The recent GAIT study on glucosamine and chondroitin for chronic joint disease sent shock waves throughout the industry, but what did it really say about their effectiveness? Rob Child, PhD, reviews the body of research
Joint-related disease affects more than 20 million Americans, and osteoarthritis is the most common, affecting 75 per cent of adults by the time they reach 65 years of age. Glucosamine and chondroitin have served as the core ingredients for a variety of functional food products formulated to maintain or improve joint health. In 2003, this sector of the supplements industry was reported to be worth more than $1.5 billion in consumer sales each year.1 Several peer-reviewed studies have reported benefits from glucosamine and chondroitin supplementation for reducing knee-joint pain, and these early findings captured the interest of the popular press and the public. However, the American College of Rheumatology was keen to point out: "While a number of studies support the efficacy of glucosamine and chondroitin sulphate for the palliation of joint pain in patients with knee osteoarthritis, the subcommittee believes that it is premature to make specific recommendations about their use at this time."
Concerns were expressed regarding the design and execution of some early research trials, and this prompted a larger-scale study — the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT). The findings of this study are of major importance to the suppliers of raw ingredients and manufacturers of joint-maintenance products. The much anticipated results finally became available in February 2006. Almada reported: "The outcomes have the potential of creating either a devastating tectonic plate shift in the evidence foundation for glucosamine and chondroitin, or could usher in a renaissance in awareness and demand for these chondroprotective agents."1
The underlying causes
Osteoarthritis is the most common chronic joint disease worldwide2 and generates a considerable health-care burden. The World Healthcare Organization identified osteoarthritis as a key area during what has been termed 'The Bone and Joint Decade,' which was initiated in January 2000.3 Osteoarthritis should not be thought of simply as a disease of ageing as it is closely linked to mechanical loadings on the joint. The Framingham Knee osteoarthritis cohort study reported that a 10-pound loss in body weight cut the risk of knee osteoarthritis by half.4
Mechanical stress is important in the pathogenesis of degenerative joint disease, and weight loss would be anticipated to reduce the maximum loading on the knee joint. It is not surprising that overuse trauma and certain occupations and activities are associated with degenerative joint disease.5 In severe cases it can lead to osteoarthritis, which is often referred to as 'wear and tear' arthritis. Articular cartilage damage is often the precursor of osteoarthritis, and individuals who suffer severe cartilage injury usually progress to this degenerative condition.6
Osteoarthritis is characterised by joint swelling, stiffness and pain, which is often debilitating. Some studies have also reported a widening of the knee joint space in osteoarthritis, which is considered a structural manifestation of cartilage loss. The ability to reduce these symptoms of disease are often used as efficacy markers in research trials,7 and reducing pain is considered particularly important as this profoundly affects mobility and overall life quality.
Over the next two decades the incidence of osteoarthritis is expected to double in the US.8,43 When considering the close association between osteoarthritis and excess body weight4 and the rapidly increasing incidence of obesity in Western society, the predicted figures for osteoarthritis appear conservative.
Methods of treatment, medicinal vs natural
Medical therapies currently available primarily address the treatment of joint pain in patients with osteoarthritis,9 not the underlying cause of joint degeneration. Traditional painkillers such as aspirin reduce pain by inhibiting prostaglandin production. However, with longer-term use they can cause damage to the stomach. COX-2 inhibitors are a different class of painkillers and specifically inhibit cyclo-oxygenase-2, which is linked with pain and inflammation. Their advantage over traditional painkillers is that they have no effect on cyclo-oxygenase 1 (also known as COX-1), thereby minimising damage to the stomach. Although COX-2 inhibitors are effective at reducing pain and inflammation, long-term use can actually impair healing and augment inflammation.10 For these reasons traditional analgesics, as well as cyclo-oxygenase—2 selective nonsteroidal anti-inflammatory drugs (NSAIDS), are considered to have suboptimal effectiveness.11,12,13
The key functional foods used to combat osteoarthritis are glucosamine and chondroitin, which have demonstrated efficacy when given individually and in combination. Human trials using placebo-controlled, double-blind research designs have reported reductions in knee pain after supplementing glucosamine at a dose of 1.5g per day for three years in patients with osteoarthritis of the knee.14 A 2g daily dose was found to be effective for reducing knee pain after three-months supplementation in individuals who experienced regular knee pain.6 A reduction in knee-joint pain was also found in patients with osteoarthritis, but this time after supplementation with 1g chondroitin daily for three months. A combination supplement, comprising 1.5g glucosamine and 1.2g chondroitin daily, reduced knee pain when military personnel followed this regime for four months.15 These comparatively well-controlled trials provide evidence of efficacy using a variety of supplementation protocols.
