Special Report: Beyond GAIT

It only focused on two supplement ingredients, but last year’s Glucosamine/Chondroitin Arthritis Prevention Trial (GAIT) may have been a watershed event for the entire joint-health category. GAIT received a great deal of attention because-at a cost of more than $12 million-it was the first large, multicenter clinical trial of glucosamine and chondroitin sulfate to be funded by the National Institutes of Health’s (NIH; Bethesda, MD) National Center for Complementary and Alternative Medicine (NCCAM).

GAIT’s results were surprising and somewhat controversial. When they published their findings in the February 23, 2006, issue of the New England Journal of Medicine, the GAIT researchers reported that supplements containing glucosamine and chondroitin, alone and in combination, failed to benefit people with mild-to-moderate arthritis pain when compared with a placebo and celecoxib. The researchers added, however, that in a subgroup of volunteers with moderate-to-severe pain, the supplements provided significant relief.

Although some experts criticized NCCAM’s interpretation of the data, GAIT raised a few questions about the effectiveness of glucosamine and chondroitin for the general population. On the other hand, the study also appears to have ignited interest in other ingredients with antiinflammatory properties.

“The study was one of the very few getting this kind of attention and funding from the federal government,” says Jeremy Appleton, scientific adviser to Bergstrom Nutrition (Vancouver, WA), which manufactures OptiMSM. “Despite the mixed results, we think opinion leaders and healthcare professionals believe even more strongly that nutritional supplements play a key role in joint health, probably more so than other health concern areas. Many companies are looking for weak spots in the performance of glucosamine and chondroitin and are working to commercialize products that address these areas.”

FIRST MAJOR STUDY ON MSM

While MSM hasn’t been studied as extensively as glucosamine and chondroitin, its research profile is impressive and growing. MSM has more published efficacy research than many other joint-health ingredients, and the first randomized, double-blind, placebo-controlled trial on MSM appeared in the March 2006 issue of the journal Osteoarthritis and Cartilage. Additionally, Now Foods (Bloomington, IL) is currently working on single-lab validation of an official method for MSM that should help spur future clinical research efforts.

Bergstrom Nutrition has sponsored more than a dozen safety studies on OptiMSM, a highly distilled form of MSM, says Appleton. “The studies demonstrate no adverse effects, no drug interactions, and no toxicity, even at extremely high dosage levels,” he notes. “These studies are on par with, and in some cases exceed, those for glucosamine and chondroitin.”

In the Osteoarthritis and Cartilage study, researchers gave 50 patients either 3000 mg of OptiMSM or a placebo twice per day for 12 weeks. The researchers found that volunteers who received MSM experienced less pain and disability, along with an improved ability to perform daily activities. “These effects continued to improve at the end of the 12 weeks, suggesting that a longer study could have detected even further benefit,” explains Appleton.

According to Appleton, the GAIT study has had a positive impact on MSM’s profile, despite its narrow focus on glucosamine and chondroitin. “Certainly MSM, as one of the big-three joint ingredients, is further validated by the GAIT study,” Appleton says. “MSM enhances and complements glucosamine and chondroitin, so if consumers are concerned about the application of the other ingredients, they increase their chances of success by taking MSM too.”

NCCAM TACKLES TURMERIC

Turmeric (Curcuma longa), an herb that has been used for centuries in ayurvedic medicine, contains several components that may have antiinflammatory properties. In the November issue of the journal Arthritis & Rheumatism, a team of researchers from the University of Arizona in Tucson reported that turmeric extracts had positive effects on arthritis in animals. The NCCAM-funded study, another major contribution from NIH, was also the first to document the composition and mechanism of a turmeric-containing compound.

“Just as the willow bark provided relief for arthritis patients before the advent of aspirin, so it would appear that the underground stem of a tropical plant may also hold promise for the treatment of joint inflammation and destruction,” wrote the team, which was led by Janet Funk, MD, a professor at the University of Arizona’s college of medicine, and Barbara Timmermann, PhD, former director of the University of Arizona’s Center for Phytomedicine Research. Timmermann is now a professor at the University of Kansas in Lawrence.

Using turmeric powder obtained from San Francisco Herb and Natural Food Co. (Fremont, CA), the team prepared three extracts: a whole extract of turmeric root, an essential oil extract, and an oil-depleted extract of three major curcuminoids. The researchers found the third extract, which closely resembled commercially available turmeric products, to be the most effective.

