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Chondroitin Sulfate

Nutrient Name: Chondroitin sulfate.
Synonyms: Chondroitin, chondroitin sulphate, CS, CSA, CSC; ACS4-ACS6, CDS, chondroitin sulfate A, chondroitin sulfate C, chondroitin sulphate A sodium, chondroitin-4-sulfate, chondroitin-6-sulfate, chonsurid, condroitin, Condrosulf.
Related Substances: Chondroprotective agents, chondroitin sulfuric acid, GAG, galacotosaminoglucuronoglycan sulfate (Matrix), glycosaminoglycan, mesoglycan (heparan sulfate-52%, dermatan sulfate-35%, heparin-8%, chondroitin sulfate-5%).

Summary Table

Drug/Class Interaction Type	Mechanism and Significance	Management
Cisplatin Platinum chemotherapy /	Complexing with chondroitin sulfate appears to alter pharmacokinetic properties of cisplatin and reduce nephrotoxicity without diminishing therapeutic efficacy. Consistent findings in animal and in vitro studies suggest that human trials are warranted.	Administration of cisplatin complexed with chondroitin may be beneficial. Close monitoring appropriate.
Nonsteroidal anti-inflammatory drugs (NSAIDs) /	Coadministration of chondroitin sulfate and NSAIDs may enable anti-inflammatory effect at lower drug doses. Concurrent use of chondroitin sulfate with NSAIDs appears to result in an additive or synergistic effect. More strategically, NSAIDs may promote cartilage destruction and impair cartilage repair.	Coadministration may enable decreased dose and shortened period of NSAID use.

nutrient description

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.

nutrient in clinical practice

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).”

safety profile

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.

interactions review

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.

nutrient-drug interactions

Cisplatin and Related Platinum Chemotherapy Compounds

Evidence: Cisplatin ( cis-diaminedichloroplatinum, CDDP; Platinol, Platinol-AQ). Extrapolated, based on similar properties: Carboplatin (Paraplatin), oxaliplatin (Eloxatin).

	Prevention or Reduction of Drug Adverse Effect
	Beneficial or Supportive Interaction, with Professional Management

Probability: 2. Probable
Evidence Base:

Emerging

Effect and Mechanism of Action

Cisplatin has a reputation as an effective antineoplastic agent, particularly against solid tumors such as testicular cancer, ovarian cancer, both small cell and non–small cell lung cancer, and head and neck cancer. However, renal, GI, and neurological toxicity limit its clinical application, with nephrotoxicity being the most common dose-limiting adverse effect. When administered as a complex, cisplatin and CS act to alter the pharmacokinetic properties of cisplatin and reduce the nephrotoxic effects usually associated with platinum-based chemotherapy.

Research

Hausheer et al. ²⁴ investigated a variety of substances to address the fact that almost all platinum-protecting drugs have their own intrinsic toxicities, which can be additive to the toxicity of platinum-type drugs. They observed that the sulfate groups were highly favored to react with platinum species. Albertini et al. ²⁵ demonstrated that chondroitin sulfate A (CSA, 4-sulfate) and chondroitin sulfate C (CSC, 6-sulfate) exhibited completely different physiological roles against copper-dependent oxidation of lipoprotein, probably because of the different Cu ²⁺ binding ability of each form.

