Chemistry and Forms

Chondroitin sulfate (CS) is composed of a protein core covalently linked to complex of large-molecular-weight glycosaminoglycans (GAGs) and disaccharide polymers, large linear heteropolysaccharide chains composed of equimolar amounts ofD-glucuronic acid,D-acetylgalactosamine, and sulfates in 10 to 30 repeating disaccharide units. These repeating chains of GAGs are found embedded with type II collagen fibers in cartilaginous tissue. Chondroitin sulfate structures appear in two primary forms: chondroitin sulfate A (CSA) or chondroitin-4-sulfate has a sulfate group in the 4 position of galactosamine, and chondroitin sulfate C (CSC) or chondroitin-6-sulfate has a sulfate group in the 6 position.

Physiology and Function

Chondroitin sulfate is normally synthesized endogenously and secreted by chondrocytes, but such endogenous production tends to decrease with age, thereby playing a role in the declining ability to maintain normal structure and function of joint cartilage typically associated with the aging process.

Chondroitin sulfates are widely distributed in tissues and fluids, particularly throughout connective tissue, joint cartilage, internal walls of blood vessels and skin, urinary bladder, and embryonic tissue tissues, as well as amniotic fluid, cornea, heart valves, placenta, synovial fluid, teeth, and umbilical cord. They are the most abundant GAGs in the body.

Among its several functions, CS is most well known for its central role in articular cartilage. The high concentration of CS in the collagen network provides structure and a load-bearing surface that is both tough and compliant. By absorbing water and holding nutrients, chondroitin enhances the thickness and elasticity of cartilage and increases its ability to absorb and distribute compressive forces. Chondroitin regulates formation of new cartilage matrix by stimulating chondrocyte metabolism and synthesis of collagen and proteoglycan and facilitating transport through the low-blood-flow environment. In particular, chondroitins enhance levels of hyaluronic acid, a protective fluid that lubricates the joints. Furthermore, chondroitin sulfate inhibits the degradative action of elastase and hyaluronidase, synovial enzymes that participate in inflammation and contribute to cartilage destruction and loss of joint function by breaking down cartilage matrix and synovial fluid.

Known or Potential Therapeutic Uses

Evidence from clinical trials is gradually emerging to confirm the widespread anecdotal reports of chondroitin efficacy in the treatment of musculoskeletal injuries and degenerative joint disease, such as osteoarthritis. Administration of exogenous CS supplements the naturally occurring CS in maintenance of strong, flexible cartilage and support of healthy joint function. Some clinicians and researchers studying and treating osteoarthritis (OA) refer to CS as a “symptomatic slow-acting drug for osteoarthritis (SYSADOA).” Chondroitin sulfate addresses OA symptoms by reducing pain and increasing overall mobility while also slowing the pathological process by stabilizing and possibly improving bone and joint metabolism. Reports consistently indicate that response to treatment with chondroitin may have a delayed effect (typically reaching maximal effects after 2-6 months of regular use) compared with conventional analgesics, but that the therapeutic response exhibits longer duration (typically 3 months) after cessation of treatment. Evidence from human trials has thus far not matured sufficiently to determine whether chondroitin primarily slows or halts the process of cartilage destruction and joint damage or is capable of promoting repair and regeneration of damaged cartilage and reversal of arthritic changes, and if so, under what circumstances and treatment protocols.

As a compound rich in sulfur, and thus related to glucosamine sulfate, chondroitin may help cartilage by acting in a nutritive capacity to provide raw materials for tissue repair and regeneration.

Chondroitin may also lower blood cholesterol levels, prevent atherosclerosis, and reduce the risk of heart attacks in individuals who already have atherosclerosis.

The GAGs affect how the body processes oxalate and chondroitin intake is associated with reduced risk of stone formation by reducing urinary oxalate excretion.

Historical/Ethnomedicine Precedent

Many traditional cultures have encouraged the dietary consumption of connective tissue and use of bones in soups.

Possible Uses

Alzheimer's disease, angina, anti-inflammatory, atherosclerosis, chronic venous ulcers, connective tissue injury recovery, coronary artery disease (secondary prevention), gonarthrosis, heart disease, hypercholesterolemia, hyperlipidemia, interstitial cystitis, iron deficiency anemia, joint injury rehabilitation, leukemia, malaria, myocardial infarction, nephrolithiasis (oxalate stones), osteoarthritis (OA), osteoporosis, preterm labor prevention, snoring, sprain/strain injury.