Mechanisms of action
Proteoglycans form the articular surface of the joints, and undergo continual breakdown and renewal (turnover). During cartilage degeneration metabolic turnover is increased and matrix degeneration exceeds synthesis, resulting in a progressive loss of proteoglycans and charged sulphate groups.16
There are a variety of potential mechanisms through which supplemental glucosamine or chondroitin could maintain or improve joint health in conditions such as osteoarthritis. During ageing there may be reduced numbers of the chondrocytes that are able to manufacture full-sized extracellular matrix molecules.17 Cohen proposed that there could also be problems regarding proteoglycan sulfation, which is necessary for fluid retention in the cartilage and smooth joint functioning. Such events might arise from reduced activity of specific glycosyl and/or sulfotransferases that add individual sugar units and sulphate groups to the growing glycosaminoglycans chains.16,18
Alternatively, reduced nutrient sugar supply to chondrocytes may lead to a loss of proteoglycan production and cartilage degeneration.19 Therefore, the administration of 'ready to use' sugar units such as glucosamine and chondroitin sulphate have the potential to feed the glycosaminoglycan machinery of the chondrocytes.16
In vitro studies have confirmed that exogenous (radiolabelled) glucosamine and chondroitin sulphate are both taken up by chondrocytes and used to build the extracellular cartilage matrix.20,21,22 Furthermore, orally administered radiolabelled chondroitin sulphate was found in joint fluid and partially incorporated into the joint cartilage.23 Human studies indicate that when glucosamine and chondroitin sulphate are combined in a single supplement they are more effective than the individual ingredients given alone.13,15,24
Glucosamine and chondroitin sulphate may also be chondoprotective by reducing matrix destruction. Glucosamine inhibits interleukin-1-beta-induced proteoglycan catabolism by inhibition of the cleavage enzyme aggrecanase25 and the production of inflammatory mediators such as prostaglandin E2,26,27,28,29 metalloproteinases26,27,28 and the downregulation of glucuronosyltransferase.26 Chondroitin sulphate is anti-inflammatory and may inhibit the action of several proteases (which destroy cartilage) and cytokines secreted by leukocytes and chondrocytes.30
The safety issue
NSAIDs can impair bone formation and tendon-to-bone healing.10 Injuries to bone tendon and muscle often accompany joint injury in physically active populations such as athletes. Therefore the ability of glucosamine and chondroitin to reduce pain (and in some instances produce structural changes that are indicative of reversal of disease) provides several advantages over conventional medical treatments. These effects also provide unique opportunities for marketing glucosamine and chondroitin-based products. With appropriate customer education and communication these could clearly be used to drive sales in this sector.
Animal studies have shown that high levels of glucosamine administered parenterally raises plasma glucose levels, and there is a theoretical risk that glucosamine supplementation could alter glucose metabolism in humans. The widespread use of glucosamine supplements on a nonprescription basis has raised some safety concerns among the medical community. Subjects with compromised glucose regulation would appear most at risk of possible adverse effects from glucosamine supplementation. This issue was addressed in a placebo-controlled trial of patients with type 2 diabetes mellitus, using hemoglobin A1c, a well-established marker of glucose regulation. Following 90 days of supplementation with 1500mg glucosamine and 1200mg chondroitin daily, hemoglobin A1c levels were unaltered.31 This finding was consistent with earlier studies30,32 and probably reflects the difference in pharmacokinetics and tissue distribution when glucosamine is given orally.33
Sources in supplements
Chondroitin sulphate has been extracted from marine sources such as the spiny dogfish shark (Squalus acanthias), hammerhead shark (Sphyrna lewini), and calf trachea, while popular sources of glucosamine are shrimp and crab. The technology to produce shellfish-free glucosamine hydrochloride has been available for several years.1 Some processes use corn as a starting material, which is subjected to microbial fermentation to produce glucosamine, while others are based on processing of bovine material to produce glucosamine and chondroitin.
