“Patented ingredients help support, ease, and rebuild joints….”

“Soothe away joint pain and watch as your skin regains a nourished, youthful appearance….”

When patients hear and read claims like these, it’s no wonder that they show up in your office with Web page printouts, torn out advertisements, and plenty of questions. The desire to find a miraculous cure to alleviate reduced mobility and arthritis pain is a natural one and leads many consumers to wonder if there’s a product out there that their physicians have overlooked. Consumers are all too eager to believe testimonials—whether from a star athlete or an unknown fellow sufferer—and just as reluctant to have their bubbles burst by scientific evidence.

Further compounding the problem is the fact that peer-reviewed journals—the most probable bearers of reasonable (if occasionally conflicting) information—are unlikely to be easily accessible to consumers. They are also likely to be difficult for the average person to read and understand. As a result, it becomes relatively easy for a purveyor of questionable “cures” to sway consumers, especially when the product being hawked remains shrouded behind a cloud of ambiguous efficacy.

The U.S. Food and Drug Administration (FDA) classifies dietary supplements as a subcategory of “food,” providing manufacturers with greater leeway and less oversight than products in the pharmaceutical category. This leads to what might be called the asterisk syndrome. For example, a product is advertised to promote and maintain “joint strength,* joint flexibility,* joint lubrication,* range of motion,* production of lubricating fluid,* and renewal of cartilage and connective tissue.*” The asterisk at the bottom of the page has the following disclaimer: “*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.”

Physicians need to be able to discuss the pros, cons, and ambiguities of various supplements, not only for patient safety reasons, but also to keep patients from wasting time and money on substances that are unlikely to provide the intended effect. A brief discussion of some commonly available joint supplements follows. This list is not intended to be all-inclusive or to provide a comprehensive analysis.

Glucosamine
Glucosamine is an essential component of cartilage, mucous membranes, and synovial fluid. It can be manufactured in the laboratory, but commercial producers often extract it from the exoskeletons of lobsters, crabs, shrimp, and other sea creatures. It can be found in a variety of formulations or salts—most commonly as glucosamine sulfate, but also as glucosamine hydrochloride and n-acetyl glucosamine.

Efficacy of glucosamine is generally considered to be good and is supported by several studies. However, little research exists that compares outcomes of different salts, so it is not known whether they are interchangeable.

One meta-analysis of randomized, placebo-controlled clinical trials from January 1980 to March 2002 found glucosamine to have “highly significant efficacy” for all outcomes, including joint space narrowing and Western Ontario MacMaster University Osteoarthritis Index (WOMAC).¹ Another study reported on 1,583 patients with symptomatic knee osteoarthritis who were randomly assigned to take glucosamine, chondroitin, a combination of glucosamine and chondroitin, celecoxib, or placebo over 24 weeks. Overall rate of response to glucosamine, chondroitin, and the combination were not found to be significantly better than placebo, although patients with moderate to severe pain at baseline were observed to respond significantly better with the combination.²

Primary side effects of all salts of glucosamine are mild gastrointestinal complaints such as constipation, diarrhea, cramping, gas, heartburn, and nausea. Glucosamine sulfate has been associated with drowsiness and headache. The effects of glucosamine on nursing or pregnant women have not been well-studied.

Glucosamine may increase blood sugar levels. Although studies of glucosamine on patients with diabetes are inconclusive, it is believed that higher doses may prompt the pancreas to produce less insulin, so caution is advised.

Because glucosamine is often made from shellfish and the source of the product is not required to be on the label, individuals who are allergic to seafood are advised to exercise caution as well.

Chondroitin
Like glucosamine, chondroitin is another essential component of cartilage. Chondroitin can be manufactured synthetically, but is commonly extracted from cow and shark cartilage. It is believed to promote the production of new cartilage and delay the breakdown of existing cartilage, and it has also been linked to helping lubrication by drawing water into joint spaces.

