Chondroitin sulfate

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Chemical structure of one unit in a chondroitin sulfate chain. Chondroitin-4-sulfate: R1 = H; R2 = SO3H; R3 = H. Chondroitin-6-sulfate: R1 = SO3H; R2, R3 = H.

Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of a chain of alternating sugars (N-acetylgalactosamine and glucuronic acid). It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have over 100 individual sugars, each of which can be sulfated in variable positions and quantities. Chondroitin sulfate is an important structural component of cartilage and provides much of its resistance to compression.[1] Along with glucosamine, chondroitin sulfate has become a widely used dietary supplement for treatment of osteoarthritis.

Medical use[edit]

Chondroitin is in dietary supplements used as an alternative medicine to treat osteoarthritis and also approved and regulated as a symptomatic slow-acting drug for this disease (SYSADOA) in Europe and some other countries.[2] It is commonly sold together with glucosamine. Chondroitin and glucosamine are also used in veterinary medicine.[3]

Chondroitin, along with commonly used glucosamine, should not be used to treat patients who have symptomatic osteoarthritis of the knee as evidence shows that these treatments fail to provide relief for that condition.[4]

Adverse effects[edit]

Clinical studies have not identified any significant side effects or overdoses of chondroitin sulfate, which suggest its long-term safety.[5] The Task Force of the European League Against Rheumatism (EULAR) committee recently granted chondroitin sulfate a level of toxicity of 6 in a 0-100 scale, confirming it is one of the safest drugs for osteoarthritis.[2] Moreover, its safety is supported by an absence of drug-drug interactions (chondroitin sulfate is not metabolized by cytochrome P450),[6] and the lack of safe alternatives for patients multi-medicated for osteoarthritis and other accompanying diseases, e.g. diabetes, hypertension, hyperlipidemia, etc.

Physical and chemical properties[edit]

Chondroitin sulfate chains are unbranched polysaccharides of variable length containing two alternating monosaccharides: D-glucuronic acid (GlcA) and N-acetyl-D-galactosamine (GalNAc). Some GlcA residues are epimerized into L-iduronic acid (IdoA); the resulting disaccharide is then referred to as dermatan sulfate.

Protein attachment[edit]

Chondroitin sulfate chains are linked to hydroxyl groups on serine residues of certain proteins. Exactly how proteins are selected for attachment of glycosaminoglycans is not understood. Glycosylated serines are often followed by a glycine and have neighboring acidic residues, but this motif does not always predict glycosylation.

Attachment of the GAG chain begins with four monosaccharides in a fixed pattern: Xyl - Gal - Gal - GlcA. Each sugar is attached by a specific enzyme, allowing for multiple levels of control over GAG synthesis. Xylose begins to be attached to proteins in the endoplasmic reticulum, while the rest of the sugars are attached in the Golgi apparatus.[7]

Sulfation[edit]

Each monosaccharide may be left unsulfated, sulfated once, or sulfated twice. In the most common scenario, the hydroxyls of the 4 and 6 positions of the N-acetyl-galactosamine are sulfated, with some chains having the 2 position of glucuronic acid. Sulfation is mediated by specific sulfotransferases. Sulfation in these different positions confers specific biological activities to chondroitin GAG chains.

Structural[edit]

Chondroitin sulfate is a major component of extracellular matrix, and is important in maintaining the structural integrity of the tissue. This function is typical of the large aggregating proteoglycans: aggrecan, versican, brevican, and neurocan, collectively termed the lecticans.

As part of aggrecan, chondroitin sulfate is a major component of cartilage. The tightly packed and highly charged sulfate groups of chondroitin sulfate generate electrostatic repulsion that provides much of the resistance of cartilage to compression. Loss of chondroitin sulfate from the cartilage is a major cause of osteoarthritis.

Regulatory[edit]

Chondroitin sulfate readily interacts with proteins in the extracellular matrix due to its negative charges. These interactions are important for regulating a diverse array of cellular activities. The lecticans are a major part of the brain extracellular matrix, where the chondroitin sugar chains function to stabilize normal brain synapses as part of perineuronal nets. The levels of chondroitin sulfate proteoglycans are vastly increased after injury to the central nervous system where they act to prevent regeneration of damaged nerve endings. Although these functions are not as well characterized as those of heparan sulfate, new roles continue to be discovered for the chondroitin sulfate proteoglycans.

