• Chondroitin sulfate (CS) is a major component of the extracellular matrix of connective tissues and is found in cartilage, bone, ligands, tendons, cornea, skin, and arterial walls.
• CS is a member of a family of molecules called glycosaminoglycans.
• CS is purified from animal cartilage such as beef, pig, or shark.
• CS is composed of alternating subunits of N-acetylgalactosamine sulfate and D-glucuronic acid.
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• CS regulates collagen synthesis (type I and III). ²²
• CS inhibits proteolytic and lysosomal enzymes which may be involved in degradation of joint cartilage. ¹³
• CS exhibits anti-inflammatory actions. ^{14 23}
• CS also exhibits anti-adhesive properties. ²⁴
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In clinical trials, daily intake of 800 to 1200 mg of CS has been shown to be safe and to ease pain or improve mobility of joints.

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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.

A case report suggests that asthma may be exacerbated by CS supplements.20 People with asthma should use caution when starting to use CS or should avoid CS supplements.

Some individuals are allergic to sulfur-containing (sulfa) drugs. With sulfa drug allergies, it is the sulfonamide moiety that is responsible for allergic reactions, not the sulfur atom. CS does not contain a sulfonamide group. Currently there have been no reports or references in the literature on cross hypersensitivity between sulfate salts and sulfonamides. However, individuals with sensitivity to sulfonamides should start with a minimal dose of CS and observe any side effects or adverse reactions. ¹²

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

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• Caution during pregnancy and nursing are warranted; consult a physician before using CS during pregnancy or nursing.
• Because CS has some structural similarity to heparin, it might have weak anticoagulant activity. At recommended doses of CS it is unlikely that there will be an interaction with warfarin. There have been no reports of interactions between warfarin and CS.

Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.

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Osteoarthritis:

Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.

The Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) was a multi-center, double-blind, placebo-controlled study designed to evaluate the efficacy of glucosamine, CS, and the two combined in treating knee pain related to osteoarthritis. The 1,538 patients with symptomatic knee osteoarthritis were randomly assigned to receive 1500 mg glucosamine hydrochloride, 1200 mg CS, both, 200 mg celecoxib, or a placebo every day for 24 weeks. The primary outcome measure for this study was a 20% or greater decrease in knee pain. In the placebo group, 60.1% of participants experienced a 20% or greater reduction of knee pain by the end of the trial. In comparison, 64.0% (P=0.30) of participants in the glucosamine group, 65.4% (P=0.17) in the CS group, and 66.6% (P=0.09) of participants in the glucosamine plus CS group experienced at least a 20% reduction of knee pain. Thus, primary outcome measures did not find either supplement alone or the combination to be better than placebo. However, the placebo response rate was very high in this study. Analysis of a subgroup of patients with moderate-to-severe pain demonstrated that combination therapy (glucosamine plus CS) significantly decreased knee pain related to osteoarthritis relative to placebo (79.2% vs. 54.3%, P=0.002). This finding suggests that glucosamine plus CS may be effective for those with moderate-to-severe symptoms. ²¹

Chondroitin sulfate in osteoarthritis of the knee: a prospective, double blind, placebo controlled multicenter clinical study.

In a randomized, placebo-controlled, double-blind, parallel design, multicenter study, the efficacy of CS against osteoarthritis pain was assessed. One-hundred thirty patients enrolled in the study and were given 1 g of CS or placebo daily for 3 months; 114 participants completed the study. When all study participants (n=130) were included in analysis, nonsignificant trends toward improvement of knee function as measured by Lequesne's algofunctional index (AFI) and knee pain with CS supplements relative to placebo was observed. When only those participants who completed the three month study were included (n=114), the trend for improvement of AFI became significant (p=0.02) and pain at rest was significantly decreased (p=0.03). One month after treatment ended, CS had a significantly higher persistent effect than placebo on AFI (p=0.01) and pain with activity (p=0.001). The results of this study indicate that CS is beneficial for symptoms of pain and dysfunction for people with osteoarthritis. ⁶

Comparison of the antiinflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis.

In this randomized, multi-center, double-blind, double-dummy trial, 146 people with osteoarthritis of the knee participated in a comparison of CS versus non-steroidal anti-inflammatory drugs (NSAID) or placebo. Patients with knee osteoarthritis were given either the non-steroidal anti-inflammatory drug (diclofenac, 50 mg 3xdaily), 1200 mg CS, or placebo for six months. Daily doses varied through the trial. The NSAID was found to promptly reduce clinical symptoms, but did not show lasting improvement after the end of treatment. CS demonstrated slow improvement of symptoms but efficacy lasted for 3 months after treatment. The effects of CS treatment were found to persist for much longer than those of traditional NSAID therapy. ⁷

Efficacy and tolerability of oral chondroitin sulfate as a symptomatic slow-acting drug for osteoarthritis (SYSADOA) in the treatment of knee osteoarthritis.