Digestion and bioavailability
Pharmacokinetic studies on glucosamine and chondroitin have been performed on animals and man. For chondroitin sulphate, bioavailability has been reported to range from 5-15 per cent.23,34,35 Research suggests that low molecular weight chondroitin (14-17kDa) improves gastrointestinal absorption,23,34,35 even though it is further depolymerised but not completely degraded during digestion.20,23,42 Around 90 per cent of ingested glucosamine is absorbed, which results in an absolute bioavailability of 12-44 per cent.34 This is sufficient to produce measurable incorporation in articular cartilage.30,33
Some early trials
A large number of the existing trials on glucosamine or chondroitin sulphate were criticised for issues relating to study design. These included patient selection based on nonstandardised classification criteria,36 poor or absent descriptions of radiographic grade of damage when starting the study, small sample sizes,37 short duration of follow up37 and failure to use standardised outcome measures.38 Several review papers have attempted to collate the available data on glucosamine and chondroitin, to evaluate the functional and symptomatic efficacy of these compounds. One of the main criticisms against these reviews was publication bias, generated by the preferential reporting of trials in favour of the investigated drug. The use of 'funnel plots' is one statistical tool that can detect publication bias in the literature, and involves reporting the sample size of a randomised-control trial relative to its effect size. In the absence of publication bias the observed distribution displays a symmetrical inverted funnel.
Using this approach Richy, et al7 reported slight asymmetry in the data; however, the authors were keen to point out that differences in the response to treatment, inadequate analyses, chance, varying quality of research designs and lack of data also result in funnel plot asymmetry. These researchers concluded: "Our global estimators show substantial beneficial effects on symptoms of glucosamine and chondroitin therapy compared with placebo."7
To date the published positive effects of glucosamine or chondroitin sulphate on joint structure and cartilage morphology in man have been for osteoarthritis of the knee,14,39 fingers40 and spinal discs.16 It is important to note that these joints affect key areas of body function, ie, mobility and fine-motor skills that are most likely to have an impact on life quality. Although the scientific data of structural efficacy is limited to these areas of the body, there is no reason why these interventions would not be effective in other joints affected by osteoarthritis.
The GAIT study
One of the primary aims of the GAIT study was to conduct a well-controlled, large-scale research trial to address some of the limitations and issues that arose from earlier work on glucosamine and chondroitin. A total of 1583 patients were recruited to the study and received either 1.5g of glucosamine daily, 1.2g of chondroitin sulfate daily, or both 1.5g of glucosamine and 1.2g of chondroitin. In addition to a placebo group there was also a Cox-2 pain killer (celecoxib) control, to render comparisons of efficacy relative to conventional medicinal interventions easier to make.
The intervention lasted for 6 months, which previous studies suggest is sufficient to observe effects on knee pain. A key difference relative to most of the earlier trials was the use of a multicentre design and large subject numbers, making the results more applicable to the general population. The GAIT study also used a more detailed classification of study participants using WOMAC pain scores and radiographic evidence of osteoarthritis.41
The mean age of the patients was 59 years and 64 per cent were women. Several standardised pain markers were used to assess the effectiveness of the interventions, including a variety of WOMAC pain scores, the HAQ pain score, the OMERACT-ORSI response, and the patients' global assessment of response to therapy and disease. These tests provide an overall evaluation of changes in knee-joint pain and function. On completion of the study the authors concluded: "…glucosamine and chondroitin were not significantly better than placebo in reducing knee pain by 20 per cent and that glucosamine and chondroitin did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee."
Of note, when the subject population was subclassified to those with 'mild pain' (WOMAC score 125 to 300) and those with 'moderate-to-severe pain' (WOMAC score of 301 to 400), very different conclusions can be drawn. The combination of glucosamine together with chondroitin resulted in significant reductions in a variety of pain scores, for patients with moderate-to-severe pain. It is important to note that in this subgroup of subjects with more severe knee pain neither glucosamine nor chondroitin alone produced significant treatment effects. From this study it is unclear if the effectiveness of the combined therapy represents genuine synergy between glucosamine and chondroitin or simply a dose response effect. It is of course interesting that celecoxib was not criticised, even when it was outperformed by the combination of glucosamine and chondroitin therapy.