Subsequently, Zhang, Otagiri, et al. ^26,27 conducted a series of studies exploring the application of CSA and CSC employed as to form complexes with cisplatin (CDDP) in reducing toxic effects of cisplatin monotherapy. They stated that the “purpose of the study is to apply both carboxylate and sulfate groups to form a complex via displacement of two labile chlorides of CDDP.” ²⁶ In their initial research, they “found that CSA with a mean molecular weight of 23 kDa was capable of increasing the plasma retention of CDDP while reducing its nephrotoxicity.” ²⁷ Later, using a rat model, Zhang et al. ²⁶ compared the effects of two different doses of a cisplatin-CS complex with cisplatin monotherapy in reducing the nephrotoxic effects associated with cisplatin therapy, specifically comparing in vivo pharmacokinetics and in vitro cytotoxicity. They found that complexing cisplatin with either of two doses of chondroitin (2 and 5 mg/kg) altered the pharmacokinetic properties of cisplatin. This modified activity provided a protective effect by slowing the distribution and perfusion of cisplatin to tissues, particularly the kidneys, and reducing renal clearance while maintaining the same level of therapeutic activity. Their conclusion stated that this study provided “evidence that the sulfated position of chondroitin sulfates really affects the stability and the disposition of the CDDP complexes. The complex prepared with chondroitin sulfate A, with a molecular weight of over 20 kDa, is superior to that prepared by chondroitin sulfate C, because of improved pharmacokinetic properties and similar pharmacological activity to native drug.” ²⁶ Such consistent findings from these preliminary animal studies indicate that further clinical studies are warranted.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The emerging body of research strongly suggests that coadministration of CS with platinum-based chemotherapeutic agents such as cisplatin has the potential to serve as a safe and effective adjuvant therapy capable of decreasing the nephrotoxic effects resulting from drug-induced oxidative damage. Well-designed randomized trials with both arms carefully stratified to have equivalent prognostic factors will be necessary to be certain that concomitant chondroitin therapy with platinum-based therapies (as well as other neurotoxic chemotherapies, e.g., taxanes, vinca alkaloids) does not compromise efficacy of the chemotherapy. When offered such therapy, patients should be informed of the preliminary work done, and that although chondroitin likely can provide protection from nephrotoxic chemotherapy, we cannot be certain at this time that it would definitely not compromise chemotherapy efficacy. This is much less of an issue when palliative chemotherapy is concerned, but when chemotherapy is given with curative intent, such as for germ cell tumors, careful monitoring of clinical response and full disclosure to the patient and their family regarding current evidence are essential. Such integrative approaches to oncology care require a high level of collaboration among health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics, usually only obtained in multidisciplinary oncology clinics.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

COX-1 inhibitors:Diclofenac (Cataflam, Voltaren); combination drug: diclofenac and misoprostol (Arthrotec); diflunisal (Dolobid), etodolac (Lodine), fenoprofen (Dalfon), furbiprofen (Ansaid), ibuprofen (Advil, Excedrin IB, Motrin, Motrin IB, Nuprin, Pedia Care Fever Drops, Provel, Rufen); combination drug: hydrocodone and ibuprofen (Reprexain, Vicoprofen); indomethacin (indometacin; Indocin, Indocin-SR), ketoprofen (Orudis, Oruvail), ketorolac (Acular ophthalmic, Toradol), meclofenamate (Meclomen), mefenamic acid (Ponstel), meloxicam (Mobic), nabumetone (Relafen), naproxen (Aleve, Anaprox, Naprosyn), oxaprozin (Daypro), piroxicam (Feldene), salsalate (salicylic acid; Amigesic, Disalcid, Marthritic, Mono Gesic, Salflex, Salsitab), sulindac (Clinoril), tolmetin (Tolectin). COX-2 inhibitor:Celecoxib (Celebrex).

	Beneficial or Supportive Interaction, Not Requiring Professional Management
	Prevention or Reduction of Drug Adverse Effect

Probability: 2. Probable
Evidence Base:

Emerging

Effect and Mechanism of Action

In addition to supporting formation, repair, and functionality of cartilage, tendons, bone, and joints, the nutritive activity of CS can counter the tendency of NSAID therapy to impair formation and repair of connective tissue and bone and joint rehabilitation.

Research

Numerous in vivo, animal, and human studies suggest that many NSAIDs exert deleterious effects on synthesis of vasodilator prostaglandins, joint perfusion, chondrocyte and proteoglycan metabolism, bone formation, cartilage synthesis, tendon-to-bone healing, and organization in articular cartilage, especially influencing the course of osteoarthritis. ^28-34

In a 1997 discussion of the issue of coadministration of NSAIDs and CS, Towheed and Hochberg ^34a noted that these agents provided a complementary (rather than directly pharmacologically additive) effect within a comprehensive strategy for treating OA and other musculoskeletal conditions. Leeb et al. ²¹ conducted a meta-analysis of seven randomized, placebo-controlled and double-blind or double-dummy trials involving a total of 703 patients (372 treated with CS and 331 controls) with OA of the knee and/or hip. ^3,35-40 CS treatment duration varied from 3 to 12 months and prescribed daily CS doses ranged from 800 to 2000 mg. Because of substantial differences in reporting among the studies reviewed, the underlying therapy with NSAIDs and analgesics could not be evaluated on a clear-cut, quantitative basis. These authors noted that “CS was given along with analgesics or nonsteroidal anti-inflammatory drugs, making required dosage of comedication an important factor.” Thus, “all seven publications reported statistically significant reductions in consumption of NSAIDs and/or analgesics compared to baseline in the CS groups and much less marked ones for placebo.” They concluded that “CS in combination with analgesics or low-dose NSAIDs is superior to analgesics or NSAIDs alone over longer periods in the treatment of OA. Moreover, a reduction of the required daily dose of analgesics or NSAIDs could be achieved.” Therefore, coadministration might enable reducing dose of these medications, especially in managing pain associated with osteoarthritis, and reduce risk of adverse effects associated with prolonged NSAID use.