In cortical development, chondroitin sulfate is expressed by the Sub Plate and acts as a stop signal for neurons migrating from the Ventricular Zone. Neurons stopping here may then be programmed for further migration to specific layers in the cortical plate.

Interactions[edit]

Chondroitin's functions depend largely on the properties of the overall proteoglycan of which it is a part. These functions can be broadly divided into structural and regulatory roles. However, this division is not absolute, and some proteoglycans have both structural and regulatory roles (see versican).

Mechanisms of action[edit]

The effect of chondroitin sulfate in patients with osteoarthritis is likely the result of a number of reactions including its anti-inflammatory activity, the stimulation of the synthesis of proteoglycans and hyaluronic acid, and the decrease in catabolic activity of chondrocytes inhibiting the synthesis of proteolytic enzymes, nitric oxide, and other substances that contribute to damage cartilage matrix and cause death of articular chondrocytes. A recent review summarizes data from relevant reports describing the biochemical basis of the effect of chondroitin sulfate on osteoarthritis articular tissues.[8] The rationale behind the use of chondroitin sulfate is based on the belief that osteoarthritis is associated with a local deficiency or degradation of natural substances, including internal chondroitin sulfate.

Recently, new mechanisms of action have been described for chondroitin sulfate. In an in vitro study, chondroitin sulfate reduced the IL-1β-induced nuclear factor-kB (NF-κB) translocation in chondrocytes.[9] In addition, chondroitin sulfate has recently shown a positive effect on osteoarthritic structural changes occurred in the subchondral bone.[10]

A review published in the Annals of Rheumatic Diseases describes all the documented evidence regarding the mechanisms of action of chondroitin sulfate[11]

Bioavailability and pharmacokinetics[edit]

Pharmacokinetic studies performed on humans and experimental animals after oral administration of chondroitin sulfate revealed that it can be absorbed orally. Chondroitin sulfate shows first-order kinetics up to single doses of 3,000 mg.[12][13][14][15] Multiple doses of 800 mg in patients with osteoarthritis do not alter the kinetics of chondroitin sulfate. The bioavailability of chondroitin sulfate ranges from 15% to 24% of the orally administered dose. More particularly, on the articular tissue, Ronca et al.[16] reported that chondroitin sulfate is not rapidly absorbed in the gastro-intestinal tract and a high content of labeled chondroitin sulfate is found in the synovial fluid and cartilage.

Clinical Effect[edit]

Various clinical trials performed with chondroitin sulfate have evaluated its efficacy for the treatment of osteoarthritis compared to placebo or non-steroidal anti-inflammatory drugs (NSAIDs). Most of the studies have evidenced a significant benefit in terms of pain reduction and improvement of functional capacity, as well as a reduction of joint swelling / effusion, all of them characteristic symptoms of this disease. Specifically, the available data evidence that, even though the clinical effect of the product takes about 2 to 3 weeks to appear, it can reach a global efficacy comparable to that of NSAIDs (Morreale et al., 1996).[17] Additionally, its effect has been proven to persist for 3 months after treatment suppression (carry-over effect) (Uebelhart D, et al., 2004).[18] In the synovial membrane, chondroitin sulfate can significantly reduce joint swelling and effusion (Clegg et al., 2006),[19] which represents an important benefit considering that the prevalence of synovitis in osteoarthritis has been estimated to be around 50% (Loeuille D, et al., 2005)[20] or higher. Synovitis has also evidenced to aggravate osteoarthritis and accelerate disease progression (Ayral X et al., 2005)[21]

Most of the clinical trials published with chondroitin sulfate have analysed its symptomatic effect on knee osteoarthritis (Morreale P, et al. 1996;[17] Bourgeois F, et al. 1998[22] (Bucsi L, et al. 1998),[23] (Pavelka et al., 1998),[24] (Uebelhart D. et al., 1998),[25] Mazieres B, et al., 2001,[26] (Uebelhart D et al., 2004),[27] (Clegg DO et al., 2006)[28] and (Möller I, et al. 2010)[29] However, other studies have also provided evidence of efficacy in finger joints (Verbruggen G et al., 1998);[30] (Verbruggen G et al., 2002),[31] (Gabay C et al., 2011)[32]

Additionally, some clinical trials have also assessed the disease modifying effect of chondroitin sulfate (Uebelhart D et al. 1998);[25] (Verbruggen G. et al., 1998),[30] (Uebelhart D, et al. 2004),[27] (Michel B, et al. 2005),[33] (Verbruggen G, et al. 2002);[31] (Kahan A et al., 2009),[34] (Wildi L, et al. 2011)[35] The most relevant recently conducted CLINICAL TRIALS performed with chondroitin sulfate are summarized below.

