Glucosamine and Chondroitin: Update 2006

By Sharon L. Kolasinski, MD, Dr. Kolasinski is Assistant Professor of Medicine at the University of Pennsylvania School of Medicine in Philadelphia, and Chief of Clinical Service for the Division of Rheumatology; she reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.

Osteoarthritis (OA) is the most common form of arthritis and a substantial cause of disability in the United States. Treatments for OA are aimed primarily at controlling symptoms of pain and stiffness in the joints but do not affect the natural history of the disease. Standard management includes the use of pharmaceutical agents, such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). The American College of Rheumatology and European League Against Rheumatism guidelines for the management of OA emphasize the importance of nonpharmacological therapies, such as various forms of exercise, as well. Recent concerns about the potential side effects of NSAIDs continue to fuel the search for effective, less toxic treatments.

Glucosamine and chondroitin sulfate remain among the most popular dietary supplements sold in the United States.1 They are used by more than 5 million Americans each year and accounted for close to $750 million in annual sales in 2004.2 Glucosamine is an amino-monosaccharide and one of the basic constituents of the disaccharide units of articular cartilage glycosaminoglycans. Like glucosamine, chondroitin is an important constituent of normal cartilage and other joint tissues. Glucosamine and chondroitin can be reduced in osteoarthritic cartilage and, therefore, the notion of replenishing them by taking dietary supplements is appealing. However, just how useful glucosamine and chondroitin are as therapy for OA, either for symptom relief or disease modification, remains controversial.

Pharmacokinetics

Since the last update on glucosamine in Alternative Medicine Alert,3 little has been added to the considerable amount of in vitro and animal data regarding potential mechanisms of action through which glucosamine might affect those with OA. Earlier laboratory work suggested that glucosamine could stimulate proteoglycan synthesis by human chondrocytes and become incorporated into glycosaminoglycans, the building blocks of cartilage and other connective tissues.4 However, human data are sparse regarding precisely how exogenously administered glucosamine might act on chondrocytes in vivo to restore cartilage lost through the pathophysiologic processes of OA. Recently, glucosamine has been detected in human serum using high-performance liquid chromatography after oral glucosamine ingestion.5 In this experiment, the 18 subjects tested with OA had undetectable serum glucosamine levels at the start of the trial. Participants then received 1,500 mg of crystalline glucosamine sulfate mixed with water. In most of those tested, serum glucosamine levels reached a maximum of 4.8 μmol/L at a mean of two hours after ingestion. Based on the low serum levels achieved, the investigators felt that it was unlikely that glucosamine contributes to proteoglycan synthesis in vivo.

Chondroitin appears to be less readily absorbed after oral administration than glucosamine.6 Using chondroitin derived from shark cartilage, healthy volunteers showed considerable variability in absorption measured by disaccharide pattern evaluation on agarose gel electrophoresis and high-performance liquid chromatography. All participants in one trial had detectable levels of chondroitin by 48 hours, but some had peak levels as early as four hours post ingestion.

Mechanism of Action

Other experiments have suggested that glucosamine may have effects apart from those on proteoglycan synthesis that may account for its proposed efficacy in OA. Rather than simply providing the raw materials for cartilage building, glucosamine might affect the degradative processes that are part of OA pathogenesis. Glucosamine might interfere with degradative enzyme and cytokine production by altering gene expression. Glucosamine is known to affect matrix metalloproteinase-13 and aggrecanase-1 production, as well as inducible nitric oxide synthase and cyclooxygenase-2 stimulated by interleukin-1ß (IL-1ß). When glucosamine is added to normal equine chondrocyte culture at concentrations of only 10 μg/mL, reductions occur in mRNA levels corresponding to degradative enzymes and cytokines.7

Chondroitin levels are altered in OA cartilage, plasma, and synovial fluid.8 In vitro work has similarly suggested a variety of mechanisms, in addition to a contribution to structural integrity, through which this glycosaminoglycan might be useful in the treatment of OA. However, the link between potential therapeutic effects and a clear demonstration of efficacy in OA is no more certain for chondroitin than for glucosamine.