In a short-term in vitro culture using cartilage specimens, El Hajjaji et al. ⁴¹ found that celecoxib, a cyclooxygenase (COX-2) selective inhibitor, increased the synthesis of hyaluronan (HA) and proteoglycans (PGs) in human cartilage explants with midrange severity of OA in a relatively dose-dependent manner. celecoxib also reduced the net loss of labeled HA and PG molecules from cartilage explants.

Jordan et al. ⁴² conducted a survey of 828 patients over 55 years of age with clinically diagnosed knee OA in two general-practice populations in Wessex, England, comparing conventional and complementary therapy use by a deprived urban population with that of an affluent rural population. They found a high prevalence of NSAID use, and in “the affluent population there were statistically more NSAIDs, [and] glucosamine and chondroitin sulphate were also used.”

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The body of available evidence clearly supports concomitant use of CS and NSAIDs as a therapeutic option of probable value in the treatment of OA and related conditions. Such an approach is well supported by consistent findings from the research literature and emerging standards of conscientious and innovative clinical practice, and it appears to offer enhanced combined efficacy at minimal risk and cost and, because of the ability to reduce NSAID dosage levels, a likelihood of reduced risk of adverse effects.

Notably, discrimination in selecting the most efficacious anti-inflammatory agent appears to be critical, since both animal and human research indicate that aspirin and acetaminophen may interfere with the activity and efficacy of concomitant glucosamine sulfate (GS). Evidence to this point, as reviewed in the Glucosamine Sulfate monograph, suggests that coadministration of ibuprofen with GS may provide a synergistic therapeutic effect and that acetaminophen should be avoided. Thus, for example, a reasonable option where the activity of an NSAID seems indicated might be combining the standard dosage of CS (400 mg) and GS (500 mg) with ibuprofen (200 mg), three times daily, with phasing out of the ibuprofen to an as needed basis when clinically improved. This long-term clinical strategy thus shifts from symptom management to maintenance, with emphasis on tissue strengthening and maximal restoration of healthy function.

theoretical, speculative, and preliminary interactions research, including overstated interactions claims

Anticoagulants, heparin, unfractionated (UFH):Heparin (Calciparine, Hepalean, Heparin Leo, Minihep Calcium, Minihep, Monoparin Calcium, Monoparin, Multiparin, Pump-Hep, Unihep, Uniparin Calcium, Uniparin Forte).

Anticoagulants, heparinoids:Danaparoid (Orgaran), fondaparinux (Arixtra).

Anticoagulants, low-molecular-weight (LMW) heparin:Ardeparin (Normiflo), certoparin (Mono-Embolex), dalteparin (Fragmin), enoxaparin (Clexane, Lovenox), nadroparin (Fraxiparine), tinzaparin (Innohep).

Anticoagulants, oral vitamin K antagonist anticoagulants:Anisindione (Miradon), dicumarol, ethyl biscoumacetate (Tromexan), nicoumalone (acenocoumarol; Acitrom, Sintrom), phenindione (Dindevan), phenprocoumon (Jarsin, Marcumar), warfarin (Coumadin, Marevan, Warfilone).

Observations of structural similarities in the chemical composition of CS and heparin have been extrapolated into speculative claims of a potential risk of adverse interactions in the presence of anticoagulant medications such as heparin (or warfarin), as well as antiplatelet agents, and warnings that chondroitin might be contraindicated in individuals with bleeding disorders. Chondroitin sulfate is a subcomponent of the antithrombotic danaparoid, which is classified as a “heparinoid” medication. Danaparoid sodium is a mixture of glycosaminoglycuronans, heparan sulfate, dermatan sulfate, and CS, isolated from porcine or other animal intestinal mucosa. Danaparoid is devoid of a heparin fraction; its antithrombotic effect is derived primarily from antithrombin III–mediated inhibition of factor Xa and to a significantly lesser extent by inactivation of factor IIa (thrombin). Dermatan sulfate (sometimes called chondroitin B sulfate) potentiates heparin cofactor II and may prolong bleeding time but is not used in treating joint pain or degeneration. Overall, the available data suggest that CS may potentially exert a mild anticoagulant effect. ⁴³