Among the team’s findings was the discovery that the extract prevented activation of NF-kB, a protein that controls the expression of genes that produce an inflammatory response. The team also found that the extract blocked a pathway related to bone resorption, which can lead to osteoporosis.

According to Funk and Timmermann, the results of the study were preliminary, and additional preclinical and clinical trials are needed before turmeric can be recommended for arthritis. However, the researchers added that the data were important because they gave scientists useful information about the chemical composition and biological activity of turmeric compounds.

As a side note, one ayurvedic herb with similar anti-inflammatory properties that wasn’t part of the NCCAM study is Boswellia serrata. Eric Anderson, new business and brand manager at P. L. Thomas (Morristown, NJ), says he has seen a “significant increase” in demand for the boswellia extract 5-LOXIN since the GAIT trial and other recent joint-health studies.

“5-LOXIN inhibits several inflammatory mediators and inhibits collagen degradation,” Anderson says, adding that the extract inhibits 5-lipoxygenase (5-LOX). “Less-known than COX-2, 5-LOX inhibitors follow a distinctly different inflammation pathway, one without the potentially negative effects associated with COX-2 inhibitors. Also, 5-LOXIN is a selective, nonredox 5-LOX inhibitor, which means that its action is very targeted and doesn’t affect other systems.”

OLIVES AND INFLAMMATION

Olives have been revered as a healthy food for thousands of years, and with good reason. They contain high concentrations of polyphenols with antioxidant and antiinflammatory properties. Some data suggest that when combined with other ingredients, olive polyphenols may also act synergistically to inhibit inflammation. Thus, it’s no surprise that olives, a key ingredient in the famed Mediterranean diet, may also become a key ingredient in the latest wave of joint-health products.

For instance, in the September 1, 2005, issue of the journal Nature, researchers from the Monell Chemical Senses Center (Philadelphia) reported that oleocanthal, a compound found in extra-virgin olive oil, is a natural anti-inflammatory agent, inhibiting the activity of cyclooxygenase (COX) enzymes. According to Monell biologist Gary Beauchamp, PhD, “some of the health-related effects of the Mediterranean diet may be due to the natural anti-COX activity of oleocanthal from premium olive oils.”

Other compounds in olives may possess similar anti-inflammatory effects. In an article published in the July 2005 issue of the Journal of Nutrition, researchers from CreAgri (Hayward, CA) reported that olive vegetation water, the liquid content of the paste obtained when olives are pressed for oil, was shown to inhibit the production of the inflammatory cytokine tumor necrosis factor alpha (TNF-a) by 95% in mice and 50% in human monocyte cells. When combined with glucosamine, the olive vegetation water exhibited an even stronger effect.

There are some recent signs that olive-based ingredients are likely to get a higher profile. In March 2006, DSM Nutritional Products Inc. (Parsippany, NJ) signed an agreement with CreAgri to distribute Hidrox, an ingredient processed from olive vegetation water that is standardized to contain the polyphenol hydroxytyrosol. DSM launched the product in the United States last August and announced the global launch of the product on December 8.

MUSSELS AND JOINTS

Greenshell mussel (Perna canaliculus), a large mussel species native to the coastal waters of New Zealand, contains several nutrients that may be useful for maintaining joint health, including glucosaminoglycans (GAGs) and omega-3 fatty acids. According to Craig McIntosh, CEO of Waitaki Biosciences (Christchurch, New Zealand), greenshell mussel also contains a unique phosphorylated glycogen molecule that has antiinflammatory properties.

McIntosh notes that, like other joint-health ingredients, greenshell mussel has benefited from the publicity surrounding the GAIT study. “The report effectively added credibility to nutraceutical solutions for joint care,” he says. But even though they share some similar compounds, it’s not easy to compare greenshell mussel with glucosamine and chondroitin, he adds.

“Greenshell mussel consists of the dried whole-tissue powder of the Perna canaliculus species of mussel, whereas glucosamine and chondroitin are specific biochemicals extracted from cartilagenous tissues or synthesized from crustacean shell by-products,” McIntosh says. “This makes a like-for-like comparison difficult, as there are many factors involved for whole-product processing in terms of standardization than for single extracts.”

Because greenshell mussel is only available in limited quantities, the industry currently lacks the financial clout to fund research on the large scale of the GAIT study, McIntosh says, adding that much of the research on greenshell mussel has been in the field of animal health. “Greenshell mussel has long been accepted in the equine industry as an extremely effective antiinflammatory product that helps in the preparation and recovery of performance animals-both race and show,” McIntosh says.

