Glucosamine: Still Standing Strong?

When the United Kingdom’s Food Standards Agency (FSA) announced new import restrictions affecting shellfish-sourced glucosamine earlier this year, makers of joint-health supplements that feature the ingredient girded themselves for a supply-chain hiccup. After all, despite holding its top spot in the joint-support category, glucosamine (often paired with chondroitin, which also fell under FSA’s directive) is facing, if not outright headwinds, then at least stiff competition from up-and-coming alternative ingredients, not to mention the new import rules and hurdles like persistently so-so evidence as to its efficacy.

But looked at in a different light, these clouds could portend silver linings in glucosamine’s future. For if today’s challenges motivate suppliers to step up with new ingredient formats, improved quality standards, and more rigorous demonstrations of the compound’s pharmacology and effectiveness, glucosamine may come out of this current storm under sunnier skies than before.

Opportunity in Disguise

Even FSA’s new rules may be an opportunity in disguise. How so? The directive’s stated purpose is to require that imported ingredients of animal origin-like glucosamine, most of which is derived from shrimp shells-come from EU-certified countries with strict quality controls in place. But that’s just their stated purpose; the subtext, some say, is to keep closer watch on one export country in particular: China.

No stranger to periodic accusations of lax quality and safety standards, China remains “thesupplier of shellfish-origin glucosamine,” says Larry Kolb, president, TSI USA Inc. (Missoula, MT). Even with India and Vietnam entering the supply chain, Chinese producers still represent approximately 80% of global glucosamine production “based on information we’ve seen,” says Chuck Ray, technical services manager, Cargill Corn Milling North America (Cedar Rapids, IA).

With so much product coming from China, it’s no wonder UK supplement marketers were wringing their hands over concerns about shipments impounded at ports and production schedules halted in the absence of key ingredients. “UK brand owners and toll manufacturers are very concerned about the potential implications the new regulations may have on their supply chain,” Kolb says.

But much of their hand-wringing may have been overblown, as demonstrated by a container of Chinese-sourced glucosamine powder that cleared UK border inspection without hassle not long after the clampdown went into effect, as reported by Nutraingredients.com. Nevertheless, for manufacturers to take that as a cue to resume business as usual, Kolb cautions, would be to miss the broader lesson the regulations impart.

To wit, “Shellfish-origin glucosamine is open to all the variability associated with supply chains for marine animal–source products,” he says, and that includes any threats that unsafe products pose to a brand’s reputation. The “obvious answer,” according to Kolb, isn’t to hunt for alternative shellfish-origin exporters, but to sidestep shellfish altogether and instead “ensure supply by using vegetal glucosamine.”

Vegetarian glucosamine-produced via fungal or bacterial fermentation-has been available for years, but its share of the glucosamine market vanishes by comparison to that of shellfish products. Even so, vegetarian glucosamine offers several advantages, only the first of which is exemption from FSA’s restrictions. Formulating with a vegetarian ingredient also exempts finished products from the need to bear shellfish allergen warnings on pack labels. And the products’ plant-based origins appeal to some consumers-vegetarian and omnivorous-as somehow safer, cleaner, greener, and more trustworthy.

Ray notes that customers find his firm’s domestically produced vegetarian glucosamine “reassuring.” And though he concedes that based on current publicly available information, it appears industry’s production capacity may be insufficient to satisfy total global demand, “vegetarian-source producers continue to explore new technology and efficiencies to meet that demand,” he says.

Maturing Market

Interest in vegetarian products has been a shot in the arm for glucosamine, injecting much-needed buzz into this well-established sector. And producers appreciate the fresh attention. As Cal Bewicke, president, Ethical Naturals Inc. (San Anselmo, CA), says, “As a supplier of vegetable-source material, we have seen sales grow steadily.”

But the paradox of being an established ingredient is that, periodic shots in the arm notwithstanding, even stable sales can sometimes feel like the beginning of a slump. So while glucosamine remains “a recognized, mature ingredient,” says Rodney Benjamin, director of research and development and technical support, Bergstrom Nutrition (Vancouver, WA), the competitive nature of the joint-health category forces glucosamine to work harder just to keep pace.

“When you have an ingredient in the marketplace for close to two decades,” that’s par for the course, Kolb says, acknowledging glucosamine’s “flat-to-downward trend.” As for other culprits in its apparent stagnation, fingers point to everything from quality issues like those the FSA directive aims to redress to consumer mistrust of labeling.

