Special Report: Nutraceuticals and Osteoarthritis
Abstract & Commentary
Source: McAlindon TE, et al. Glucosamine and chondroitin for treatment of osteoarthritis. A systematic quality assessment and meta-analysis. JAMA 2000;283:1469-1475.
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Attention Subscribers. . . In an effort to provide our subscribers with a premiere periodical that keeps them current in sports medicine literature, we are pleased to provide this exclusive issue on the timely topics of nutraceuticals, nutritional supplements, banned, and nonbanned substances. This is a bonus to our subscribers. We welcome John MacKnight, MD, as the co-editor of this special issue. Dr. MacKnight is an internist with sports medicine training who brings needed expertise in these areas. His contribution deals with growth hormones. In addition, we welcome Drs. Robert Posey and Thomas Armsey from the University of Kentucky. They provide an in-depth study on nutritional supplements. Dr. Arthur Weltman from the University of Virginia provides information and analysis on prohibited substances and methods for performance enhancement. Dr. Robert Schenck is an associate editor of Sports Medicine Reports. |
This is a thorough analysis of trials using nutraceuticals in the management of osteoarthritis (OA) over the past 20 years. McAlindon and associates combed the literature through MEDLINE (1966-1999), and bibliographies from Arthritis and Rheumatism, the British Journal of Rheumatology, and Osteoarthritis and Cartilage (1978-1998) to identify such studies involving the evaluation of glucosamine and chondroitin sulfate. Follow-up with authors, manufacturers, and content experts was performed to help clarify findings and identify sources of bias. Only controlled trials (minimum 4 week duration) vs. placebo in patients with OA of the knee or hip and evaluating at least one realistic outcome measure (i.e., Lesquesne Index, WOMAC, global pain scores) were selected. Fifteen of a potential 37 studies qualified and were submitted to meta-analysis. Study quality was investigated using a previously described (JAMA) point scale assessed by two reviewers of the McAlindon team. This scoring system allows for a range of 0 (worst) to 65 (best) points to evaluate the scientific quality and has been shown in previous studies to be reliable in several study analyses. Of the 17 studies, quality of science was moderate to poor, averaging 36% (range, 12-55%, standard deviation [SD], 12%). Only one of the 17 studies used an intent-to-treat analysis. None of the studies reviewed were funded by an independent or government source. Evaluation of funding source (self-described or through author contact) revealed some form of manufacturer or industry funding in 15 of 17 studies analyzed. Seven of the 17 studies included an investigator from the company as an author.
Those limitations accepted, all studies reviewed showed a positive effect on outcome of OA with glucosamine and/or chondroitin sulfate. Of those six studies involving glucosamine, a total of 911 patients participated, and improvement in outcome ranged from 12-52%. Combining the patients into one group, there was a moderate benefit with glucosamine on OA, an effect size of 0.44 with confidence intervals of 95%. Studies evaluating chondroitin sulfate involved 799 patients with benefit scores improving by 14-55%. Chondroitin sulfate appeared to have a larger benefit than glucosamine. McAlindon et al concluded that glucosamine and chondroitin sulfate improved outcomes in the treatment of OA, "but the studies reviewed contain methodologic problems that have been associated with exaggerated estimates of benefit." McAlindon et al further noted that, "it seems probable that these compounds do have some efficacy in treating OA symptoms, and that they are safe, and because of this, may have considerable use in OA treatment." As many authors have noted, future controlled trials are needed with independent funding sources to clearly identify the degree of benefit these substances produce.
Comment By Robert C. Schenck, Jr., MD
Only recently has interest in glucosamine and chondroitin sulfate 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 glucosamine and chondroitin sulfate on a molecular level.3-5 Currently, both European and American nutraceutical companies are carrying out clinical studies on the effectiveness (symptom modification vs disease modification) of nutritional supplementation in the management of OA. Finally, the National Institutes of Health has funded a multicenter trial to clinically evaluate the symptom modification of these nutritional supplements. These studies and trials will be outlined below as they provide a greater understanding of these somewhat "mysterious" nutritional agents.
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 OA are nonsteroidal anti-inflammatories (NSAIDs), and these medications function to limit or ameliorate the breakdown products from articular degeneration. "Chondroprotective" agents describe any medication or "compound" which can block progression of degenerative joint disease (DJD) and stimulate repair of damaged cartilage; these include glucosamine, chondroitin sulfate, hyaluronan, and diacerhein. The theoretical basis of chondroprotection is the provision of substrate or components of the hyaline matrix; for example, supplying substrate or providing a stimulus to increase the synthesis of complete aggrecan macromolecules.