- Clinical trials performed to assess the symptomatic effect of chondroitin sulfate in osteoarthritis: The largest trial conducted with the product is the Glucosamine and Chondroitin Arthritis Intervention Trial (GAIT), a double-blind, randomized, multicenter clinical trial sponsored by the US National Institutes of Health in 1583 patients with knee osteoarthritis, which was published in the New England Journal of Medicine (Clegg DO, et al. 2006).[28] Patients were randomly assigned to one of five orally administered treatments: two 250 mg capsules of glucosamine hydrochloride three times daily, two 200 mg capsules of chondroitin sulphate three times daily, two capsules of 250 mg of glucosamine hydrochloride plus 200 mg of chondroitin sulphate three times daily, 200 mg of celecoxib daily, or placebo. Treatment was administered for 24 weeks.

Primary Outcome: The primary outcome measure was a 20% decrease in the WOMAC pain subscale from baseline to week 24. The analysis of the primary outcome data for all patients showed the percentage of responders in each group to be: glucosamine: 64.0%; chondroitin sulphate: 65.4%; glucosamine + chondroitin sulphate: 66.6%; and celecoxib: 70.1% (p=0.008). Thus, despite the considerable effect elicited by all the products, only the celecoxib group reached statistical significance. This has been discussed by the authors and attributed mainly to the unprecedented high response in the placebo group (60.1%) and the relatively mild degree of pain among participants, which may have limited the ability to detect treatment benefits. Indeed, treatment effects were more substantial in patients with moderate-to-severe pain. Analysis of the results for the primary outcome, based on higher baseline pain, showed the percentage of responders in each treatment group to be 54.3% for placebo; 61.4% for chondroitin sulphate; 65.7% for glucosamine hydrochloride; 69.4% for celecoxib; and 79.2% for combined glucosamine and chondroitin sulphate. Thus, in the higher WOMAC pain stratum, only the combination glucosamine + chondroitin group presented significant efficacy (p=0.002).

Secondary Outcomes: Secondary efficacy outcome measures were as follows: OMERACT-OARSI response, 50% decrease in WOMAC pain score, WOMAC pain, stiffness and function score, normalized WOMAC score, patient and investigator global evaluations of disease status and response to study medication, evaluation of the index knee for swelling and tenderness, Health Assessment Questionnaire (HAQ) Alternative Disability score and HAQ Pain score, clinical evaluation for adverse reactions and reconciliation of study medications and rescue analgesia use. Analysis of the OMERACT-OARSI measure in all randomized patients revealed statistical significance for both celecoxib (p=0.007) and glucosamine and chondroitin in combination (P=0.02) compared to placebo. Swelling of study joints was significantly less in patients in the chondroitin sulphate (P=0.01) and celecoxib (P=0.03) treatment arms. Differences in the other secondary outcomes were not statistically significant when compared across the 5 treatment arms for all patients. For patients with moderate-to-severe pain at baseline (n=354), a statistically significant difference was observed in favor of the glucosamine and chondroitin combination group versus placebo for the following efficacy outcomes: 20% decrease in WOMAC pain score (0.002); OMERACT-OARSI response (0.001); 50% decrease in WOMAC pain score (0.02); WOMAC pain score (0.009); WOMAC function score (0.008); normalised WOMAC score (0.017); Health Assessment Questionnaire Pain score (0.03).

A subanalysis of GAIT results based on interaction of Kellgren & Lawrence Grade and Chondroitin Sulfate response relative to placebo was performed by the same study investigators (Clegg DO, et al. 2005).[36] The results indicated better response for chondroitin sulfate relative to placebo for Kellgren & Lawrence grade 2 compared with grade 3. In general, chondroitin sulfate response within the Kellgren & Lawrence grade 2 group was very similar to that seen for celecoxib. These results suggest that chondroitin sulfate may improve osteoarthritis knee pain in patients with relatively early radiographic disease.