Addition of chondroitin sulfate to cultured chondrocytes derived from osteoarthritic joints results in significant increases in total proteoglycan production.4,9 When mixed in chondrocyte culture with IL-1ß, chondroitin will counteract the effects of IL-1ß,9 including reversing the decrease in proteoglycan and collagen type II production seen with IL-1ß. Furthermore, chondroitin itself decreases prostaglandin E2 production and counters IL-1ß induced increases. Chondroitin also appears to inhibit collagenolytic activity4 and matrix metalloproteinase production in chondrocyte culture derived from patients with hip OA.10

Animal studies have suggested that supplementation with chondroitin can reduce the progression of articular cartilage lesions in the rabbit instability model, but not in the rabbit continuous immobilization model of OA.11,12 Why this should be the case remains unclear.

Clinical Trials

Although a number of clinical trials using glucosamine, chondroitin, and, for the first time, the combination have been published since our last update, the efficacy of these agents in OA is perhaps less clear than in the past. This is because many of the trials appearing in the literature contradict earlier studies and each other.

Prior to 2006, the two largest long-term trials assessing the clinical efficacy of glucosamine had been carried out in Europe using the Rotta Pharmaceuticals preparation of glucosamine sulfate. Both suggested that glucosamine was promising in the management of OA. The first of these, by Reginster et al, involved 212 Belgian subjects with OA of the knee.13 Participants received either oral glucosamine at a dose of 1,500 mg daily or placebo for three years. Subjects were evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), a validated questionnaire instrument assessing the degree of pain and stiffness as well as functional impairment due to OA. Participants also had weight-bearing anteroposterior view radiographs of the knees taken at the beginning and end of the trial.

The trial showed that subjects who received glucosamine had modest pain reduction with an average of 11.7% reduction in WOMAC score compared to baseline. Those in the placebo group worsened an average of 9.8% as measured by their WOMAC score. The difference between the average scores was statistically significant. Radiographs of those who received placebo showed a mean of 0.31 mm of joint space narrowing in the medial joint compartment at the end of three years in the intention-to-treat analysis. Those who received glucosamine had a mean of 0.06 mm of joint space narrowing. The difference between these two mean figures was statistically significant. Interestingly, there was no correlation between the improvement of symptoms and radio-graphic findings. The side effects of glucosamine were not different from those of placebo.

The second large glucosamine study, by Pavelka and colleagues, included 202 Czech subjects and similarly suggested that glucosamine could improve both the symptoms of OA and slow the progressive cartilage loss associated with the disease.14 The trial was randomized and placebo-controlled. Participants received either 1,500 mg of Rotta brand crystalline glucosamine sulfate or placebo for three years. Radiographs of the knees were obtained annually throughout the trial. The improvement in symptoms was a bit better in this trial, but still modest, in the group treated with glucosamine. In the intention-to-treat analysis at three years, the subjects who received glucosamine had a mean reduction of 26% in their WOMAC scores. The participants in the placebo group had a mean reduction of 16% in their WOMAC scores compared to baseline. This difference was statistically significant. As in the previous trial, those who did not get glucosamine had a measurable (though small) loss in joint space, while those who received glucosamine did not. Intention-to-treat analysis of X-rays of those who received placebo showed a mean of 0.19 mm of joint space narrowing on anteroposterior weight-bearing radiographs of the knee. In the glucosamine-treated group, there was a mean gain in joint space of 0.04 mm. This difference was statistically significant. Again, glucosamine did not differ from placebo in the frequency or type of side effects noted.

Both of these studies have been interpreted to support the contention that glucosamine is a disease-modifying treatment for OA. However, several criticisms of these two trials have been raised. First, some have voiced concern about the involvement of pharmaceutical company personnel among the investigators. Second, the ability to assess how rapidly and severely OA progresses using X-rays is an imprecise undertaking. The positioning of the patient, as well as the positioning of the X-ray beam, can have substantial effects on the appearance of the joint space and, thus, the interpretation of the degree of cartilage loss.15,16 Unequivocal evidence of the ability of glucosamine to modify structure in OA will likely await the development of more precise outcome measures.

