Chondroitin

Scientific Name(s):Chondroitin sulfate, chondroitin sulfuric acid, chonsurid, structum

Common Name(s): Chondroitin

Uses

Chondroitin sulfate has been studied for the treatment of arthritis; however, information on its effectiveness is conflicting. It is commonly given in combination with other agents, such as glucosamine sulfate or glucosamine hydrochloride. It has also been studied for use in drug delivery, antithrombotic and extravasation therapy, and treatment of dry eyes and interstitial cystitis.

Dosing

Chondroitin sulfate has been administered orally for treatment of arthritis at a dosage of 800 to 1,200 mg/day. Positive results often require several months to manifest, and a posttreatment effect has been observed. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 Animal studies have suggested that the bioavailability of chondroitin sulfate may be increased when given multiple times a day. 10

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

An increase in the international normalized ratio (INR) may occur in patients taking anticoagulants, such as warfarin (eg, Coumadin ), with either chondroitin alone or in combination with glucosamine. 11

Adverse Reactions

Potential adverse reactions associated with chondroitin sulfate include alopecia, constipation, diarrhea, epigastralgia, extrasystoles, eyelid edema, lower limb edema, and skin symptoms. 12 Chondroitin sulfate may also exacerbate asthma. 13 , 14

Toxicology

There is little information regarding the long-term effects of chondroitin. Most reports conclude that it is safe.

Chondroitin is a biological polymer that acts as the flexible connecting matrix between the protein filaments in cartilage. 15 Chondroitin can be isolated from natural sources, such as shark or bovine cartilage. 16 Danaparoid sodium, a mixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate (ratio, 21:3:1), is derived from porcine intestinal mucosa. 17

History

Chondroitin sulfates were first extracted and purified in 1960. Studies suggested that if enough chondroitin sulfate was available to cells manufacturing proteoglycan (one of the substances that form the cartilage matrix), stimulation of matrix synthesis could occur, resulting in an accelerated healing process. 18 This idea of natural regeneration of cartilage was popularized with the publication of the book, The Arthritis Cure in 1997. 19

Chemistry

Chondroitin sulfate is a high-viscosity, anionic mucopolysaccharide (glycosaminoglycan) with N-acetylchondrosine as a repeating unit and one sulfate group per disaccharide unit. 20 Chondroitin 4-sulfate and chondroitin 6-sulfate are the most abundant mucopolysaccharides and occur in skeletal and soft connective tissue. 20 Chondroitin's molecular weight is about 50,000, depending on product source or preparation. 15 Sulfation of the sugar residues occurs to varying degrees, depending on tissue sources and conditions for formation. 21 Danaparoid sodium (a heparin preparation containing chondroitin) has a lower molecular weight (5,500 to 6,000). 17 Analytical determination, including high-pressure liquid chromatography, spectrophotometric analysis, chemical methods, ultraviolet spectrometry, and infrared spectroscopy, has been performed on chondroitin and related structures. 22 , 23 , 24 , 25 , 26 A method for potentiometric titration of chondroitin sulfate has been reported. 27

Uses and Pharmacology

The pharmacokinetics of chondroitin sulfate have been determined in rats and dogs. 28 Another pharmacokinetic study involving rats and healthy human volunteers determined that the absolute bioavailability of chondroitin sulfate was 15% and 12%, respectively. When dissolved in water, there was rapid absorption in rats and humans. 29 Another report concluded that oral chondroitin sulfate B (dermatan sulfate) reached plasma levels of 7% bioavailability. 30 In 22 patients with renal failure, chondroitin sulfate half-life was prolonged, but it could be administered for clot prevention during hemodialysis in this population. 31 Glycosaminoglycans are found in urine as free molecules. The average adult metabolizes about 250 mg of glycosaminoglycans each day, with 10% of the metabolites excreted in urine. Chondroitin sulfate accounts for 60% of the glycosaminoglycans in human urine. 32

Antiarthritic

Chondroitin's role in treating arthritis has gained increasing popularity. Results of ongoing research have been controversial.