Sawitzke A, et al. 2010[37] evaluated the efficacy and safety of glucosamine and chondroitin sulfate, alone or in combination, as well as celecoxib and placebo on painful knee osteoarthritis over 2 years as a continuation of the GAIT trial. This was a 24-month, double-blind, placebo-controlled study, enrolling 662 patients with knee osteoarthritis who satisfied radiographic criteria (Kellgren/Lawrence grade 2 or 3 changes and baseline joint space width of at least 2 mm). This subset continued to receive their randomized treatment (glucosamine 500 mg three times daily, chondroitin sulfate 400 mg three times daily, the combination of glucosamine and chondroitin sulfate, celecoxib 200 mg daily, or placebo) over 24 months. The primary outcome was a 20% reduction in pain over 24 months as measured by the Western Ontario and McMaster University Osteoarthritis Index (WOMAC). Secondary outcomes included an Outcome Measures in Rheumatology/Osteoarthritis Research Society International response and change from baseline in WOMAC pain and function. Over 2 years, none of the treatments (not even the positive control celecoxib) achieved a clinically important difference in WOMAC pain or function as compared with placebo. Adverse reactions were similar among treatment groups and serious adverse events were rare for all treatments.

The authors explain these negative and contradictory results by indicating that while in this study, regression to the mean is a possibility, baseline levels of pain were also low (mean WOMAC pain 42.4), making it more difficult to detect a treatment effect due to a floor effect of the outcome measurement. Moreover, this study was limited by its design as an ancillary preplanned continuation of a randomized controlled trial in which not all of the initially randomized patients were eligible to participate. There was significant dropout manifested as discontinuation of drug use as well as missed assessments. Overall, this study was found to be underpowered with an unusually high drop-out rate of over 50% in some treatment groups and very low pain levels at baseline (normalized WOMAC score less than or equal to 15). Under these circumstances, in addition to the limitations imposed by the original cohort, it is complex to derive any definitive conclusions from these findings.

A double-blind, randomized clinical trial (Möller I, et al. 2010[38] evaluated the efficacy of chondroitin sulfate against placebo in 129 patients with knee osteoarthritis and concomitant plaque psoriasis. In it, chondroitin sulfate significantly reduced the symptoms of osteoarthritis (pain and functional disability) after 3 months treatment in comparison to placebo. A significant reduction of acetaminophen consumption as rescue medication was also observed in the chondroitin sulfate-treated group (CS 43% vs PBO 64%, p<0.05). In relation to the primary efficacy variable in psoriasis, chondroitin sulfate-treated patients experienced a reduction of 33% in the Psoriasis Area and Severity Index (PASI) after 3 months of treatment, without achieving statistically significant differences as compared with placebo. When psoriatic lesions at different body sites were assessed, a significant reduction was observed in the percentage of patients with plantar psoriasis among those treated with chondroitin sulfate compared with placebo. At the final visit, plantar psoriasis was present in 22% of patients treated with placebo and in 4% of patients treated with chondroitin sulfate (P<0.05). The authors conclude that the study confirms the efficacy and safety of chondroitin sulfate as a symptomatic slow-acting drug in patients with knee osteoarthritis and shows that chondroitin sulfate improves plantar psoriasis. The use of chondroitin sulfate could represent a special benefit to patients with both pathologies since non-steroidal anti-inflammatory drugs have been reported to induce or exacerbate psoriasis.

A more recently published randomized, double-blind, placebo-controlled clinical trial (Gabay C, et al. 2011)[32] evaluated the symptomatic effects of chondroitin sulfate in 162 patients with osteoarthritis of the hand. Patients received either 800 mg of chondroitin sulfate or placebo once daily for 6 months. The two primary outcomes were the change in the patient’s assessment of global spontaneous hand pain and in hand function (by FIHOA score) from baseline to month 6. Secondary outcomes were improvement in grip strength, duration of morning stiffness, acetaminophen consumption, and the investigator’s global impression of treatment efficacy. Results showed there was a significantly more pronounced decrease in the patient’s global assessment of hand pain in the chondroitin sulfate group than in the placebo group (p=0.016). Hand function improved significantly more in the chondroitin sulfate group than in the placebo group (difference in FIHOA scores p= 0.008). There was a statistically significant between-group difference in favor of chondroitin sulfate for the duration of morning stiffness and for the investigator’s global impression of treatment efficacy. Changes in grip strength, acetaminophen consumption, and safety end points were not significantly different between the two groups. The study concludes that chondroitin sulfate improves hand pain and function in patients with symptomatic osteoarthritis of the hand and shows a good safety profile.

