Clinical trials on glucosamine and chondroitin

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compared to a placebo or celecoxib. As in the original GAIT study, this follow-up study was confounded by unexpected results that made it 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 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.

324:

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. 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.

394:, commented on his website on the evidence concerning glucosamine-based supplements for humans and animals, including a list of studies since 2009. As at 2016 he concludes that some degree of evidence exists for benefits from supplements, and that " oral joint supplements have little or no efficacy, we might consider that feeding them at least allows owners to feel they are doing something positive for their animals and that any improvement may be due to the placebo effect and therefore there is little risk". However against this he highlights concerns of overdosing, that shark cartilage products may promote rather than reduce inflammation, and produces have been found to be contaminated with 402:...based on simple mistakes such as lack of control groups, lack of blinding (use of a placebo), insufficient power (not enough subjects to demonstrate a significant effect even if one was present) and inappropriate statistics (for example, multiple t-tests without correction or use of parametric statistics on non-normally distributed data). Finally, if a study satisfies all the required criteria, we may still end up with a statistically significant but biologically insignificant finding; for example, a significant increase in range of motion of a joint by 1%... 292:. 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. 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. 628:). The combination treatment did result in a small but statistically significant (0.1 mm) 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. 132: 407:...research and development investment will at most be modest and in the majority of cases, non-existent. The efficacy of different oral joint supplements will depend on the specific ingredients used and their individual efficacy, the number of different ingredients, the level at which the active ingredients are to be fed, whether the finished product on the shelf actually meets the label claims". 66: 25: 602:

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

594:

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

586:

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

561:

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

416:

Due to the controversy engendered by these results, additional meta-analyses have been undertaken in an attempt to evaluate glucosamine. A 2009 review found little evidence that glucosamine was better than placebo at reversing or restoring degenerative changes to articular cartilage. One published in

376:

existed, or there was inadequately controlled control group, or inadequate baseline data, meaning that reliable conclusion could not be drawn about any purported benefits actually resulting from the product. Controls are a fundamental part of such studies, and the authors comment that "many cases of

427:

Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or affect the 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

224:

as a significant issue in such studies, in that most studies were undertaken by manufacturers, on products they already produced commercially, and they were usually undertaken to support claims of benefits which could be used to market the product. More recently, other reviews found little evidence

610:

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

459:

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

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European Equine Nutrition & Health Congress (2008) concluded that research into glucosamine-based supplements, for horses at least, has so far "failed to produce substantial evidence for the functionality of these products in this species", and that almost every study they had examined had been

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The authors observed that existing studies of glucosamine products are "usually on products already commercially available and often seeking evidence for efficacy ... but most do not meet a quality standard that provides sufficient confidence in the results". A paper by the same authors at the 4th

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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

323:

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

440:

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

275:

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. However, when the low quality and older studies were discounted and only those

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A systematic review in 2007 found that effect sizes from glucosamine supplementation were highest in industry-funded studies and lowest in independent studies, which may lead one to believe that bias is responsible for the heterogeneity of the clinical study findings regarding the efficacy of

215:

Some of the evidence for the effectiveness of glucosamine is disputed. A 2008–2009 review of all known studies of glucosamine supplements for horses, for example, found that almost all studies had failed to meet usual standards and were fatally compromised by basic errors in their execution,

2749:

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).

354:

compromised to varying degrees by numerous experimental factors including underpowered studies, unbalanced research design, non-existent or inappropriate controls, unclear or non-representative experimental conditions (i.e. models) and uncharacterized or complex, heterogeneous experimental

1167:

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).

562:

2006 – prior to the GAIT trial). 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.

2109:"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)" 463:

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

603:

to a placebo. 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.

606:

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

538:

no longer recommends its use although the Arthritis Foundation compares the effectiveness of glucosamine to traditional NSAID therapy. Despite the difficulty in determining the efficacy of glucosamine, it remains a viable treatment option according to some experts.

347:(studies are funded by manufacturers with an incentive to show that benefits exist and commercial pressures that disfavor larger and more thorough studies which would be expensive) and fatal flaws in the design of the study which undermined the conclusions. 381:

tested in this study had a good chance of being rejected even in the absence of any treatment" and that "having no such controls leaves the authors and readers with no way in which to tease out effects of growth and/or exercise from effects of

288:

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

619:

The Long-term Evaluation of Glucosamine Sulfate (LEGS) study ran between 2007 and 2011, to study whether glucosamine sulfate, chondroitin sulfate or a combination of both are effective treatments for chronic knee pain due to

481:

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

2752:"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)" 510:

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

1789:

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 (October 2008).

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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".

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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

1736:

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).

2518:

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".

884:

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".

38: 1625:

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".

2643:

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).

1041:

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).

284:, 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." 1881: 1484:

Poolsup N, Suthisisang C, Channark P, Kittikulsuth W (2005). "Glucosamine long-term treatment and the progression of knee osteoarthritis: Systematic review of randomized controlled trials".