In the end, good news
Glucosamine and chondroitin are safe and effective treatments for osteoarthritis, especially if this results in moderate-to-severe pain. The GAIT study provides some evidence that, like NSAIDs, combined glucosamine and chondroitin therapy has the ability to reduce joint pain and improve function. However, glucosamine and chondroitin therapies have the advantage of minimal side effects, especially when compared with NSAIDs.
Most importantly they have the potential to slow or even reverse degenerative joint disease, especially with long-term use. In addition to the knee, these disease-modifying effects have been observed in joints of the back and fingers. Clearly, if the manufacturers and marketers of glucosamine- and chondroitin-based joint-health products are able to disseminate these messages to the consumer, considerable opportunities will still be available in this sector.
1. Almada. Glucosamine shell game revisited. Functional Foods and Nutraceuticals December 2003; 54.
2. Felson. Epidemiology of osteoarthritis. In: Osteoarthritis Eds. Brandt, Doherty, Lohmander, 1998, Oxford University Press, New York.
3. Brooks and Hart. The bone and joint decade 2000-2010. Med J Aust 2000;172:307-308.
4. Felson, et al. Obesity and knee osteoarthritis. The Framingham Study. Ann Intern Med. 1988; Jul 1;109(1):18-24.
5. Gelber AC, et al. Joint injury in young adults and risk for subsequent knee and hip osteoarthritis. Ann Intern Med 2000 Sep 5;133(5):321-8.
6. Braham, et al. The effect of glucosamine supplementation on people experiencing regular knee pain. Brit J Sports Med 2003: 37, 45-49.
7. Richy, et al. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis. A comprehensive meta-analysis. Arch Intern Med 2003; 163: 1514-1522.
8. Lawrence, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998; 41: 778-799.
9. Hochberg, et al. Guidelines for the medical management of osteoarthritis. Osteoarthritis of the knee. Arthritis Rheum 1995; 38: 1541-1546.
10. Cohen, et al. Indomethacin and Celecoxib impair rotator cuff tendon-to-bone healing. The American Journal of Sports Medicine 2006; 34: 362-369.
11. Williams, et al. Comparison of napoxen and acetaminophen in a two-year study of treatment of osteoarthritis of the knee. Arthritis Rheum 1993; 36:1196-1206.
12. Bradley, et al. Comparison of an anti-inflammatory dose of ibruprofen, an analgesic dose of ibruprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med 1991; 325: 87-91.
13. Clegg, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl JMed 2006; 354: 795-809.
14. Reginster, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo controlled clinical trial. Lancet 2001; 357: 251-256.
15. Leffler, et al. Glucosamine, chondroitin and manganese ascorbate for degenerative joint disease of the knee, or low back: a randomized, double-blind, placebo controlled pilot study. Mil Med 1999; 164: 85-91.
16. van Blitterswijk, et al. Glucosamine and chondroitin sulphate supplementation to treat symptomatic disc degeneration: biochemical rationale and case report. BMC Complementary and Alternative Medicine 2003; 3, http://www.biomedcentral.com/1472-6882/3/2.
17. Okuda, et al. Mechanisms of age-related decline in insulin-like growth factor 1 dependent proteoglycan synthesis in rat intervertebral disc cells 2001; 26: 2421-2426.
18. Sugahara and Kitagawa. Recent advances in the study of the biosynthesis and functions of sulphated glycosaminoglycans. Curr Opin Struct Biol 2000; 10: 518-527.
19. Horner and Urban. Volvo award winner in basic science studies: Effect of nutrient supply on the viability of cells from the nucleus pulposus of the intervertebral disc. Spine26, 2001: 2543-2549.
20. Bali, et al. Biochemical basis of the pharmacological action of chondroitin sulphates on the osteoarticular system. Sem Arthritis Rheum 2001; 31: 58-68.
