Glucosamine and chondroitin for osteoarthritis?

Glucosamine and chondroitin for osteoarthritis?

McAlindon, Tim

SUMMARY POINTS

* Quality issues, like publication bias, diminish the results of previous trials of glucosamine and chondroitin.

* A recent 3-year, placebo-control led trial of glucosamine demonstrated modest improvement in symptoms.

* Glucosamine and chondroitin appear to be safe, but further studies are needed to confirm their role in the treatment of OA.

Introduction

The idea that glucosamine and chondroitin might have therapeutic effects in treating osteoarthritis (OA) by providing substrate for reparative processes in cartilage has been around since at least the 1960s. Two enticing properties of these “nutraceuticals” are their excellent safety profile and the assertion that they may reduce progression of cartilage damage (1).

The Dietary Supplement Health and Education Act of 1994 provides for the sale of dietary supplements to the public without the intervention of licensed health care providers. As a result, consumption of glucosamine and chondroitin products by the public at large has grown exponentially during the last few years such that they are now top sellers in a $26 billion annual market. It is apparent, however, that the medical community has played little role in this dramatic rise in the popularity of the products (2). One important reason for this may have been the lack of convincing studies explaining their therapeutic effects.

Laboratory Studies

Laboratory studies have suggested that both glucosamine and chondroitin can be absorbed through the gastrointestinal tract (3). Radioisotope studies of glucosamine show rapid distribution throughout the body with selective uptake by articular cartilage. In vitro studies have indicated that glucosamine can stimulate glucosaminoglycan and proteoglycan synthesis. The biologic fate of orally administered chondroitin sulfate is less clear, but some evidence exists to suggest that the compound may be absorbed, possibly as a result of pinocytosis. Chondroitin sulfate is able to cause an increase in RNA synthesis by chondrocytes, which appears to correlate with an increase in the production of proteoglycans and collagens. Such effects may result partly from competitive inhibition of degradative enzymes. In addition, there is evidence that chondroitin sulfate partially inhibits leukocyte elastase (3). It is uncertain whether these compounds are absorbed intact, whether they are metabolized to any degree, and what role they actually play in vivo.

Clinical Studies

Placebo-controlled Trials

McAlindon et al recently performed a metaanalysis and quality evaluation of trials of glucosamine and chondroitin products for symptoms due to knee and/or hip OA (4). In a search for published or unpublished double-blind, randomized, placebo-controlled trials of 4 or more weeks duration that reported extractable data on the effect of treatment on symptoms, the authors found 6 eligible glucosamine and 9 chondroitin trials (Table 1).

Quality scores ranged from 12.3% to 55.4% of maximum possible with mean 35.5%. Only 2 studies described adequate allocation concealment, while 3 reported an intent-to-treat analysis. All were supported to some extent by a manufacturer. Statistical evaluation suggested publication bias resulting from underrepresentation of small null, or negative trials (p

A number of further trials have emerged since the publication of the meta-analysis, some of which have had less compelling results. Houpt’s 2-month double-blind, randomized, placebo-controlled trial (RCT) of glucosamine hydrochloride among 118 participants with knee OA found trends in favor of active treatment but did meet the primary endpoint (statistically significant change in the WOMAC pain scale) (5). A 6-month placebo-controlled RCT of glucosamine among 80 participants with knee OA in the United Kingdom found no difference at all between the groups (6). Rindone et al also concluded from their 2month RCT among 98 veteran patients with knee that glucosamine was no better than placebo in reducing knee pain (7).

In contrast, a 2-month RCT of a glucosamine/hondroitin combination among a group of 34 military recruits with knee or spinal OA found significantly greater improvements in selected outcome measures (8). Most recently, Reginster et al published the results of a 3-year, industry-sponsored, placebo-controlled clinical trial of glucosamine, whose primary focus was the influence of treatment on radiographic progression of knee OA. This high-quality trial of 200 participants used the WOMAC questionnaire to assess the effect of glucosamine on pain and function. While the magnitude of effect on symptoms was modest, it is notable that this benefit was present even after 3 years of treatment (1).

Comparator Trials: Glucosamine

Glucosamine has been compared to a nonsteroidal anti-inflammatory drug (NSAID) in the treatment of OA in a number of trials (9-11). Muller-Fassbender et al enrolled 199 hospitalized patients with knee OA into a 4-week randomized trial of glucosamine sulfate (500 mg, 3 times/day) versus ibuprofen (400 mg, 3 times/day) (10). They were assessed using a version of the Lequesne Index (12). Participants receiving ibuprofen responded more quickly to treatment, but, by the 4-week time-point, both groups had experienced an identical reduction in their baseline Lequesne Index score.

