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Glucosamine: Update 2006

Alternative and Complementary Medicine for Arthritis, with an emphasis on Glucosamine and its combinations

Summary

There is evidence that glucosamine and its combinations are effective in the treatment of osteoarthritis. The supplements relieve pain and may retard progression of disease. If this is what you wished to know, you can stop here. Otherwise read from the following review.

The recent literature on herbal and complementary medicines has been overwhelming. Products available on the shelves of pharmacies, health food stores, grocery stores, and products advertised in the media are sufficiently numerous to bewilder us.

This explosion of products and information occurred after passage of the 1994 Dietary Supplemement Health and Education Act, permitting classification of these as food supplements. Because of this act these products do not require the approval of the Food and Drug Administration. Thus most of them are unexamined for content or safety. Glucosamine, chondroitin, and MSM (methylsulfonylmethane) are among the best known of these “pure foods”. Glucosamine is particularly well known to people who suffer from arthritis, and has been one of the most extensively investigated alternative medicines (nutraceuticals). There is increasing evidence that it works, but more investigation is needed before the agent can be considered a proven remedy. No one can be assured of what each of the many available preparations actually contains, or how pure and free of contaminants they might be. What types of arthritis is glucosamine designed to treat?  Is it a panacea—a cure-all for any sort of arthritis? The following is a detailed discussion of the use of glucosamine for various arthritic disorders, as we understand it, in late 2006.

Alternative Medicine and Glucosamine Update

Through the past one and one-half centuries we have used a variety of medicines for the treatment of musculoskeletal pain and inflammation, including such early agents as Acetophenetidin (phenacetin) and acetylsalicylic acid (aspirin 1899). Acetaminophen, investigated and discarded in the nineteenth century because of toxicity, was restudied and introduced to clinical practice in the 1950’s. 

More recently Butazolidine (Phenylbutazone), then Indomethacin (Indocin) appeared. In the 1970’s we saw the discovery and use of cyclooxygenase in development of new NSAIDS, later referred to as COX-1 inhibitors. A COX inhibitor limits the action of the enzyme cyclooxygenase which converts cell products into inflammatory mediators, thus inhibiting the inflammatory reaction. A whole generation of agents followed this discovery. In the 1990s a second cyclooxygenase (COX-2) was followed by the development of drugs relatively specific for this enzyme, thus sparing to some extent COX-1. Gastric side effects occur less often with the COX-2 agents, but other serious side effects do occur. Among these are cardiovascular, renal and hepatic injury, fluid retention, hypertension and gastric toxicity. Recently, the removal of Vioxx from the market (Sept 2004), because of cardiovascular toxicity, has called into question the safety of the entire COX-2 class with regard to these vascular side effects. Information changes daily. Still, all agents have had side effects. Perhaps the safest are drugs similar to the old extracts of the leaves and bark of the willow tree, the original source of the earliest salicylates.

 The principal claim made for complementary and alternative medicines (CAM,s) is that they are safe, gentle, effective, and most of all “natural”. Nevertheless the classification of herbs as food supplements is a fiction that prevents the proper study of effectiveness and safety.

A therapeutic agent that is effective and free of side effects would certainly be welcomed.  Glucosamine, alone and in combination with other nutraceuticals, has been proclaimed to be just such a therapeutic agent (1, 2). The term “nutraceutical” has become increasingly prominent since passage of the nutritional supplement act in 1994. “Nutraceutical”, a term probably coined by Stephen D. DeFelice, M.D. refers to a “food or part of a food that has a medical health benefit including the prevention and treatment of disease”. Scientific research on nutraceuticals is encouraged by The Foundation for Innovation in Medicine (FIM). Thus we could be seeing the beginning “of a research-based neutraceutical industry” which could compete with the pharmaceutical industry. The claim is that a new health science in medicine has been born. A search for web sites dealing with nutraceuticals, using the Google search engine, identified 3,990,000 hits in mid 2006. One of these, the American Nutraceutical Association, publishes a journal, the JANA, which of course closely resembles the abbreviation JAMA, the Journal of the American Medical Association. The JANA can be accessed on the Internet at www.americanutra.com. A collection of technical papers, web links and references are found at www.arthritis-glucosamine.net. A search for “glucosamine”, using the Google search engine, found 7,390,000 links in mid 2006.

In 2001, the United States spent $17.8 billion on dietary supplements, 4.2 billion for botanical remedies and other herbs (3). Reasons for the popularity of these products include the high costs of prescription drugs, limited access to physicians as a result of managed care, media reports of side effects of prescription drugs, lack of availability of effective prescription drugs for certain illnesses (e.g. osteoarthritis), the perceived safety of “natural materials”, and most of all the 1994 passage of the the Dietary Supplement act.  The existence of this legislation continues to spur the growth of the industry. Although the industry is certainly not new, its logarithmic growth since 1994 is unprecedented in the history of Medicine.

