The JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Reports
Glucosamine & Chondroitin
Help Prevent Osteoarthritis

By Will Block

lucosamine and chondroitin dietary supplements have sufficiently positive outcomes in controlled clinical trials to warrant their use in osteoarthritis. With few adverse effects compared to the conventionally prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetaminophen or ibuprofen - which can cause ulcers and other serious gastrointestinal disruptions, especially in the elderly - glucosamine and chondroitin are the only treatments that have been shown to retard progression of the disease, as opposed to merely alleviating its symptoms.2 This is the latest news according to the Journal of the American Medical Association (JAMA). And it is very good news, but it is not really new.

For those who haven't followed the growing body of scientific literature that supports the therapeutic use of nutrients, it may come as a surprise that research on glucosamine and chondroitin (G&C) has been compiling for more than 30 years. Positive results and unobjectionable side effects have been the rule with glucosamine. They are becoming the rule for chondroitin as well, although the results have shown wider fluctuations, because some forms of chondroitin work much better than others.

The result of all this G&C research has been the wide availability of nutrient forms of these compounds that possess anti-inflammatory, antiarthritic, analgesic, and anabolic (molecule production) behavior in chondrocytes (cartilage cells).3 The abundance, high quality, and low prices of these nutrients have encouraged individuals to experiment and assess their usefulness for themselves. Anecdotal data have been overwhelmingly favorable, and best-selling books about G&C have made knowledge of these supplements even more common. So the JAMA article is long overdue.


The human knee (minus the kneecap), shown somewhat separated for clarity.

THE SOURCE OF OSTEOARTHRITIS
At the ends of your bones, where they meet other bones at the joints, lies the extraordinary and valuable biomaterial called cartilage. This elastic tissue cushions your joints and, together with synovial fluid (found in the joint spaces), reduces and ideally minimizes the friction caused by the pivoting, rotating, and inevitable rubbing of your bones where they come together. Indeed, cartilage acts as a shock absorber that helps reduce the wear and tear that come with functional stress and aging.

When healthy cartilage serves its proper function, your joints work well. When it is unduly stressed by high levels of activity, however, or is diminished in quantity by age or physical condition, degradation may result, causing inflammation, pain, loss of movement, and loss of a key element of youthfulness. This may occur in any of your joints, but especially the hands, neck, feet, knees, elbows, and hips. The spine may also be affected. Conceivably, degradation could occur anywhere in the body where bones rub together - meaning any joint.

The condition described is the most common form of arthritis, osteoarthritis. As the name implies, osteoarthritis affects bones, or more specifically, the joints of bones. If not treated, it can eventually lead to joint deformities and severe loss of mobility. Although osteoarthritis (OA) is generally age-related and doesn't normally manifest itself until the 40s, undue stress or injury or a number of other conditions can bring it on much earlier: it can affect individuals as young as 25. No less than 21 million Americans are reported to suffer from OA, and their collective loss of freedom of movement, not to mention the associated pain and impaired quality of life, is enormous.

GLUCOSAMINE AND CHONDROITIN BUILD NEW CARTILAGE AND MORE
Glucosamine is a complex sugar that the body uses as a chemical building block in the biosynthesis of some of the important constituents of cartilage. Chondroitin is one of these constituents. In the manufacture of G&C supplements, both compounds are extracted from animal products. While the mechanisms of action of glucosamine and chondroitin in the treatment of osteoarthritis are not fully understood, both compounds demonstrate anti-inflammatory action and are thought to help build new cartilage as well as dismantle old cartilage. Osteoarthritis results from the progressive breakdown of cartilage owing to an imbalance between synthesis and degradation.

GLUCOSAMINE AND CHONDROITIN PREVENT PAIN AND LOSS OF JOINT FUNCTION
Europeans have been using G&C in various forms for osteoarthritis more avidly than Americans for the last decade, and press coverage of their benefits has increased their popularity. The JAMA study on G&C was conducted in response to this phenomenon. It was a meta-analysis - a rigorous review of previously published, double-blind, placebo-controlled studies selected on the basis of their meeting certain methodological criteria. Three classes of values were assigned to the outcomes of the studies reviewed: 0.8 for a large treatment effect, 0.5 for a moderate effect, and 0.2 for a small effect. Actual values would, of course, be different. Glucosamine was found to possess moderate benefits (a weighted average of 0.44), while chondroitin appeared to be more than twice as effective in reducing pain and improving mobility (0.96). However, the results varied widely, with the smallest range for glucosamine (0.23 to 1.28) and the largest range for chondroitin (0.53 to 4.56).