- Clinical trials performed to assess the disease modifying effect of chondroitin sulfate in osteoarthritis: Sawitzke A, et al. 2008[39] evaluated the effect of glucosamine and chondroitin sulfate, alone or in combination, as well as celecoxib and placebo on progressive loss of joint space width (JSW) over 2 years as a continuation of the GAIT trial. This was a 24-month, double-blind, placebo-controlled study, enrolling 572 patients with knee osteoarthritis who satisfied radiographic criteria (Kellgren/Lawrence grade 2 or 3 changes and baseline joint space width of at least 2 mm). This subset continued to receive their randomized treatment (glucosamine 500 mg three times daily, chondroitin sulfate 400 mg three times daily, the combination of glucosamine and chondroitin sulfate, celecoxib 200 mg daily, or placebo) over 24 months. The primary outcome measure was the mean change in JSW from baseline. At 24 months, no JSW loss was radiographically detectable in any of the study groups, not even in the placebo group, due to questionable X-Ray methodology used. Thus, the study could not provide any conclusive results.

The Study on Osteoarthritis Progression Prevention (STOPP) (Kahan A, et al. 2009)[40] aimed to assess the potential effect of chondroitin sulfate to slow down disease progression for 2 years in patients with knee osteoarthritis. It was a multicenter, randomized, double blind, placebo-controlled study performed in Frange, Belgium, Switzerland, Austria and United States including 622 patients (n=309 CS; n=313 Placebo). The primary efficacy outcome was the change in minimum joint space width (JSW) of the medial compartment of the tibiofemoral joint evaluated by posteroanterior (Lyon Schuss view) X-rays obtained at baseline, 12, 18 and 24 months. In the intent-to-treat analysis, the percentage of patients with radiographic progression (minimum joint space width ≥ 0.25 mm) was significanlty lower in the chondroitin sulfate group compared to the placebo group (28% vs. 41%; p <0.0005). The study evidenced that long-term administration of chondroitin sulfate for 2 years can prevent degradation of articular structure in patients with knee osteoarthritis. Chondroitin sulfate reduced pain vs placebo, confirming its symptomatic effect for the treatment of osteoarthritis and it confirmed also its excellent safety profile. Wildi L, et al. 2011[41] evaluated the disease modifying effect of chondroitin sulfate in knee osteoarthritis by Magnetic Resonance Imaging (MRI). This was a multicenter, randomized, double blind clinical trial performed in Canada in 70 patients with osteoarthritis and synovitis treated with chondroitin sulfate or placebo for 6 months, followed by an open period of 6 months where patients in both groups received chondroitin sulfate 800 mg / day. Patients receiving treatment with chondroitin sulfate for 12 months showed significantly less cartilage volume loss than the placebo group as early as 6 months for the global knee (p=0.030), lateral compartment (p=0.015) and tibial plateaus (p=0.002), with significance persisting at 12 months. Significantly lower bone marrow lesions (BML) scores were found for the chondroitin sulfate group at 12 months in the lateral compartment (p=0.035) and the lateral femoral condyle (p=0.044). At the same time, patients in the chondroitin sulfate group who were receiving concomitant treatment with NSAIDs (n=8) presented a significant decrease of synovial membrane thickening against placebo (p=0.029), as well as less incidence of swelling (p=0.092) at month 6. To conclude, the results of this study indicate that chondroitin sulfate may slow down disease progression.

New disease modifying evidence for Chondroitin Sulfate coming from new studies: Two recent studies, have analysed the association between use of chondroitin sulfate and need for total knee replacement [Raynauld JP, et al. 2013 (ref) and Prieto-Alhambra D, et al. 2013 (ref)]. They both conclude that chondroitin sulfate reduces the need for knee replacement. Raynauld et al.[42] performed a post hoc intention-to-treat analysis to evaluate the incidence of total knee replacement (TKR) on knee OA patients who had participated in the former trial. Thirteen TKRs were performed in the population after a 4-year follow-up. More TKRs were performed in the placebo group than in the CS group (69% vs. 31%). Prieto-Alhambra D, et al. 2013[43] performed a cohort study in Catalonia in 122,633 patients using real prescription data from chondroitin sulfate capsules, and data support evidence that chondroitin sulfate reduces the need for total knee arthroplasty (TKA). Specifically, chondroitin sulfate use for ≥6 months appears related to a reduction of 13% in rates of TKA in the first 2 years after knee OA diagnosis [HR 0.87 (95% CI 0.80 - 0.95)]. Chondroitin sulfate use for at least 1 year is associated with a 23% lower rate of TKA overall [HR 0.77 (95% CI 0.68 - 0.87)].