Articular cartilage is found between joints (eg, finger, knee, hip), allowing for easy, painless movement. It contains 65% to 80% water, collagen, and proteoglycans. Chondrocytes are also found within this matrix, where they produce new collagen and proteoglycans from building blocks that include chondroitin sulfate, a glycosaminoglycan. 18 Chondrocytes must derive nutrition from this synovial fluid because there is no vasculature to supply them. 33 Glucosamine, another of the beneficial substances in this area, stimulates chondrocyte activity. It is also the critical building block of proteoglycans and other matrix components. 18 Both chondroitin and glucosamine play vital roles in joint maintenance, which is the reason the combination is found in many nutritional supplements.

In inflammation and repeated wear of the joint, chondrocyte function is disturbed, altering the matrix and causing breakdown. 33 Supplementation with glycosaminoglycans (eg, chondroitin sulfate) may enable chondrocytes to replace proteoglycans, offering chondroprotection. 34 Cartilage contains the biological resources to enhance repair of degenerative injuries and inflammation. Additionally, chondroitin is responsible for providing cartilage elasticity. It has been proposed that a certain chondroitin sulfate sequence, released from cartilage proteoglycans, inhibits elastase, thereby regulating the matrix. 35 Chondroitin is also believed to exert anti-inflammatory properties. 20

There is considerable controversy regarding absorption of chondroitin. Absorption of glucosamine is 90% to 98%, but chondroitin absorption is only 0% to 13% because chondroitin is 50 to 300 times larger than glucosamine. Chondroitin may be too large to be delivered to cartilage cells. In addition, there may be purity and identity problems with some chondroitin products, some of which have tested as subpotent. 18

General reviews are available on chondroitin sulfate and chondroitin sulfate B. 36 , 37

Animal data

When studied in mice, chondroitin sulfate may offer a beneficial effect against rheumatoid arthritis. 38 Additionally, chondroitin sulfate may be effective for the management of osteoarthritis in animals, particularly horses. 39

Clinical data

With increased popularity, many large-scale trials and meta-analyses evaluating the efficacy of chondroitin for treating arthritis have been published. However, the data are inconsistent, revealing mixed results. 12 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50

In a randomized, double-blind, placebo-controlled trial, 300 patients with osteoarthritis of the knee received either chondroitins 4 and 6 sulfate ( Condrosulf ) 800 mg or placebo daily for 2 years. Condrosulf is a prescription drug commonly used in Europe that contains chondroitin sulfate of fish origin. After 2 years of treatment, patients treated with placebo experienced a mean ± standard deviation (SD) joint space loss of 0.14 ± 0.61 mm ( P = 0.001 compared with baseline). However, patients receiving chondroitin sulfate did not experience any change in the mean ± SD joint space loss (0 ± 0.53 mm, P not significant compared with baseline). The difference in joint space loss between the 2 groups was 0.14 ± 0.57 mm ( P = 0.04). Adverse reactions were similar between the 2 groups. 41 Findings from this trial suggest that chondroitin sulfate may be beneficial in slowing disease progression.

An international, randomized, double-blind, placebo-controlled study was conducted in 622 patients with knee osteoarthritis. Patients were randomized to receive either chondroitin sulfate 800 mg, which contained chondroitins 4 and 6 sulfate from a bovine origin, or placebo for 24 months. Based on an intent-to-treat analysis, patients receiving chondroitin sulfate experienced a significant decrease in the minimum joint space width (JSW) of the medial compartment of the tibiofemoral joint from baseline (mean ± SEM −0.07 ± 0.03 mm) compared with those receiving placebo (−0.31 ± 0.04 mm, P < 0.0001). Fewer patients treated with chondroitin sulfate (28%) experienced radiographic progression of osteoarthritis, described as a minimum JSW reduction of at least 0.25 mm (28%), compared with placebo (41%, 95% confidence interval [CI], 16% to 46%; P < 0.0005). Additionally, pain improved faster in patients treated with chondroitin sulfate compared with placebo ( P < 0.01). Thus, the authors concluded that chondroitin sulfate given for at least 2 years can prevent progression of knee osteoarthritis as seen on radiographs. 42