A randomized, double-blind, placebo-controlled, multi-center study examined the effect of supplementation with 800 mg/day CS for 6 months on osteoarthritis of the knee. Eighty men and women completed the study. 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. Spontaneous joint pain decreased by 43% in the CS group and by 3% in the placebo group (significant difference; P<0.01). Walking time (defined as the time in seconds to complete a 20 m walk) significantly decreased in the CS group compared to placebo (P<0.05). Compared with placebo, the group receiving CS experienced a reduction in Lequesne’s Index (37% with CS vs. 0% with placebo; P<0.01), which was used to measure the daily functional status of patients. A significantly positive global efficacy judgment for CS was observed and overall tolerability of CS was also excellent. ¹¹

Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: a randomized, controlled trial.

Michel and colleagues conducted a randomized, double-blind, placebo-controlled trial to determine whether CS is effective for inhibition of cartilage loss in knee osteoarthritis. Three hundred patients with knee osteoarthritis were randomly assigned to receive either 800 mg CS or placebo once daily for 2 years. The 150 patients receiving placebo had progressive joint space narrowing (mean +/- SD joint space loss of 0.14 +/- 0.61 mm after 2 years, P = 0.001 compared with baseline) while the 150 patients taking CS had no change in mean joint space (0.00 +/- 0.53 mm, P not significant compared with baseline). The authors concluded that while there was no significant symptomatic effect (e.g. pain reduction) in this study, long-term treatment with chondroitin sulfate may retard radiographic progression, and presumably cartilage degradation, for those with knee osteoarthritis. ¹⁵

Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo.

Uebelhart and colleagues investigated the efficacy and tolerability of intermittent treatment with 800 mg chondroitin sulfate for a 3-month duration, twice per year in patients with knee osteoarthritis. One-hundred-twenty patients with symptomatic knee osteoarthritis received either CS 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 the placebo group (P<0.01). Walking time (defined as the time in seconds to complete a 20 m walk) was significantly reduced in the CS (18%) but not the placebo group (significant difference between groups, P<0.05). The placebo group experienced significantly decreased joint space width after one year, but no changes in the chondroitin group occurred. The authors concluded that oral CS in this study decreased pain, improved knee function, and suggested that CS may have structure-modifying properties in knee osteoarthritis. ¹⁷

Efficacy and tolerability of chondroitin sulfate 1200 mg/day vs. chondroitin sulfate 3 x 400 mg/day vs. placebo.

In a multi-center, double-blind, placebo-controlled trial, the efficacy of two different CS formulations for treatment of osteoarthritis was evaluated. One-hundred-twenty-seven people participated in the three month trial. Forty received 1200 mg CS daily as an oral gel; forty-three consumed a total of 1200 mg CS daily as 3 x 400 mg capsules; forty-four consumed a daily placebo. The two CS groups experienced similar benefits. Lequesne’s algo-functional index significantly decreased in the CS groups but did not in the placebo group (40 to 45% for CS, P<0.01; 10% for placebo, P=ns). Spontaneous joint pain also significantly decreased in the CS groups (P<0.05). These results indicate that CS was effective to relieve osteoarthritis associated joint pain and that one 1200 mg dose was as effective as 3 x 400 mg doses daily. ⁴

Effects of oral chondroitin sulfate on the progression of knee osteoarthritis: a pilot study.

The efficacy of CS for knee osteoarthritis was assessed in a one year pilot study. Forty-two people with osteoarthritis of one or both knees participated in the randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to receive either 800 mg CS daily or a placebo. CS supplements significantly reduced pain and significantly increased overall motility. There was also a stabilization of joint space, indicating slowing of disease progression, in a subset of participants. This pilot study indicates that larger trials are warranted. ⁵

Effect of chondroitin sulphate in symptomatic knee osteoarthritis: a multicentre, randomised, double-blind, placebo-controlled study.

In a 24 week, multi-center, randomized, double-blind, placebo-controlled study, the efficacy of CS on knee osteoarthritis pain was evaluated. Participants consumed 1 g CS or a placebo daily for 24 weeks; 307 participants with osteoarthritis of one or both knees enrolled in the study. No significant difference between CS and placebo was found. However, CS was found to be slightly more effective for measures of pain, number of responders (68% vs. 56%, respectively), investigator’s assessment, and quality of life. A significant difference was found between non-responders and responders according to the OARSI criteria for 24-week changes of CTX-I (p = 0.018) and CTX-II (p = 0.014). The results of this study suggest that CS may be beneficial for some people with osteoarthritis of the knee. ⁸

Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis.

A comprehensive meta-analysis of 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 joint space narrowing (JSN), 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 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 1500 mg/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 of chondroitin sulfate in the treatment of osteoarthritis.

A meta-analysis was conducted to assess the efficacy of 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 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

Psoriasis:

Clinical and histopathological improvement of psoriasis with oral chondroitin sulfate: a serendipitous finding.

Eleven patients with moderate to severe psoriasis, who were resistant to conventional therapy, received 800 mg CS daily of for 2 months in a prospective trial. Skin biopsies were obtained before and after treatment. 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 (mean difference of 29%, t = 3.807, p = 0.003) and a significant improvement of the degree of psoriasis activity. One to two months after the end of the trial, psoriasis symptoms returned to pre-trial levels. 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

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