Study participants have generally reported a decrease in pain and increases in joint movement when taking chondroitin, although it is not uncommon for participants to take chondroitin in combination with aspirin or other conventional arthritis treatments, so the true extent of the efficacy of chondroitin remain unclear. Furthermore, some studies seem to show that chondroitin must be taken for up to 4 months before benefits are realized.

A recent 24-week trial of 279 patients found no significant difference between chondroitin and placebo as far as the study’s primary efficacy criteria (pain on daily activities and Lequesne’s index) were concerned. The supplement demonstrated slight efficacy on the secondary criteria of pain, Outcome Measures in Rheumatology - Osteoarthritis Research Society International (OMERACT-OARSI) response rate, investigator’s assessment, and quality of life.³

A meta-analysis of glucosamine and chondroitin in double-blind, randomized, placebo-controlled trials of 4 or more weeks’ duration conducted from 1966 to 1999 showed that both supplements demonstrated moderate to large effects. When only the highest-quality and largest trials were considered, however, efficacy was reduced.⁴

Primary side effects of chondroitin are uncommon and include hair loss and minor gastrointestinal complaints. The effects of chondroitin on nursing or pregnant women have not been well-studied.

Chondroitin can decrease the blood’s ability to clot, and it is not advisable to take it concurrently with aspirin, antiplatelet, or anticoagulant drugs.

Because glucosamine and chondroitin are both components of cartilage, they are sometimes combined in one product. Efficacy of such combined products is inconclusive, although some patients with moderate to severe pain may experience some benefits.

Chondroitin products are also sometimes combined with manganese, which may assist in cartilage production, but is toxic in large doses. The U.S. National Academy of Sciences has set the adult tolerable upper limit for manganese at 11 mg/day; patients should be advised not to exceed that level.

MSM
Methylsulfonylmethane (MSM) has been touted as a treatment for a variety of conditions from osteoarthritis to stress and snoring. Few clinical trials examine the supplement’s efficacy for osteoarthritis. Promoters of MSM state that the supplement helps to provide sulfur that may be lacking in many diets, but evidence for this is spotty at best.

One randomized, double-blind, placebo-controlled pilot trial of 50 patients was conducted over 12 weeks and found that MSM produced significant decreases in pain and physical function impairment on the WOMAC scale, but no notable changes in stiffness and aggregated total symptoms scores.⁵

There is little or no evidence to determine the effects of long-term use of MSM.

Omega-3 fatty acids
Omega-3 (or n-3) fatty acids are derived from fish and other seafood. They have been promoted as treatment for arthritis, cardiovascular disease, and high triglyceride levels. One prescription product, Omacor®, has received FDA approval for use in lowering triglycerides, but despite claims, little clinical evidence exists to support assertions that omega-3s are effective against arthritis.

Because omega-3 fatty acids are extracted from seafood, individuals with seafood allergies should avoid them.

Oral hyaluronic acid
Hyaluronic acid is a component of synovial fluid and as such is commonly injected as a treatment for osteoarthritis. Several manufacturers have begun producing oral versions, but clinical evidence for efficacy of oral hyaluronic acid in the treatment of arthritis is unavailable.

Shark cartilage
Shark cartilage has in the past been touted by disreputable vendors as a cure for cancer, but it has also been promoted as a treatment for both rheumatoid arthritis and osteoarthritis. Chondroitin can be derived from shark cartilage, but there is no proof that taking a shark cartilage supplement provides similar benefits. In addition, no studies have been conducted to determine whether shark cartilage has any serious or long-term side effects.

Summary
Quality evidence for the efficacy of joint supplements—even for glucosamine and chondroitin—is hard to find and often contradictory. Of the commonly available supplements, glucosamine, chondroitin, or a combination of the two appear to have the greatest efficacy based on clinical trials, but a number of researchers remain guarded even when recommending those products. MSM may provide some benefits, but more studies need to be done before evidence accrues as to its long-term effectiveness.

