• Chondroitin sulfate (CS) is one of the glycosaminoglycans, which is essential in the extracellular matrix of connective tissues. CS is found in cartilage, bone, the cornea, skin and the arterial walls.
• CS is made up of D-galactosamine and D-glurcoronic acid.
• CS has been used by itself or in combination with glucosamine to treat or prevent osteoarthritis.

• CS regulates collagen synthesis in chondrocytes, forming cartilage.
• CS inhibits proteolytic and lysomal enzymes which damage joint cartilage.
• CS possesses anti-inflammatory actions.

CS is well tolerated. Side effects reported in clinical studies are mostly mild, including nausea, diarrhea and gastrointestinal discomfort. Because of the lack of sufficient safety data, children, pregnant and lactating women should avoid taking CS.

According to a review article on the safety of glucosamine and chondroitin sulfate, glucosamine has not exhibited toxicity when tested in doses that far exceed what has been used in human clinical trials. Glucosamine also fared much better than indomethacin regarding prolonged treatment with a therapeutic margin of 10-30 times more favorable than indomethacin.[~10~] [~12~]

Some individuals are allergic to sulfur-containing (sulfa) drugs, where it is the sulfonamides that cause an allergic reaction, not the sulfur group. Currently there are no reports or references in the literature on cross hypersensitivity between sulfate salts and sulfonamides. However, individuals with a sensitivity to sulfonamides should be prudent and start with a minimal dose of chondroitin and observe any side effects or adverse reaction.[~12~]

Recently there has been a growing concern about the possibility of bovine spongiform encephalopathy (BSE) cases in the U.S. Chondroitin sulfate is derived from tracheal cartilage, which has shown to be free of BSE. With regards to dietary supplements containing chondroitin sulfate, currently there appears to be no risk of BSE, provided that the material for manufacturing chondroitin is handled correctly. Therefore, it is important to choose chondroitin sulfate supplements from a good quality manufacturer.[~12~]

• No health hazards or side effects are known.
• Caution with pregnancy or nursing, consult physician before using.

• In cell culture using bovine chondrocytes, glycosaminoglycan synthesis was measured by incorporation of 35-sulfate. Either glucosamine or chondroitin sulfate alone slightly increased glycosaminoglycan synthesis while the combination of glucosamine and chondroitin dramatically stimulated the incorporation of 35-sulfate.⁴
• Mast cells are stimulated by various chemicals, such as IgE, and specific antigens-secreting pro-inflammatory molecules, including cytokines and proteolytic enzymes. Incubation of umbilical cord-derived human mast cells with chondroitin sulfate showed that chondroitin sulfate had an inhibitory effect on histamine release, indicating that chondroitin sulfate may be a potent mast cell inhibitor of allergic stimulation.⁵
• Monfort and colleagues analyzed the effect of chondroitin sulfate and hyaluronic acid on stromelysin-1 (metalloprotease-3 [MMP-3]) synthesis induced by interleukin-1 beta in chondrocytes from patients with hip osteoarthritis. MMP-3 is a cartilage enzyme which induces cartilage destruction and acts as a mediator of the inflammatory response. Both chondroitin sulfate and hyaluronic acid inhibited MMP-3 synthesis and reduced MMP-3 expression levels in human osteoarthritis chondrocytes. The authors conclude that this mechanism of action of these substances could help explain their clinical efficacy in osteoarthritis.[~13~]
• Chan and colleagues studied the effects of physiologically relevant concentrations of glucosamine and chondroitin sulfate on gene expression and synthesis of nitric oxide and prostaglandin E-2 (PGE-2) in cytokine stimulated articular cartilage explants. Results show that chondroitin sulfate and the glucosamine/chondroitin combination at concentrations attainable in the blood down-regulated interleukin-1 induced mRNA expression of inducible nitric oxide synthase at 24 and 48 hour post culture. Additionally, synthesis of nitric oxide was reduced with chondroitin sulfate alone and the glucosamine/chondroitin combination. Repression of COX-2 transcripts by glucosamine and chondroitin was accompanied by a simultaneous reduction in PGE-2. The authors conclude that physiologically relevant concentrations of glucosamine and chondroitin sulfate can regulate expression of genese related to inflammation, and the synthesis of nitric oxide and PGE-2 (both having pro-inflammatory roles in diseased joints), providing a plausible explanation for their supposed anti-inflammatory properties.[~14~]

