Introduction
Osteoarthritis continues to be a painful and disabling condition for many of our patients. Medical treatments remain limited primarily to pain-control medication and surgery. Fortunately, certain promising alternative therapies have received a good deal of attention from the scientific research community. In the WSCC Clinics Protocol on Glucosamine and Chondroitin Sulfate¹, adopted in 2001, the case was made for selecting either glucosamine sulfate, 1500 mg per day, or chondroitin sulfate, 800-1200 mg per day, as the initial choice of dietary supplement therapy for osteoarthritis. This recommendation was based on the strength of evidence from several randomized controlled trials (RCTs) and two meta-analyses. Since then new studies have been published that improve our understanding of the value of these supplements.

New Glucosamine Research
One of the most promising results discussed in the WSCC Clinics Protocol were the findings reported early in 2001 of a three-year Belgian RCT of glucosamine sulfate, in which the treatment group did not experience the deterioration of radiographic knee changes seen in the placebo group at the end of the trial². In 2002, a second long-term RCT was published reporting similar benefits in a group of Czech subjects³. In addition to experiencing significant symptom relief, subjects receiving 1500 mg per day of glucosamine sulfate averaged no progressive joint space narrowing after three years, while in comparison the placebo group lost a significant amount of joint space and had only a modest reduction in pain. While a few subjects taking glucosamine sulfate did not experience these protective joint space effects, almost three times as many in the placebo group developed severe narrowing, defined as greater than 0.5 mm in three years. A follow-up analysis revealed that subjects with initially milder joint narrowing received the greatest protection from glucosamine sulfate⁴. As in the prior long-term study, no significant side effects from the supplement were reported.

Osteoarthritis of the temporomandibular joint (TMJ) was treated with glucosamine sulfate in a recent Canadian RCT⁵. Glucosamine therapy (1500 mg per day) was compared to ibuprofen (1200 mg per day) in this 90-day trial, which resulted in equal improvement in both groups measured by assessments of pain and TMJ function. As reported in other trials, subjects treated with glucosamine sulfate did not experience a return of pain for 30 days after treatment was stopped, which represents a remarkable "carry-over" effect. This study also demonstrates that glucosamine sulfate may benefit patients with osteoarthritis in areas other than the knee.

A recent short-term study conducted in Great Britain did not report significant pain reduction from glucosamine sulfate therapy for osteoarthritis of the knee⁶. After six months of supplementation with 1500 mg per day, the glucosamine group had a small but significant improvement in knee flexion, but self-assessment of pain was not different from that in the placebo group, many of whom experienced pain reduction as well. These patients had more severe osteoarthritis than those in most of the successful trials of glucosamine sulfate, and other reports suggest glucosamine is more effective in mild to moderate cases⁴. This study is only the second RCT to report disappointing results from glucosamine sulfate therapy, compared with at least sixteen double-blind studies reporting significant positive outcomes.

Clinicians and patients alike are interested to learn whether glucosamine might be helpful in joint disorders other than osteoarthritis, but until recently this type of investigation had not been attempted. An Australian group has just reported results of a RCT of glucosamine hydrochloride therapy on people with "regular" knee pain⁷. Subjects, who averaged 42-43 years of age, were selected for the presence of knee pain "more often than not" while pursuing the activities of daily living. About half of the subjects had prior medical workups for their knee pain that indicated some degree of cartilage damage, but this study did not perform any further diagnostic evaluations on any subject. Deviating from most prior glucosamine studies, this three-month trial supplied glucosamine as the hydrochloride rather than the sulfate salt. Until this study appeared, only one trial of glucosamine hydrochloride monotherapy had been published, and the earlier study reported only marginal effects of glucosamine hydrochloride against osteoarthritis pain⁸. Glucosamine-treated subjects in the new study reported some significant improvements compared to the placebo group in pain relief and quality of life, but performance of either a "duck-walk" or a stair climb did not improve. It is tempting to speculate that glucosamine sulfate, having a more impressive record of significant benefit, may have had greater potential to improve both pain and function had it been used in this study.

As described in the WSCC Protocol, animal studies have questioned whether glucosamine is safe for use in patients with diabetes or other glucose intolerance disorders. To date no formal human investigations have been carried out to determine whether this concern is valid. It appears from the long-term studies described above that glucosamine sulfate produces no significant changes in plasma glucose among healthy subjects, but anecdotal reports of elevated blood glucose readings by diabetics taking glucosamine suggest that patients with that disease monitor their glucose levels carefully while using glucosamine.

New Chondroitin Sulfate Research
Despite skepticism over the likelihood that macromolecular chondroitin sulfate is effectively absorbed from the gastrointestinal tract, an abundance of RCTs as well as a recent meta-analysis (reviewed in the original WSCC Clinics Protocol) indicate that oral chondroitin sulfate therapy is at least equivalent in effectiveness to glucosamine sulfate therapy, including evidence for disease stabilization measured by various imaging methods¹. Three new studies have been added to the scientific literature.

