Dietary supplements for joint health are a successful and growing part of the dietary supplement industry. Their success can be attributed to the fact that users' joints feel better. This update will look at recent developments for the mainstays in joint health-glucosamine and chondroitin sulfates-and look at other promising nutrients, forgotten facts and future prognostications.
Glucosamine
The obvious: In 1999 and 2000, several meta-analyses on glucosamine and osteoarthritis appeared, examining the quality of available studies and analyzing the combined overall results. Although different authors applied different standards of quality for the studies, the conclusion of each review was grudging acceptance that 1500 mg of glucosamine sulfate per day reduced pain and improved joint function (movement) in most people with mild to moderate osteoarthritis. Results were stronger after four weeks of supplementation. Importantly, all reviewers fully agreed that glucosamine was safe, and safer than the usual NSAIDs (e.g., ibuprofen, piroxicam) used for osteoarthritis. The consistency of different critical reviewers coming up with the same conclusions makes a very strong argument that glucosamine is effective for reducing symptoms of osteoarthritis.
Some very recent North American studies on glucosamine did not find significant differences between placebo and glucosamine groups. Lack of efficacy was attributed to the enormous popularity of glucosamine causing a positive placebo effect much higher than expected in the control groups and negative placebo responses in glucosamine groups, obscuring true effects of glucosamine. These findings are mute testimony to the apparent effectiveness of glucosamine and to difficulty in conducting future studies.
One of the raps against glucosamine has been a lack of long term studies. The Lancet recently published the long-awaited results of a three year study from Yves Reginster and coworkers in Belgium. The most amazing conclusion was X-ray imaging evidence of restoration of cartilage and joint space with glucosamine, as opposed to the usual and inevitable loss of each in the placebo group. This result was entirely predictable and publication of this study in a major medical journal has silenced naysayers and tipped medical opinion favorably towards glucosamine.
Finally, the possible link between glucosamine and diabetes (or insulin resistance) should be put to rest. Yes, very high doses of glucosamine (20 grams or so) can cause temporary insulin resistance in humans, but this is a normal, safety-valve feature of cells to use glucosamine as a signal to prevent toxic cellular effects of high glucose loads and not an aberration or adverse side effect. In fact, oral doses of glucosamine up to five grams have no effect on blood sugar or insulin sensitivity, meaning glucosamine in recommended amounts is safe, as verified by the thousands of subjects followed in human studies and use of glucosamine sulfate without evidence of harm in diabetics.
The forgotten: A little known fact is that 500 mg of glucosamine hydrochloride yields 415 mg of glucosamine (83.1%), whereas 500 mg of glucosamine sulfate salts yield anywhere from 254-326 mg of glucosamine (50.7-65.1%). In other words, a consumer gets about 20% more glucosamine out of 1500 mg glucosamine hydrochloride than 1500 mg glucosamine sulfate for a lower price. This increase in glucosamine dose from the hydrochloride version exceeds the daily 1500 mg used in clinical studies with glucosamine sulfate.
Chondroitin Sulfates
The obvious: Like glucosamine, a crop of meta-analyses sprang up in the medical literature in 1999 and 2000 concerning chondroitin sulfates and human clinical trials on osteoarthritis. Similar to glucosamine, the conclusions were positive. Chondroitin sulfates, at doses of 800-1200 mg per day, reduced pain and improved joint function in mild to moderate osteoarthritis. In fact, some reviewers stated that the studies on chondroitin sulfates were of higher quality than those for glucosamine. Results were significant after four weeks and maybe took a little longer than glucosamine. Like glucosamine, chondroitin sulfates were also safe, and safer than NSAIDs used for osteoarthritis.
Lately, the scare of variant Bovine Spongiform Encephalopathy (BSE) from ingesting bovine foodstuffs has pointed an accusing finger at chondroitin sulfates, since the primary source is bovine tracheas. Fortunately, the process of purification for chondroitin sulfates involves digestion with hot sodium hydroxide (lye), which has been shown by the World Health Organization to be the preferred way to destroy the BSE prion in medical settings. High vigilance of beef suppliers further assures that risk of BSE contamination from chondroitin sulfates supplements is nil (for an overview of BSE, see accompanying sidebar).
The forgotten: The French medical care system prefers chondroitin sulfates over glucosamine and has documented an overall cost savings in treatment of osteoarthritis, from reducing NSAID dosages and their resulting side effects needing medical attention.
Another entire topic of chondroitin sulfates completely ignored is the ability to potentially reduce plaque in coronary and cerebral arteries, leading to longer lifespans in coronary artery disease patients and improved mental capacity in atherosclerotic senile dementia. These uses for chondroitin are not well developed, but based on sound mechanistic evidence and some human clinical trials, including a six year study.
For some odd reason, the availability of several one and two year studies on chondroitin sulfates seems to have gone unnoticed. Similar to the Reginster study on glucosamine, long term chondroitin sulfates showed restoration of joint cartilage and joint space sooner than glucosamine (one year instead of three).