Meta-analyses, systematic reviews and international recommendtions Various meta-analysis of chondroitin sulfate clinical trials assessing its symptomatic and chondroprotective effect have been published (McAlindon T, et al. 2000;[44] Leeb B, et al. 2000;[45] Richy F, et al. 2003;[46] Bruyere O, et al. 2007;[47] Reichenbach S, et al. 2007;[48] Hochberg MC, et al. 2008;[49] Hochberg MC, et al. 2010;[50] Lee YH, et al. 2010;[51] Wandel S, et al. 2010[52]).

McAlindon T, et al. 2000[53] concluded that the effect of the product was moderate to large with an effect size of 0.96 (equivalent to a large effect) when including all studies, and an effect size of 0.78 (equivalent to a moderate effect) when the most positive study was excluded.

Leeb B, et al. 2000[54] evaluated the available data from 7 clinical trials with chondroitin sulfate and confirmed that it was significantly superior to placebo in terms of pain reduction and increase of functional capacity, with at least 50% improvement versus the control group.

The meta-analysis by Richy F, et al. 2003,[55] performed with randomized, placebo controlled clinical trials with chondroitin sulfate and glucosamine, analysed overall 8 trials with chondroitin sulfate in patients with knee or hip OA. The effect sizes observed in this study coincide with those of the meta-analysis by McAlindon T, et al. 200044, resulting in a moderate to large effect (0.54 to 0.92). The authors also conclude that the available data with chondroitin sulfate support the clinical efficacy observed with this drug regarding improvement of osteoarthritic symptoms.

A meta-analysis published by Reichenbach S, et al. 2007,[56] which used explicit methods to conduct and report[57] a systematic review of 20 trials, questioned the efficacy of chondroitin sulfate for the treatment of osteoarthritis. The meta-analysis identified a large effect size of 0.75 for chondroitin sulfate. However, the authors argued a high degree of heterogeneity among trials, which made the interpretation of results difficult. Thus, they pooled results from the 3 trials with large sample sizes and an intention to-treat analysis, which resulted in an effect size near 0. It is worth noting that these 3 trials were the GAIT study,[28] which did not reach statistical significance mainly due to the high placebo response, as detailed above, and the STOPP[58] and Michel BA, et al. 2005[59] studies, both primarily designed to assess disease modification and not symptomatic efficacy, which therefore included patients with low pain levels, making it difficult to identify symptomatic effects. On the other hand, both the STOPP[60] and Michel BA, et al. 2005[61] studies provided very positive and significant results in terms of slowing disease progression in favor of chondroitin sulfate.

In 2010, Wandel S, et al.[62] (the same group of authors as that of Reichenbach S, et al. 2007[63]) published in the British Medical Journal a systematic review and network meta-analysis including data from randomised trials to determine the effect of chondroitin sulfate and glucosamine, on joint pain and on radiological progression of osteoarthritis. The results included 10 trials in 3803 patients. The authors’ conclusions were that compared with placebo, glucosamine, chondroitin sulfate, and their combination do not significantly reduce joint pain or have an impact on narrowing of joint space.

However, as detailed by many experts (see Responses to the study in: http://www.bmj.com/content/341/bmj.c4675?tab=responses) and the subsequently published Letters to the Editor (Pelletier JP, et al. 201054; Giacovelli G, et al. 201055; Reginster Y, et al. 201056) various methodological concerns were raised concerning this publication. Initially, the criteria used by Wandel et al. for the selection of trials were questionable. Second, the exclusion of small studies was considered highly debatable, as the authors included only trials with a minimum of 100 patients per arm. Additionally, baseline pain values were not taken into account; a difference of 0.9 units for severe pain (>7) is clinically different from the same difference for pain <4. Indeed, in one of the three trials of chondroitin sulfate on disease modification the baseline pain score was 2.5, thus unlikely to decrease by >0.9. Wandel S, et al. 201052 defined an effect size (ES) >0.39 as clinically relevant. However, in osteoarthritis, ES <0.4 are routinely considered to be clinically meaningful, e.g. acetaminophen is recommended for the initial treatment of symptomatic osteoarthritis by ACR, EULAR and OARSI, yet its ES for pain is < 0.20. Wandel et al., also conclude that the ES of chondroitin and glucosamine as disease modifying drugs for osteoarthritis are not clinically meaningful. These results contradict other meta-analyses (Hochberg MC, et al., 200849 and 201050; Lee YH, et al. 201051) evaluating the disease modifying effect of chondroitin sulfate analysing the same trials. Additionally, the British Medical Journal Senior Research Editor also expressed concerns about some of the conclusions of the authors in the post-publication review process of the article (http://www.bmj.com/rapid-response/2011/11/03/report-bmj-post-publication-review-meeting).