Most of these recent products should be treated with great caution. Dr. C. Everett Koop, former Surgeon General added his own thoughts to this matter in an editorial in Science Magazine, Jan. 2002 (4). He advocated that a “wiser approach would be for the natural products industry to work with medical research, including the FDA in order to detect potential harm and assess benefits of alternative/complementary products”.

The U.S. Food and Drug Administration deals with many aspects of dietary supplements and herbs questions at www.cfsan.fda.gov, and the location leads to a variety of informative links. One can subscribe to a news service from this site that issues bulletins on release of new information. One of the most revealing statements made at this site however is the following: “Please do not ask questions about specific dietary supplements. The safety of a dietary supplement is the responsibility of the manufacturer.” Still the FDA does take responsibility for acting against any unsafe product after it reaches the market. How will the FDA monitor these products? The entire matter is confusing. Such is the nature of the new industry. These matters are now even more complicated since September 11, 2001. Bioterrorism legislation concerning food and food supplements is being enacted and updated at a rapid pace.

Before the new industry, we were largely confined to the idea that traditional “anti-inflammatories” worked mainly according to one principal, the inhibition of cyclooxygenase. Most of us, however, can describe several potential mechanisms of action other than cyclooxygenase inhibition, including inhibition of signal transduction and nitric oxide activity. The NSAIDs currently available, which work according to these principles, may relieve inflammation and pain in some patients with osteoarthritis, but there is little evidence that they stop disease progression, and some good evidence, in fact, that they speed the death of chondrocytes and loss of articular cartilage. Dr. Kenneth Brandt and others have posed the question whether NSAIDs should be used in osteoarthritis. Brandt concluded that they could be used with caution, and for only short periods of time (5). He prefers the use of paracetomol (Tylenol, acetominophen) for pain relief in OA. The dose should not go above four grams a day.

Glucosamine, and its various combinations, in contrast to NSAIDs, is claimed to restore cartilage structure, promote new cartilage growth and even increase joint space width on radiographs. Thus, it has been dubbed a DMOAD, a “disease modifying osteoarthritis drug”. A second new acronym, SMOAD, meaning “structure- modifying osteoarthritis drug” has been coined. Although use of these agents began many years ago, in 1997 the publication of “The Arthritis Cure” by Jason Theodosakis, hailing them as a medical miracle, greatly increased the public interest. This book was followed by a second one by the same author: “Maximizing the Arthritis Cure” published in 1998. Both books described a nine-step program, the centerpiece of which was the “nutritional supplement”. The supplement recommended in these books requires both glucosamine and chondroitin. Glucosamine can be in any form. Those currently available in the United States include the sulfate, hydrochloride, hydroiodide, n-acetyl and several other salts. The sulfate form regulated and sold as a prescription drug in Europe and in other countries, is the form that has been most widely used in clinical research (6). Much of this research has been supported by the industry. Many reports of efficacy are carried in the lay press and in industry-supported newsletters. Amazon.com at www.amazon.com listed nine books on glucosamine and it’s combinations that were available in Feb. 2003, but many more now.Amazon also sells glucosamine and its combinations online.

At least as early as the 1960’s, injectable and oral glucosamine sulfate were suggested as a basic therapy for osteoarthritis because it was shown to restore articular function “to a certain extent”. Studies have shown that oral D-glucosamine sulfate is readily absorbed, and then split into D-glucosamine (DG) and the sulfate ion. This also occurs following IV or intramuscular injection. DG is a small molecule which diffuses easily into body compartments and has a special tropism for cartilaginous and bone tissues “where it probably represents the preferred substrate for the biosynthesis of the proteoglycans of the cartilage matrix.” (7). There are increasing numbers of studies that propose a more fundamental mechanism of action for glucosamine, studies at the molecular level, involving cytokines and genes.  One recent study showed that glucosamine sulfate “inhibits the synthesis of proinflammatory mediators in human osteoarthritic chondrocytes stimulated with interleukin-1beta through an NFkappaB mechanism”, thereby modifying gene expression (8).

More recently, many clinical trials show favorable efficacy (1, 2). A meta-analysis by McAlindon et al, of 15 clinical trials of glucosamine, chondroitin sulfate or both emphasizes the safety and suggests the possible effectiveness of glucosamine and chondroitin. Various studies claimed to show improvement in pain scales and preservation of joint space width. The author pointed out the need for further studies to confirm their role in the treatment of osteoarthritis. Since these publications were summarized, some trials have shown less compelling results.