A meta-analysis evaluated 7 clinical trials that included a total of 703 patients (372 treated with chondroitin and 331 controls) with hip and/or knee osteoarthritis. Chondroitin given for at least 3 months improved the algofunctional (Lesquesne) index, reduced pain and nonsteroidal anti-inflammatory drug (NSAID) or analgesic consumption, and improved patient and physician global assessments. 12 Another large meta-analysis evaluated 9 clinical trials assessing the efficacy of chondroitin sulfate for the management of knee and/or hip osteoarthritis. The investigators found a large treatment effect size (scale: small, 0.2; moderate, 0.5; large, 0.8) for chondroitin (0.96; 95% CI, 0.63 to 1.3). The test for heterogeneity of the data included in this analysis was statistically significant ( P < 0.001) and attributed to 1 trial with a large treatment effect. When this trial was removed from the analysis, the effect size was reduced to 0.78 (95% CI, 0.6 to 0.95). A smaller effect size of 0.40 (95% CI, 0.17 to 0.62) was noted for 1-month outcomes associated with chondroitin therapy. Similar results were noted when evaluating trials that assess pain outcomes. The authors concluded that chondroitin sulfate may have moderate to large treatment effects but methodological problems may have led to exaggeration of possible benefit. Additionally, it appears that it may take longer than 1 month to achieve full benefit associated with therapy. 43

In a meta-analysis of chondroitin sulfate for the treatment of gonarthrosis detailed data regarding joint space narrowing were missing. Thus, conclusions could not be made about the benefit of chondroitin sulfate for the prevention of radiographical progression of gonarthrosis. However, chondroitin sulfate was effective on other outcomes, such as Lequesne index, visual analog pain scales, mobility, and responding status. 44 A meta-analysis assessing the efficacy of chondroitin sulfate was conducted and included 20 trials of 3,846 patients. A high degree of heterogeneity among the trials was found. Smaller trials that had unclear concealment of allocation and those not analyzed according to the intention-to-treat principle demonstrated larger effects supporting the use of chondroitin sulfate. When the investigators analyzed 3 trials with large sample sizes that used intention-to-treat analyses, the effect size was -0.03 (95% CI -0.13 to 0.07). Thus, it was concluded that larger scale trials demonstrated minimum to no benefit with chondroitin supplementation for the treatment of hip and/or knee osteoarthritis. 45

A meta-analysis included 4 clinical trials assessing the efficacy of chondroitin sulfate in patients with knee osteoarthritis. Data revealed a small but statistically significant protective effect on minimum joint space narrowing in the knee (standardized mean difference, 0.261; 95% CI 0.131 to 0.392, P < 0.001) after 2 years of treatment. 46

Many studies have evaluated the efficacy of chondroitin in combination with glucosamine.

The largest study to date is the Glucosamine/Chondroitin Arthritis Intervention Trial, which was funded by the National Institutes of Health. In this 24-week, randomized, double-blind, placebo- and celecoxib-controlled multicenter study, 1,583 patients with symptomatic knee osteoarthritis were randomized to receive glucosamine 1,500 mg daily, chondroitin 1,200 mg daily, both glucosamine and chondroitin, celecoxib 200 mg daily, or placebo. The primary outcome was response to treatment defined as a 20% reduction in knee pain from baseline to 24 weeks. Patients were stratified according to knee pain severity. At the end of this study, 60.1% of patients receiving placebo experienced the primary outcome of a 20% reduction in pain. The rate of response to therapy was 64% for those treated with glucosamine ( P = 0.3), 65.4% with chondroitin ( P = 0.17), 66.6% with combination therapy ( P = 0.09), and 70.1% with celecoxib ( P = 0.008) experienced a reduction in pain ( P values for comparisons to baseline). In a subgroup analysis of patients with moderate to severe pain, the response rate with combination therapy was significantly higher compared with placebo (79.2% vs 54.3%, P = 0.002). There were some limitations to this study. There was a large placebo effect, and the majority of patients included in this study had mild osteoarthritis of the knee. Although close, the investigators did not randomize the prespecified number of patients (1,588) required to achieve power. The authors concluded that glucosamine and chondroitin, given either alone or in combination, did not appear to reduce knee pain in patients with osteoarthritis. However, the combination therapy may be beneficial to patients with moderate to severe pain. 47