448:(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 590:

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

196:. These compounds are commonly marketed as nutritional supplements and numerous 'soft therapeutic claims' are made about their health benefits - especially in aging populations. Since 2988:

M., Fransen (May 2015). "Glucosamine and chondroitin for knee osteoarthritis: a double-blind randomised placebo-controlled clinical trial evaluating single and combination regimens".

518:

without using explicit methodology for reviewing trials concluded "there is compelling evidence that glucosamine sulfate and chondroitin sulfate may interfere with progression of OA."

343:

reviewed all existing studies on the efficacy of glucosamine treatments and supplements for horses, and concluded negatively, that these studies were usually fatally flawed due to

1739:"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" 1262:

McAlindon TE, LaValley MP, Gulin JP, Felson DT (March 2000). "Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis".

2684: 83: 44: 2236:"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" 240:

no longer recommends its use. Despite the difficulty in determining the efficacy of glucosamine, it remains a viable treatment option. Similar trials have been done with

1792:"The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial" 574:

to test the effects of chondroitin and glucosamine on osteoarthritis of the knee. It reported initially in 2006, with further findings in 2008 and again in 2010. This

624:. 502 patients (from 605 enrolled) were followed for two years. The main outcomes were disease progression, as measured by joint space narrowing (JSN) and knee pain ( 530:. A difference may exist between glucosamine sulfate and glucosamine hydrochloride, with glucosamine sulfate showing a benefit and glucosamine hydrochloride not. The 468:, specifically the sulfate form, has disease-modifying effects and provides symptomatic relief for at least some individuals suffering from OA. The report classified 980:

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.

436:

meta-analysis have been criticized for poor methodology by including too many dissimilar studies in their analysis. In a subsequent discussion the editors of the

486:

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.

531: 233: 767:

Pearson W, Lindinger M (September 2009). "Low quality of evidence for glucosamine-based nutraceuticals in equine joint disease: review of in vivo studies".

1264: 2569: 535: 237: 1885: 570:

The major trial included in the two reviews above was the Glucosamine/Chondroitin Arthritis Intervention, or GAIT Trial. GAIT was funded by the

2030:

Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space

823:

Critical review of research evaluating glucosamine-based nutraceuticals for treatment of joint pain and degenerative joint disease in horses

727:

Burdett N, McNeil JD (September 2012). "Difficulties with assessing the benefit of glucosamine sulphate as a treatment for osteoarthritis".

2335:

Lane N (2007). "Review: based on evidence from higher-quality trials, chondroitin does not reduce pain in knee or hip osteoarthritis".

398:. He also states that "on closer scrutiny" studies continue to raise concerns for similar reasons as described in the 2008/2009 study: 1686:

National Center for Complementary Alternative Medicine (2008). "The NIH Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)".

296: 2645:"OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines" 1043:"OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines" 2921:"Dietary Supplements Glucosamine and/or Chondroitin Fare No Better than Placebo in Slowing Structural Damage of Knee Osteoarthritis" 1840:"Dietary Supplements Glucosamine and/or Chondroitin Fare No Better than Placebo in Slowing Structural Damage of Knee Osteoarthritis" 167: 113: 52: 220:

or baseline measurements, very small sample sizes, and ignoring prior research or self-evident omissions. The authors highlighted

76: 3031: 661: 1115: 362:

Not verifying whether the quantities and condition of active ingredients was as described ("a well-known characteristic of the

1527:

Vlad SC, LaValley MP, McAlindon TE, Felson DT (2007). "Glucosamine for pain in osteoarthritis; why do trial results differ?".

264:. At the same time, several independent studies did not detect any benefit of glucosamine supplementation on osteoarthritis. 2593:"Crystalline glucosamine sulfate in the management of knee osteoarthritis: efficacy, safety, and pharmacokinetic properties" 2292:, Trelle S, Bürgi E, Bürgi U, Dieppe PA, Jüni P (2007). "Meta-analysis: chondroitin for osteoarthritis of the knee or hip". 1309:"A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee" 994:"Crystalline glucosamine sulfate in the management of knee osteoarthritis: efficacy, safety, and pharmacokinetic properties" 336:

Glucosamine supplements are widely used for both human and animal joint conditions, at times supported by clinical studies.

369:

Ignoring known research in the field and standard precautions, such as accounting for quantities available in blood plasma;

2086: 1912: 1443: 571: 256:

were later deemed to be of poor quality due to shortcomings in their methods, including small size, short duration, poor

3075: 2108: 445: 2471:"Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis" 1992:"Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis" 837:"Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis" 558: 495: 257: 95: 2042:

Giacovelli G, Rovati LC (2010). "Glucosamine and osteoarthritis. Conclusions not supported by methods and results".

1393:

Towheed, TE; Maxwell, L; Anastassiades, TP; Shea, B; Houpt, J; Robinson, V; Hochberg, MC; Wells, G (18 April 2005).