Deficiency Symptoms

Chondroitin is not considered an essential nutrient because of endogenous synthesis. Consequently, consensus is lacking for characteristics of a chondroitin deficiency.

Dietary Sources

Animal cartilage is the only dietary source of chondroitin. The precise amount and bioavailability of chondroitin in foods is unknown.

Nutrient Preparations Available

Oral chondroitin sulfate is absorbed particularly rapidly in humans when it is dissolved in water before ingestion. It is rapidly degraded during its absorption and by extensive first-pass metabolism. ^1,2The active moiety remains unknown. In a double-blind clinical study published in 1992, L’Hirondel ³ demonstrated that up to 15% of oral chondroitin is absorbed intact through the digestive tract. Subsequent research determined that approximately 12% of oral CS becomes available to the joint tissues from the blood. ⁴ These studies have disproved previous speculation that oral chondroitin was not efficacious because of the large size of its molecules.

Different chondroitin products can very significantly in their chemical structure, thus affecting absorption and effectiveness. Chondroitin products with physically smaller molecules (<16,900 daltons) are more likely to provide superior bioavailability. ⁵ Thus, low-molecular-weight (LMW) CS is preferred. Findings from clinical trials using proprietary or otherwise specific forms of CS may not be reliably extrapolated to other products.

A review of two U.S. products conducted in 2000 reported that both had lower chondroitin levels than declared on the labels; similarly, 6 of 13 glucosamine and chondroitin combination products assayed contained low chondroitin levels. ^6,7

Dosage Forms Available

Capsule (often containing CS gel), tablet; often with glucosamine sulfate and or MSM; eyedrop solutions; intravesicular bladder administration; intramuscular (IM) injection; nasal spray; topical cream.

Source Materials for Nutrient Preparations

Chondroitin sulfate was first extracted and purified in the 1960s. Commercially available forms are usually manufactured from shark, pig, or bovine cartilage or bovine trachea, or by synthesis.

Dosage Range

Adult

Dietary: No minimal dietary requirement established.

Supplemental/Maintenance: 300 mg one to three times daily.

Pharmacological/Therapeutic: 300 to 1500 mg daily, usually in divided doses, as indicated by manufacturer recommendations and use in clinical trials. A typical dosage level for osteoarthritis is 400 mg three times daily. Researchers investigating atherosclerosis have sometimes initiated therapy administering 5 g twice daily, with meals, lowering the amount to 500 mg three times daily after a few months.

Toxic: No toxic dosage level established.

Pediatric (<18 Years)

Dietary: No minimal dietary requirement established.

Supplemental/Maintenance: Not currently recommended for children.

Pharmacological/Therapeutic: Potential use in treating musculoskeletal injuries, but specific treatment recommendations have not been established.

Toxic: No toxic dosage level established specifically for infants and children.

Laboratory Values

Serum and synovial fluid levels have been used in clinical trials. Uesaka et al. ⁸ concluded that “synovial fluid levels of C4S and C6S may provide useful data in assessing the pathology of OA.” However, du Souich and Verges ⁹ found that measuring plasma concentrations of CS “allows prediction of the maximal effect (Emax) elicited by the drug and the concentration eliciting 50% of Emax (EC50).”

Overview

Chondroitin sulfate is generally well tolerated at usual dosage levels, and reports of serious adverse effects are absent. Nausea may occur at intakes greater than 10 g daily. However, no clinical trials have been of sufficient duration to assess conclusively the long-term safety of chondroitin administration.

Nutrient Adverse Effects

General Adverse Effects

Rare reports of gastrointestinal (GI) effects (diarrhea, constipation, abdominal pain) and headache constitute the primary known adverse effects. Rare reports attribute edema of legs and eyelids, arrhythmia, and alopecia.

In canine experiments, McNamara et al. ¹⁰ reported significantly decreased hematocrit, hemoglobin, white blood cell (WBC) count, and platelet count after 30 days’ administration of chondroitin and suggested a potential risk of internal bleeding. However, no case reports or clinical trials have reported occurrences of bleeding in humans as a result of exogenous chondroitin intake.