• The Glucosamin/chondroitin Arthritis Intervention Trial (GAIT) was a multi-center, double-blind, placebo-controlled study designed to evaluate the efficacy of glucosamine, chondroitin, and the two combined in treating knee pain related to osteoarthritis. The researchers randomly assigned 1,538 patients with symptomatic knee osteoarthritis to receive 1500 mg glucosamine hydrochloride, 1200 mg chondroitin sulfate, a combination of the two, 200 mg celecoxib or placebo every day for 24 weeks. Primary outcome measures did not show that either supplement alone or combined was efficacious. However, analysis of a subgroup of patients with moderate-to-severe pain demonstrated that combination therapy (glucosamine + chondroitin) significantly decreased knee pain related to osteoarthritis. This finding, which suggests efficacy for glucosamine and chondroitin in those with moderate-to-severe symptoms, is the first one to demonstrate efficacy of the combination, and adds to the existing body of research which demonstrates efficacy of these components. [~21~]
• In a multicenter study, 130 patients were given 1 g of chondroitin sulfate or placebo daily for 3 months. Compared to placebo, chondroitin sulfate significantly improved Lequesne's algofunctional index, the degree of functional handicap. Even at one month after treatment, chondroitin sulfate showed a significantly higher persistent effect than placebo.⁶
• Patients with knee osteoarthritis were given either a non-steroidal anti-inflammatory drug (NSAID)(diclofenac, 50 mg 3xday), 1200 mg chondroitin sulfate, or placebo. NSAID promptly reduced clinical symptoms, but did not show lasting improvement after the end of treatment. On the contrary, chondroitin sulfate slowly improved symptoms and efficacy lasted for 3 months after treatment. The effects of chondroitin sulfate treatment persisted longer than those of traditional therapy.⁷

• A randomized, double-blind placebo-controlled multi-center study on ~80 male and female patients examined the effect of 800 mg/day chondroitin sulfate (CS) supplementation for 6 months on treating osteoarthritis of the knee. Patients with symptomatic knee osteoarthritis for at least 6 months and a Kellgren and Lawrence radiological score I-III upon entry were enrolled in the study. Compared with placebo, the group receiving CS reduced pain and walking time significantly; they also experienced a reduction in Lequesne’s Index, which was used to measure the daily functional status of patients. A significantly positive global efficacy judgement for CS was observed and overall tolerability of CS was also excellent.[~11~]
• Michel and colleagues conducted a randomized, double-blind, placebo-controlled trial to determine whether chondroitin sulfate is effective in inhibiting cartilage loss in knee osteoarthritis. 300 patients with knee osteoarthritis were randomly assigned to receive either 800 mg chondroitin sulfate or placebo once daily for 2 years. The 150 patients receiving placebo had progressive joint space narrowing while the 150 patients taking chondroitin had no change in mean joint space. The authors conclude that while there was no significant symptomatic effect (i.e., pain reduction) in this study, long-term treatment with chondroitin sulfate may retard radiographic progression (and presumably cartilage degradation) in those with knee osteoarthritis.[~15~]
• Uebelhart and colleagues investigated the efficacy and tolerability of intermittent treatment with 800 mg chondroitin sulfate for a 3-month duration, twice/year in patients with knee osteoarthritis. 120 patients with symptomatic knee osteoarthritis received either chondroitin sulfate or placebo daily for two periods of 3 months during 1 year. Lequesne’s algo-functional index decreased significantly by 36% in the chondroitin group after 1 year verses 23% in placebo group Similar results were found for secondary outcome parameters which included walking time and global clinical judgment. The placebo group experienced significantly decreased joint space width after one year, but no changes in the chondroitin group occurred. The authors conclude that oral chondroitin sulfate treatment in this study decreased pain, improved knee function, and shows evidence that chondroitin sulfate may have structure-modifying properties in knee osteoarthritis.[~17~]