1350:

Cibere J, Kopec JA, Thorne A, Singer J, Canvin J, Robinson DB, Pope J, Hong P, Grant E, Esdaile JM (October 2004).

236:

advises arthritis sufferers to discontinue glucosamine therapy if they notice no benefit within six months and the

2935: 432:

These conclusions, however, are not shared by all researchers in the field. Specifically, the authors of the 2010

91: 583: 611:

power to determine whether glucosamine and chondroitin are effective treatments for knee osteoarthritis or not.

280:

treatment. A second 2005 review of glucosamine clinical trials reached a different conclusion. Published in the

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and chondroitin sulfate and reduced risk of osteoarthritis, joint degeneration, and cartilage deterioration.

2799:

Baime MJ (2006). "Glucosamine and chondroitin sulphate did not improve pain in osteoarthritis of the knee".

1908:"Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a meta-analysis" 419: 2842:

Baime MJ (2006). "Glucosamine and chondroitin sulfate did not improve pain in osteoarthritis of the knee".

1313: 930:"Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review [Internet]" 825:– Pearson and Lindinge, Proceedings of the 4th European Equine Nutrition & Health Congress, April 2008 595:

results indicate that glucosamine and chondroitin do not effectively relieve pain in the overall group of

268: 212:

symptoms. Authoritative opinions on the actual therapeutic value of these compounds have been very mixed.

2185:"Glucosamine for Osteoarthritis: Biological Effects, Clinical Efficacy, and Safety on Glucose Metabolism" 2700:"Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis?" 2133:"Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis?" 1111:"Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis?" 685: 1352:"Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis" 835:

Wandel S, Jüni P, Tendal B, Nüesch E, Villiger PM, Welton NJ, Reichenbach S, Trelle S (Sep 16, 2010).

311:

as a treatment for knee-pain in two groups of patients with osteoarthritis of the knee: Patients with

599:

patients, though it may be an effective treatment for those suffering from moderate-to-severe pain.

642: 637: 625: 542: 455:

Also in 2012, a review highlighted the ongoing conflicting clinical data regarding the efficacy of

387: 377:

lameness ... improve over time without any treatment at all ... which suggests that the

304: 3013: 2867: 2824: 2544: 2451: 2396: 2317: 2265: 2067: 1711: 1674: 1650: 1607: 1552: 1509: 1289: 1244: 1199: 910: 792: 460:

of subjects who failed to respond to treatment, thereby questioning the benefit of glucosamine.

2900:"Questions and Answers: NIH Glucosamine/Chondroitin Arthritis Intervention Trial Primary Study" 216:

including failure to test whether active ingredients were as stated, lack of adequate (or any)

3005: 2859: 2816: 2781: 2731: 2666: 2622: 2573: 2536: 2500: 2469:

Wandel S, Jüni P, Tendal B, Nüesch E, Villiger PM, Welton NJ, Reichenbach S, Trelle S (2010).

2443: 2388: 2352: 2309: 2257: 2216: 2164: 2059: 2021: 1990:

Wandel S, Jüni P, Tendal B, Nüesch E, Villiger PM, Welton NJ, Reichenbach S, Trelle S (2010).

1972: 1931: 1821: 1768: 1703: 1642: 1599: 1544: 1501: 1455: 1424: 1375: 1332: 1281: 1236: 1191: 1170:"Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis" 1144: 1086: 1064: 1023: 971: 933: 902: 866: 784: 744: 575: 534:

recommends that glucosamine be discontinued if no effect is observed after six months and the

507: 344: 300: 221: 201: 181: 1842:(Press release). National Center for Complementary and Integrative Health (NCCIH). 2008-09-29 587:

than those taking glucosamine, glucosamine and chondroitin combined or the inactive placebo.

2997: 2851: 2808: 2771: 2763: 2721: 2711: 2656: 2612: 2604: 2528: 2490: 2482: 2435: 2427: 2380: 2344: 2305: 2301: 2247: 2206: 2196: 2154: 2144: 2051: 2011: 2003: 1962: 1921: 1811: 1803: 1758: 1750: 1695: 1634: 1591: 1583: 1536: 1493: 1414: 1406: 1365: 1322: 1273: 1228: 1181: 1134: 1124: 1054: 1013: 1005: 963: 894: 856: 848: 776: 736: 2416:"Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis" 1572:"Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis" 526:

is controversial. Most recent reviews found it to be equal to or only slightly better than

378: 232:

Glucosamine sulfate may be efficacious in ways that glucosamine hydrochloride is not. The

822: 557:

Prior to publication of the negative review by Reichenbach and the equivocal GAIT trial,

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In general, the clinical trials of the mid-1990s that furnished positive results showing

145:

Please help update this article to reflect recent events or newly available information.

2899: 2776: 2751: 2726: 2699: 2617: 2592: 2495: 2470: 2289: 2234:

Eriksen, P; Bartels, E. M.; Altman, R. D.; Bliddal, H; Juhl, C; Christensen, R (2014).