Finally, the concept of disease modification vs. symptom modification is an important distinction when using nutritional supplements. Disease modifying aspects of glucosamine and chondroitin sulfate alone or in combination have been claimed by industry and researchers alike. Symptom modification (as attested by the meta-analysis above) is generally accepted with the use of these compounds for mild to moderate OA, but independent non-industry supported studies are needed. Disease modification in non-inflammatory OA would be a significant clinical finding in the use of glucosamine and chondroitin sulfate but, as of yet, has not been shown conclusively.
Recent mechanistic studies have given further credence to the use of nutritional supplementation in the management of mild to moderate OA. Mimms et al recently showed increased production of proteoglycans when bovine cartilage explants were cultured with glucosamine and chondroitin sulfate alone and in combination.3 Mimms et al noted that combination therapy demonstrated the greatest proteoglycan synthesis compared to glucosamine or chondroitin sulfate alone. Mimms et al 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. In another study, Sandy and colleagues evaluated the mechanism by which one component of nutritional supplements may effect chondroprotection.4 Glucosamine 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 independently funded investigations to show a mechanism by which glucosamine and chondroitin sulfate both influence the production of proteoglycans while also inhibiting the degradation of aggrecan, two important components of normal cartilage metabolism.
Clinically, glucosamine can be administered via intravenous, intramuscular, intra-articular, and oral routes. Oral intake of the sulfated or hydrochloride forms shows approximately 70% absorption with excretion through the renal system. Glucosamine is produced commercially from animal sources. It is sold as a nutritional supplement, is not regulated through the FDA, and does not require standard prescription dosing.
More than 30 clinical studies have been performed in humans and animals since the 1960s. Although many are small studies, there are several double-blinded placebo-controlled trials. Furthermore, the specialized outcome and objective measurements used in the 1990s have only recently been applied to clinical trials of glucosamine and chondroitin sulfate.12 Most studies have shown symptomatic improvement in the management of arthritis with minimal side effects. However, as will be shown below, there is a significant placebo affect with any medication, and this must be remembered when evaluating any new treatment in patient care.
An example of such early studies is that by Vas et al (1982) evaluating the efficacy of glucosamine (1.5 g/d) vs. ibuprofen (1200 mg/d) in 32 patients with OA;8 18 patients were administered glucosamine sulfate and 20 patients were given ibuprofen. After two weeks of therapy, ibuprofen provided greater pain relief. However, at eight weeks follow-up, glucosamine gave greater pain relief. In this study, a pain scale from 0-3 was used as well as physician observations in determining pain relief.
In an open trial of 1208 patients (involving 252 physicians, 1982), 1.5 grams of glucosamine sulfate/d were administered with "good or sufficient" pain relief noted in 94% of patients at six and eight weeks follow-up.7 Furthermore, there was an increase in arthritic symptoms after discontinuance of glucosamine. Symptoms were physician rated, and the supplement was well tolerated with few side effects. One study from Thailand in the early 1980s evaluated intra-articular glucosamine for knee arthritis administered once a week for five weeks, double-blinded, vs. saline injection.6 An improvement in pain and knee flexion were seen. At eight weeks post-injection treatment, more than 50% of patients treated with glucosamine injections noted continued relief with less than 10% noting relief after using saline injections. In another recent study using combined glucosamine hydrochloride, low molecular weight chondroitin sulfate, and manganese ascorbate (Cosamin DSÒ, Nutramax Laboratories, Inc., Edgewood, MD), Das et al randomized 93 patients to either treatment with 1 g glucosamine hydrochloride, 0.8 g chondroitin sulfate twice daily, or placebo.9 Twenty-eight percent of patients in the placebo group responded favorably compared to 52% of the supplemented group with both groups having similar rates of adverse reactions.
It is with the McAlindon meta-analysis and patient use of nutritional supplements that the National Institutes of Health current multicenter trial is so important. Three treatment arms and placebo will compare glucosamine alone, chondroitin sulfate alone, and combination therapy (glucosamine/chondroitin sulfate) against placebo. This trial is centered at the University of Utah and involves 13 medical centers around the country. The trial will evaluate symptom modification and not disease modification. The findings of this important study will provide great information for the treating clinician in the use of glucosamine and chondroitin sulfate in the treatment of mild to moderate OA.