• More than 15 papers were reviewed. In most studies, glucosamine sulfate and chondroitin sulfate moderately improved symptoms of osteoarthritis. Analysis also suggested that efficacy of glucosamine sulfate or chondroitin sulfate might be recognized in patients consuming these products for longer than a month.⁸
• A comprehensive meta-analysis on randomized placebo controlled trials was performed to assess the efficacy of glucosamine and/or chondroitin in knee osteoarthritis (OA). Analyses were based on the outcomes that are required for demonstrating the efficacy of a prescription drugs commonly to be used in the treatment of OA: radiological evolution assessed by JSN (joint space narrowing); evaluation of pain by visual analog scale (VAS pain); joint mobility; Lequesne Index (LI) and Western Ontario MacMaster University Osteoarthritis Index (WOMAC). Results from analyses demonstrated the efficacy of glucosamine on all outcomes, including JSN and WOMAC. Chondroitin was found to be efficacious on the LI, VAS pain and joint mobility. Regarding LI scores, similar results were seen for 2000, 1200, 1000, and 800 mg doses of chondroitin. An outstanding finding was the structural efficacy (disease-modifying property) of glucosamine on JSN. This finding suggests that long-term (at least 3 years) glucosamine supplementation at a dose of 1500mg/day can slow the degenerative process of the joint cartilage. Further studies are warranted to confirm the long-term effects of glucosamine. Further studies are also needed to confirm and evaluate the structural efficacy of chondroitin. Safety for both of these compounds was well-established.[~9~]
• A meta-analysis was conducted to assess the efficacy of chondroitin sulfate (CS) in the treatment of osteoarthritis. Out of 16 publications, 7 controlled clinical trials were included in the meta-analysis, which involved 372 patients taking CS. In some studies, CS was given along with non-steroidal anti-inflammatory drugs (NSAIDS) or analgesics, therefore, dosage of co-medication must be considered. Patients taking CS were followed for at least 120 days, and results of pooled data indicated that the CS was superior to placebo according to the Lequesne Index and Visual Analog Scale (VAS) for pain. It was determined that CS may be useful in treatment of osteoarthritis. Further investigations in larger patient cohorts over longer time periods are warranted to confirm its effectiveness in treating symptoms of osteoarthritis.[~10~]
• In a review of the clinical use of glucosamine and chondroitin sulfate, Brief and colleagues conclude that both agents demonstrate efficacy with regard to reduction of joint pain/tenderness and improved mobility. Additionally, there was no evidence of toxicity.[~18~]

• Eleven patients with moderate to severe psoriasis, who were resistant to conventional therapy, received 800 mg daily of chondroitin sulfate for 2 months. All but one patient experienced a dramatic improvement in the condition of the skin with a reduction in swelling, redness, flaking, itching, scaling, and an increase in the hydration and softening of the skin. Other effects included a statistically significant decrease in epidermal thickness and a significant improvement of the degree of psoriasis activity. The authors suggest that confirmation of these findings in controlled prospective studies could represent an important advance in the treatment methods used for psoriasis patients.[~16~]

• One study was conducted to determine the effect of glucosamine hydrochloride supplementation on hemoglobin A₁C (HbA₁C) concentrations in 38 elderly patients with stable, well-controlled type 2 diabetes mellitus over a 90-day period. Patients must have been consistently taking an oral antihyperglycemic agent or under strict diet control; have a stable HbA₁C level for at least 2 consecutive measurements separated by atleast 90 days. Twenty-six patients were randomized to 1500 mg glucosamine daily and 12 to placebo. At baseline, both groups had similar HbA₁C levels and the HbA₁C mean values did not significantly change during the study. There was no significant difference in the glycemic control between the glucosamine and placebo group (p=.20). In the glucosamine group, mean HbA₁C increased from 6.45% to 6.5%; in the placebo group the mean HbA₁C decreased from 6.25% to 6.09%. This study suggests that oral glucosamine hydrochloride supplementation at the recommended dose (1500 mg/day) does not adversely effect glycemic control in patients with type II diabetes..[~19~]
• To evaluate glucosamine's effects on glucose tolerance, 1500 mg of glucosamine sulfate was given to healthy adults for 12 weeks. Results reveal supplemention with glucosamine sulfate did not alter serum insulin or plasma glucose during the oral glucose tolerance test. Glycated hemoglobin measurements showed no significant change over time. The authors conclude their data suggests that normal recommended doses of glucosamine supplementation does not cause glucose intolerance in healthy adults. These findings are not conclusive until further studies are done using alternative types of testing.[~20~]