Adverse Effects Among Specific Populations

A single case report describes an exacerbation of asthma attributed to use of a glucosamine-chondroitin supplement. ¹¹

Pregnancy and Nursing

No adverse effects have been reported. However, sufficient research-based evidence is lacking to guarantee the safety of chondroitin in pregnancy and breastfeeding. Pending conclusive findings, prudence suggests that chondroitin be avoided during pregnancy. Some commentators have suggested that the structural similarity between heparin and chondroitin is sufficient to warrant contraindication during pregnancy because heparin is contraindicated during pregnancy, except in women with protein C or S deficiency who are normally maintained on warfarin (Coumadin), which is indeed contraindicated in pregnancy, where heparin is substituted for the duration of the pregnancy.

Infants and Children

No adverse effects have been reported. However, sufficient research-based evidence is lacking to guarantee the safety of chondroitin in infants and children.

Contraindications

No qualified contraindications have been published. Out of caution, and despite a lack of substantive evidence, some commentators have suggested that individuals with bleeding problems, such as hemophilia, or temporarily at risk for bleeding during surgery or labor and delivery should avoid chondroitin. Pending conclusive findings, such speculation may deserve consideration, and chondroitin avoidance may be appropriate for short periods before and after surgery.

An emerging body of evidence suggests that exogenous CS be avoided by individuals with a history or high susceptibility of prostate cancer, breast cancer, or melanoma. Myers ^12,13reported the case of aggravated prostate cancer in an individual whose prostate cancer had been in remission until he initiated use of CS. In a review of relevant literature, Myers reported several studies that together could reasonably be interpreted to support his hypothesis that the chondroitin had exerted a tumor-promoting effect. Myers proposes that the action of CS involves formation of a complex with the protein versican, which along with decorin, is one of two proteins that CS is attached to in joint cartilage. Notably, prostate cancer cells, breast cancer cells, and melanoma cells also express versican on their surface. Thus, the introduction of exogenous chondroitin could increase levels of versican-chondroitin complex adhering to the surface of the cancer cells, facilitating their growth and metastasis.

De Klerk et al. ^14,15studied the concentration of GAGs in fetal, normal adult, and benign hyperplastic prostate tissue. They found that dermatan sulfate is the predominant GAG in the adult normal prostate, with the central zone exhibiting a slightly higher CS content than the peripheral zone and an increased CS content in benign prostatic hyperplasia (BPH). ¹⁴ Subsequently, they investigated GAGs in human prostatic cancer and observed that the concentration of CS was higher in cancerous prostate tissue than in normal prostate tissue. ¹⁵ In 1997, Ricciardelli et al. ¹⁶ noted that elevated stromal CS GAG predicts progression in early-stage prostate cancer. The following year these researchers investigated versican and decorin, two proteins CS is attached to within the prostate, and found that versican may increase the spread of cancer, whereas decorin may suppress the spread of prostate cancer. ¹⁷ Then, in 1999, they observed that elevated levels of peritumoral CS predict a higher rate of recurrence after radical prostatectomy for early-stage prostate cancer and poor prognosis. Men demonstrating a high concentration of peritumoral CS had a 47% probability of recurrence within 5 years, in contrast to 14% in the men with low CS levels. ¹⁸ These issues were further explored in an in vitro study by Sakko, Ricciardelli, et al. ¹⁹ that examined whether versican, a recognized anti–cell adhesion molecule for various mesenchymal and nerve cell types, influences prostate cancer cell adhesion to extracellular matrix components. Further research involving versican purified from human prostate fibroblast conditioned medium confirmed its antiadhesive activity for prostate cancer cells. These researchers concluded that versican is an important modulator of tumor cell attachment to the interstitial stromal matrix of the prostate, the latter being an essential step in cancer cell motility and local invasion of the prostatic stroma.

At this point, no clinical trials or epidemiological studies have specifically determined whether administration of CS is carcinogenic or likely to aggravate existing prostate carcinoma. In particular, evidence is lacking to confirm a pattern of occurrence or mechanism of action linking chondroitin preparations and the development of CS-containing versican within tumors.

Pending substantive demonstration of safety, health care professionals treating men with prostate cancer or hyperplasia are advised to recommend glucosamine sulfate as a safe and effective substitute for chondroitin or for use as a monotherapy instead of in combination with CS. Similar considerations may be warranted for patients with a history of breast cancer or melanoma. No evidence suggests, nor have cautions been raised, that glucosamine contributes to the progression of prostate or other cancers.