In a 6-month double-blind, placebo-controlled trial, 89 patients at least 50 years of age with knee osteoarthritis were randomized to receive either glucosamine hydrochloride 1,500/chondroitin sulfate 1,200 mg or placebo daily. Following this phase, exercise programs were added to both groups for an additional 6 months. The Western Ontario and McMaster University Osteoarthritis Index mean function did not differ between groups at 6 months ( P = 0.52) or 12 months ( P = 0.5). Additionally, there were no statistically significant differences between the groups in 6-minute walk distance or knee strength. Interestingly, patients treated with placebo had better balance than the glucosamine/chondroitin group at 6 months ( P = 0.01). Thus, the use of glucosamine/chondroitin supplementation with or without exercise did not appear to affect pain, function, or mobility in patients with knee osteoarthritis. 48

Forty-six patients with osteoarthritis and 22 with rheumatoid arthritis were randomized to receive a product containing glucosamine hydrochloride (1,200 mg/day), shark cartilage powder (300 mg/day containing chondroitin 75 to 111 mg and querectin glucoside 45 mg/day), or placebo for 3 months. Patients with osteoarthritis who were treated with the combination product demonstrated a reduction in pain symptoms and an improvement in daily activities, visual analog scale scores, and changes in the synovial fluid (ie, reduced protein concentration). However, pain scores, joint swelling scores, rheumatoid arthritis activity index, duration of morning stiffness, grip strength, erythrocyte sedimentation rate, C-reactive protein levels, or rheumatoid factor titers were not different in patients with rheumatoid arthritis receiving the combination product. 49

A topical preparation containing chondroitin sulfate has been studied. Sixty-three patients were randomized to receive a topical preparation containing glucosamine sulfate, chondroitin sulfate, and camphor or placebo for 8 weeks. Patients receiving the topical preparation had a larger mean reduction in the visual analog scores (mean change, −3.4 cm ± 2.6 cm) compared with placebo (−1.6 cm ± 2.7 cm) after 8 weeks of therapy. Reduction in pain was noted as early as 4 weeks. 50

Antithrombotic
Animal data

The role of chondroitin sulfate as an antithrombotic agent has been studied in rats. 51 Intravascular injections of fucosylated chondroitin sulfate extracted from a sea cucumber inhibited the formation of thrombi in venous and arterial shunt models in rats. A dose-dependent increase in activated partial thromboplastin time, thrombin time, and anti-IIa activity were noted after oral administration. Thus, fucosylated chondroitin sulfate may offer a protective effect against thrombus formation. 52

Clinical data

Chondroitin sulfate B (dermatan sulfate) has potential as an antithrombotic agent, as it inhibits venous thrombi, with less effect upon bleeding than heparin. It is an effective anticoagulant in hemodialysis. 53 Another study found dermatan sulfate to have no direct, observable relation to heparin aggregation. 54 Dermatan sulfate's efficacy, compared with heparin, has been determined in acute leukemia patients. 55

Other uses

Chondroitin sulfate has been used to treat extravasation after ifosfamide therapy, decreasing pain and inflammation. 56 It has also been used to treat extravasation from vindesine, 57 doxorubicin and vincristine, 58 and an etoposide needlestick injury in a health care worker. 57 Chondroitin sulfate has been used as a drug delivery system for diclofenac and flurbiprofen. 59 Additionally, the polymer has been used as a stabilization agent for iron injection hyperalimentation. 60 Levels of chondroitin sulfate increase 10 to 100 times in tumors compared with normal tissue. In one report, all of the 44 cancer patients analyzed showed elevated levels of urinary chondroitin sulfate. This may provide a potential new marker for diagnosis and follow-up of cancer therapy. 61 The topical application of chondroitin sulfate over 2 weeks was studied in patients with keratoconjunctivitis sicca (dry eyes). Improvements in symptoms were noted. Thus, chondroitin sulfate given topically has a potential role for the treatment of dry eyes. 62 The role of chondroitin sulfate for the treatment of interstitial cystitis has been investigated in an open-label study. Eighteen patients with interstitial cystitis and a positive potassium stimulation test received weekly treatment with 40 mL of chondroitin sulfate 0.2% intravesically followed by once per month treatment for 1 year. Thirteen of the 18 patients were followed for the entire 13-month treatment period. At the end of this study, 46.2% of patients reported a good response, 15.4% reported a fair response, 30.8% a partial response, and 7.7% reported no response. Parameters, such as quality of life measures, voiding indices, and pain, were followed. Thus, chondroitin sulfate may have a role in the management of patients with interstitial cystitis 63 , 64 Chondroitin sulfate may be beneficial for the treatment of urolithiasis. Potential therapeutic options for this glycosaminoglycan include interference with calcium oxalate, as well as calcium phosphate crystallization, prevention of crystal retention, decreasing the excretion of urinary oxalate, and protection of renal tissue. 32