2211: 2184: 2159: 2132: 2016: 1991: 1816: 1791: 1763: 1738: 1419: 1394: 1139: 1110: 1018: 993: 861: 836: 621: 596: 546: 483: 2384: 1882:""Equine joint supplements – what scientific evidence is there to support their use?"" 1232: 3064: 2565:

Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review

2431: 2269: 2111:. United States Department of Health and Human Services, Food and Drug Administration 1715: 1587: 740: 373: 363: 272: 217: 3017: 3001: 2828: 2548: 2400: 2071: 1654: 1556: 1513: 1327: 1308: 1293: 1248: 914: 2871: 2455: 2321: 1611: 1410: 1203: 579: 261: 2970: 1669: 796: 2855: 2348: 1926: 1907: 2902:. National Center for Complementary and Integrative Health (NCCIH). October 2008 1906:

Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y, Reginster JY (July 2003).

1087:"Osteoarthritis – National clinical guideline for care and management in adults" 523: 469: 465: 456: 449: 253: 241: 197: 189: 185: 2661: 2644: 2563: 1967: 1950: 1169: 1059: 1042: 929: 319:(n=354). When the data from both groups were pooled and analyzed, there was no 276:

using the highest-quality design were considered, there was no difference from

2885: 1699: 1219: 967: 711: 3055: 2608: 1277: 1009: 780: 2920: 2767: 1839: 1754: 1463: 954:

Miller KL, Clegg DO (February 2011). "Glucosamine and chondroitin sulfate".

591: 472:

as a Symptomatic Slow Acting Drugs for Osteoarthritis (SYSADOA) and states:

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have been conducted with mixed results. These trials have been summarized:

2201: 2812: 1186: 307:, glucosamine hydrochloride, chondroitin/glucosamine in combination, and 3032:"The LEGS Study: Do Glucosamine and Chondroitin Show Promise for Pain?" 2532: 1638: 898: 527: 395: 391: 277: 226: 2486: 2439: 2252: 2235: 2055: 2007: 1807: 1595: 1540: 1497: 1370: 1351: 852: 582:, six-month-long trial found that glucosamine plus chondroitin had no 332:

Quality of clinical studies of glucosamine and chondroitin supplements

1673:

for "Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)" at

386:

David Marlin, a past senior scientist and head of physiology at the

225:

that glucosamine and chondroitin supplements were any better than a

208:, ingesting glucosamine might nourish joints, and thereby alleviate 98:. Statements consisting only of original research should be removed. 2716: 2149: 1129: 2183:

Salazar J, Bello L, Chávez M, Añez R, Rojas J, Bermúdez V (2014).

1860: 125: 59: 18: 2886:"Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)" 662:"Glucosamine Chondroitin Supplement: Uses & Side Effects" 712:

The effects of Glucosamine Sulphate on OA of the knee joint

180:

A significant amount of research has been performed on

2971:"The Long-term Evaluation of Glucosamine Sulphate Study" 928:

Chou R, McDonagh MS, Nakamoto E, Griffin J (Oct 2011).

87: 2685:"Glucosamine for Arthritis | Glucosamine Sulfate" 2562:Chou R, McDonagh MS, Nakamoto E, Griffin J (2011). 1688:

Journal of Pain and Palliative Care Pharmacotherapy

932:. Agency for Healthcare Research and Quality (US). 84:

Talk:Clinical trials on glucosamine and chondroitin

729:International Journal of Evidence-Based Healthcare 366:industry is one of inconsistent quality control"); 2087:"Report from BMJ post publication review meeting" 1395:"Glucosamine therapy for treating osteoarthritis" 1109:Henrotin Y, Mobasheri A, Marty M (Jan 30, 2012). 204:, and glycosaminoglycans are major components of 2568:. Comparative Effectiveness Reviews. Rockville: 1217:Adams ME (July 1999). "Hype about glucosamine". 2936:"Did You Understand the Arthritis Study? I Did" 2638: 2636: 2591:Rovati LC, Girolami F, Persiani S (June 2012). 2283: 2281: 2279: 1731: 1729: 1727: 1725: 1162: 1160: 1158: 998:Therapeutic Advances in Musculoskeletal Disease 949: 947: 405: 400: 992:Rovati LC, Girolami F, Persiani S (Jun 2012). 818: 816: 814: 812: 810: 808: 806: 722: 720: 707: 705: 506:used explicit methods to conduct and report a 532:Osteoarthritis Research Society International 234:Osteoarthritis Research Society International 8: 2957:"Glucosamine and Chrondroitin for Arthritis" 299:(NIH) funded a 24-week, 12.5 million-dollar 1784: 1782: 1399:The Cochrane Database of Systematic Reviews 1265:Journal of the American Medical Association 53:Learn how and when to remove these messages 2570:Agency for Healthcare Research and Quality 1955:Journal of Orthopaedic Surgery (Hong Kong) 1876: 1874: 1872: 1870: 1627:International Journal of Clinical Practice 887:International Journal of Clinical Practice 536:National Institute for Clinical Excellence 238:National Institute for Clinical Excellence 2775: 2725: 2715: 2698:Henrotin Y, Mobasheri A, Marty M (2012). 2660: 2616: 2494: 2251: 2210: 2200: 2158: 2148: 2131:Henrotin Y, Mobasheri A, Marty M (2012). 2015: 1966: 1925: 1815: 1762: 1418: 1369: 1326: 1185: 1138: 1128: 1058: 1017: 860: 762: 760: 758: 168:Learn how and when to remove this message 114:Learn how and when to remove this message 303:(the GAIT trial) to study the effect of 2306:10.7326/0003-4819-146-8-200704170-00009 1080: 1078: 653: 545:is not recommended as a treatment for 1442:Dahmer S, Schiller RM (August 2008). 423:arrived at the following conclusions: 7: 1949:Kirkham SG, Samarasinghe RK (2009). 372:In many of the studies, no reliable 82:Relevant discussion may be found on 553:Guidelines prior to recent studies 297:U.S. National Institutes of Health 14: 229:or at most only slightly better. 34:This article has multiple issues. 2990:Annals of the Rheumatic Diseases 2704:Arthritis Research & Therapy 2432:10.2165/00002512-200724070-00005 2414:Bruyere O, Reginster JY (2007). 2137:Arthritis Research & Therapy 1588:10.2165/00002512-200724070-00005 1570:Bruyere O, Reginster JY (2007). 1116:Arthritis Research & Therapy 741:10.1111/j.1744-1609.2012.00279.x 444:Nevertheless, in 2012, the U.S. 358:The most common flaws included: 130: 64: 23: 3002:10.1136/annrheumdis-2013-203954 2107:Hubbard, WK (October 7, 2004). 1307:Hughes R, Carr A (March 2002). 1085:Conaghan P (27 February 2008). 42:or discuss these issues on the 1411:10.1002/14651858.CD002946.pub2 1: 2934:Jay Gordon, MD (2006-02-26). 