Almost all of the reported literature on pure glucosamine alone deals with glucosamine sulfate, marketed as DONA, Viatril-S, Xicil, and also by other names, by Rottapharmaceuticals ( Rotta Research Group) in Monza, Italy. Information about this agent is available online at  www.originalglucosamine.com.  McNeil, the maker of tylenol, marketed glucosamine tablets which contained 300 mgm of the sulfate and 200 mgm of the hydrochloride. The agent was called AFLEXA. Marketing of this agent has ceased because of intense competition and poor sales. Glucosamine sulfate is now available at many pharmacies as a generic preparation. DONA is crystalline and is taken as a single dose dissolved in water. Tablets are also available. The European firm argues that almost all of the published literature is on the pure sulfate form; however there is little reason to think that the combined form containing both the sulfate and hydrochloride salts, or other salts of glucosamine would be less effective. DONA and other products containing glucosamine sulfate alone are available in the United States.

Very few of the preparations available in pharmacies, grocery stores or from catalogues limit contents of their product to pure glucosamine. They contain a variety of additives including chondroitin sulfate, MSM (methylsulfonylmethane), and others, and none guarantees purity. The manufacturers assure us of “purity”, i.e. lack of contaminants, in the products of Rotta Pharmaceuticals, Inc (DONA). Shelves of preparations containing a variety of these materials can be found at any pharmacy or “health food” store, grocery store, or any business devoted in part to alternative products. At one large local pharmacy in the Pittsburgh area over twenty-five different preparations were found at the time of this writing. These were packaged as tablets, caplets, powders or flavored, chewable preparations. One supplement, Maxiflex, contains 17 ingredients. Another agent, “FlexAnew”, recently renamed FeelAnew contains glucosamine and chondroitin and also a “naturally occurring” COX-2 inhibitor. This new ingredient Nexrutine™, a Parmaflex™ product, is “patent pending”, and is derived from the bark of the Amur cork tree (Phellodendron amurense), an eastern Asian tree in the rue (Rutaceae) family of herbs. A search produced one reference to unpublished data confirming COX-2 inhibitory activity of this agent in human umbilical endothelial cell cultures (9). This reference appeared on the web. Search FeelAnew or Feelanew  Names change quickly. This agent is the subject of a book by James B. Lavalle entitled The COX-2 Connection, published September 2001. As of this writing Cosamine DS and Osteo-Bi-Flex are among the most widely sold of the glucosamine-containing agents, but this may change as the industry expands. Since the FDA does not allow advertising nutraceuticals in the same way as approved drugs, books are written about them and are propelled to best-seller status, and they are widely covered in the lay press and industry-supported newsletters. The subject has become so important that seminars on it are featured at recent annual meetings of the American College of Rheumatology each year (2005-2006).

Dietary supplements available since the 1994 congressional act do not need FDA approval, but all carry a disclaimer, as follows: “The product is not intended to diagnose, treat, cure or prevent any disease”. Simply turn the package over to find the possible efficacies of the panacea. The panaceas are said to treat established arthritis, produce pain relief within 2 weeks, and prevent the development of musculoskeletal disease in individuals who are perfectly healthy. Glucosamine is considered a food supplement rather than a drug, and, therefore is not regulated by the Food and Drug Administration.  These agents are considered “dietary supplements”, nutritional supplements or foods. According to the Dietary Supplement Health and Education Act (DSHEA) of 1994, a supplement is a product taken by mouth that contains a dietary ingredient intended to supplement the diet. Such materials may include vitamins, minerals, herbs or other botanicals, extracts of organ tissues, and many others. The one possible exception to this generalization is the product produced by The Rotta Group, which in Europe is a drug (DONA) that requires a prescription. In the USA it can be purchased over the counter or off the shelf without a prescription.

Recently, a three year randomized placebo-controlled trial of glucosamine sulfate was published, concluding that the agent is effective in relieving pain and that it prevents loss of joint space. (10). The authors suggested that it be regarded as a disease modifying Osteoarthritis drug, thus a DMOAD. The study was sponsored by Industry, Rotta Pharmaceuticals, Monza, Italy. Another recent publication, supported by Rotta Pharmaceuticals, showed that Glucosamine sulphate provided symptomatic relief of arthritic symptoms regardless of any effect on joint space width. In the October 2002 issue of The Archives of Internal Medicine, investigators from Charles University, Prague, Czech Republic, published a 3-year, randomized, placebo-controlled, double-blind study showing that glucosamine sulfate prevented loss of joint space and controlled symptoms. Changes in joint space width were measured in the medial compartment of the tibio-femoral joint. Symptoms were assessed using the Lequesne and WOMAC indexes. The claims are that the chemical is anti-inflammatory, symptom modifying, and protective of articular cartilage (11). Glucosamine did not differ from placebo regarding side effects and did not unmask (promote) diabetes. If these results continue to be confirmed, glucosamine will be the first such disease modifying agent in the history of the treatment of osteoarthritis. To date the European literature claims that the agent has been evaluated in more than 6,000 patients. Since 1995 there have been at least 20,000,000 patient-months of exposure to the drug.  No large federally funded study of glucosamine, chondroitin sulfate or the combination was published in the United States until 2006. Such a study was underway in the years during which the studies presented above were reviewed. This large U.S.multicenter study, the GAIT study (Glucosamine/chondroitin Arthritis Intervention Trial) conducted by the National Institutes of Health (NIH), and sponsored by the National Center for Complementary and Alternative Medicine (NCCAM), was completed in 2005. The results were published online, and in abstract form in Arthritis and Rheumatism (12), and were also presented at the annual meeting at San Diego in November 2006. The hope was that this study would provide definitive data.