Glucosamine And Chondroitin Sulfates Combinations
The most popular joint products are combinations of 1500 mg of glucosamine and 1200 mg of chondroitin sulfates daily. Interestingly, no human clinical trials were available on the combination until 1999, and so far, there are only a few and they have not compared the combination to either component alone. However, very recent in vitro and animal studies have shown a synergism between glucosamine and chondroitin sulfates, which fits the predictions of many.
The National Institutes of Health has started a large multicenter human clinical trial in the U.S. comparing placebo, glucosamine, chondroitin sulfates and the combination. When the results are available in a few years, it will help determine just which ingredient, if any, is better. Although the issue of a high placebo response haunts this study, it is hoped that the moderately long time period of six months will reduce potential placebo effects.
Other Joint Health Winners
Methylsulfonylmethane (MSM) has also enjoyed enormous popularity fueled mostly by word of mouth, because there are no published human clinical studies on MSM and osteoarthritis. The reason could be the low price and the intuitive sense that sulfur is missing from typical diets and good for joints and the hope of ameliorating other ailments. Until human clinical trials are published on MSM, there is virtually no direct scientific substantiation for its efficacy in joints. At least MSM is safe.
Collagen hydrolysate (aka collagen, gelatin, gelatin hydrolysate or Arthred-G) continues to be an alternative to taking pills, since the effective dose of 10 grams is best served as a powder. Several human studies from Europe point to efficacy somewhat less than glucosamine.
S-Adenosyl-L-methionine (SAMe) blazed into the public consciousness as an antidepressant, but is also an effective symptom-reducing agent in osteoarthritis. Human clinical studies on osteoarthritis show similar effects of SAMe as for glucosamine or chondroitin sulfates, with perhaps better pain relief. The only catch is the very high price for a truly effective dose of SAMe-1200-1600 mg per day was used in studies. Perhaps the recent downturn in SAMe sales reflects the unwillingness of consumers to pay for larger daily doses of SAMe and the perceived lack of efficacy for doses of 200 mg per day (the most frequent recommended dose) after the placebo effect wears off. Nevertheless, SAMe effectiveness against depression is an additional bonus to most persons with osteoarthritis. Taking the full dose of SAMe appeared to yield faster relief of pain than other nutrients, with benefits noticeable after 3-7 days. Long term studies (one to two years) have used 400 mg of SAMe per day and found results apparently equivalent to glucosamine. In addition, 400 mg of SAMe protected stomachs from damage from aspirin in humans, making SAMe a viable joint health supplement with other benefits.
Boswellia serrata extracts are potent inhibitors of lipoxygenase and other enzymes that promote joint inflammation (in the test tube). Several human trials show promising reductions in pain similar to glucosamine and chondroitin sulfates. Boswellia extracts show some real promise.
The forgotten: Vitamin E has been studied in Germany and other countries and found to relieve some symptoms of osteoarthritis and rheumatoid arthritis, especially pain. Synthetic vitamin E has been used and it is unknown if natural vitamin E would be better or not. Regardless, the ready availability of vitamin E and its benefits for overall health means that 400-1200 IU per day should be added to diets of persons with osteoarthritis.
The completely forgotten: Pity vitamin C. Its mechanisms are vital for joint health and well-known. Animal studies show protective effects against osteoarthritis. Yet there is nothing on humans but a few anecdotal case histories of vitamin C supplementation and osteoarthritis, and of course, these are positive, but virtually meaningless scientifically. Extrapolating from animal studies, a daily dose of 4-6 grams of vitamin C is needed to match animal doses.
Future of Joint Health Supplements
The enormous success of glucosamine and chondroitin sulfates has spurred introduction of many potential winners in the joint health category. None have the extent of human clinical trial substantiation as glucosamine, chondroitin sulfates, or even SAMe yet, but some are showing merit.
Chicken Type II collagen, or derivatives of chicken cartilage, have some studies in humans that show relief of symptoms for rheumatoid arthritis. It is thought that oral ingestion of Type II collagen (the type of collagen unique to cartilage) acts as a sort of oral vaccine to desensitize the immune system to attacking its own cartilage. Low doses and low cost are favorable factors for Type II collagen, but more studies in osteoarthritis are needed to see if the oral vaccine mechanism is working. If very large doses are taken, then the mass action of getting some collagen hydrolysate (from digestion) and some chondroitin sulfates is operating, which may be no different than other cartilage sources (bovine trachea powder, shark cartilage).
Sea cucumber extracts have chondroitin-like polymers that inhibit enzymes that degrade cartilage. Until issues of identity, potency, purity and reproducibility of supply are worked out, sea cucumber extracts offer unstudied promise.
Cetyl myristoleate (CMO) is making headway with consumers, but still faces issues of high price, effective dose, quality control, reproducibility and identity of raw material supply, patent rights and limited human studies before it can be recommended for osteoarthritis in a mass market.
