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Medical Evidence

Evidence For Synergistic Effect Of Glucosamine And Chondroitin Sulfates In Joint Health

Background: Chondroprotective agents have been defined as a compound that can accomplish the following six objectives in joint tissues (Ghosh, P., M. Smith, C. Wells. Second-line agents in osteoarthritis, Chapter 15 in Second-Line Agents in the Treatment of Rheumatic Diseases, J.S. Dixon, D.E. Furst, Eds., Marcel Dekker, New York, 1992, pp.363-427):

1. Enhance chondrocyte macromolecular synthesis (glycosaminoglycans, proteoglycans, collagens, proteins, RNA, DNA) 2. Enhance synthesis of hyaluron In synthesis by synoviocytes 3. Inhibit enzymes that degrade cartilage macromolecules 4. Mobilize thrombi, fibrin, lipids, cholesterol deposits in synovial spaces and blood vessels surrounding joints (subchondral vessels) 5. Reduce joint pain 6. Reduce synovitis

At present, no known drug is able to accomplish all of these objectives. Macromolecules endogenous to cartilage and their semisynthetic or synthetic mimics have been shown to accomplish some, but not all, of these objectives. Because the roles and functions of endogenous macromolecules (or their mimics) are integral to cartilage metabolism, they alone appear able from a pharmacological perspective to exhibit multiple objectives. However, at present, no single macromolecule can accomplish all of the stated objectives. Combinations of anti-inflammatory or analgesic drugs with macromolecules have exhibited many of the objectives, but still not all. Part of the problem with drug-nutrient combinations is the adverse side effects generated by drugs, which reduces therapeutic benefits. Thus, a new approach to combine compounds with both overlapping and complimentary functions without adverse side effects is needed.

Such a combination may exist by combining glucosamine salts and chondroitin sulfates.

Glucosamine is the predominant amino sugar utilized by connective tissues for synthesis of glycosaminoglycans and proteoglycans. Chondroitin sulfates are the major glycosaminoglycan species in cartilage, and consist of repeating disaccharide units of N-acetylgalactosamine and glucuronate. Both of these connective tissue components have been purified to homogeneity, and are available for use as oral or injectable agents.

Glucosamine synthesis by chondrocytes appears to be the key, rate-limiting step for synthesis of cartilage matrix. Glucosamine itself constitutes half of hyaluronan, keratan sulfates, heparan sulfates, and heparin Glucosamine is easily converted into galactosamine by epimerases, and thus, constitutes half of chondroitin sulfates and dermatan sulfates. In addition, almost every protein, including collagen, is glycosylated with either glucosamine itself or a derivative amino sugar. Thus, glucosamine is probably the key single compound necessary for cartilage matrix synthesis. Glucosamine has exhibited four of the six stated objectives. Evidence has shown that exogenous glucosamine salts significantly enhance chondrocyte synthesis of glycosaminoglycans, collagen, and DNA. Glucosamine has been hypothesized to enhance synthesis of synovial fluid hyaluronan. Although animal studies found that glucosamine did not possess analgesic properties, it did exhibit anti-inflammatory effects against animal models of inflammatory arthritis at high but safe doses. In addition, the numerous human studies of glucosamine used for osteoarthritis all exhibited reductions in pain and joint inflammation (synovitis markers). Thus, glucosamine has exhibited Chondroprotective abilities for objectives 1, 2, 5, & 6.

Chondroitin sulfates have also exhibited enhancement of chondrocyte macromolecule synthesis in cultures. Chondroitin sulfates have exhibited inhibition of degradative enzymes in cartilage. This appears to be more than fortuitous, since a major target of degradation in cartilage is the proteoglycans, and hyaluronan in synovial fluid. Chondroitin sulfates, by virtue of their chain lengths, competitively inhibit degradative enzymes. Chondroitin sulfates have been shown repeatedly to mobilize plaque and thrombi in-numerous studies. Oral administration had little effect on thrombi, but cholesterol-clearing effects were still evident. In human clinical studies, administration of chondroitin sulfates was associated with reduction of joint pain and improved joint mobility. Reduction in incidence of joint arthritis with associated synovitis in mice was achieved by oral chondroitin sulfates.

Chondroitin sulfates have exhibited five of the six stated objectives for chondroprotection. The degree of effect was less than for drugs, but the long-term safety profile of chondroitin sulfate meant that higher doses could be taken longer than drugs to achieve similar objectives. Thus, chondroitin sulfates exhibited chondroprotective abilities for objectives 1, 3, 4, 5, & 6.

Neither glucosamine or chondroitin sulfates exhibited all six stated objectives of a chondroprotective agent by themselves. However, combining the two agents has the potential to meet all six of the objectives. Overlapping roles include objectives 1, 5, & 6. It appears that objectives 5 & 6 are accomplished by fulfilling objectives 1 4. In other words, except at high doses, there are no apparent direct anti-inflammatory or analgesic effects on cartilage. Thus, the combination of glucosamine and chondroitin sulfates can accomplish the first four objectives, but neither can accomplish all four alone.

Glucosamine and chondroitin sulfates appear to stimulate chondrocyte macromolecular synthesis by different mechanisms. Glucosamine is a direct precursor as well as a stimulatory agent for chondrocyte glycosaminoglycan synthesis. Chondroitin sulfates appeared to stimulate glycosaminoglycan and proteoglycan synthesis by extracellular mechanisms as well as intracellular mechanisms, which is different from glucosamine effects. Thus, for the chondroprotective objective with overlap, differing mechanisms of action have been identified.

Synergism, rather than additive effects, are expected, since both agents are endogenous to chondrocytes, and chondroitin sulfates possess extracellular properties not found with glucosamine. Clinical trials indicate that glucosamine alone has been successful in treatment of osteoarthritis. Chondroitin sulfates tested in clinical trials have shown somewhat less success, but still significant success. Both agents have been listed as slow acting agents for osteoarthritis. Synergism would be expected to exhibit as a reduction in healing time compared to each individual agent. Preliminary studies have indicated accelerated results compared to the time course of healing in published studies (Nutramax Laboratories, unpublished data). Therefore, clinical experiences have fit the concept of a synergistic effect between glucosamine and chondroitin sulfates.

Conclusions: Conclusions of this review and their approximately 90 references have been listed extensively in the Glycosaminoglycans chapter of Nutrition Applied to Injury Rehabilitation and Sports Medicine, CRC Press, Boca Raton, 1994, pp. 177-203. Reference citations are available upon written request.

Source: Nutramax Laboratories, Inc., Baltimore, MD

Dr. Theo’s Comments: This analysis is several years old and does not even include some of the newest information on glucosamine and chondroitin. Nevertheless, this is a convincing academic argument for the rationale in using glucosamine and chondroitin (in combination) for the treatment of osteoarthritis


 
 

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