Much of the work since the publication of the Reginster and Pavelka trials has not been as positive as those trials with regard to the ability of glucosamine to modify symptoms in OA. No further data are yet available on structure modification. One subsequent study that showed no apparent benefit to taking glucosamine was a discontinuation trial.17 This study enrolled 137 current users of glucosamine who felt that their knee pain had improved since they started taking glucosamine. Participants were randomized to receive either 1,500 mg of glucosamine sulfate or placebo for six months. During the trial they were periodically assessed for the presence of a disease flare. A flare was defined in one of two ways: the patient's perception of worsening of symptoms with a concomitant increase of at least 20% in WOMAC pain on walking measured by a visual analog scale, or a worsening of the physician global assessment by at least 1 grade on a 1-5 scale. In the intention-to-treat analysis, 42% of the 66 subjects in the placebo group and 45% of the 71 subjects in the glucosamine group experienced a disease flare. This did not represent a statistically significant difference, suggesting that glucosamine did not prevent flares of OA symptoms.

The most recent meta-analysis to review the glucosamine literature was published by the Cochrane Collaboration.18 This update reviewed 20 randomized, controlled trials that included 2,570 subjects. Taken as a whole, the studies showed that glucosamine outperformed placebo with a 28% improvement in pain and a 21% improvement in function using the Lequesne Index. However, when the WOMAC scales for pain, function, and stiffness outcomes were used the results did not reach statistical significance. Once again it was noted that trials involving the glucosamine sulfate preparation from Rotta Pharmaceuticals appeared to have different results from those that used other preparations. Ten trials used the crystalline glucosamine sulfate preparation from Rotta Pharmaceuticals. When these trials were analyzed separately, glucosamine was found to be superior to placebo in improving pain and function using the Lequesne Index. When the analysis was restricted to eight studies with the highest-quality design, none showed improvement in pain or function. The authors noted that compared to the 1999 Cochrane review of glucosamine, this updated analysis suggested that there was high-quality evidence that glucosamine was not as useful for symptom improvement as had been previously thought.

A meta-analysis of clinical trials evaluating the efficacy of chondroitin prior to 2000 suggested that chondroitin has modest efficacy for symptomatic management of OA.19 Nine trials were analyzed and all found that chondroitin was significantly more efficacious than placebo in the treatment of OA pain. However, when the studies were evaluated for quality, the authors found that the higher-quality trials showed lower efficacy for chondroitin. Nonetheless, the overall effect size for chondroitin was considered large. Subsequent work has been mixed in its findings of efficacy for chondroitin. No more recent meta-analyses of chondroitin trials are available.

An abstract published in 1998 suggested that administration of 1,200 mg daily of chondroitin was associated with a slowing of the progression of finger joint OA.20 In this randomized, double-blind, placebo-controlled study, 119 subjects had anteroposterior radiographs of the hands at entry and at yearly intervals. At the conclusion of the study at three years, those treated with chondroitin were found to have significantly fewer new erosions on X-ray. Unfortunately, however, the full results of this trial have not been published. In contrast, a more recent study of 24 subjects with erosive hand OA found opposite results. All participants in this smaller trial worsened over a two-year period whether they received chondroitin 800 mg daily plus naproxen or naproxen alone.21

A subsequent trial used an intermittent dosing treatment schedule to test whether chondroitin was efficacious in knee OA.22 In this study, 120 subjects received either 800 mg daily of granulated bovine chondroitin 4 and 6 sulfate mixed in water or an identical placebo. Chondroitin was given only during months 0-3 and 6-9. Chondroitin was found to be effective with significantly greater improvements in the Lequesne Index, visual analog scale measurements for pain, and walking time than seen for those in the placebo group. Furthermore, those in the chondroitin-treated group showed no radiographic changes while those in the placebo group had significant reductions in the joint space surface area, mean joint space width, and the minimum joint space width. Chondroitin also had an excellent safety profile in this trial.

A larger and more recent trial of chondroitin alone also showed that chondroitin reduced the radiographic progression in OA, but failed to improve symptoms.23 In this randomized, double-blind, placebo-controlled trial, 300 participants received either chondroitin 800 mg daily or placebo for two years. Those who received chondroitin had no significant change in joint space narrowing measured on anteroposterior radiographs of the knee in flexion. In contrast, the placebo-treated group had a statistically significant mean progression of joint space narrowing of 0.14 mm after two years. Results were similar for minimum joint space width. However, there was no significant symptomatic effect measured using the WOMAC scale, and similar amounts of rescue drug were needed by chondroitin-treated and placebo-treated subjects. The authors suggest that this reflected the relatively low level of pain of those entered in the study. Adverse events did not differ significantly between the groups.

