Joint and Bone Health Dietary Supplement Ingredients: From All Angles

Creaking joints may be an inevitability of aging, but that’s no comfort to the millions who suffer from the resulting pain and immobility. Joints can also be affected by wear and tear from injury or weight bearing, as well as by degenerative joint diseases such as the most common form, osteoarthritis. Supplements combining glucosamine (typically as glucosamine sulfate) and chondroitin sulfate still reign in this market. However, these ingredients have seen slowing sales-some argue because of market maturity, while others cite controversial science. While it’s unlikely that any other ingredients will eclipse these established mainstays any time soon, companies are also seeing opportunities for alternatives.
 

Still Leading

Glucosamine and chondroitin aren’t just the market leaders; these ingredients lead by quite a lot. According to market researcher SPINS, in the natural channel alone, sales of products combining glucosamine and chondroitin are almost $9 million, while sales of most other joint-health ingredients remain in the six- or five-digit realm. (This data comes courtesy of SPINS’s new Health Focus market research tool, which examines retail and ingredient data based on condition-specific marketing claims.) Still, SPINS cites sales of glucosamine/chondroitin-combined products as declining from a year ago almost 14% in the food-drug-mass channel and 8% in the natural channel.

“We do see the market off for both chondroitin and glucosamine,” says Larry Kolb, president of TSI USA Inc. (Missoula, MT), producer of the Pureflex glucosamine and chondroitin sulfate product lines. “These two ingredients are household names, and there is a strong connection to glucosamine and chondroitin and their effectiveness for overall joint health-which is the primary reason they continue to have strong demand globally despite sporadic lulls in the overall market.”

Science and resulting publicity have been at odds when it comes to glucosamine and chondroitin-arguably, two of the most-studied ingredients for joint health. The $12.5 million Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) in 2006 is highest profile, as it was the first large, multicenter trial on glucosamine and chondroitin sulfate funded by the National Center for Complementary and Alternative Medicine. GAIT found that supplements containing glucosamine and chondroitin, alone and in combination, did not benefit those with mild-to-moderate osteoarthritis knee pain compared with a placebo and the nonsteroidal anti-inflammatory drug (NSAID) celecoxib. However, the combination was effective for moderate-to-severe pain.

Opinions are also split in more recent studies. A meta-analysis published last year in British Medical Journal (Wandel S et al.) concluded that glucosamine and chondroitin do not reduce joint pain nor have an impact on the narrowing of joint space. However, the Council for Responsible Nutrition (CRN; Washington, DC) criticized the study for focusing on too few trials and combining studies “too dissimilar to legitimately combine in a meta-analysis,” said Andrew Shao, PhD, in a press statement. (Shao was CRN’s senior vice president of scientific and regulatory affairs and is now vice president, global product science and safety, for Herbalife.)

“The fact is the majority of published studies involving glucosamine and/or chondroitin are positive,” Shao went on to state.

Earlier this year, a positive study on chondroitin sulfate in the Annals of the Rheumatic Diseases (Wildi LM et al.) found that chondroitin sulfate supplementation significantly reduced the cartilage volume loss in knee osteoarthritis as soon as six months into treatment. Another study, published this year in Arthritis & Rheumatism (Gabay C et al.), found that chondroitin sulfate-specifically, chondroitin sulfate 4 and 6-improved on pain and function in those with hand osteoarthritis.

On a side note, according to Soft Gel Technologies (Los Angeles), the type of chondroitin sulfate may determine efficacy. The company provides IncaCartilago chondroitin sulfate, derived from Humboldt squid. (Chondroitin sulfate is usually obtained from bovine, porcine, or shark cartilage.) Soft Gel calls IncaCartilago a potent form of chondroitin sulfate-not only for joints but also for bone health by stimulating osteoblast and osteocalcin formation. The company says IncaCartilago is more potent than other sources because it is rich in chondroitin sulfate E, which studies have shown acts more quickly and potently, and is sulfated at two carbons, 4 and 6, as opposed to one.

As science continues to argue both sides, joint-health supplement marketers are very much still supporting glucosamine and chondroitin. Just last year, liquid supplement brand Joint Juice, which has seen much success with its glucosamine products, released a new product version with chondroitin sulfate added.

Also, while dietary supplements still account for the majority of joint-health products, does the future hold promise for functional food and beverage? TSI USA’s Kolb believes so. Last summer, the company celebrated new GRAS designation for Pureflex chondroitin sulfate and glucosamine and says it has observed continual growth in this area despite the overall market fluctuations.

