Nutraceuticals: Glucosamine and Chondroitin Sulfate
June 26, 2000
Nutraceuticals: Glucosamine and Chondroitin Sulfate
Author: Robert C. Schenck, Jr., MD, Associate Professor/Deputy Chairman, Department of Orthopaedics, The University of Texas Health Science Center at San Antonio.
Peer Reviewers: Marc Galloway, MD, Associate Professor, Department of Orthopaedics and Rehabilitation, Yale School of Medicine, New Haven, CT; and William T. Elliott, MD, FACP, Chair, Pharmacy Education, California Division of Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco.
Editor’s Note—Despite the preeminence of U.S. medicine, there is surprisingly limited human clinical experience in the use of glucosamine (G) and chondroitin sulfate (CS) as a treatment for arthritis in this country (see Figures 1A, 1B).2 Interestingly, there is a much longer U.S. clinical experience in the dog and horse than in humans. Only recently has interest in the use of such agents (termed "chondroprotective") increased in the treatment of humans and, in many circumstances, it appears that the interest has been patient driven. Chondroprotective agents are viewed as nutritional supplements, in general are not FDA regulated, and are termed "nutraceuticals" by their industry.3 Furthermore, nutritional supplements as a form of alternative medicine have been slow to gain acceptance by U.S. physicians. In contrast, American consumers embrace other therapies and in one recent survey by Reuters, 36% of those polled used nutritional supplements and approximately half believed supplements had "cured."4 Patient demand for information and product recommendation make this review of glucosamine and chondroitin sulfate in the treatment of osteoarthritis (OA) timely.
Only recently has interest in G and CS increased such that clinical and basic science studies are being performed. Three recent studies at the Orthopaedic Research Society have focused on the mechanism of G and CS on a molecular level.5-7 Currently, both European and American nutraceutical companies are carrying out clinical studies on the effectiveness (symptom modification vs disease modification) of nutritional supplementation of OA. Lastly, the National Institutes of Health (NIH) has funded a multi-center trial evaluating the symptom modification of these nutritional supplements clinically. These studies and trials will be outlined here, as they provide a greater understanding of these somewhat "mysterious" agents.
Many structural and biochemical changes occur in hyaline cartilage with the onset of arthritis. The complex interrelation of water, matrix, and cells create in cartilage an extremely durable shock-absorbing surface with only limited capacity for repair. The biomechanical function of hyaline cartilage requires resistance to water flow microscopically in the tissue, which simplistically is provided by the intricate function of hydrophilic proteoglycans in a collagen netting (see Figure 2).35 Mucopolysaccharides (archaic term) or glycosaminoglycans (GAGs) form hydrophilic macromolecules termed aggrecan. Aggrecan contain large amounts of CS and keratin sulfate chains, hyaluronic acid, and collegen.8,9 Simplistically nutritional supplements such as oral G and CS theoretically provide substrate for the metabolism and production of the proteoglycan component.3
The culture of nutritional supplementation requires definition of commonly used terms with which physicians may not readily be familiar. Most agents used initially in the management of osteoarthritis are NSAIDs and these medications function to limit or ameliorate the breakdown products from articular degeneration. Chondroprotection is used to describe any medication or "compound" that can block progression of degenerative joint disease (DJD) and stimulate repair of damaged cartilage. Theoretically, a chondroprotective compound should: 1) enhance chondrocyte synthesis of matrix components such as collagen and GAGs; 2) enhance synthesis of hyaluronan by synoviocytes; 3) inhibit degenerative enzymes; and 4) mobilize thrombi, fibrin, and lipid deposits in synovial spaces and blood vessels surrounding joints. No drug exists that provides all four mechanisms. Two acronyms for such agents are symptomatic slow-acting drug for osteoarthritis (SYSADOA) and slow-acting drugs for the treatment of osteoarthritis (SADOA). Both include G, CS, hyaluronan, and diacerhein. The basis of chondroprotection is providing substrate or components of the hyaline matrix; for example, supplying substrate or providing a stimulus to increase the synthesis of complete aggrecan macromolecules.10
Lastly, the concept of disease modification vs. symptom modification is important to the usefulness of nutritional supplements as well as in patient education. Disease-modifying aspects of G and CS alone or in combination have been claimed by industry and researchers alike.24,28,29,32 The use of radiographic studies has been the crux of these claims and the data will be reviewed later in this report.24,28,29 Symptom modification is generally accepted with the use of these compounds for mild to moderate osteoarthritis, but independent nonindustry-supported studies are needed.1,26 Disease modification in noninflammatory osteoarthritis would be a significant finding in the use of G and CS clinically, but as of yet has not been shown conclusively. Lastly, the relative effects of G and CS alone or in combination have been questioned and will be discussed in this monograph.