2385:10.1016/S0140-6736(99)04149-5 2240:Arthritis Care & Research 1951:"Review article: Glucosamine" 1913:Archives of Internal Medicine 1328:10.1093/rheumatology/41.3.279 1233:10.1016/S0140-6736(99)90040-5 572:National Institutes of Health 260:, and unclear procedures for 2856:10.7326/ACPJC-2006-145-1-017 2349:10.7326/ACPJC-2007-147-2-044 1927:10.1001/archinte.163.13.1514 559:clinical practice guidelines 496:randomized controlled trials 446:Food and Drug Administration 315:(n=1229), and patients with 2044:BMJ (Clinical Research Ed.) 1861:"David Marlin » About" 841:BMJ (Clinical Research Ed.) 94:the claims made and adding 3092: 2662:10.1016/j.joca.2007.12.013 2597:Ther Adv Musculoskelet Dis 2288:Reichenbach S, Sterchi R, 1968:10.1177/230949900901700116 1529:Arthritis & Rheumatism 1060:10.1016/j.joca.2007.12.013 956:Rheum. Dis. Clin. North Am 615:The LEGS study (2007–2011) 301:multicenter clinical trial 1700:10.1080/15360280801989351 1486:Annals of Pharmacotherapy 1448:American Family Physician 968:10.1016/j.rdc.2010.11.007 584:statistically significant 321:statistically significant 282:Annals of Pharmacotherapy 139:This article needs to be 2609:10.1177/1759720X12437753 1796:Arthritis and Rheumatism 1357:Arthritis and Rheumatism 1278:10.1001/jama.283.11.1469 1010:10.1177/1759720X12437753 781:10.2746/042516409x424153 2768:10.1136/ard.2003.011742 1996:British Medical Journal 1755:10.1136/ard.2009.120469 420:British Medical Journal 317:moderate to severe pain 192:, for the treatment of 1667:Clinical trial number 578:, placebo-controlled, 566:GAIT trial (2006–2010) 514:Also in 2007, Bruyere 479: 430: 409: 404: 522:The effectiveness of 502:In 2007, Reichenbach 474: 425: 258:analysis of drop-outs 2938:. Huffingtonpost.com 2813:10.1136/ebm.11.4.115 1187:10.1056/NEJMoa052771 339:However a 2008/2009 254:glucosamine efficacy 3076:Dietary supplements 2521:Int. J. Clin. Pract 2202:10.1155/2014/432463 643:N-Acetylglucosamine 638:Chondroitin sulfate 412:Further metastudies 388:Animal Health Trust 305:chondroitin sulfate 200:is a precursor for 2975:ClinicalTrials.gov 2649:Osteoarthr. Cartil 2533:10.1111/ijcp.12115 2379:(9193): 1896–900. 2002:(sep16 2): c4675. 1675:ClinicalTrials.gov 1639:10.1111/ijcp.12115 1047:Osteoarthr. Cartil 899:10.1111/ijcp.12115 490:Summary of results 202:glycosaminoglycans 182:glycosaminoglycans 75:possibly contains 2487:10.1136/bmj.c4675 2253:10.1002/acr.22376 2085:Groves T (2010). 2056:10.1136/bmj.c6338 2008:10.1136/bmj.c4675 1808:10.1002/art.23973 1576:Drugs & Aging 1541:10.1002/art.22728 1498:10.1345/aph.1E576 1371:10.1002/art.20697 853:10.1136/bmj.c4675 508:systematic review 345:confirmation bias 248:History of trials 222:confirmation bias 178: 177: 170: 160: 159: 124: 123: 116: 77:original research 57: 3083: 3044: 3043: 3041: 3039: 3028: 3022: 3021: 2985: 2979: 2978: 2967: 2961: 2960: 2953: 2947: 2946: 2944: 2943: 2931: 2925: 2924: 2917: 2911: 2910: 2908: 2907: 2896: 2890: 2889: 2882: 2876: 2875: 2839: 2833: 2832: 2796: 2790: 2789: 2779: 2746: 2740: 2739: 2729: 2719: 2695: 2689: 2688: 2681: 2675: 2674: 2664: 2640: 2631: 2630: 2620: 2588: 2582: 2581: 2559: 2553: 2552: 2515: 2509: 2508: 2498: 2466: 2460: 2459: 2411: 2405: 2404: 2367: 2361: 2360: 2332: 2326: 2325: 2285: 2274: 2273: 2255: 2231: 2225: 2224: 2214: 2204: 2180: 2174: 2172: 2162: 2152: 2128: 2122: 2120: 2118: 2116: 2104: 2098: 2097: 2095: 2093: 2082: 2076: 2075: 2039: 2033: 2032: 2019: 1987: 1981: 1980: 1970: 1946: 1940: 1939: 1929: 1903: 1897: 1896: 1894: 1893: 1884:. 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Archived from 1439: 1433: 1432: 1422: 1390: 1384: 1383: 1373: 1347: 1341: 1340: 1330: 1304: 1298: 1297: 1259: 1253: 1252: 1227:(9176): 353–54. 1214: 1208: 1207: 1189: 1164: 1153: 1152: 1142: 1132: 1106: 1100: 1099: 1097: 1096: 1091: 1082: 1073: 1072: 1062: 1038: 1032: 1031: 1021: 989: 983: 982: 951: 942: 941: 925: 919: 918: 881: 875: 874: 864: 832: 826: 820: 801: 800: 764: 753: 752: 724: 715: 709: 700: 699: 697: 696: 682: 676: 675: 673: 672: 666:Cleveland Clinic 658: 173: 166: 155: 152: 146: 134: 133: 126: 119: 112: 108: 105: 99: 96:inline citations 68: 67: 60: 49: 27: 26: 19: 16:Medical research 3091: 3090: 3086: 3085: 3084: 3082: 3081: 3080: 3071:Clinical trials 3061: 3060: 3052: 3047: 3037: 3035: 3030: 3029: 3025: 2987: 2986: 2982: 2977:. 