Yes. Charlene Morris, MPAS, PA-C, says the over-the-counter supplement is a safe treatment option within the armamentarium of modalities for osteoarthritis of the knee. No, Blaine Carmichael, PA-C, says the literature and the general makeup of a glucosamine/chondroitin supplement makes it a less than viable treatment option for osteoarthritis of the knee.

Yes. This author says the over-the-counter supplement is a safe treatment option within the armamentarium of modalities for osteoarthritis of the knee.

By Charlene Morris, MPAS, PA-C

Glucosamine and chondroitin sulfate are relatively safe and inexpensive, and can be helpful in treating painful joints. It makes sense that the supplements are useful in treating symptoms associated with osteoarthritis (OA) of the knee.
       The combination dietary supplement is often praised and vilified in the same sentence often by the same clinicians who recommend its use or utilize it themselves. Clinicians take both sides of the debate while recommending the product’s use or utilizing it themselves. Largely unregulated, many clinicians and many patients are asking for information regarding the effectiveness of glucosamine/chondroitin for the treatment of OA.
       The likelihood of joint problems is a reality for all of us as we get older. The old adage (“Would you prescribe this for a family member?”) rings true when recommending any treatment available to our patients.
       Much of the literature reports that glucosamine and chondroitin is ineffective for OA. Still, even authors of the oft-discussed GAIT study on this topic concede there were limitations of their study despite the many parameters they considered. Perhaps most important is that the authors noted “more substantial” results with the combination of glucosamine and chondroitin among patients with moderate to severe disease. However, this was a smaller subset of patients in comparison to the thousands of patients screened and the 1,583 patients who were actually involved with the study.¹
       Bear in mind that other studies that have demonstrated the effectiveness of glucosamine and chondroitin were criticized for the small number of enrolled patients and their relatively lower reported knee pain levels.
       The National Institutes of Health has a credible and comprehensive information page concerning glucosamine and chondroitin. Despite confirming that the actual formulation used in the GAIT study is not available to the general public, it states most formulations of glucosamine/chondroitin are similar enough to be efficacious.
       It is also noteworthy that that one ancillary part of the GAIT study is ongoing and examines whether one can halt or even reduce the progression of knee OA by using glucosamine and chondroitin. These exciting results will be reported in early 2008 and may shed light on the effectiveness of glucosamine/chondroitin over a longer period of time and in the more serious OA patient.²

What About The Safety Of The Supplement?

With recent studies and warnings of medication safety issues, glucosamine and chondroitin continue to demonstrate minimal if any ill effects. The most reported adverse reactions are nausea and epigastric discomfort. While diarrhea, constipation, blepharitis, palpitations and hair loss have also been mentioned, current research has not demonstrated a proven link between these effects and the use of glucosamine and chondroitin.
       With glucosamine/chondroitin being structurally similar to heparin, except for one case of excessive glucosamine and chondroitin dosing, there has been unfounded concern about possible interference of anticoagulant therapy. Minimal evidence also suggests that glucosamine and chondroitin may facilitate the recurrence or spread of existing prostate cancer. Obviously, that would be a consideration for not using this usually safe supplement.
       One small consideration is that chondroitin originates from bovine tracheal cartilage. Not only might there be religious limitations with Hindu patients, clinicians may also consider the possibility of mad cow disease transmission or bovine spongiform encephalopathy (BSE). However, there are no reports of this contamination in the current medical literature.³
       Glucosamine is derived from the chitin in shellfish exoskeletons. Studies show that glucosamine enhances the production of proteoglycans and exhibits antinflammatory properties without inhibiting prostaglandin synthesis.⁴
       The primary considerations against using glucosamine includes the interference of most available insulin therapies including insulin, sulfonylurea, thiazolidinediones. and metformin. In combination with chondroitin, glucosamine also may dangerously enhance warfarin and aspiring anticoagulant properties.⁵