Many had hoped that the National Institutes of Health-sponsored Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) would clarify whether glucosamine and chondroitin are useful agents for symptom or structure modification of OA. Radiographic data have yet to be published, but the data on symptom relief recently reported in the New England Journal of Medicine failed to end the controversy about the utility of glucosamine and chondroitin.24 The GAIT trial was the first major clinical trial to attempt to answer the question of whether glucosamine, chondroitin, or the combination was best for OA. The GAIT trial included five arms in its study design. The intervention subgroups included either glucosamine hydrochloride 1,500 mg daily (as opposed to glucosamine sulfate used in most other reported trials); chondroitin sulfate 1,200 mg daily; the combination of glucosamine and chondroitin; a cyclooxygenase inhibitor, celecoxib; or placebo for six months. The WOMAC scale of pain, stiffness, and function was used as the primary outcome measure. Additional outcome measures included: patient and physician global assessments by visual analog scale (VAS); health-related quality of life measured by the Short Form General Health Survey (SF-36); physical functioning measured by the Health Assessment Questionnaire (HAQ); the use of acetaminophen, which was permitted as a rescue medication for uncontrolled symptoms up to a dose of 4 g/d; and the presence of joint swelling or effusion.

Overall, glucosamine, chondroitin, and the combination of the two were no better at relieving OA symptoms than placebo for any of the outcome measures. A single predetermined subgroup had a positive result in the GAIT study. In subjects with moderate-to-severe pain, the combination of glucosamine and chondroitin, but neither alone, was better than placebo at relieving symptoms. It was problematic, however, that the cyclooxygenase inhibitor, celecoxib, was found to be ineffective in this group, raising questions about the validity of the observation. Several difficulties have been raised about the trial design and the observed results of this study. The placebo response was high. The sample size for the trial was selected to detect a difference between the treatments and placebo if the placebo response was 35%, as is often the case in placebo-controlled trials. However, in this trial, the placebo response was closer to 60%, suggesting that the sample size used was inadequate. Second, most of the participants in the trial had a relatively mild degree of pain. When study subjects are less symptomatic it may be more difficult to detect differences between treatment arms. Additional methodological concerns have also been raised,25 including the attrition rate and limitations in the data analysis. Finally, the significance of using a glucosamine hydrochloride preparation, rather than glucosamine sulfate, in this trial remains unclear.

Conclusion

The gap between the laboratory data suggesting that glucosamine and chondroitin have important effects on cartilage and connective tissue and the contradictory and controversial results of clinical trials using these agents to treat the symptoms and structural abnormalities of OA remains to be bridged. In vitro and animal model data suggest that glucosamine and chondroitin have potential effects on important pathways in the pathogenesis of OA. A number of clinical trials can be cited that support the contention that glucosamine and chondroitin modify symptoms in OA and slow the damaging progression of disease. But data from high-quality studies can also be cited to support the contention that these dietary supplements are of no value in OA. There is no question that the issue will continue to be debated.

Recommendation

Many patients seek advice about glucosamine and chondroitin and expect that their physicians will be well informed and straightforward in their discussions. It is appropriate to inform patients that there is controversy in the literature about efficacy for both pain relief and structure modification, but that safety appears to be confirmed. Under these circumstances, an "n of 1" trial is reasonable if patients want to investigate whether glucosamine and/or chondroitin have a positive effect on their symptoms. The patient and physician should, however, clearly define the dose, duration, and the goals of therapy (e.g., a certain amount of pain reduction, being able to perform certain activities) before starting either supplement.

The doses used in previous clinical trials are generally glucosamine sulfate 1,500 mg daily and chondroitin sulfate 1,200 mg daily. The length of the trial is arbitrary but some symptomatic relief has been reported within weeks to months. If, after a predetermined period of time, the patient and physician note no improvement, the supplements should be discontinued.

It is known that chondroitin sulfate and other extracellular matrix proteins are overexpressed in benign prostatic hypertrophy and in prostate cancer, but the implications of these observations for treatment decisions is entirely unclear. It may be prudent to avoid the use of these supplements in men with these conditions.

References

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