29 June 2010. 2969: 2968: 2964: 2955: 2954: 2950: 2941: 2939: 2933: 2932: 2928: 2919: 2918: 2914: 2905: 2903: 2898: 2897: 2893: 2884: 2883: 2879: 2841: 2840: 2836: 2798: 2797: 2793: 2762:(12): 1145–55. 2748: 2747: 2743: 2697: 2696: 2692: 2683: 2682: 2678: 2642: 2641: 2634: 2590: 2589: 2585: 2561: 2560: 2556: 2517: 2516: 2512: 2468: 2467: 2463: 2413: 2412: 2408: 2369: 2368: 2364: 2334: 2333: 2329: 2287: 2286: 2277: 2246:(12): 1844–55. 2233: 2232: 2228: 2182: 2181: 2177: 2130: 2129: 2125: 2121:(Updated 2012.) 2114: 2112: 2106: 2105: 2101: 2091: 2089: 2084: 2083: 2079: 2041: 2040: 2036: 1989: 1988: 1984: 1948: 1947: 1943: 1920:(13): 1514–22. 1905: 1904: 1900: 1891: 1889: 1880: 1879: 1868: 1859: 1858: 1854: 1845: 1843: 1838: 1837: 1833: 1802:(10): 3183–91. 1788: 1787: 1780: 1743:Ann. Rheum. Dis 1735: 1734: 1723: 1685: 1684: 1680: 1666: 1662: 1624: 1623: 1619: 1569: 1568: 1564: 1526: 1525: 1521: 1483: 1482: 1478: 1469: 1467: 1441: 1440: 1436: 1405:(2): CD002946. 1392: 1391: 1387: 1349: 1348: 1344: 1306: 1305: 1301: 1272:(11): 1469–75. 1261: 1260: 1256: 1216: 1215: 1211: 1166: 1165: 1156: 1108: 1107: 1103: 1094: 1092: 1089: 1084: 1083: 1076: 1040: 1039: 1035: 991: 990: 986: 953: 952: 945: 927: 926: 922: 883: 882: 878: 834: 833: 829: 821: 804: 766: 765: 756: 726: 725: 718: 710: 703: 694: 692: 684: 683: 679: 670: 668: 660: 659: 655: 651: 634: 617: 568: 555: 492: 414: 379:null hypothesis 334: 250: 174: 163: 162: 161: 156: 150: 147: 144: 135: 131: 120: 109: 103: 100: 81: 69: 65: 28: 24: 17: 12: 11: 5: 3089: 3087: 3079: 3078: 3073: 3063: 3062: 3059: 3058: 3051: 3050:External links 3048: 3046: 3045: 3023: 2980: 2962: 2948: 2926: 2912: 2891: 2877: 2834: 2801:Evid-Based Med 2791: 2741: 2717:10.1186/ar3657 2690: 2676: 2632: 2583: 2554: 2510: 2461: 2406: 2362: 2327: 2294:Ann Intern Med 2275: 2226: 2175: 2150:10.1186/ar3657 2123: 2099: 2077: 2034: 1982: 1941: 1898: 1866: 1852: 1831: 1778: 1749:(8): 1459–64. 1721: 1678: 1660: 1617: 1562: 1535:(7): 2267–77. 1519: 1492:(6): 1080–87. 1476: 1434: 1385: 1342: 1299: 1254: 1209: 1180:(8): 795–808. 1154: 1130:10.1186/ar3657 1101: 1074: 1033: 984: 943: 920: 876: 827: 802: 754: 716: 701: 677: 652: 650: 647: 646: 645: 640: 633: 630: 622:osteoarthritis 616: 613: 597:osteoarthritis 567: 564: 554: 551: 547:osteoarthritis 520: 519: 512: 491: 488: 484:osteoarthritis 413: 410: 384: 383: 370: 367: 364:nutraceuticals 333: 330: 249: 246: 218:control groups 176: 175: 158: 157: 151:September 2021 138: 136: 129: 122: 121: 72: 70: 63: 58: 32: 31: 29: 22: 15: 13: 10: 9: 6: 4: 3: 2: 3088: 3077: 3074: 3072: 3069: 3068: 3066: 3057: 3054: 3053: 3049: 3033: 3027: 3024: 3019: 3015: 3011: 3007: 3003: 2999: 2996:(5): 851–58. 2995: 2991: 2984: 2981: 2976: 2972: 2966: 2963: 2958: 2952: 2949: 2937: 2930: 2927: 2923:. 2011-11-11. 2922: 2916: 2913: 2901: 2895: 2892: 2888:. 2012-01-03. 2887: 2881: 2878: 2873: 2869: 2865: 2861: 2857: 2853: 2849: 2845: 2838: 2835: 2830: 2826: 2822: 2818: 2814: 2810: 2806: 2802: 2795: 2792: 2787: 2783: 2778: 2773: 2769: 2765: 2761: 2757: 2756:Ann Rheum Dis 2753: 2745: 2742: 2737: 2733: 2728: 2723: 2718: 2713: 2709: 2705: 2701: 2694: 2691: 2686: 2680: 2677: 2672: 2668: 2663: 2658: 2655:(2): 137–62. 2654: 2650: 2646: 2639: 2637: 2633: 2628: 2624: 2619: 2614: 2610: 2606: 2603:(3): 167–80. 2602: 2598: 2594: 2587: 2584: 2579: 2575: 2571: 2567: 2566: 2558: 2555: 2550: 2546: 2542: 2538: 2534: 2530: 2527:(6): 585–94. 