Waitaki uses a low-temperature process to maximize product integrity and shelf life. After removing the entire meat fraction from the outer shell, Waitaki snap-freezes it and prepares it for freeze-drying, which reduces the moisture content to less than 3%. The company then mills, packs, and tests the finished product to customer specifications. “Waitaki utilizes the whole intact tissue of the mussel, removing nothing but water throughout the entire process,” McIntosh says. “This is absolutely critical, as some products currently on the market have had valuable contents removed, either deliberately or through poor processing techniques.”

McIntosh is critical of some methods used by other greenshell mussel suppliers. Some manufacturers use the term extraction for the mechanical separation of meat from the shell, notes McIntosh. “This often confuses the market into believing that the process is more sophisticated than it is and implies that particular bioactives are isolated,” he says, adding that the creation of oil extracts is another common practice. “Our position has always been that the sum of the parts is clearly greater than any additional processing of fractions,” he says.

OTHER CONNECTIVE-TISSUE INGREDIENTS

Interest has also been building in two other supplement ingredients that are closely related to glucosamine: hyaluronic acid (HA) and collagen type II, which help to lubricate and support joints. Glucosamine is a precursor to HA and is also found in collagen type II, which contains several different types of GAGs.

HA works in combination with other nutrients to protect bone surfaces. In fact, new research indicates that HA may exert a synergistic effect to counteract friction. At last year’s annual meeting of the American Chemical Society (Washington, DC), which was held in March in Atlanta, researchers from Duke University’s (Durham, NC) Pratt School of Engineering presented an analysis of how joint fluids interact with the surfaces of realistic joint models. Using atomic force microscopy, the researchers found that three joint fluids, lubricin, HA, and lipids, work in concert to protect joint surfaces.

Pureflex Achieves USP Certification

TSI Health Sciences Inc.’s (TSI; Missoula, MT) Pureflex chondroitin sulfate passed a good manufacturing practices (GMPs) audit and review conducted by the U.S. Pharmacopeia (USP; Rockville, MD), TSI announced on December 6.

The certification process included a review of TSI’s manufacturing and quality-control documentation and lab evaluation of ingredient samples to ensure compliance with label claims and USP requirements.

“TSI remains committed to providing our clients with pure, consistent, and safe ingredients,” says Larry Kolb, president of TSI’s U.S. operations. “We wanted to validate our industry-leading quality systems by inviting a well-known and respected third-party organization to audit our facilities and confirm the quality of our ingredients. Unfortunately, some companies make claims that they offer high-quality, unadulterated ingredients when in reality they do not. Consumers continue to be misled and cheated as a result. TSI asks other ingredient manufacturers to certify their facilities, for the benefit of the industry.”

The Duke researchers discovered that HA appeared to amplify the effects of lubricin, which reduces adhesion between joint surfaces and creates a protective layer over the surfaces that prevents cartilage tissues from bumping into each other. Damage to the top layer of cartilage and the absence of lubricants can lead to the onset of osteoarthritis by causing “a cascade of mechanical failures,” noted the researchers.

In the body, enzymes synthesize HA by creating chains of glucoronic acid and N-acetylglucosamine. Outside of the body, however, there are a variety of methods of manufacturing HA, including extraction from animal sources and microbial fermentation, an appealing choice for manufacturers who are looking for kosher and vegetarian ingredients.

According to Junny Liu, sales manager for FenChem (Nanjing, China), fermentation can produce HA in molecular weights that range from 8000 to 3 million Da. Last July, FenChem announced that it had begun a series of animal and human studies to determine the optimum molecular weight for its HyaMax HA ingredient, which is manufactured using a three-part fermentation process.

Collagen type II, on the other hand, is a major constituent of cartilage that contains a variety of GAGs, including chondroitin sulfate, HA, and cartilage-stimulating elements, says Jennifer Gu, PhD, director of research at AIDP Inc. (City of Industry, CA). AIDP’s patented type II collagen ingredient, Kolla 2, is manufactured using a low-temperature process that generates denatured collagen type II chains.

As with other ingredients, collagen type II might help fill in the gaps not addressed by glucosamine and chondroitin. “As we age, the body’s ability to make collagen proteins and GAGs slows down,” Gu explains. “Supplementing with Kolla 2 replenishes the body’s supply, helping to maintain the integrity of the cartilage. A glucosamine- and chondroitin-based formulation misses one of the most abundant components in the joint-collagen type II.”