Unfortunately it did not.

3238 patients were screened at 16 academic rheumatology centers. 1258 (80%) completed the study. Patients with osteoarthritis of the knee were randomly assigned to one of five treatment groups: placebo; glucosamine hydrochloride 500 mgm three times a day; chondroitin sulfate 400 mgm three times a day; combination glucosamine and chondroitin at the above doses three times a day; or celecoxib (Celebrex) 200 mgm once a day. Note that chondroitin hydrochloride-not sulfate- was used in this study.

Results were interpreted as follows:

• Prior to the meeting the online publication was interpreted as supporting the superiority of the combination of glucosamine and chondroitin for patients with moderate to severe pain. Alternative medicines (complimentary and alternative medicines) took immediate advantage of this interpretation. The combination was superior to placebo and celebrex. Television ads appeared immediately.
• The published abstract (identical to the online publication) was similarly interpreted.
• The oral presentation on the floor concluded that the study was “null”, statistically uninterpretable. Dr. Clegg, the principle author, was asked to stress the “null” or negative outcome of the study. He did so. He said that the statistics showed that the results were meaningless. There was thorough confusion. I spoke with Dr Lucio Rovatti from Monza, Italy about the study. Dr Rovatti is a senior scientist with Rottapharmaceuticals, the makers of DONA, glucosamine sulfate. He said “They used the wrong glucosamine”, the hydrochloride, not the sulfate. He said the placebo value was too high. 60% of the patients on placebo responded with a clinically significant decrease in pain. How could anything exceed that?
• The February 2006 New England Journal of Medicine included the definitive publication of the GAIT study (13).The conclusions were still not clarified. There was a huge placebo response, thereby possibly negating any other conclusion. But the combination of glucosamine and chondroitin was more effective than placebo in a small subgroup of patients with moderate to severe pain. In this subgroup celebrex did not work significantly better than placebo. In patients with mild pain celebrex was only marginally better than placebo(p=.04).
• My own view of the entire affair is that no conclusion can be drawn except the following: placebo alone was remarkably effective within its own study group (60% of the patients improved by 20%---an extraordinary response for placebo in any study).
• The question of slowing deterioration of joint space loss has not been answered as of the time of this writing. Unlike the previous studies, the NIH study will use a different radiographic image to measure joint space width, the “more precise” MTP flexed-knee (Buckland-Wright) view, a view which opens the tibio-femoral compartment maximally, and is said to be superior to other views. The standard AP view used in the European studies has been criticized for lack of accuracy in determining joint space width.

Dona (Glucosamine sulfate) is produced “semisynthetically” from chitin, derived from the exoskeletons of sea crustaceans. It is purified to the extent that it is free of proteinaceous materials.  According to the company, persons with allergies to shellfish can use it without fear of allergic reactions. Possibly all marketed glucosamine products have a similar source, but to what extent, and the method by which they are purified is not clear. Most of the other products that could be found listed the precaution “Do not use if you are allergic to shellfish”. Some suggested caution and discussion with a physician if such an allergy existed. The extraction and the purification processes are probably elaborate and there are chances for contaminants being included in the end product.

**The current literature suggests efficacy and safety for glucosamine sulfate in the treatment of osteoarthritis. It also supports the potential for anti-inflammatory activity at the molecular level. Preliminary data support this idea. Further research is clearly needed, however, and the many additives in available preparations play an unknown role. A large trial is still ongoing, investigating the effectiveness and safety of several agents under the guidance of the NIH and the National Center for Complementary and Alternative Medicine. An important question to be answered is whether the supplements will slow cartilage loss in osteoarthritis. **

With regard to alternative and complimentary medicines in general, there are increasing reports of adverse effects due to direct toxicity, herb/drug interactions and contaminants. Nevertheless it is clear that the industry has entered a rapidly expanding phase of growth.

—Robert B. Buckingham, M.D.

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