What You Should Keep In Mind About Dosing And The GAIT Study

In October 2006, the Arthritis Foundation cited an ongoing study, which has found that up to 25 percent of people using glucosamine and chondroitin note improvement. It also references the long-anticipated results of the additional trial to measure reduction and lack of progression of knee OA.⁶
       According to the Arthritis Foundation, supplements should contain a combination of 500 mg glucosamine and 400 mg chondroitin. One should take the glucosamine/chondroitin supplement three times a day and patients should reportedly notice results within days to weeks.⁷
       Interestingly, the studies that examined the usage of glucosamine and chondroitin utilized different dosing regimens. The Glucosamine-Chondroitin Arthritis Intervention Trial (GAIT), which garnered support from the National Center for Complementary and Alternative Medicines and the National Institute for Arthritis and Musculoskeletal and Skin Diseases, randomized patients to a regimen of 1,000 mg of glucosamine hydrochloride, 1,200 mg of chondroitin sulfate, both glucosamine and chondroitin, 200 mg of Celebrex or a placebo for 24 weeks. Patients were allowed to take up to 4,000 mg acetaminophen daily for breakthrough pain.¹
       For a clinician in the working world, these results translated to worthy information in everyday practice. Ultimately, there was demonstrated relief with glucosamine/chondroitin for those with severe OA pain but the findings were not as robust for patients whose symptoms were not as advanced. However, I do feel it is more impressive to achieve pain relief for those with more advanced disease.¹

Other Considerations To Be Aware Of With The GAIT Study

In an accompanying editorial in the same issue of the New England Journal of Medicine, Marc C. Hochberg, MD, MPH, pointed out several salient considerations. These considerations include a high dropout rate, which may have adversely impacted a reliable reporting of results. Dr. Hochberg also cited the high rate of response by the placebo arm, which had not been anticipated.⁸
       Dr. Hochberg also opined that researchers should have used the Rottapharm brand of glucosamine sulfate, which was cited as effective in seven previous trials, as opposed to the chosen glucosamine hydrochloride.
       In the editorial, Dr. Hochberg advised that if a patient experiences no improvement after a three-month trial, that clinicians should discontinue the glucosamine and chondroitin. He also encouraged clinicians to advise patients that utilizing glucosamine sulfate and chondroitin “may have an additive effect.”⁸ This was also discussed by Jellin and Gregory in the Prescriber’s Letter.³

Final Notes

My own husband, Rick, has used the generic version of glucosamine and chondroitin with impressive relief. After he researched the topic, he learned that people usually notice results after approximately a week of use although may take as long as three months. Rick prefers to buy “whatever is on sale” at the local pharmacy and has not noticed differences in the various versions. He states that if he does not take it for four to six days, his knees again begin to hurt and swell.
       As a former marathoner and tri-athlete, my aging spouse of over two decades says: “For an over-the-counter remedy that is so inexpensive, it is definitely worth trying.” I concur.

       Ms. Morris is a Past President of the Association of Family Practice Physician Assistants. She is the current CME Chair and Treasurer of the Society for PAs in Pediatrics.

References

1. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795-808.

2. http://nccam.nih.gov/research/results/gait/qa.htm#d1 Accessed 11/19/07

3. Jellin JM, Gregory PJ, et al. Pharmacist's Letter/Prescriber's Letter Natural Medicines Comprehensive Database. www.naturaldatabase.com. (Accessed 11/19/07).

4. Das A Jr, Hammad TA. Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage 2000 Sep;8:343-50.

5. www.epocrates.com, accessed 11/19/07.

6. http://www.arthritis.org/top-10-2006.php Accessed 11/19/07.

7. http://www.arthritis.org/good-news-for-knees.php

8. http://content.nejm.org/cgi/content/full/354/8/858


No, this author says the literature and the general makeup of a glucosamine/chondroitin supplement makes it a less than viable treatment option for osteoarthritis of the knee.