Glucosamine and Chondroitin Sulfate
G is an amino sugar precursor to GAGs with three theoretical actions: 1) stimulate chondrocyte collagen and proteoglycan production; 2) stimulate synoviocytes; and 3) a mild anti-inflammatory action. McNamara and Barr demonstrated this in an industry-funded study using dog serum (time 0 or after 30 days of oral Glu/CS in the dog) to incubate calf cartilage segments and evaluate changes in chondrocyte metabolic activity. Lipello and colleagues noted an increase in GAG levels (8/10 responding), increased chondrocyte synthetic activity, an increase in incorporation of radioactive G, and a decrease in proteolytic activity (P = 0.06).3
Recent mechanistic studies have given further credence to the use of nutritional supplementation in the management of mild to moderate osteoarthritis. Mimms and colleagues recently showed increased production of proteoglycans when bovine cartilage explants were cultured with G and CS alone and in combination. Mimms et al noted that combination therapy demonstrated the greatest proteoglycan synthesis compared to G or GS alone. They went on to show the ability of nutritional supplements to prevent interleukin-1 (IL-1) induced aggrecan depletion. Mimms et al concluded that dietary supplementation may play a role in promoting cartilage health, maintenance, and repair.5
In another study, Sandy and colleagues evaluated the mechanism by which one component of nutritional supplements may affect chondroprotection. G was shown to block the aggrecanase response of chondrocytes to IL-1 in an in vitro model using rat chondrosarcoma cells and bovine cartilage explants. These studies are the first independent studies to show a mechanism by which G and CS both influence the production of proteoglycans as well as inhibit the degradation of aggrecan, the important components of normal cartilage metabolism.5-7
Clinically, G can be administered via intravenous, intramuscular, intra-articular, and oral routes. Oral absorption via the sulfated or hydrochloride forms is through the gut with approximately 70% absorbed with excretion through the renal system.11 G is produced commercially from the chitin of crab, lobster, or shrimp shells.10 G is not regulated through the FDA, is sold as a nutritional supplement, and doesn’t require a prescription. Multiple clinical trials (many in the 1980s) studied the supplement for the treatment of arthritis and will be reviewed here.
CS is the most abundant GAG in cartilage with three theoretical actions: 1) inhibit degradative enzymes; 2) add to the GAG pool; and 3) prevention of synovial thrombi. Animal studies have shown CS to decrease human leukocyte elastase activity, to decrease hyaluronidase activity in mouse synovial fluid, and to increase human synovial hyaluronic acid.9 CS carries a similar molecular structure to heparin. Therefore, it was theorized that CS should be used with caution in patients on anticoagulation therapy. However, one human study that evaluated coagulation parameters as a secondary outcome indicated that there were no significant changes in clinical bleeding parameters.10
Clinical Studies
More than 30 clinical studies have been performed in humans and animals since the 1960s.2,3,10,11,14-23 Although many are small studies, there are several well designed double-blinded trials. Furthermore, the specialized outcome and objective measurements used in the 1990s have only recently been applied to clinical trials of G and CS. Most studies have shown symptomatic improvement in the management of arthritis with minimal side effects. As will be shown there is a significant placebo effect with any medication and must be remembered when evaluating one’s personal clinical experience when using any new treatment in patient care.10 Thus, when evaluating clinical trials of oral supplements, the reader should look for randomized double-blind, placebo-controlled trials.