A RCT conducted in France sought to evaluate the long-term effects of chondroitin sulfate on stabilization of the osteoarthritic internal femoro-tibial joint (the details of this study were only available in English as an abstract)⁹. After two years of treatment with 800 mg per day of chondroitin sulfate or placebo, a significant difference in radiologically evaluated cartilage maintenance was detected between the treatment and placebo groups, with no apparent progression of disease in the group taking chondroitin sulfate.

A recent Italian study reported the effects of chondroitin sulfate therapy on the progression of erosive osteoarthritis of the hands. As reviewed in the original WSCC Clinics Protocol, a Belgian RCT had previously demonstrated that 1200 mg per day of chondroitin sulfate reduced the development of new erosive joints in this type of osteoarthritis over a three-year period. The new study was an open trial of 800 mg per day chondroitin sulfate combined with 500 mg per day naproxen, compared to naproxen therapy alone for two years¹⁰. While both groups developed radiographically apparent new erosions, those taking chondroitin sulfate had significantly fewer new erosions after one and two years than the group taking only naproxen.

TMJ pain and dysfunction was the subject of a small, US RCT involving chondroitin sulfate, which had disappointing results¹¹. Subjects diagnosed with capsulitis, disk displacement, disk dislocation, or painful osteoarthritis of the TMJ were given either a placebo or a combination of 1500 mg per day glucosamine hydrochloride and 1200 mg per day of chondroitin sulfate. Almost one quarter of the subjects recruited for this study dropped out before the end of the 12-week trial. Both the active treatment and placebo resulted in improvement in some measures of TMJ pain, tenderness, or other signs. Given the questionable effectiveness of the hydrochloride salt discussed above, the number of dropouts, and the assortment of cartilaginous and non-cartilaginous disorders treated, it is difficult to regard these results as definitive. Other, similar studies testing combinations of chondroitin sulfate, glucosamine hydrochloride, and other constituents against placebo have demonstrated greater effectiveness against osteoarthritis symptoms, but have not addressed the possibility that chondroitin sulfate alone might be equally effective.

Conclusion
Overall, the studies reviewed above continue to validate the original recommendations of the WSCC Clinics Protocol on Glucosamine and Chondroitin Sulfate, and provide additional evidence of delayed progression of osteoarthritis with long-term use of either of these supplements. Cost and convenience considerations may favor glucosamine sulfate, which is less expensive, usually requires fewer pills per daily dose, and has been found effective when taken either in a single daily dose or in divided doses. Patient factors arguing for an initial choice of chondroitin sulfate would be hypersensitivity to seafood (the source used for most glucosamine sulfate products) or type 2 diabetes mellitus.

¹ WSCC Clinics Protocol. Glucosamine and Chondroitin Sulfate. Western States Chiropractic College, 2001. [Back to article]
² Reginster JY, Deroisy R, Rovati L, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001;357:251-6. [Back to article]
³ Pavelka K, Gatterova J, Olejarova M, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2002;162:2113-23. [Back to article]
⁴ Bruyere O, Honore A, Ethgen O, et al. Correlation between radiographic severity of knee osteoarthritis and future disease progression. Results from a 3-year prospective, placebo-controlled study evaluating the effect of glucosamine sulfate. Osteoarthritis Cartilage 2003;11:1-5. [Back to article]
⁵ Thie NM, Prasad NG, Major PW. Evaluation of glucosamine sulfate compared to ibuprofen for the treatment of temporomandibular joint osteoarthritis: a randomized double blind controlled 3 month clinical trial. J Rheumatol 2001;28:1347-55. [Back to article]
⁶ Hughes R, Carr A. A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. Rheumatology (Oxford) 2002;41:279-84. [Back to article]
⁷ Braham R, Dawson B, Goodman C. The effect of glucosamine supplementation on people experiencing regular knee pain. Br J Sports Med 2003;37:45-9. [Back to article]
⁸ Houpt JB, McMillan R, Wein C, et al. Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. J Rheumatol 1999;26:2423-30. [Back to article]
⁹ Mathieu P. [Radiological progression of internal femoro-tibial osteoarthritis in gonarthrosis. Chondro-protective effect of chondroitin sulfates ACS4-ACS6] Presse Med 2002;31:1386-90. [Article in French] [Back to article]
¹⁰ Rovetta G, Monteforte P, Molfetta G, Balestra V. Chondroitin sulfate in erosive osteoarthritis of the hands. Int J Tissue React 2002;24:29-32. [Back to article]
¹¹ Nguyen P, Mohamed SE, Gardiner D, Salinas T. A randomized double-blind clinical trial of the effect of chondroitin sulfate and glucosamine hydrochloride on temporomandibular joint disorders: a pilot study. Cranio 2001;19:130-9. [Back to article]

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