Most notable is the difference in adverse experience rates between the two groups 35 in the ibuprofen group reported adverse effects (with 7 dropouts) compared with only 6 in the glucosamine group (1 dropout). Most of these were gastrointestinal in nature. The authors concluded that glucosamine and ibuprofen have comparable short-term efficacy, albeit with a slower onset for glucosamine. No power calculations were performed to determine the magnitude of difference that this size of study might be able to detect, nor is information presented about how the 4-week study duration was determined.

Qiu et al compared glucosamine with ibuprofen in a 4-week double blind RCT of 178 patients with knee OA (11). Both groups responded equally to the treatments, with an approximately 50% reduction in scores. Adverse event and dropout rates were strikingly greater (p=0.002) in the ibuprofen arm. Lopes-Vaz compared the efficacy of oral glucosamine (1.5 g/day) with ibuprofen (1.2 g/day) in an 8-week double-blind RCT among 38 patients with knee OA (9). Both groups improved, but the scores intersected at the 4-week timepoint, such that significantly greater improvement was seen in the glucosamine arm by the end of-the trial (p

Comparator Trials: Chondroitin

Morreale et al performed a 6-month RCT comparing chondroitin sulfate with diclofenac in 146 patients with knee OA (14). The design was rather complex in that participants assigned to the chondroitin took this for 3 months, while those assigned to the NSAID group received diclofenac for 1 month only. All participants took placebo during months 3 through 6. A double-dummy approach was used to preserve blinding, with all participants observed for the full 6-month period. Participants were allowed acetaminophen for breakthrough pain.

During the first month, both groups showed a fall in the Lequesne Index score, but this was significantly greater in the diclofenac group. The Lequesne Index scores then rebounded following cessation of diclofenac in the NSAID group, but continued to decline in those receiving chondroitin such that there were significant differences at days 60 and 90 favoring chondroitin. This benefit appeared to persist for 2 to 3 months after the chondroitin had been stopped. There were 3 adverse events in each group thought possibly or probably related to treatment, all of mild or moderate severity. These results contribute to the description of chondroitin as a “symptomatic slow-acting drug” for treating OA.

Human DiseaseModification Studies

Glucosamine

Probably the most enticing aspect of these compounds is the claim that they may have disease-modifying properties in OA. Reginster et al recently published the results of the first human RCT designed to investigate this possibility (1). They enrolled 200 knee OA patients into a 3-year placebo controlled trial in which the primary outcome measure was joint space width (JSW) in the medial compartment of the knee, evaluated from standardized straightleg, weight-bearing radiographs. At trial end they measured a mean decrease in JSW of 0.31 (95% confidence limits 0.48 0.13) among those receiving placebo, compared to 0.06 (0.22 – 0.09) among the treated group (p for difference = 0.04).

While these results are intriguing, there remain a number of puzzling aspects to this study. The relationship between joint space width at the knee and the clinical impact of the disease has consistently been shown to be poor. Thus, the clinical implications of modest retardation of joint space loss remain to be fully understood. Another problem is that adequacy of radiographic positioning could be influenced by knee symptoms resulting in an underestimation of JSW in those with more severe pain. The absence of further relevant radiographic data (eg, osteophytosis, global severity) in this paper is problematic. There is also considerable variability around each of the mean JSW estimates which will reduce expected statistical power in future trials hoping to replicate their findings.

Chondroitin

Uebelhart et al performed a 1-year RCT of chondroitin sulfate (800 mg/day) among 42 participants with knee OA (15). Computer-generated joint space measurements were used to evaluate radiographic progression. They found progression of joint space loss among the placebo group but no change in those taking chondroitin sulfate. This study has been criticized for short duration of follow-up. Verbruggen et al evaluated progression of radiographic hand OA during a 3-year period among 34 patients taking chondroitin sulfate (400 mg, 3 times/day), compared to 85 patients taking placebo (16). They found reduced development of erosive OA in the treated group. Limitations of this study include small numbers of participants, unbalanced treatment assignment and questions about the methodology used to obtain radiographs.