By Blaine Carmichael, PA-C

Reportedly 25 percent of adults in the United States suffer from knee pain and at least half of these people have osteoarthritis (OA).^1,2 Osteoarthritis, the most common form of arthritis, affects more than 20 million adults in the U.S. It is caused in part by the breakdown of articular cartilage, which is the connective tissue that cushions the ends of bones within the joint.
       In a healthy joint, the ends of bones are encased in smooth cartilage. Together, they are protected by a joint capsule lined with a synovial membrane which produces synovial fluid. The capsule and fluid protect the cartilage, muscles and connective tissues. When it comes to a joint with severe OA, the cartilage becomes worn away. Spurs grow out from the edge of the bone and synovial fluid increases. Altogether, the joint feels stiff and sore.
       People with knee pain often use over-the-counter (OTC) nutritional supplements to treat joint pain. These supplements may be a more appealing option for those without health care coverage or those who are attempting to avoid the costs of clinical visits, diagnostic testing and more expensive prescription medication. The most popular supplement is a combination of glucosamine and chondroitin. The demand for the chondroitin component alone constitutes a $1 billion per year market in the U.S.

A Closer Look At Glucosamine And Chondroitin

Glucosamine and chondroitin sulfate are natural substances found in and around the cells of cartilage. Chondroitin sulfate is a component of cartilage. It is mainly composed of repeated chains of glucosamine sulfate. Glucosamine sulfate is a form of an amino sugar that plays a role in cartilage formation. Glucosamine stimulates the production of water-binding glycosaminoglycans and proteoglycans, two essential building blocks of cartilage, and also inhibits the production of the destructive enzymes collagenase and phospholipase.
       Glucosamine is distributed in cartilage and other connective tissue, and chondroitin sulfate is a complex carbohydrate that helps cartilage retain water.
       In the U.S, glucosamine and chondroitin sulfate are sold as dietary supplements. Accordingly, they are not rigorously tested or regulated as drugs. Since they are considered foods, these supplements are only inspected for safety in regard to packaging and contents. They are not tested for efficacy.
       Glucosamine is extracted from crab, lobster and shrimp shells. Some brands of glucosamine add chondroitin, which reportedly improves the effects of glucosamine. Chondroitin is taken from the cartilage of sharks, cows, pigs and chicken. Chondroitin is almost always sold in a combination pill with glucosamine.

A Few Practical Considerations About Oral Ingestion Of Glucosamine/Chondroitin

The idea of ingesting a chemical taken from non-human (often non-mammalian) cartilage so it may be incorporated into human cartilage is appealing. However, glycosaminoglycans are not synthesized from intact chondroitin molecules. Therefore, it is impossible that oral ingestion of chondroitin would be incorporated into human cartilage.
       Additionally, because chondroitin is a large macromolecule, only about 12 to 13 percent of ingested chondroitin could be absorbed through the small bowel into the bloodstream.³ While chondroitin therapy supposedly targets cartilage, OA affects the whole joint. Accordingly, a molecule targeted only at constituents of cartilage is unlikely to affect all manifestations of OA. Indeed, treatment targeting cartilage alone is unlikely to alleviate pain because cartilage is without nerve enervation.