Several case reports have been published describing a possible augmentation effect, as indicated by an elevated international normalized ratio (INR), in patients taking formulations containing both GS and CS while undergoing anticoagulant therapy with oral vitamin K antagonist medication. ^44,45

The limited and nonqualified nature of the available data in these published reports supports caution and indicates that further investigation through well-designed clinical trials is warranted. However, stark, generalized contraindications are not supported by the data available at this time. Health care providers treating individuals taking anticoagulant (or antiplatelet) medications are advised to caution patients against self-medication with CS and to monitor such patients in the event that CS administration is deemed clinically appropriate.

nutrient-nutrient interactions

Glucosamine Sulfate

The number of studies supporting increased efficacy from concomitant administration of GS and CS in the treatment of joint pain and degenerative conditions has grown steadily in number and power. Most have found the combination more effective than either agent alone, particularly in OA treatment. ^22,46-55 Although often limited by size and design, the findings from clinical trials remain consistent with known physiological function and reasonably predictable therapeutic activity.

Nevertheless, in the 4-year Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) involving almost 1600 participants with documented knee OA, Clegg et al. ^55,56 found that glucosamine hydrochloride (500 mg three times daily), CS (400 mg three times daily), or the combination for 24 weeks did not provide statistically significant relief (defined as a decrease in pain of at least 20%) from OA-associated pain among all subjects, compared to placebo and celecoxib (200 mg daily) as positive control. However, an analysis of the subgroup with initial moderate to severe pain (excluding those with mild pain) revealed relief with the combined nutrients at statistically significant levels compared to placebo (79.2% vs. 54.3%) or celecoxib (69.4%). Also, 60% of all subjects administered placebo reported 20% or greater pain reduction; this high response rate in the placebo group may have obscured a therapeutic response in subjects administered the glucosamine and/or CS, especially among subjects with initial mild pain. As with many similar trials, participants were allowed to use up to 4000 mg of acetaminophen daily for pain, except for the 24 hours before assessment, further confounding the data and possibly adversely affecting therapeutic response. Notably, however, resort to such “rescue” acetaminophen was relatively low, overall averaging fewer than two 500-mg tablets daily. ^56,57 The pivotal clinical issue of disease progression (vs. pain relief), including joint function and regeneration, was not addressed in this study. Such elements of pathophysiology are central to the therapeutic strategy of nutritional interventions, such as those involving the sulfate compounds, and are illuminated by research demonstrating that meniscal pathology increases the risk of cartilage loss in patients with symptomatic knee OA. ⁵⁸ Continued research is warranted, but changes in trial design might provide more meaningful clinical findings.

Manganese

Leffler et al. ⁴⁷ conducted a 16-week, randomized, double-blind, placebo-controlled crossover trial involving 34 male subjects investigating the combined effects of glucosamine HCl (1500 mg/day), CS (1200 mg/day), and manganese ascorbate (228 mg/day) in the treatment of degenerative joint disease (DJD) of the knee or low back. They found, by several objective and subjective measures, that such short-term combination therapy “relieves symptoms of knee osteoarthritis” and “appears safe.” In a 6-month, double-blind, placebo-controlled clinical trail involving 93 people with knee arthritis, Das and Hasmmand ⁴⁹ found that a combination of glucosamine and chondroitin (along with manganese) was more effective than placebo. It is not possible to determine from such studies whether or not manganese contributes additively, synergistically, or not at all to the established clinical activity of glucosamine and chondroitin.

Some sources suggest that total daily intake of manganese from foods and supplements should not exceed 11 mg, the upper limit of safety for manganese established by the Food and Nutrition Board of the U.S. Institute of Medicine.

Vitamin D; Vitamins C and E

Epidemiological studies suggest that a low serum level of vitamin D and low dietary intake of both vitamins C and E in healthy individuals 50 years of age is a predisposing factor for occurrence of knee OA at age 70. ⁵⁹

herb-nutrient interactions

Devil's Claw

Devil's Claw (Harpagophytum procumbens).

Ginger

Ginger (Zingiber officinale).

Traditional patterns of use in indigenous and classic medical practice suggest efficacy of these botanicals in the treatment of OA and related joint pain and degenerative conditions. Enhanced therapeutic benefits resulting from additive or synergistic effects of combined use with CS (as well as GS) are reasonably probable based on clinical anecdotal reports and known pharmacological activity. Further clinical trials of good design, adequate size, and extended duration are warranted to investigate efficacy and establish guidelines for therapeutic application. Adverse effects caused by toxicity, at usual dosage levels in appropriate conditions, are improbable based on currently available scientific data.

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