Safety Issues

The more rigorous controlled clinical trials of oral glucosamine and chondroitin preparations published as manuscripts in peer-reviewed journals include 600 participants taking oral glucosamine or chondroitin sulfate (4), for up to 3 years duration (1). These have shown minor or moderate adverse rates to be similar to those taking placebo. Reported adverse events have generally been gastro intestinal in nature. Comparator studies suggest that glucosamine is substantially safer than NSAIDs, particularly in respect of GI toxicity. Although there is a suggestion that glucosamine may interfere with glucose tolerance, no evidence was found supporting any influence of glucosamine on fasting blood glucose levels in the recent 3-year trial (1).

Parenteral administration of polysulfated glycosaminoglycan preparations has been shown to affect prothrombin time and activated partial thromboplastin time in animal studies. No hematologic abnormalities have been reported in the human studies of these compounds.

Summary

The current body of evidence currently supports modest efficacy for glucosamine and chondroitin in the treatment of OA symptoms. The products are safe and could play a valuable role in the management of this disorder. Nevertheless, further independent studies are needed to confirm these findings and to determine the clinical applicability of these compounds. Physicians need to become involved in these treatment decisions but are confused by wide variability in the formulation and purity of the numerous preparations available to consumers. The notion that glucosamine and chondroitin might have disease-modifying effects in OA is highly appealing and supported by preliminary data. Research is needed to confirm these findings and to evaluate the impact of glucosamine and chondroitin on all aspects of OA progression.

References

1. Reginster JY, Deroisy R, Rovati LC, et aL Longterm effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001;357 (9252):251-6.

2. McCarty ME The neglect of glucosamine as a treatment for osteoarthritis-a personal perspective. Med Hypotheses 1994;42(5):323-7.

3. Deal CL, Moskowitz RW Nutraceuticals as therapeutic agents in osteoarthritis. The role of glucosamine, chondroitin sulfate, and collagen

hydrolysate. Rheum Dis Clin North Am 1999; 25(2):379-95.

4. McAlindon TE, LaValley MP Gulin JP Felson DT Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000;283(11): 1469-75.

5. Houpt JB, McMillan R, Paget-Dellio D, Russell A, Gahunia HK. Effect of glucosamine hydrochloride (GHcl) in the treatment of pain of osteoarthritis of the knee. J Rheumatol 1998;25 (supplement 52):8.

6 Hughes RA, Carr A randomized double-blind placebo-controlled trial of glucosamine to control pain in osteoarthritis of the knee. Arthritis Rheum 2000;:43(9(Suppl)):5384.

7. Rindone JP Hiller D, Collacott E, Nordhaugen N, Arriola G. Randomized, controlled trial of glucosamine for treating osteoarthritis of the knee. West J Med 2000;172(2):91-4.

8. Leffler CT, Philippi AF, Leffler SG, Mosure JC, Kim PD. Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, doubleblind placebo-controlled pilot study. Mil Med 1999;164(2):85-91.

9. Lopes Vaz A. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthrosis of the knee in out-patients. Curr Med Res Opin 1982; 8(3):145-9.

10. Muller-Fassbender H, Bach GL, Haase W Rovato LC, Setnikar L Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis and Cartilage 1994;2:61-9.

11. Qiu GX, Gao SN, Giacovelli G, Rovati 1, Setnikar L Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. Arzneimittelforschung 1998;48(5):469-74.

12. Lequesne MG. The algofunctional indices for hip and knee osteoarthritis. J Rheumatol 1997;24(4):779-81.

13. Bellamy N, Buchanan WW Chalmers A, et al. A multicenter study of tenoxicam and diclofenac in patients with osteoarthritis of the knee. J Rheumatol 1993;20(6):999-1004.

14. Morreale P, Manopulo R, Galati M, Boccanera L Saponati G, Bocchi L Comparison of the antiinflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis. J Rheumatol 1996;23(8): 1385-91.

IS. Uebelhart D, Thonar EJ, Delmas PD, Chantraine A, Vignon E. Effects of oral chondroitin sulfate on the progression of knee osteoarthritis: a pilot study. Osteoarthritis Cartilage 1998;6 Suppl A:39-46.

16. Verbruggen G, Goemaere S, Veys EM. Chondroifin sulfate: S/DMOAD (structure/disease modifying anti-osteoarthritis drug) in the treatment of finger joint OA. Osteoarthritis Cartilage 1998;6 Suppl A:37-8.

Tim McAlindon, MD, MPH

Arthritis Center

Boston University Medical Center

Boston, MA

Copyright Arthritis Foundation 2001

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