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. Most dosing regimens are based on weight as recommended by Theodosakis et al.10 (See Table.)
| Table | |
| Less than 120 lbs. | GS 1000 mg CS 800 mg |
| 120-200 lbs. | GS 1500 mg CS 1200 mg |
| More than 200 lbs. | GS 2000 mg CS 1600 mg |
Side effects of glucosamine and chondroitin sulfate appear to be minimal in humans. As noted above, inpatient double-blinded studies showed no significant changes in CBC, BUN/creatinine, glucose, PT, or PTT. In the study by Tapadinhas et al, there was a low incidence of side effects with the use of 1.5 g of glucosamine sulfate daily in 1208 patients. The use of glucosamine in patients with diabetes is unclear, but many researchers recommend closely following blood sugars when using the supplement in diabetics.
Finally, purity and the presence of active ingredients vary greatly between products. In one recent study, Eddington and colleagues evaluated the label claims of 32 chondroitin containing products.11 Twenty-six of the 32 products were found to contain less than 90% of the chondroitin sulfate stated on the label with 17 products containing less than 40% of the label claim. Fourteen products containing glucosamine were also analyzed. Twelve of the 14 glucosamine products contained 90% or more of the glucosamine. In summary, deviations from label claims highlight the inconsistencies of many dietary supplements and actual content found in the product.
Conclusion
The use of glucosamine and chondroitin sulfate is not included in most treatment algorithms where acetaminophen, ambulatory aides, NSAIDs, including the new COX-2 inhibitors, injections, and joint replacement, have been the traditional treatment approach. Many patients currently use glucosamine/chondroitin sulfate with or in place of NSAIDs. The use of glucosamine and chondroitin sulfate in those patients failing acetaminophen and unable to tolerate NSAIDs may create an additional niche for oral supplementation. With further studies on efficacy and safety profiles, the clinical indications for glucosamine and chondroitin sulfate will become better defined. When recommending a product such as glucosamine or chondroitin sulfate 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 and that has documented purity. Using a supplement based on data obtained with a different product does not confer efficacy. Nutritional supplements vary in purity and content, and 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?" As McCarty noted, glucosamine was first used in Germany in 1969, and as reviewed above, 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." That is until the recent discovery of glucosamine and chondroitin sulfate by the American consumer.
References
1. Buckwalter JA, et al. New approaches to the treatment of osteoarthritis. AAOS instructional course lecture 2000;49:491-494.
2. McCarty MF. The neglect of glucosamine as a treatment of osteoarthritis—A personal perspective. Med Hypotheses 1994;42:323-327.
3. Mims TT, et al. Effects of dietary supplements on cartilage metabolism and its potential role in osteoarthritis. Trans Orthop Res Soc 2000;46:240.
4. Sandy JD, et al. The mechanism of chondroprotective effect. Trans Orthop Res Soc 2000;46:1009.
5. Patwari P, et al. Mannosamine inhibits aggrecanase-mediated degradation of mechanical properties of cartilage. Trans Orthop Res Soc 2000;46:1084.
6. Vajaradul, Y. Double-blind clinical evaluation of intra-articular glucosamine in outpatients with gonarthrosis. Clin Ther 1980;3(5):260-336.
7. Tapadinhas JM, Rivera IC, Bignamini AA. Oral glucosamine sulphate in the management of arthrosis: Report on a multi-centre open investigation in portugal. Pharmatherapeutica 1982;3(3):157-168.
8. Vaz A. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthrosis of the knee in out-patients. Curr Med Res Opin 1980;8(3):145-149.
9. Das A, Hammad TA. Efficacy of a combination of FCHG49 glucosamin hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis and Cartilage 2000;8: 343-350.
10. Theodosakis J, et al. The Arthritis Cure. New York, NY: St. Martins Press; 1997:282.
11. Adebowale AO. Analysis of glucosamine and chondroitin sulfate content in marketed products and the caco-2 permeability of chondroitin sulfate raw materials. JAMA 2000;3(1):37-44.
12. Kreder HJ. Glucosamine and chondroitin were found to improve outcomes in patients with osteoarthritis. J Bone Joint Surg 2000;82-A:1323.
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