2526: 2522: 2514: 2511: 2506: 2502: 2497: 2492: 2488: 2484: 2480: 2476: 2472: 2465: 2462: 2457: 2453: 2449: 2445: 2441: 2437: 2433: 2429: 2426:(7): 573–80. 2425: 2421: 2417: 2410: 2407: 2402: 2398: 2394: 2390: 2386: 2382: 2378: 2374: 2366: 2363: 2358: 2354: 2350: 2346: 2342: 2338: 2331: 2328: 2323: 2319: 2315: 2311: 2307: 2303: 2300:(8): 580–90. 2299: 2295: 2291: 2284: 2282: 2280: 2276: 2271: 2267: 2263: 2259: 2254: 2249: 2245: 2241: 2237: 2230: 2227: 2222: 2218: 2213: 2208: 2203: 2198: 2194: 2190: 2186: 2179: 2176: 2170: 2166: 2161: 2156: 2151: 2146: 2142: 2138: 2134: 2127: 2124: 2110: 2103: 2100: 2088: 2081: 2078: 2073: 2069: 2065: 2061: 2057: 2053: 2049: 2045: 2038: 2035: 2031: 2027: 2023: 2018: 2013: 2009: 2005: 2001: 1997: 1993: 1986: 1983: 1978: 1974: 1969: 1964: 1960: 1956: 1952: 1945: 1942: 1937: 1933: 1928: 1923: 1919: 1915: 1914: 1909: 1902: 1899: 1888:on 2016-04-10 1887: 1883: 1877: 1875: 1873: 1871: 1867: 1862: 1856: 1853: 1841: 1835: 1832: 1827: 1823: 1818: 1813: 1809: 1805: 1801: 1797: 1793: 1785: 1783: 1779: 1774: 1770: 1765: 1760: 1756: 1752: 1748: 1744: 1740: 1732: 1730: 1728: 1726: 1722: 1717: 1713: 1709: 1705: 1701: 1697: 1693: 1689: 1682: 1679: 1676: 1672: 1671: 1664: 1661: 1656: 1652: 1648: 1644: 1640: 1636: 1633:(6): 585–94. 1632: 1628: 1621: 1618: 1613: 1609: 1605: 1601: 1597: 1593: 1589: 1585: 1582:(7): 573–80. 1581: 1577: 1573: 1566: 1563: 1558: 1554: 1550: 1546: 1542: 1538: 1534: 1530: 1523: 1520: 1515: 1511: 1507: 1503: 1499: 1495: 1491: 1487: 1480: 1477: 1466:on 2020-05-30 1465: 1461: 1457: 1454:(4): 471–76. 1453: 1449: 1445: 1444:"Glucosamine" 1438: 1435: 1430: 1426: 1421: 1416: 1412: 1408: 1404: 1400: 1396: 1389: 1386: 1381: 1377: 1372: 1367: 1364:(5): 738–45. 1363: 1359: 1358: 1353: 1346: 1343: 1338: 1334: 1329: 1324: 1321:(3): 279–84. 1320: 1316: 1315: 1310: 1303: 1300: 1295: 1291: 1287: 1283: 1279: 1275: 1271: 1267: 1266: 1258: 1255: 1250: 1246: 1242: 1238: 1234: 1230: 1226: 1222: 1221: 1213: 1210: 1205: 1201: 1197: 1193: 1188: 1183: 1179: 1175: 1171: 1163: 1161: 1159: 1155: 1150: 1146: 1141: 1136: 1131: 1126: 1122: 1118: 1117: 1112: 1105: 1102: 1088: 1081: 1079: 1075: 1070: 1066: 1061: 1056: 1053:(2): 137–62. 1052: 1048: 1044: 1037: 1034: 1029: 1025: 1020: 1015: 1011: 1007: 1004:(3): 167–80. 1003: 999: 995: 988: 985: 981: 977: 973: 969: 965: 962:(1): 103–18. 961: 957: 950: 948: 944: 939: 935: 931: 924: 921: 916: 912: 908: 904: 900: 896: 893:(6): 585–94. 892: 888: 880: 877: 872: 868: 863: 858: 854: 850: 846: 842: 838: 831: 828: 824: 819: 817: 815: 813: 811: 809: 807: 803: 798: 794: 790: 786: 782: 778: 775:(7): 706–12. 774: 770: 769:Equine Vet. J 763: 761: 759: 755: 750: 746: 742: 738: 735:(3): 222–26. 734: 730: 723: 721: 717: 713: 708: 706: 702: 691: 687: 686:"Glucosamine" 681: 678: 667: 663: 657: 654: 648: 644: 641: 639: 636: 635: 631: 629: 627: 623: 614: 612: 608: 604: 600: 598: 593: 588: 585: 581: 577: 573: 565: 563: 560: 552: 550: 548: 544: 540: 537: 533: 529: 525: 517: 513: 511:discouraged." 509: 505: 501: 500: 499: 497: 489: 487: 485: 478: 473: 471: 467: 461: 458: 453: 451: 447: 442: 439: 435: 429: 424: 422: 421: 411: 408: 403: 399: 397: 393: 389: 382:glucosamine". 380: 375: 374:control group 371: 368: 365: 361: 360: 359: 356: 352: 348: 346: 342: 337: 331: 329: 325: 322: 318: 314: 310: 306: 302: 298: 295:In 2006, the 293: 291: 285: 283: 279: 274: 273:meta-analysis 270: 265: 263: 259: 255: 247: 245: 243: 239: 235: 230: 228: 223: 219: 213: 211: 207: 203: 199: 195: 191: 187: 184:, especially 183: 172: 169: 154: 142: 137: 128: 127: 118: 115: 107: 97: 93: 89: 85: 79: 78: 73:This article 71: 62: 61: 56: 54: 47: 46: 41: 40: 35: 30: 21: 20: 3036:. 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