Lyprinol (specially preserved green lipped mussel lipids) has shown enticing experimental evidence that should make it a potent anti-inflammatory, albeit slow-acting. The slow action and lack of human trials, combined with relatively high price and distinctive dead fish burp have failed to attract consumers' attentions to date.
Ginger extracts are used in Europe (as patented extracts Zinax and Zinaxin) as drugs to treat arthritis. Recent human studies have found some efficacy for the extract in osteoarthritis, especially for reducing pain and improving movements. Ginger extracts are a viable option for the future of joint health supplements, since ginger has additional benefits as an antinausea agent and stomach protector.
Curcumin has a few human studies showing antiinflammatory effects at doses over one gram daily in humans, including for rheumatoid arthritis. The slow onset of action and relatively high cost of purified curcumin means that other joint supplements are more viable.
COX-2 inhibitors (super aspirins) are all the rage with prescription drug treatment of osteoarthritis and represent a large improvement in safety over previous NSAIDs and corticosteroids. However, these new drugs are very expensive and are not completely free of the typical NSAID side effects. Accordingly, the search is on for natural COX-2 inhibitors and ginger, curcumin, Lyprinol and many emerging herbal extracts and combinations are good candidates. However, in vitro inhibition of the COX-2 enzyme is a long way from an effective oral dietary supplement. Besides, this is still a symptomatic relief approach akin to drugs, with no evidence of rebuilding cartilage.
Inducible Nitric Oxide Synthase Inhibitors (iNOSIs) are a new field of research into halting osteoarthritis symptoms and maybe progression. It turns out that both glucosamine and chondroitin sulfates inhibit iNOS in arthritic cartilage in test tubes, which may account for their observed disease-modifying properties. The goal with iNOSIs is to inhibit the inducible form of the enzyme and not the "housekeeping" NOS, which is vital for blood vessel tone and many other essential tissue functions. If iNOS can be effectively inhibited, then an early signal for osteoarthritis progression and cartilage damage can be blunted, in theory slowing osteoarthritis.
New product delivery forms for glucosamine and chondroitin sulfates are starting to appear. Liquids, chews, bars, cookies, effervescents and candies are appearing almost daily. Many do not deliver effective doses of glucosamine or chondroitin sulfates. Stability of glucosamine in these food matrices is an issue that is best solved by larger supplement companies with more resources.
The Forgotten
Cartilage powders are out of favor for oral use since they have never been able to show they are more than crude ways to deliver collagen and chondroitin sulfates. Effective amounts need to be determined, but look like 10-100 grams per day. The threat of BSE is an issue with bovine cartilage preparations, since they are not treated with sodium hydroxide.
Omega 3 fatty acids have had a large human clinical database against rheumatoid arthritis since the 1980s. The medical consensus is that fish oils give mild to moderate responses in rheumatoid arthritis, but onset of action is slow and deliberate, taking three to six months. Since there are many other healthy aspects to omega 3 fatty acids, they should be a routine part of sn arthritic's diet and supplement plan. Tolerability of fish oils has reduced public acceptance.
Niacinamide (not niacin) continues to show efficacy in a limited number of human studies, as started by Dr. William Kaufmann in the 1950s. Niacinamide is very inexpensive, safe, and readily available. The drawback is the very slow onset of action (over one year) and the need to take rather large amounts (250 mg several times daily) for years and years.
Boron started to show promise for reducing osteoarthritis symptoms, but no follow up studies have appeared. The association between low dietary boron intake and high osteoarthritis incidence around the world needs to be confirmed, and if true, another inexpensive, safe (at 3-6 mg per day) and bone healthy nutrient will be added to the ranks of joint health supplements.
Summary
The popularity of glucosamine and chondroitin sulfates has improved the health of millions of Americans safely. The level of substantiation, and thus consumer confidence, needed for new dietary supplement ingredients for joint health will never reach that attained by glucosamine, chondroitin sulfates or even SAMe. The future of other joint ingredients is in combinations, or to exploit specific and trendy mechanisms, such as COX-2 inhibition, inducible nitric oxide synthase inhibition or NF kappa factor reduction. Speeding up the results of glucosamine and chondroitin sulfates is something consumers want and should be feasible with natural ingredients that inhibit enzymes and signaling pathways. As research on the ability of natural ingredients to affect these new and exciting pathways develops, some will eventually survive the evolution from in vitro to animal to human testing and then will need to survive safety concerns, all at a reasonable price and steady availability. Synergy with glucosamine and/or chondroitin sulfates is also another goal other joint health nutrients should strive for, but to make these claims, appropriate direct comparisons should be tested instead of relying on theoretical mechanisms. In conclusion, the future of joint health supplements is solid and progressive.
Editor's Note: Due to space limitations, extensive references to this article were not included. If you have any questions about citations, please contact the author directly.
About the author: Luke R. Bucci, Ph.D., CCN, C(ASCP), CNS, is vice president, research at Weider Nutrition International, Salt Lake City, UT, a manufacturer of a wide range of dietary supplements. He can be reached at lukeb@weider.com.