NEJMoa052771 }}</ref><ref name="pmid17213128">{{cite journal | author = Baime MJ | title = Glucosamine and chondroitin sulphate did not improve pain in osteoarthritis of the knee | journal = Evid Based Med | volume = 11 | issue = 4 | pages = 115 | year = 2006 | pmid = 17213128 | doi = 10.1136/ebm.11.4.115 | url = }}</ref><ref name="pmid16813365">{{cite journal | author = Baime MJ | title = Glucosamine and chondroitin sulfate did not improve pain in osteoarthritis of the knee | journal = ACP J. Club | volume = 145 | issue = 1 | pages = 17 | year = 2006 | pmid = 16813365 | doi = | url = }}</ref> GAIT was funded by the [[National Institutes of Health]] to test the effects of chondroitin and glucosamine on osteoarthritis of the knee. This [[multicenter trial|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.<ref name="pmid20525840">{{cite journal | author = 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 | title = 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 | journal = Ann. Rheum. Dis. | volume = 69 | issue = 8 | pages = 1459–64 | year = 2010 | pmid = 20525840 | pmc = 3086604 | doi = 10.1136/ard.2009.120469 }}</ref>

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 osteoarthiritic pain in the overall group of osteoarthritis patients, though it may be an effective treatment for those suffering from moderate-to-severe pain.<ref>{{cite web|url=http://nccam.nih.gov/research/results/gait/qa.htm#c1 |title=Questions and Answers: NIH Glucosamine/Chondroitin Arthritis Intervention Trial Primary Study |publisher=National Center for Complementary and Alternative Medicine (NCCAM) |date=October 2008 |accessdate=2014-05-20}}</ref>

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.<ref name=GAIT2008>{{cite journal | author = 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 | title = The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial | journal = Arthritis Rheum. | volume = 58 | issue = 10 | pages = 3183–91 | date = October 2008 | pmid = 18821708 | pmc = 2836125 | doi = 10.1002/art.23973 | first2 = Helen | last3 = Finco | last2 = Shi | first3 = Martha F. }}</ref> 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.<ref>http://nccam.nih.gov/news/2008/092908.htm</ref>

In another two-year follow-up study, there was no significant pain reduction or improved function when compared to either inactive placebo or celecoxib <ref name=GAIT2010>{{cite journal | author = 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 | title = 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 | journal = Arthritis Rheum. | volume = 69 | issue = 8 | pages = 1459–64 | date = August 2010 | pmid = 20525840 | pmc = 3086604 | doi = 10.1136/ard.2009.120469 }}</ref><ref name="pmid20525840">{{cite journal | author = 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 | title = 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 | journal = Ann. Rheum. Dis. | volume = 69 | issue = 8 | pages = 1459–64 | year = 2010 | pmid = 20525840 | pmc = 3086604 | doi = 10.1136/ard.2009.120469 }}</ref> Some of the researchers' ties to Pfizer (which makes celecoxib) have brought into question the validity of the study.<ref>{{cite web|url=http://www.huffingtonpost.com/jay-gordon/did-you-understand-the-ar_b_16399.html |author=Jay Gordon, MD |title=Did You Understand the Arthritis Study? I Did |publisher=Huffingtonpost.com |date=2006-02-26 |accessdate=2014-05-20}}</ref>

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.<ref>http://www.arthritistoday.org/news/glucosamine-chondroitin-ineffective.php</ref>

==Development of guidelines based on these results==
[[Clinical practice guideline]]s based on trials prior to publication of the negative review by Reichenbach<ref name="pmid17438317"/> and the equivocal GAIT trial<ref name="pmid16495392"/> 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).<ref name="pmid18279766">{{cite journal | author = 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 | title = OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines | journal = Osteoarthritis Cartilage | volume = 16 | issue = 2 | pages = 137–62 | year = 2008 | pmid = 18279766 | pmc = | doi = 10.1016/j.joca.2007.12.013 }}</ref> 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.<ref name="pmid14644851">{{cite journal | author = Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, Gunther K, Hauselmann H, Herrero-Beaumont G, Kaklamanis P, Lohmander S, Leeb B, Lequesne M, Mazieres B, Martin-Mola E, Pavelka K, Pendleton A, Punzi L, Serni U, Swoboda B, Verbruggen G, Zimmerman-Gorska I, Dougados M | title = EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT) | journal = Ann Rheum Dis | volume = 62 | issue = 12 | pages = 1145–55 | year = 2003 | pmid = 14644851 | pmc = 1754382 | doi = 10.1136/ard.2003.011742 | url = }}</ref>

==References==
{{Reflist|35em}}

==External links==
*[http://nccam.nih.gov/research/results/gait GAIT study]

[[Category:Clinical trials]]
[[Category:Dietary supplements]]

Revision as of 03:24, 18 February 2015

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.

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.[11][12] At the same time, several independent studies did not detect any benefit of glucosamine supplementation on osteoarthritis.[13][14]

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.[15] 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.[16] 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.″[17]

A systematic review in 2007 found that effect sizes from glucosamine supplementation were highest in industry-funded studies and lowest in independent studies. [18] 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.[19] 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.[20]

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).[21] 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.[22] 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.[23]

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.[24] 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 (0.013mm) as the placebo group (0.166mm), none of the groups experienced joint space narrowing to the degree the researchers expected (0.4mm) 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[25] 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.[26]

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 glucosamne.[27] A 2009 review found little evidence that glucosamine was better than placebo at reversing or restoring degenerative changes to articular cartilage.[28] 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.[29]

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.[30] The methodological problems with the paper eventually led the editors of the BMJ to withdraw their support for the conclusions and recommendations of Wandel and colleagues.[31]

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.[32]

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.[33]

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. [34]

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.[35]

Summary of results

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

  • In 2007, Reichenbach et al.[36][37] used explicit methods to conduct and report[38] a systematic review of 20 trials and concluded "large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent. Use of chondroitin in routine clinical practice should therefore be discouraged."
  • Also in 2007, Bruyere et al.[39] without using explicit methodology for reviewing trials concluded "there is compelling evidence that glucosamine sulfate and chondroitin sulfate may interfere with progression of OA."