On that point, Ray notes that groups like Consumer Reports make studies on glucosamine labeling “easily accessible for consumers doing simple Internet research.” Unfortunately, he says, “a minority of products evaluated in these studies is not meeting label-claim amounts for the ingredients of interest. Although we don’t have any hard data on how this affects consumption, it certainly doesn’t help the ingredient’s reputation, nor that of the joint-health segment or dietary supplements in general.”

When it comes to the quality issue, Tim Hammond, vice president of sales and marketing at Bergstrom, points out, “Any time concerns arise, it has some impact on an ingredient’s ability to gain or even hold market share.” That impact only amplifies as competition from supplement alternatives increases “and the push to differentiate products continues to be a driving force.”

Such competitive forces are acting on glucosamine now more than ever, as new joint-health supplements vie for a slice of glucosamine’s dominance. “There are many ‘me-too’ ingredients and a lot of confusion in the marketplace with the myriad joint-care formulations that tout the same benefits [as glucosamine],” Kolb says. Eggshell membrane, curcumin, ginger, licorice, SAMe (S-adenosyl methionine)-even shark cartilage and krill oil: “All of these take a piece of market share from glucosamine.”

Yet scientific evidence supporting their effects “is very limited,” according to Kolb. “While some initial studies show potential benefits, they haven’t yet been tested to the degree that glucosamine has over several decades.” And though the up-and-comers may attract notice, Alice Chin, director of quality control, GWI (Green Wave Ingredients; La Mirada, CA), emphasizes that their market share remains “very small.” As she says, “It’s difficult to replace the ‘golden formula’ of glucosamine, MSM”-methylsulfonylmethane-“chondroitin, and sodium hyaluronate, as it’s so cost-effective, so sophisticated, and works so well.”

Scientific Support

Or does it? The operating theory is that glucosamine supplementation maintains the structural and functional integrity of the joint, Kolb says, resulting “in significantly less knee-joint degeneration, less joint-space narrowing, and significant symptom improvement.” We also know that glucosamine, an endogenous aminomonosaccharide, participates in the biosynthesis of glycoproteins and glycosaminoglycans and is itself highly concentrated in cartilage.

But studies examining glucosamine’s ability to improve joint health and/or ameliorate the symptoms of osteoarthritis have been conflicting, at best. The National Institutes of Health–sponsored Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)-the largest randomized, double-blind, placebo-controlled study on the supplement-has yet to confirm whether glucosamine is effective in treating osteoarthritis.

Nevertheless, Kolb maintains, “Numerous studies lasting from a few weeks to three years have reported that oral glucosamine supplementation can significantly improve symptoms of pain and joint functionality. Besides bolstering the scientific evidence for glucosamine’s effectiveness and safety, recent studies have provided new insights on how glucosamine actually works.”

For example, we’re learning that glucosamine inhibits interleukin 1-beta, a cytokine protein whose increased production triggers inflammatory reactions and, perhaps, cartilage degradation. By stimulating the production of proteoglycans, key components of the extracellular matrix, glucosamine also helps boost the body’s internal mechanisms of “hydration and swelling pressure to the tissue,” Kolb says, “enabling it to withstand compressional forces.”

Benjamin notes that MSM-“another mature ingredient”-has also been the focus of research, with several new studies demonstrating its potential, in combination with glucosamine, to reduce joint pain and oxidative damage. One recent study of patients with osteoarthritis of the knee (Usha PR et al.) involved a randomized, double-blind trial comparing MSM, glucosamine, both, or placebo, Benjamin explains. Its conclusion: the combination of MSM and glucosamine reduced pain and swelling and improved joint functionality better than either compound alone. “Additionally,” Benjamin says, “the study reported that the onset of analgesic and anti-inflammatory activity was also more rapid with the combination.”

Then there are studies looking at the combination of glucosamine and chondroitin sulfate, the former’s frequent sidekick in joint-health formulations. Kolb points to the Long-term Evaluation of Glucosamine Sulfate (LEGS) study as showing that 1,500 mg of glucosamine sulfate plus 800 mg of his company’s bovine-source, low-molecular-weight chondroitin sulfate taken daily for two years “provided a meaningful reduction in potential cartilage loss in participants with early symptoms compared to a placebo.” Again, the “team formulation” of glucosamine and chondroitin beat out glucosamine on its own. By contrast, a different study (Gruenwald J et al.) comparing the effects of glucosamine versus a combination of glucosamine and omega-3s from fish oil provided no evidence of improved efficacy over glucosamine alone.