Dosage

Chondroitin sulfate has been administered orally for treatment of arthritis at dosages of 800 to 1,200 mg/day. Positive results often do not occur for several months, and a posttreatment effect has been observed. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 A study conducted in beagle dogs found the bioavailability of chondroitin sulfate ranged from 4.8% to 5% after single dosing, compared with 200% to 278% with multiple dosing. Thus, administering chondroitin sulfate in multiple doses may increase the bioavailability of this agent. 10

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Avoid use.

Interactions

Drug/Lab Test Interactions

An increase in the INR may occur in patients taking anticoagulants, such as warfarin, with chondroitin alone or chondroitin in combination with glucosamine. A conglomerate of 43 cases from the World Health Organization adverse drug reactions database, the United States Food and Drug Administration MedWatch database, and other published case reports have suggested that chondroitin alone, chondroitin in combination with glucosamine, and glucosamine alone may have been responsible for increasing the INR of patients treated with anticoagulant therapy. Caution should be used in patients treated with anticoagulants, and all patients should be encouraged to inform their health care providers if they are using chondroitin supplementation. 11

Adverse Reactions

A meta-analysis of chondroitin sulfate suggested the following as potential adverse reactions associated with chondroitin sulfate: alopecia, constipation, diarrhea, epigastralgia, extrasystoles, eyelid edema, lower limb edema, and skin symptoms. 12

Asthma exacerbation

Chondroitin supplementation may exacerbate asthma. One study examined bronchial biopsies from patients with atopic asthma in comparison with controls and found that chondroitin sulfate deposits were increased in patients suffering from asthma compared with the controls. Additionally, proteoglycan deposition in the airways appears to be associated with airway responsiveness in patients with asthma. 13 One case study describes a 52-year-old woman with long-standing intermittent asthma who reported increased shortness of breath and wheezing with increased use of albuterol. The albuterol was ineffective in relieving symptoms. At this visit, she was given a tapered dose of oral steroids. However, her condition fluctuated over the following 3 weeks despite treatment with steroids and albuterol use. During a follow-up visit, her medical history was reviewed in detail, and it was determined that her symptoms emerged when she began taking a glucosamine 500 mg/chondroitin supplement 400 mg 3 times daily for arthritis. She was advised to discontinue therapy, and within 24 hours, her symptoms disappeared. The patient refused a rechallenge with the agent. Later, the patient reported an episode of wheezing during graduate school when she was involved in a shark dissection. Given that chondroitin sulfate is a constituent of shark cartilage, this could explain this patient's exacerbation of asthma. 14

Prostate cancer

Current research suggests that increased chondroitin sulfate levels are associated with prostate-specific antigen (PSA) failures for patients treated with surgery for localized prostate cancer. PSA failures are defined as a return to measurable PSA levels following a postsurgical level below the assay threshold or an increase in PSA levels for patients with detectable levels following surgery. 65 Supplementation with chondroitin sulfate does not appear to be associated with prostate cancer. However, men with prostate cancer or those at risk for this disease should avoid supplementation until further evidence is discovered.

Toxicology

Little information about long-term toxic effects of chondroitin sulfate is available. Most reports conclude that it is safe compared with other arthritis therapies, such as NSAIDs.

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