The JAMA study was not the first to look at the evidence that the benefits of G&C go beyond those of the conventional NSAID treatments. Another meta-analysis, encompassing seven trials in which 372 patients were followed for 120 days or more, was published about two months earlier. It reached many of the same conclusions about chondroitin, which was found to be at least 50% better than placebo in lessening and preventing pain and loss of joint function.4

Yet another review of the literature found 13 studies (six with glucosamine, seven with chondroitin) showing that the eligibility criteria for using these nutrient compounds in treating osteoarthritis of the hip or knee had been met.5 All of these studies were judged to have demonstrated significantly reduced pain, as well as increased freedom of movement by about 40%, compared with placebo. The results were similar for both of the nutrients.

GLUCOSAMINE AND CHONDROITIN - A SAFE ALTERNATIVE
In an editorial related to the JAMA review, concern is expressed not only regarding the use of NSAIDs (until recently the only recognized treatment), but also for the use of COX-2 inhibitors (a new class of nonsteroidal anti-inflammatory drugs), which, like the NSAIDs they are attempting to replace, have their own collection of serious side effects that pose a significant risk of gastrointestinal complications. Thus the editorialists conclude that there is a great need for alternatives for treating osteoarthritis safely and effectively. And they are right. The use of NSAIDs by elderly patients, e.g., doubles the risk of being hospitalized for congestive heart failure, and for those with a history of heart disease, it increases the risk by more than 10 times, researchers reported in the March 27 issue of Archives of Internal Medicine.6

Currently underway is a large-scale study by the National Institutes of Health evaluating glucosamine and chondroitin in patients with osteoarthritis of the knee. Scheduled to run for 16 weeks, this parallel-group, double-blind study includes four treatment "arms," in which patients will ingest orally one of the following combinations: placebo, 500 mg of glucosamine sulfate three times per day, 400 mg of chondroitin sulfate three times per day, or a combination of glucosamine and chondroitin.

As with many nutraceuticals that are currently widely regarded as beneficial for everyday, garden-variety, or difficult-to-treat disorders, it may be that the hype about G&C exceeds the benefits of any possible outcome. But once large-scale, high-quality studies such as that of the National Institutes of Health are published and critiqued, the word will assuredly go far and wide, and even traditional physicians will get information necessary to advise their patients about the benefits of these alternative therapies. If only they were reading the alternative, complementary publications now.

JAMA STUDY DID NOT DISTINGUISH AMONG CHONDROITINS
Returning to what's really new in this area . . . . Only a few analyses or commentaries have attempted to distinguish between the different varieties of chondroitins that comprise the test material of the studies. This is surprising, given that the range of positive effects from taking chondroitin was much wider than that from taking glucosamine, as reported in the JAMA review. The positive effects from taking chondroitin were also much larger. What was the type of chondroitin used in the nine studies selected for inclusion in the review? Overwhelmingly, it was mixed chondroitin 4-sulfate and chondroitin 6-sulfate (called chondroitin 4,6-sulfate for short), as mentioned explicitly in the research reports.

All the different varieties of chondroitin and glucosamine may leave people confused. Studies have shown that the biological activity of chondroitin sulfate depends on its molecular structure, and it is quite clear that there are different and complementary roles for the two forms.7 While chondroitin 6-sulfate is better than chondroitin 4-sulfate for inhibiting the enzymatic degradation of cartilage, the 4-sulfate is more effective for the synthesis of new cartilage.

Of Cows, Sharks, and Chondroitin

Recently, standing on the cliffs of Maui's North Shore, I was told about some local fishermen who were returning from the sea when they spotted a cow floundering in the ocean, obviously having fallen from the cliffs of grazing pastures above. Smacking their lips, they quickly lassoed the hapless beast to tow it to port. Suddenly they felt a sharp yank on the boat. Sharks repeatedly tore into the cow and ate all but the head, which the fishermen finally pulled into their boat.

An odd little story, but so what? Well, how often do sharks and cows ever meet, so to speak? Probably never, except that one time, right?

Wrong! They "meet" all the time in bottles of a nutritional supplement which contains chondroitin 6-sulfate from shark cartilage and chondroitin 4-sulfate from cow tracheas - in just the right ratio for optimal effect. (See below for an explanation of the importance of using the right forms and ratios of chondroitin.)

Cows that fall from cliffs into shark-infested waters no longer need to be concerned about their joints. However, for those of us people who are interested in healthy, great-feeling joints, I can report dramatic personal results with both glucosamine and the mixed chondroitins from sharks and cows - for counteracting the pain and debilitation that I had.