What The Literature Reveals

One study found that chondroitin may have a small protective effect on the joint in comparison to placebo. However, the clinical relevance of this effect is unknown. Additionally, this research concluded that chondroitin sulfate had no effect on comfort in patients with severe degenerative arthritis of the knee after two years of treatment.⁴
       An additional series of randomized trials suggested that chondroitin was more efficacious than placebo in treating OA pain although actual efficacy estimates varied widely from study to study. One trial amazingly reported that chondroitin was more effective than total knee replacement, a finding that lacks credibility.⁵
       The National Institutes of Health carried out the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) in an attempt to resolve uncertainty about the efficacy of both glucosamine and chondroitin. The GAIT study evaluated glucosamine and chondroitin, celecoxib (Celebrex, Pfizer) and placebo for the treatment of knee OA. The results, which were published in 2006, showed the glucosamine and chondroitin, alone or in combination, did not have significantly greater efficacy than that of placebo.⁶
       It is important to note that participants taking celecoxib within GAIT experienced statistically significant pain relief versus placebo. About 70 percent of patients taking celecoxib had a 20 percent or greater reduction in pain versus 60 percent in the placebo group.
       Overall, there were no significant differences between the other tested treatments and placebo.
       However, for another subset of patients who had moderate to severe pain, glucosamine/chondroitin provided statistically significant pain relief in comparison to placebo. According to the study, 79 percent of patients in the glucosamine/chondroitin group who had moderate to severe pain had a 20 percent or greater pain reduction in comparison to 54 percent of patients in the placebo group. However, these are preliminary findings given the small size of the subgroup and further exploration would be needed in larger studies.⁶
       For patients in a mild pain subset of the study, glucosamine/chondroitin together or alone did not provide statistically significant pain relief.⁶
       Additionally, researchers involved with the GAIT study found that glucosamine in hydrochloride form and the combination of glucosamine/chondroitin were no more effective than placebo.
       In addition to GAIT, there are several other trials that have found inferior results with glucosamine/chondroitin therapy. Reichenbach, et al. noted that three recent large, intention-to-treat trails, which adequately concealed random allocation of chondroitin, found that chondroitin was ineffective in all three trials. In their view, this evidence should convince skeptics and advocates alike not to recommend glucosamine/chondroitin.⁷
       McAlindon, et al. concluded that while glucosamine is safe, it is no more effective than placebo in treating the symptoms of knee OA.⁸ A meta-analysis of 20 randomized clinical trials in a total of 3,846 patients compared chondroitin with placebo or no treatment. The authors found no methodological deficiencies within the studies or evidence of larger pain reduction with chondroitin than with placebo.⁹
       Furthermore, the American College of Rheumatology (ACR) does not recommend the use of glucosamine/chondroitin among its accepted non-pharmacologic or pharmacologic treatment options for knee or hip OA.¹⁰

In Conclusion

No frequent or severe adverse effects have been reported from using glusosamine/chondroitin individually or in combination. Since it is not dangerous, there is no harm in taking the supplement if a patient perceives a possible benefit. However, the best current evidence suggests that glucosamine/chondroitin does not reduce joint pain in patients with knee OA.

       Mr. Carmichael is a physician assistant at the Riverwalk Clinic in San Antonio, Tx. He is a Distinguished Fellow of the American Academy of Physician Assistants and is the co-founder and past president of the Association of Family Practice Physician Assistants.

References

1. Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care. Ann Rheum Dis (60)2: 91-97, 2001.

2. Hannan MT, Felson DT, Pincus T. Analysis of the discordance between radiographic changes and knee pain in osteoarthritis of the knee. J Rheumatol (27)June: 1513-1517, 2000.

3. Ronca F, et al. Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage (6)Suppl 1: 14-21, 1998.

4. Michel BA, et al. Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: a randomized, controlled trial. Arthritis and Rheumatism (52)3: 779-786, 2005.

5. Rovetta G. Galactosaminoglycuronoglycan sulfate (matrix) in therapy of tibiofibular osteoarthritis of the knee. Drugs Exp Clin Res. (17)1: 53-57, 1991.

6. Clegg DO, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. NEJM (354)8: 795-808, 2006.

7. Reichenbach S, et al. Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med (146)8: 580-590, 2007.

8. McAlindon T, et al. Effectiveness of glucosamine for symptoms of knee osteoarthritis: results from an Internet based randomized double-blind controlled trial. Am J Med (117)9: 643-649, 2004.

9. Felson, D. Chondroitin for Pain in Osteoarthritis. Ann Int Med (146)7: 611-612, 2007.

10. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. Arth Rheum 2000;43(9)1905-1915.