Precautions and Warnings

Chondroitin could have a potential, although unproven and improbable, interaction with anticoagulant medications.

Strategic Considerations

Chondroitin sulfate has effectively graduated from the ranks of “alternative” therapies to the realm of standard care within recent years. Starting with its role in treating musculoskeletal disorders its potential scope for therapeutic application offers a promising future, especially within the context of multidisciplinary care using an integrative model.

Degenerative joint disease, more often referred to as osteoarthritis, is characterized by the progressive loss of functional articular cartilage and represents the most common type of arthritis worldwide. For example, osteoarthritis affects more than 20 million Americans, most of whom are over 45 years of age. Although conventional pharmacological therapies may provide palliative relief for many individuals, the shortage of effective clinical approaches for addressing the underlying disease process and pathophysiological changes has frustrated both health care providers and patients grappling with this painful degenerative process. During the past decade, a body of evidence from clinical trials and experimental studies has emerged supporting the use of CS and glucosamine sulfate, often in concert. Use of these agents, usually self-prescribed by patients, has grown steadily in the United States and Europe.

These cartilage extracts are considered as drugs in European continental countries and dietary supplements in the United States and England. Although many physicians initially relegated these agents to a questionable role based on their status as “nutritional supplements,” maturation of the production system to the standards of Good Manufacturing Practices is evolving to match their proven efficacy and strong safety profile. Most importantly, chondroitin has demonstrated efficacy in halting the degenerative changes within joints to produce symptomatic efficacy (e.g., in knee OA), which is complemented by the structural and symptomatic efficacy of glucosamine sulfate. Furthermore, many literature-derived data show that CS could have an anti-inflammatory activity and a chondroprotective action by modifying the structure of cartilage and increasing both the concentration of hyaluronic acid and the viscosity of synovial fluid.

Several systematic reviews and meta-analyses have described the growing body of evidence documenting the therapeutic efficacy of CS in the treatment of OA. In a systematic quality assessment and meta-analysis of 15 clinical trials in the Journal of the American Medical Association, researchers concluded that glucosamine and CS “demonstrate moderate to large effects, but quality issues and likely publication bias suggest that these effects are exaggerated.” ²⁰ However, in a meta-analysis of seven trials investigating efficacy of chondroitin in the treatment of knee and hip OA also published in 2000, Leeb et al. ²¹ reported that in patients followed to 120 or more days, “CS was shown to be significantly superior to placebo” with respect to standard indices of pain and function. They concluded that “pooled data confirmed these results and showed at least fifty per cent improvement in the study variables in the CS group compared to placebo.” ²¹ In a subsequent paper, Richy, Reginster, and a team of investigators from Belgium and France conducted seven individual, outcome-oriented meta-analyses using 15 randomized clinical trials selected from approximately 500 studies on the basis of high methodological quality. Although noting that quality scores in the chondroitin trials exhibited a mean of only 68.4%, they concluded: “Our work provides a clear, evidence-based advance regarding the interest in the wide use of glucosamine and chondroitin as disease-modifying compounds in the treatment of knee osteoarthritis through an accurate, conservative analysis of the most reliable experiments performed until now.” ²²

In a series of interviews with several leading researchers and respected clinicians in the OA field, Hungerford ²³ documented the emerging consensus supporting use of chondroitin (and glucosamine sulfate) among experienced clinicians. Noting that “chondrocytes are constantly replacing and repairing their environment,” particularly “reversible lesions that occur during daily activities,” Schenck and Verbruggen suggested that “90% of all patients with osteoarthritis can be treated nonoperatively.” However, this repair capacity decreases with age and demanding activity because both the incorporation of sulfate into proteoglycans and the capacity to synthesize new molecules and large molecule aggregates decline with age. In response to these degenerative changes, support of normal function can be achieved using a nutritive approach. Thus, Hungerford ²³ stated that in treating patients with OA, he generally uses LMW “chondroitin sulfate with glucosamine for symptomatic relief” and sees a response rate of “approximately 50%.” These experts and others experienced in the care of individuals with degenerative joint changes (and injury-related joint repair) consistently emphasize that this synergistic approach should be expanded whenever possible to include individualized exercise programs and nutritional support. Acupuncture, gentle joint mobilization, exercise programs, and botanical medicine represent other time-tested options of potential value in creating an evolving and personalized multidisciplinary therapeutic strategy for prevention and treatment.

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