Finally, other publications have questioned and risen similar methodological concerns about this meta-analysis (Markenson JA. 2011[64] and Henrotin Y. 2012[65]).

As for meta-analysis and systematic reviews assessing the disease modifying effect of the product, Bruyere O, et al. 2007[66] concluded there was compelling evidence that glucosamine sulfate and chondroitin sulfate may interfere with progression of osteoarthritis.

Hochberg MC, et al. 2008[67] and 2010[68] evaluated the disease modifying effect of chondroitin sulfate in two independent meta-analyses. The two meta-analyses conclude that chondroitin sulfate at a dose of 800 mg/day results in a significant reduction of joint space narrowing, providing evidence of a disease modifying effect in osteoarthritis.

Lee YH, et al. 2010[51] published a meta-analysis on the disease modifying effect of chondroitin sulfate and glucosamine suggesting that both products may slow down the osteoarthritic process after 2 and 3 years of daily treatment.

As regards international recommendations, both the Osteoarthritis Research Society International (OARSI),[69][70] and the European League Against Rheumatism (EULAR),[71] have included chondroitin sulfate among the current recommended pharmacological modalities for osteoarthritis treatment and have granted chondroitin sulfate the highest level of evidence “1A” (OARSI and EULAR) and highest strength of recommendation “A” (EULAR). Also the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) generated a document providing recommendations for the use of symptomatic slow acting drugs in osteoarthritis.[72] For chondroitin sulfate a strong recommendation of use in the symptomatic treatment of osteoarthritis was provided. The molecule is in fact positioned by the experts as a chronic background treatment (step 1) in patients with knee OA.

History[edit]

Chondroitin sulfate was originally isolated well before the structure was characterised, leading to changes in terminology with time.[73] Early researchers identified different fractions of the substance with letters.

Letter identification Site of sulfation Systematic name
Chondroitin sulfate A carbon 4 of the N-acetylgalactosamine (GalNAc) sugar chondroitin-4-sulfate
Chondroitin sulfate C carbon 6 of the GalNAc sugar chondroitin-6-sulfate
Chondroitin sulfate D carbon 2 of the glucuronic acid and 6 of the GalNAc sugar chondroitin-2,6-sulfate
Chondroitin sulfate E carbons 4 and 6 of the GalNAc sugar chondroitin-4,6-sulfate

"Chondroitin sulfate B" is an old name for dermatan sulfate, and it is no longer classified as a form of chondroitin sulfate.[74]

Chondroitin, without the "sulfate", has been used to describe a fraction with little or no sulfation.[75] However, this distinction is not used by all.

Although the name "chondroitin sulfate" suggests a salt with a sulfate counter-anion, this is not the case, as sulfate is covalently bonded to the sugar. Rather, since the molecule has multiple negative charges at physiological pH, a cation is present in salts of chondroitin sulfate. Commercial preparations of chondroitin sulfate typically are the sodium salt. Barnhill et al. have suggested that all such preparations of chondroitin sulfate be referred to as "sodium chondroitin" regardless of their sulfation status.[76]

Society and culture[edit]

Manufacture[edit]

Most chondroitin appears to be made from extracts of cartilaginous cow and pig tissues (cow trachea and pig ear and nose), but other sources such as shark, fish, and bird cartilage are also used. Since chondroitin is not a uniform substance, and is naturally present in a wide variety of forms, the precise composition of each supplement will vary.[76] In fact, although many food supplement companies produce their products in compliance with human food processing Good Manufacturing Practice (GMP), most of them do not produce their products in compliance with the GMP regulations for pharmaceuticals, resulting in products without pharmaceutical requirements.[77] Companies have attempted to produce chondroitin from other substances but have not yet had success.