Many of the supplements produce, in general, only minor side-effects, which, coupled with anecdotal evidence and a variety of spectacular advertising claims, makes them attractive to consumers. Physicians should be careful when recommending any of the joint supplements and always take into account dosing, allergies, and potential interactions.

Peter Pollack is a staff writer for AAOS Now. Links to the studies cited in this article can be found online at www.aaos.org/now

References

1. Letic-Gavrilovic A, Scandurra R, Abe K. Genetic potential of interfacial guided osteogenesis in implant devices. Dent Mater J. Jun 2000;19(2):99-132.
2. Palin E, Liu H, Webster T. Mimicking the nanofeatures of bone increases bone-forming cell adhesion and proliferation. Nanotechnology. 2005(16):1828-1835.
3. Murosaki T, Gong JP, Osada Y. [Creation of artificial cartilage by nanotechnology]. Nippon Rinsho. Feb 2006;64(2):206-214.
4. Tasker LH, Sparey-Taylor GJ, Nokes LD. Applications of Nanotechnology in Orthopaedics. Clin Orthop Relat Res. Jan 11 2007.
5. Park G, Webster T. A Review of Nanotechnology for the Development of Better Orthopedic Implants. J of Biomed Nanotechnology. 2005;1:18-29.

Late-breaking chondroitin study finds minimal effect

As AAOS Now went to press, the Annals of Internal Medicine (Vol. 186, No. 8) published the results of a meta-analysis of studies on the use of chondroitin for treating osteoarthritis of the knee. The analysis found that “large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent.”

The meta-analysis reviewed the results of 20 trials (3,846 patients). All of the studies included were either randomized or quasi-randomized, controlled trials, and compared the use of chondroitin with placebo or no treatment in patients with knee or hip osteoarthritis.

The effects on joint space in the reviewed studies were inconclusive.

Regarding joint pain, the team’s overall analysis revealed a large effect size of –0.75 (95 percent confidence interval; range: –0.99 to –0.50); newer studies showed smaller effects than did older studies. When researchers pooled three trials with large sample sizes and an intention-to-treat analysis, the effect size was nearly zero, leading the researchers to conclude that “no robust evidence supports the use of chondroitin in osteoarthritis…For patients with advanced osteoarthritis, a clinically relevant benefit is unlikely and the use of chondroitin should be discouraged.”

Sifting through the hype

When patients come in to your office with Internet printouts and questions on supplements, you can help them shift through the hype by referring them to reliable sources of information, including the following Web sites:

Arthritis Foundation
www.arthritis.org
The not-for-profit Arthritis Foundation publishes the print magazine Arthritis Today for consumers. Some magazine articles are available online, and information on glucosamine and chondroitin is available through the search box.

Consumer Reports
www.consumerreports.org
Like its print counterpart, the health and fitness section of this Consumers Union-sponsored Web site assesses a range of products. The Supplements section includes a listing of the “dirty dozen,” 12 supplements that should never be taken.

Drug Digest
www.drugdigest.org
This noncommercial site is hosted by Express Scripts, a for-profit company. It includes a searchable database of evidence-based information on drugs, herbs, and supplements such as glucosamine, chondroitin, and omega-3 fatty acids.

National Center for Complementary and Alternative Medicine
http://nccam.nih.gov
One of the National Institutes of Health, the NCCAM includes information on clinical trials, consumer information that includes “What the science says,” and links to other reputable sites, most of which are government-sponsored.

Quackwatch
www.quackwatch.org
This not-for-profit site operated by retired psychiatrist Stephen Barrett, MD, includes articles on a wide range of topics. Articles combine evidence from peer-reviewed studies, Consumer Reports, and some personal opinion.

Your Orthopaedic Connection
www.orthoinfo.aaos.org
The AAOS patient education Web site contains information on glucosamine and chondroitin, as well as a variety of other orthopaedic topics.