The effectiveness of glucosamine is controversial.[1][40] Most recent reviews found it to be equal to[41][42] or only slightly better than placebo.[43][44] A difference may exist between glucosamine sulfate and glucosamine hydrochloride, with glucosamine sulfate showing a benefit and glucosamine hydrochloride not.[45] The Osteoarthritis Research Society International recommends that glucosamine be discontinued if no effect is observed after six months[46] 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.[47] Despite the difficulty in determining the efficacy of glucosamine, it remains a viable treatment option according to some experts.[48]

Chondroitin is not recommended as a treatment for osteoarthritis.[36]

GAIT trial

The major trial included in the two reviews above was the Glucosamine/Chondroitin Arthritis Intervention, or GAIT Trial.[49][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 osteoarthiritic 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.[24] 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 [26][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]

Development of guidelines based on these results

Clinical practice guidelines based on trials prior to publication of the negative review by Reichenbach[36] and the equivocal GAIT trial[49] 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).[46] 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.[57]

References

  1. ^ a b The effects of Glucosamine Sulphate on OA of the knee joint. BestBets.
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ "Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review [Internet]". Agency for Healthcare Research and Quality (US). Oct 2011. PMID 22091473. {{cite journal}}: Cite journal requires |journal= (help)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: Unknown parameter |author-separator= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ a b Conaghan P. "Osteoarthritis — National clinical guideline for care and management in adults" (PDF). Retrieved 2008-04-29.
  10. ^ Henrotin Y, Mobasheri A, Marty M (Jan 30, 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.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
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  19. ^ 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.
  20. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ Clinical trial number NCT00032890 for "Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)" at ClinicalTrials.gov
  22. ^ "The NIH Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)". Journal of pain & palliative care pharmacotherapy. 22 (1): 39–43. 2008. PMID 19062354.
  23. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  25. ^ "Dietary Supplements Glucosamine and/or Chondroitin Fare No Better than Placebo in Slowing Structural Damage of Knee Osteoarthritis" (Press release). National Center for Complementary and Alternative Medicine (NCCAM). 2008-09-29. Retrieved 2014-05-20.
  26. ^ a b 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.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "GAIT2010" was defined multiple times with different content (see the help page).
  27. ^ Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y, Reginster JY (July 2003). "Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a meta-analysis". Archives of Internal Medicine. 163 (13): 1514–22. doi:10.1001/archinte.163.13.1514. PMID 12860572.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ Kirkham SG, Samarasinghe RK (2009). "Review article: Glucosamine". Journal of orthopaedic surgery (Hong Kong). 17 (1): 72–6. PMID 19398798.
  29. ^ 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{{cite journal}}: CS1 maint: multiple names: authors list (link)
  30. ^ 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.
  31. ^ MacKay D (2011). "Meta-analysis claims its latest victim: glucosamine". http://newhope360.com. New Hope 360, Penton Media Inc. Retrieved 14 May 2014. {{cite web}}: External link in |website= (help)
  32. ^ Hubbard WK, Associate Commissioner of Policy and Planning (2004; update 2012). "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. {{cite web}}: |author= has generic name (help); Check date values in: |year= (help)CS1 maint: year (link)
  33. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)/
  34. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  35. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 24905534, please use {{cite journal}} with |pmid=24905534 instead.
  36. ^ a b c 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.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid17438317" was defined multiple times with different content (see the help page).
  37. ^ 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.
  38. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  39. ^ 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.
  40. ^ 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.
  41. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  42. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  43. ^ 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.{{cite book}}: CS1 maint: multiple names: authors list (link)[page needed]
  44. ^ 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.
  45. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  46. ^ a b 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.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid18279766" was defined multiple times with different content (see the help page).
  47. ^ http://www.arthritistoday.org/arthritis-treatment/natural-and-alternative-treatments/supplements-and-herbs/supplement-guide/glucosamine.php
  48. ^ Henrotin Y, Mobasheri A, Marty M (2012). "Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis?". Arthritis Res. Ther. 14 (1): 201. doi:10.1186/ar3657. PMC 3392795. PMID 22293240.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  49. ^ a b Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, Bradley JD, Bingham CO, Weisman MH, Jackson CG, Lane NE, Cush JJ, Moreland LW, Schumacher HR, Oddis CV, Wolfe F, Molitor JA, Yocum DE, Schnitzer TJ, Furst DE, Sawitzke AD, Shi H, Brandt KD, Moskowitz RW, Williams HJ (2006). "Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis". N Engl J Med. 354 (8): 795–808. doi:10.1056/NEJMoa052771. PMID 16495392.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  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. ^ a b 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  53. ^ "Questions and Answers: NIH Glucosamine/Chondroitin Arthritis Intervention Trial Primary Study". National Center for Complementary and Alternative Medicine (NCCAM). October 2008. Retrieved 2014-05-20.
  54. ^ http://nccam.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
  57. ^ Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, Gunther K, Hauselmann H, Herrero-Beaumont G, Kaklamanis P, Lohmander S, Leeb B, Lequesne M, Mazieres B, Martin-Mola E, Pavelka K, Pendleton A, Punzi L, Serni U, Swoboda B, Verbruggen G, Zimmerman-Gorska I, Dougados M (2003). "EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT)". Ann Rheum Dis. 62 (12): 1145–55. doi:10.1136/ard.2003.011742. PMC 1754382. PMID 14644851.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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