All the Chondroitin Sulfate found commercially is a mixture of different fractions and the ratio between them is like they are found in the original specie. Chondroitin Sulfate extracted from bovine has a 70% of Chondroitin Sulfate A and 30% of Chondroitin Sulfate C. Chondroitin Sulfate extracted from marine species is 30% of Chondroitin Sulfate A and 70% of Chondroitin Sulfate C.[citation needed]

Recent testing has revealed several flaws in the older testing methods. Without knowing the source of the chondroitin (e.g., shark, porcine, or bovine) and the approximate age of the animal, it is impossible to get a reliable reference standard, and, thus, results from previous testing had yielded percentages between 50 and 400%. In 2007, David Ji et al. reported in the Journal of Analytical Chemistry an extremely accurate method of quantification. The method included using an enzyme to break the chondroitin into its individual unsaturated disaccharides, and then measuring them using HPLC with an ion-pairing column and UV detection.[78]

Legal status[edit]

While it is a prescription or over-the-counter drug in 22 countries, chondroitin is regulated in the U.S. as a dietary supplement[79] by the Food and Drug Administration. In Europe, chondroitin sulfate formulations are approved as drugs with evidenced efficacy and safety demonstrated by clinical trials in osteoarthritic patients.[80] Adebowale et al. reported in 2000 that of 32 chondroitin supplements they analysed, only 5 were labeled correctly, and more than half contained less than 40% of the labeled amount.[81] With the introduction of GMP regulations for dietary supplements in 2008, chondroitin sulfate preparations are subject in the US to mandatory labeling standards as well as testing requirements for identity, purity, strength, and composition.[citation needed] United States Pharmacopoeia (USP) testing standards for the identification and quantification of chondroitin are well-established.[citation needed]

Clinical trials for osteoarthritis[edit]

In 2007, Reichenbach et al. used explicit methods to conduct and report a systematic review of 20 trials and concluded "large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent. Use of chondroitin in routine clinical practice should therefore be discouraged." In contrast, and also in 2007, Bruyere et al. concluded that "there is compelling evidence that glucosamine sulfate and chondroitin sulfate may interfere with progression of OA."

Contamination in heparin[edit]

On Wednesday, March 19, 2008 the U.S. Food and Drug Administration (FDA) identified "oversulfated chondroitin sulfate" as a contaminant in heparin originating from China.[82]

In this regard, "it is very important to remark on the relevant chemical differences between the chondroitin sulfate formulation approved in Europe as a drug and considered the reference product, and the "oversulfated chondroitin sulfate" identified as a contaminant in heparin originating from China."

The "oversulfated chondroitin sulfate" is not a product extracted from biological sources; it is synthesized through a sulfation reaction from the biological molecule. This is a semi-synthesis process that uses naturally derived chondroitin sulfate as a reagent in combination with various potentially dangerous chemicals, though their significance in the toxicity of "oversulfated chondroitin sulfate" is not known.

The resulting product contains 3 or 4 sulfate groups per disaccharide, and, therefore, its structure differs considerably from the original one (see #Sulfation section above). Furthermore, analysis of the contaminant unexpectedly revealed an unusual type of sulfation not found in any natural sources of chondroitin sulfate. In addition, a tetrasulfated disaccharide repeat unit has not been isolated to date from animal tissues[83]

Thus, chondroitin sulfate is merely the substrate of the reaction: The final, oversulfated molecule constitutes a new entity, whose pharmacological and clinical properties are most likely very different from the biological molecule, as it is demonstrated in a recent article published in New England Journal of Medicine. In this study,[84] Sasisekharan and colleagues showed that the oversulfated chondroitin sulfate (OSCS) found in contaminated lots of unfractionated heparin, as well as a synthetically generated OSCS reference standard, directly activated the kinin–kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator. In addition, OSCS induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins. Chondroitin sulfate A was also tested and it showed no induction of amidollytic activity. Screening of plasma samples from various species indicated that swine and humans are sensitive to the effects of OSCS in a similar manner. OSCS-containing heparin and synthetically derived OSCS-induced hypotension associated with kallikrein activation when administered by intravenous infusion in swine. In contrast, none of the three pigs treated with chondroitin sulfate A showed any significant changes in blood pressure or heart rate.

See also[edit]

References[edit]

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