In a double-blind, placebo-controlled trial by Vas et al (1982) evaluating the efficacy of G (1.5 g/d) vs. ibuprofen (1200 mg/d) in 32 patients with osteoarthritis, 18 patients were administered glucosamine sulfate and 20 patients were given ibuprofen. After two weeks of therapy, ibuprofen provided greater pain relief. At eight weeks follow-up, G gave greater pain relief. In this study, a pain scale from 0 to 3 was used as well as physician observations in determining pain relief.18
In an open trial of 1208 patients (involving 252 physicians, 1982), 1.5 g of G sulfate per day were administered with "good or sufficient" pain relief noted in 94% of patients at six and eight weeks follow-up. Furthermore, there was an increase in arthritic symptoms after discontinuance of G. Symptoms were physician rated, and the supplement was well tolerated with few side effects.17 In a placebo-controlled, double-blind study, 1.5 g G orally per day was used in 80 inpatients rating articular pain on a scale of 0 to 4. Good or excellent results were noted in 29 of 40 (69%) patients on G, and in 17 of 40 patients (41%) treated with placebo (P < 0.005). No abnormalities were noted in routine laboratory studies including CBC, BUN/creatine, and glucose. Interestingly, these patients were hospitalized, and it is unclear the effects rest had on symptom relief. One study from Thailand in the early 1980s evaluated intra-articular G for knee arthritis administered once a week for five weeks, double-blinded vs. saline injection. An improvement in pain and knee flexion was seen. At eight weeks postinjection treatment, more than 50% of patients treated with G injections noted continued relief with less than 10% with relief after using saline injections.11,15,16
In two recent clinical studies, oral CS was tested against placebo in a double-blind trial. Using 0.8 g CS a day vs. placebo, patients with arthritis were followed over a six-month period. Response to the supplement was based on visual analog scale (VAS) and improvement in walking time. Thirty-nine patients were administered CS and 46 were given placebo, with statistically significant improvement on VAS scores using CS at three and six months, but with no significant difference between CS and placebo at one month. In a similarly designed study, no difference was noted between single or divided doses of 1.2 g of CS with either regimen better than placebo (oral CS, 1.2 g/d, 127 patients, 40 single dose, 43 divided, 44 PBO, for 90 days).12,24 In another recent study using combined G hydrochloride, low molecular weight CS and manganese ascorbate (Cosamin DS, Nutramax Laboratories, Inc., Edgewood, MD), Das and colleagues randomized 93 patients to either treatment with this supplement twice daily vs. placebo. Twenty-eight percent of patients in the placebo group responded favorably compared to 52% of the supplemented group with both treatment and placebo groups having similar rates of adverse reaction.25 The same compound (Cosamin DS) was shown to be effective and safe in a recently published clinical trial in an athletic population with degenerative arthritis of the knee.13
Two recent meta-analyses of G and CS give the clinician an accurate analysis of what is in the literature. McAlindon and colleagues evaluated the available double-blind placebo-controlled trials (of > 4 weeks follow-up) in an attempt to evaluate the usefulness of nutritional supplements in OA of the hip and knee. The analysis used a validated scoring system to evaluate the scientific quality (Rochon PA, et al. JAMA 1994;272:108-113) of the studies as well as the clinical result found. This JAMA system scores quality on a range of 0 to 65 with scores less than or equal to 33 considered to be of poor scientific quality. Using such parameters, 13 trials met the eligibility criteria (G: 4 papers, 2 abstracts; CS: 5 papers, 2 abstracts). All studies showed positive clinical results in the treatment of OA with a mean score reduction compared to placebo of 39.5% with G and 40.2% with CS. Scientifically, however, the papers and abstracts scored on average 21.1 (range, 8-36), implying poor scientific quality. They also found most studies were performed with industry support. McAlindon et al concluded that clinical trials of nutritional supplements show substantial benefits in the treatment of OA, but further studies are needed to test the efficacy of G and CS.26 In a meta-analysis of CS in the treatment of OA, Leeb and colleagues also noted positive clinical results with the supplement, but that further study was necessary to prove the usefulness of CS as a symptom-modifying drug in OA.26,27
It is with these meta-analyses that the NIH’s current multicenter trial is so important. Three treatment arms and placebo will compare G alone, CS alone, and combination therapy (G/CS) against placebo. This trial is centered at the University of Utah and involves 13 medical institutions around the country. The trial will evaluate symptom modification and not disease modification. The findings of this important study will provide useful information for the treating clinician in the use of G and CS in the treatment of mild to moderate OA.
Disease Modification
Claims of radiographic improvements with oral supplementation and quoted in Arthritis Today28 ("OA of the knee showed less narrowing of the joint space in those who took CS for one year") came from two recent studies by Uebelhart and associates and Verbruggen and associates.24,29 In the study of Uebelhart et al, 46 patients followed for one year were treated with 0.8 g CS per day vs. placebo. In this study a small subset of patients were followed with digitized x-rays of the knee. Twelve patients treated with placebo showed 0.05 cm of increased narrowing whereas 14 patients treated with CS showed no change in joint space at six months. Uebelhart et al admitted the strong possibility of bias in these x-ray results. In the study by Verbruggen et al, confusing data noted a decrease in finger joint radiographic changes of the DIP and PIP with long-term CS. The clinician must be careful in disseminating such information of radiographic improvement to patients without clear scientific evidence.24,29 One recent case report evaluated the MR improvement of the hip with the use of G and CS.30 Although some studies point to the possible disease modification with nutritional supplements, further study is needed to prove such statements.