Another patented collagen type II ingredient, BioCell Technologies LLC’s (Newport Beach, CA) BioCell Collagen II, is a featured ingredient in X-Motion, a new joint-health formula launched in 2006 by Xyience (Las Vegas). In addition to collagen II, X-Motion also contains bromelain, calcium, zinc, magnesium, and MSM. BioCell Collagen II is composed of 10% HA, 20% chondroitin sulfate, and 70% collagen type II.

“Xyience’s X-Motion formula with BioCell Collagen II takes a research-driven approach to help athletes achieve and maintain optimal joint health through their vigorous training regimens,” according to Asma Ishaq, BioCell’s vice president of marketing. “With its scientifically demonstrated positive benefits for joint health and absorbability, BioCell Collagen II is a natural choice for leading joint and sports nutrition formulas.”

BONE-SUPPORT INGREDIENTS

Lastly, another class of products that may gain from the expanding interest in joint health is the category of bone-support ingredients. Because strong bones are important for strong joints, ingredients that inhibit bone resorption are likely to be popular additions to new supplements that address bone and joint health.

According to Judi Quilici Timmcke, senior technical consultant for TSI Health Sciences Inc. (Missoula, MT), Ostivone (7-isoproxy isoflavone) has been well received by companies, healthcare providers, and consumers in part because of its strong research base.

“Ostivone is an isoflavone that has been synthetically manufactured in a laboratory,” Timmcke says. “In combination with calcium in research studies, it has been demonstrated to support bone density and have a positive effect on osteoclasts and osteoblasts. Compared with other isoflavones, it has been shown not to have an estrogenic effect, which is a huge benefit.”

Vitamin K2 has also been getting a lot of buzz, partially because of research indicating that it may offer cardiovascular as well as bone-health benefits. “Vitamin K2 has been gaining a lot of interest recently, as several lines of evidence indicate a protective effect against bone loss in osteoporosis and calcification in cardiovascular disease,” says AIDP’s Gu. “Epidemiological studies also showed that low vitamin K intake is associated with an increased risk of osteoporosis.”

Vitamin K2 functions as an essential cofactor for the enzyme gamma carboxylase,” explains P. L. Thomas’s Anderson. “This enzyme modifies important proteins that ensure that calcium gets in the right place: into the bones and out of the arterial vessel walls. In contrast, vitamin K1 has not been shown to have a role in inhibiting arterial calcification.”

Anderson adds that studies have shown that vitamin K2 is essential for the optimal functioning of the calcium-binding proteins osteocalcin and matrix GLA protein. “The protein related to bone health is osteocalcin, which is made by osteoblasts,” Anderson says. “This protein binds calcium to the bone matrix, but optimally only after sufficient vitamin K2 is present. The other protein is related to cardiovascular health. It is made by smooth muscle cells in vessel walls and is known to inhibit the deposition of calcium in the vessel, especially in coronary arteries. This inhibition is strongly dependent upon the presence of vitamin K2.”

AIDP’s vitamin K2 ingredient, K2, is a stable form of MK-4 (menatetrenone). “The fragile active ingredient is shielded from the environment and offers potency options so manufacturers may balance their manufacturing and dosing requirements,” Gu says.

Meanwhile, P. L. Thomas offers a vitamin K2 ingredient, MenaQ7, that is a stable form of MK-7 (menaquinone) extracted from the fermented soy product natto. “Natto is an extremely rich source of menaquinone-7, and studies have found that women who consume natto have higher vitamin K2 blood concentrations, reduced bone loss, and a lower incidence of hip fractures,” Anderson says. “Human research conducted at the University of Maastricht in The Netherlands also shows identical absorption patterns between K2 as MK-7 from natto and K2 as MK-7 from MenaQ.”

Regardless of the form used, vitamin K2 is likely to remain a key ingredient in nutraceutical products because of its bone-health and cardiovascular benefits. “Nutritional supplements targeting bone loss and fracture associated with osteoporosis have been an important market in the nutraceutical field,” says Gu. “Different calcium products have been the major options on the market in the past, and new ingredients that can provide clear benefits and a good safety profile, as well as manageable costs, will be the choice for renewed formulation in bone-health products.”

BEYOND GAIT

The saying “a rising tide lifts all boats” could apply to the entire category of joint-health supplements. GAIT generated intense publicity, and even though the study focused on just two ingredients-and even though some of the publicity was negative-the net effect could still be positive. Several joint-health ingredients seem to complement the effects of glucosamine and chondroitin, and others may one day be viable alternatives. While researchers need to conduct more clinical trials involving these ingredients, the momentum created by GAIT could be just the impetus they need.