But what, if anything, does the research reveal about glucosamine’s mechanism of action? Ray points to a 2013 study (Lotz et al.) supporting the hypothesis that glucosamine “activates the cellular housekeeping process of autophagy,” he says. Autophagy is a means by which our cells maintain homeostasis, especially in tissues with low turnover, such as cartilage. But like so many other cellular processes, it begins to falter with age, potentially leading to arthritis. This study “provides a possible answer to one of the main gaps in the current research: finding a plausible mechanism of action,” Ray says. He calls it “an important step forward” and adds that the autophagy hypothesis ranked among the International Glucosamine Working Group’s top recommendations for future research.

A surprising link between glucosamine and gut microbiota emerged in a recent study that also confirmed that 12 weeks of glucosamine sulfate supplementation improved osteoarthritis outcome measures (Coulson S et al.). The study found changes in gastrointestinal-tract microbiota profiles, “most notably a reduction in Clostridiasp.,” Kolb says. This suggests that supplementation with glucosamine sulfate might influence the intestinal flora’s metabolic and immunological activities. Indeed, the fact that the decrease in Clostridiawas consistent with a decrease in inflammation and an improvement of osteoarthritis symptoms hints at a relationship between changes in microbiota and glucosamine activity.

And, finally, Ray cites two recent studies from Japan investigating cartilage biomarkers in athletes (Yoshimura M et al.; Momomura R et al.). In focusing on a healthy population of subjects and measuring biomarkers of collagen turnover, he says, the studies “may be an important step forward in the clinical study of glucosamine on joint health.” What’s more, they offer a strategy for addressing what he says is the second main criticism of glucosamine research: a viable model for performing human studies in a generally healthy population.

And isn’t that the kind of population we all want to be? “Keeping joints healthy before symptoms appear should really be the goal,” Ray says. “Taking joint-health supplements after you have symptoms is analogous to waiting to do something about heart health until after you have chest pain or a heart attack.”

Further, Ray believes that the employment of more precise and quantifiable effectiveness measurements would go far toward increasing not only glucosamine’s but the entire joint-health category’s legitimacy with consumers and clinicians. Currently, subjective questionnaires like the WOMAC (Western Ontario and McMaster) and Lequesne indices let researchers evaluate subjects’ experiences of pain, discomfort, stiffness, functionality, and the like, and X-rays provide data on joint-space narrowing. But Ray thinks we can do better.

“Range of motion and discomfort are important for traditional consumers, as they’re something people can ‘feel.’ But we need to move beyond this,” he says. “What the joint-health science arena needs is a good, practical way of measuring how we keep joints healthy-equivalent to what lowering cholesterol tells us about heart health.” He hopes we’ll soon see more frequent use of biomarkers. “Once scientific consensus on these measures is reached,” he says, “we think we’ll see more definitive studies on the effectiveness various supplements have on joint health.”

And that can only be good for the whole industry. And it proves that rumors of glucosamine’s demise were greatly exaggerated. “The important thing in the joint-health category is that consumers are always looking for something that might help their individual health issue,” Ray says. “We will continue to see different new ingredients touted as joint-health ingredients. Some will gain a measurable audience; most will not. But in the end, glucosamine is still the most widely used, researched, and discussed joint-health ingredient.”

Sidebar: Glucosamine by the Numbers

What import data tell us about glucosamine strength.

So by some estimates, glucosamine appears to have lost its juice. But perception doesn’t always reflect reality. And though numbers are manipulable-see Twain’s aphorism about lies, damned lies and statistics-another way to view the ups and downs of glucosamine demand “is to look at imports over the last five years,” says Chuck Ray, technical services manager, Cargill Corn Milling North America (Cedar Rapids, IA).

By correlating glucosamine imports with demand, he says, “we still see a very strong market opportunity.” As recently as 2012, imports were the second highest on record, he says: “nearly the same as the record high in 2007 of 9,440 metric tons. And 2013 looks like will finish with nearly 9,000 metric tons of imports.” Despite a downturn in demand in 2007, interest seems to have picked up quite nicely.

Further, adds Alice Chin, director of quality control, GWI (Green Wave Ingredients; La Mirada, CA), “Instead of replacing glucosamine with MSM or chondroitin, those ingredients have been added to the formulation. MSM and chondroitin import quantity is also stable over the past years, generally at about 40% to 50% of glucosamine quantity.”

As for the story that the ingredient’s price tells, Chin notes that glucosamine sales “started to kick off” in 1997, at which time the glucosamine sulfate price was $120/kg-“ten times as high as it is today.” Similarly, at $150/kg, chondroitin was triple the current price. The lesson: “Today’s consumers are fortunate that they can purchase joint-health products for such low prices, even with multiple ingredients in combination, compared to 10 to 15 years ago.” Back then, she says, “either the price was sky-high per bottle or the manufacturer only added very small amounts of active ingredients, more for decorative purposes.”