Indications and Side Effects
Oral supplementation is not indicated for inflammatory arthropathies such as rheumatoid arthritis, crystalline arthropathies such as gout, nor in pregnancy or in children. If a patient is diabetic, the clinician should follow serum glucose.11,31 Most dosing regimens are based on weight and as recommended by Theodosakis et al in The Arthritis Cure:32 less than 120 lbs: G 1000 mg, CS 800 mg; 120 to 200 lbs: G 1500 mg, CS 1200 mg; and more than 200 lbs: G 2000 mg, CS 1600 mg.
Side effects of G and CS appear to be minimal in humans. As noted above, inpatient double-blinded studies showed no significant changes in CBC, BUN/creatine, glucose, PT, and PTT. In one animal study, McNamara et al noted decreases in Hct, Hgb, WBC, and platelet aggregation, but each of these values remained within normal limits and there was no change in bleeding time, or PT, and PTT in 13 immature beagle dogs.3 In the study by Tapadinhas et al, there was a low incidence of side effects with the use of 1.5 g of G sulfate daily in 1208 patients (see Table 1).17
In one recent small study of 15 nondiabetic patients, the subjects were given either 1500 mg G sulfate or an inactive placebo for 12 weeks. By the end of the study, blood insulin levels had risen in those subjects taking G sulfate, compared with those taking placebo. One of the researchers, Anthony Almad, noted that although the small study should not prompt diabetic users to abandon the supplement, "it may be wise for them to be aware of potential risks and be more rigorous in monitoring their blood sugar."33 Researchers nonetheless stressed that the results of the study need to be replicated in larger, controlled trials before any firm conclusions can be made regarding the use of G among the nation’s nearly 16 million diabetics.33
Lastly, purity and the presence of active ingredients vary greatly between products. In one recent study,34 Eddington and colleagues evaluated the label claims of 32 chondroitin containing products. Twenty-six of the 32 products were found to contain less than 90% of the CS stated on the label, with 17 products containing less than 40% of the label claim. Fourteen products containing G were also analysed. Twelve of the 14 G products contained 90% or more of the G. In summary, deviations from label claims highlight the inconsistencies of many dietary supplements and actual content found in the product.
Conclusion
Lastly, the use of G and CS is not included in most treatment algorithms where acetaminophen, ambulatory aides, followed by NSAIDs (including the new COX-2 inhibitors), steroid or hyaluronic injections, physical therapy, and lastly, joint replacement have been the long-standing treatment approach. Many patients currently use G/CS with or in place of NSAIDs. The use of G and CS in those patients failing acetaminophen and unable to tolerate NSAIDs may create an additional niche for nutritional supplementation. With further studies on efficacy and safety profiles, the clinical indications of G and CS will become better defined. When recommending products such as G and CS to a patient, the clinician frequently has little experience in alternative therapies. In my opinion, one should recommend the product that has been used in recent clinical trials such as reported by Das and colleagues. Using a supplement based on data obtained with a different product does not confer efficacy. Nutritional supplements vary in purity and content. Careful scrutiny of products and careful recommendation is in the best interest of patients.
One interesting question raised by McCarty in 1994 is, "Why has glucosamine taken so long to hit the USA?"2 As McCarty noted, it was first used in Germany in 1969 and, as reviewed here, five double-blind trials were performed in the 1980s. All studies showed uniform results with improvement in symptoms. McCarty comments, "America’s massive, richly funded medicopharmaceutical complex has evinced not one shred of interest, undoubtedly because glucosamine is an unpatentable natural agent."2 That is until the recent discovery of G and CS by the American consumer.
| Table 1. Details of Complaints Reported During Treatment (Glucosamine) | ||
| Symptom | Number of complaints | % of total treated patients |
| Digestive | ||
| Epigastric pain/tenderness | 42 | 3.48 |
| Heartburn | 33 | 2.73 |
| Diarrhoea | 30 | 2.48 |
| Nausea | 14 | 1.16 |
| Dyspepsia | 12 | 0.99 |
| Vomiting | 10 | 0.83 |
| Constipation | 8 | 0.66 |
| Gastric heaviness | 6 | 0.50 |
| Anorexia | 3 | 0.25 |
| Abdominal pain | 3 | 0.25 |
| Meteorism | 2 | 0.17 |
| Nondigestive | ||
| Drowsiness | 10 | 0.83 |
| Skin reactions | 4 | 0.33 |
| Headache | 4 | 0.33 |
| Somnolence | 2 | 0.17 |
| Insomnia | 1 | 0.08 |
| Oedema | 1 | 0.08 |
| Tachycardia | 1 | 0.08 |
| Source: Tapadinhas MJ, et al. Pharmatherapeutica 1982;3:165. | ||
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