21. Noyszewski, et al. Preferential incorporation of glucosamine into galactosamine moieties of chondroitin sulfates in articular cartilage explants. Arthritis Rheum 2001; 44: 1089-1095.
22. Schwartz: et al. Stimulation of chondroitin sulphate proteoglycan production by chondrocytes in monolayer Connect Tissue Res 1975; 3: 115-122.
23. Conte, et al. Biochemical and pharmacokinetic aspects of oral treatment with chondroitin sulphate. Arzneimittel forschung 1995; 45: 18-925.
24. Das and Hammad. Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulphate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage 2000; 8: 343-350.
25. Sandy JD, et al. Chondrocyte-mediated catabolism of aggrecan: aggrecanase-dependent cleavage induced by interleukin-1 or retinoic acid can be inhibited by glucosamine. Biochem J 1998;335 ( Pt 1):59-66.
26. Gouze, et al. Interleukin-1 beta downregulates the expression of glucuronosyltransferase 1, a key enzyme priming glycosaminoglycan biosynthesis: influence of glucosamine on interleukin-1 beta mediate effects in ratchondrocytes. Arthritis Rheum 2001; 44: 351-360.
27. Fenton, et al. Glucosamine- HCl reduces equine articular cartiage degeneration in explant culture. Osteoarthritis Cartilage 2000; 8: 258-265.
28. Orth, et al. Inhibition of articular cartilage degeneration by glucosamine-HCl and chondroitin sulphate. Equine Vet J Suppl 2002; 34: 224-229.
29. Shikhman, et al. N-acetylglucosamine prevents IL-1 beta-mediated activation of human chondrocytes. J Immunol 2001; 166: 5155-5160.
30. De los Reayes, et al. Glucosamine and chondroitin sulfates in the treatment of osteoarthritis: a survey. Prog Drug Res 2001; 55: 81-103.
31. Scroggie, et al. The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus. Arch Intern Med 2003; 163: 1587-1590.
32. Echard, et al. Effects of oral glucosamine and chondroitin sulphate alone and in combination on the metabolism of SHR and SD rats. Mol Cell Biochem 2001; 225: 85-91.
33. Setnikar and Rovati. Absorption, distribution, metabolism an excretion of glucosamine sulfate. A review. Arzeimittel forschung 2001; 51, 699-725.
34. Adebowale, et al. The bioavailability and pharmacokinetics of glucosamine hydrochloride and low molecular weight chondroitin sulfate after single and multiple doses to beagle dogs. Biopharm Drug Dispos 2002; 23: 217-225.
35. Ronca and Conte. Metabolic fate of partially depolymerised shark chondroitin sulphate in man. Int J Clin Pharamacol Res 1993; 13: 27-34.
36. Hochberg, et al. Recommendations for the medical management of osteoarthritis of the hip and knee. 2000 update. Arthritis Rheum 2000; 43: 1905-1915.
37. Qiu, et al. Efficacy and safety of glucosamine sulphate versus ibruprofen in patients with knee osteoarthritis. Arzneimittelforschung 1998; 48: 469-474.
38. Osteoarthritis Research Society. Task force report: Design and conduct of clinical trials of patients with osteoarthritis: Recommendations from a task force of the osteoarthritis Research Society. Osteoarthritis Cartilage 1996; 4: 217-243.
39. Drovanti, et al. Therapeutic activity of oral glucosamine sulphate in osteoarthritis: A placebo controlled double blind investigation. Clin Ther 1980; 3: 260-272.
40. Verbruggen, et al. Symptoms to assess the progression of finger joint osteoarthritis and the effects of disease modifying osteoarthritis drugs. Clin Rheumatol 2002; 21: 231-343.
41. Kellgren and Lawrence. Radiological assessment of osteo-arthrosis. Ann Rheum Dis 1957; 16: 494-502.
42. Volpi. Oral bioavailablity of chondroitin sulphate (Condrosulf?) and its constituents in healthy male volunteer. Osteoarthritis Cartilage 2002; 10: 768-771.
43. United States Senate Committee on Health, Education Labor and Pensions, Subcommittee on Aging, Center for Disease control's role in combating the burden of arthritis. Washington, DC: Department of Heath and Human Services, 2004.