The tabloids' use of the word "miracle" in this context is understandable. If I weren't legally prohibited from saying so, I might say that glucosamine and mixed chondroitins "cured" my problems - but I can't. So I'll just say that glucosamine and mixed chondroitins helped to support proper joint function, as I let out a big S-I-G-H. Try these nutrients if you're concerned about your own joint function. You're likely to notice a BIG difference.

THE POWER IN CHONDROITIN RATIOS
Other studies strongly suggest that the ratio of the two forms of chondroitin sulfate in synovial fluid is important and reflects the degree of joint health. When the 6-sulfate is too prevalent, it can interfere with the metabolism of joint tissue. As humans age, the ratio between the two forms of chondroitin eventually shifts almost entirely toward the 6-sulfate.8 With the summary analysis provided by the JAMA study, there can be little doubt that a 60%-40% blend of the 4-sulfate and the 6-sulfate - the same ratio that prevailed in our youth - works better than glucosamine, albeit somewhat differently.

In the research literature, it is not always clear what other forms of chondroitin are used, but the fact remains that there have been few studies with promising results that don't employ the 4,6-sulfate mixture. It seems likely that chondroitin 4,6-sulfate is vastly superior to other chondroitin formulations in providing long-range benefits for the joints.

WHICH GLUCOSAMINE
Glucosamine and its derivatives, such as glucosamine sulfate and acetylglucosamine, have been shown to be effective in supporting proper joint function.9 Unfortunately, though, both of the most widely used derivatives of glucosamine, the sulfate form and the hydrochloride form, have relatively short half-lives in the bloodstream, meaning they don't stay there very long. Acetylglucosamine, however, has a longer half-life, ensuring more continuous utilization and better joint protection. Unlike other derivatives of glucosamine, it is converted to glucosamine in the body on an as-needed basis, and the levels can more easily be increased and maintained by supplementation. Acetylglucosamine has other unique benefits, and, like chondroitin, it can inhibit the release of cartilage-degrading enzymes.10 Hyaluronic acid, an all-important component of synovial fluid, is readily formed from acetylglucosamine.5 All in all, acetylglucosamine is the best choice as a source of glucosamine.

When you consider the importance of your joints, a formulation combining acetylglucosamine and appropriately balanced chondroitin 4-sulfate and chondroitin 6-sulfate is worthy of both your attention and an ongoing effort to read and examine the evidence presented in the studies and reviews, such as the JAMA article. The more immediate impact of the glucosamine, as well as the building benefits of the chondroitin, may offer what you have been yearning for - more youthful joint functioning.

References

  1. Towheed TE, Anastassiades TP. Glucosamine and chondroitin for treating symptoms of osteoarthritis: evidence is widely touted but incomplete. JAMA. 2000 Mar 15;283(11):1483-4.
  2. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis. A systematic quality assessment and meta-analysis. JAMA 2000 Mar 15;283(11):1469-75.
  3. McCarty MF. Enhanced synovial production of hyaluronic acid may explain rapid clinical response to high-dose glucosamine in osteoarthritis. Med Hypotheses 1998 Jun;50(6):507-10.
  4. Leeb BF, Schweitzer H, Montag K, Smolen JS. A meta-analysis of chondroitin sulfate in the treatment of osteoarthritis. J Rheumatol 2000 Jan;27(1):205-11.
  5. Deal CL, Moskowitz RW. Nutraceuticals as therapeutic agents in osteoarthritis. The role of glucosamine, chondroitin sulfate, and collagen hydrolysate. Rheum Dis Clin North Am 1999 May;25(2):379-95.
  6. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an under-recognized public health problem. Arch Intern Med 2000;160:777-84.
  7. Kostoulas G, Horler D, Naggi A, Casu B, Baici A. Electrostatic interactions between human leukocyte elastase and sulfated glycosaminoglycans: physiological implications. Biol Chem 1997; 378(12):1481-9.
  8. Mourao PA, Michelacci YM, Toledo OM. Glycosaminoglycans and proteoglycans of normal and tumoral cartilages of humans and rats. Cancer Res 1979 Jul;39(7 Pt 1):2802-6.
  9. Talent JM, Gracy RW. Pilot study of oral polymeric N-acetyl-D-glucosamine as a potential treatment for patients with osteoarthritis. Clin Ther 1996;18/6:1184-90.
  10. Kamel M, Hanafi M, Bassiouni M. Inhibition of elastase enzyme release from human polymorphonuclear leukocytes by N-acetyl-galactosamine and N-acetyl-glucosamine. Clin Exp Rheumatol 1991 Jan-Feb;9(1):17-21.

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