Helping consumers such as vegetarians take part opens up opportunities as well. Cargill (Minneapolis) says its GRAS-affirmed Regenasure vegetarian glucosamine (as opposed to shellfish sources) is doing well. “As consumers continue to recognize the benefits of glucosamine for joint and bone health, we see acceptance of Cargill’s Regenasure vegetarian glucosamine by food and beverage manufacturers wanting to reach this growing market,” says Mike Fleagle, Regenasure brand manager.
 

Different Approaches

What’s clear is that there are many ways to approach joint health. Supplements tend to address either (or sometimes both): 1) regenerating healthy joint cartilage, or 2) addressing the inflammation and pain caused when cartilage erodes (which is what NSAIDs do). This inflammation can also lead to a cascade that can further break down healthy cartilage.

Chondroitin sulfate and hyaluronic acid (HA) are glycosaminoglycans (GAGs) naturally present in joints. Chondroitin sulfate is a component of the proteoglycans that comprise healthy cartilage. Chondroitin is also said to block certain enzymes that can break cartilage down. HA plays dual roles, first as an essential component of the proteoglycans in cartilage and secondly as a major lubricating component of synovial fluid.

Glucosamine sulfate, an amino sugar, serves as a precursor to chondroitin sulfate as well as HA. Thus, supplements containing glucosamine, chondroitin sulfate, and HA can alleviate the effects of deteriorating GAGs caused by aging or chronic arthritis, with science further investigating mechanisms for rebuilding degraded cartilage.

Let’s take a look at some other contenders.

MSM

Methylsulfonylmethane (MSM), an organic sulfur compound, is among the next best-known ingredients for joint health. While SPINS data show MSM still being a fraction of the business led by glucosamine-chondroitin combos, MSM has also not seen the same rate of sales decline as glucosamine and chondroitin. In fact, in the food-drug-mass channel, MSM gained 2% in sales in the past year, according to SPINS. (In the natural channel, sales were down 0.5%.)

Generally synthetically produced for supplements, MSM is purported to address joint health on several fronts, including preventing cartilage degradation and alleviating inflammation. While more human research will elucidate further benefits and mechanisms of MSM, Bergstrom Nutrition (Vancouver, WA) is one supplier whose OptiMSM ingredient has been studied in a human clinical pilot trial. Published in 2006 in Osteoarthritis and Cartilage (Kim LS et al.), the 50-patient trial examined the effects of 3 g of OptiMSM, twice daily for 12 weeks, against placebo in mild-to-moderate knee osteoarthritis. According to the researchers, OptiMSM improved symptoms of pain and physical dysfunction. “Thus, while large, long-term, dose-response studies in a more diverse patient population are warranted, MSM should be considered in certain OA patient populations,” they stated.

Brands such as Schiff Nutrition and Doctor’s Best use OptiMSM, which recently obtained FSSC 22000 food-safety certification. Moreover, Bergstrom promotes OptiMSM as the world’s only GRAS-affirmed MSM. “We are very optimistic about the opportunities for our ingredients in the food and beverage categories,” states Holly Harmon, director of marketing.
 

Collagen

Because it is the main type of collagen comprising cartilage, collagen type II has been a big focus in the supplements industry. Different companies offer different forms of type II collagen, with different mechanisms of action.

BioCell Technology’s (Newport Beach, CA) BioCell Collagen (which has been rebranded from its old name, BioCell Collagen II, to also encompass the ingredient’s clinically studied skin-health properties) is a unique ingredient. It provides not only type II collagen but also joint-helpers HA and chondroitin sulfate, in a naturally occurring matrix. Thus, as BioCell’s vice president of scientific affairs Joosang Park, PhD, MBA, says, unlike ingredients like glucosamine or chondroitin that do not address the loss of collagen, BioCell Collagen is a broad-based solution.

HA is a major molecule that gives synovial fluid its lubricating properties and is also an essential component of proteoglycans in the cartilage matrix, explains Park. “BioCell Collagen has a competitive edge, as it can address the aging-associated loss of both HA and collagen type II, lending a comprehensive support for both synovial fluid and cartilage.”

Also, because BioCell Collagen is a hydrolyzed form of collagen type II, the company says studies have shown that it is more bioavailable. As Park explains, the hydrolysis process used to make the ingredient converts constituents into very low-molecular-weight molecules that are better absorbed. In the company’s study, Park said it saw a 60-fold increase of HA in the human bloodstream at a steady state.

He describes hydrolyzed collagen’s mechanisms once digested. The resulting dipeptide form protects chondrocytes (the only cells found in cartilage) from cell death, allowing them to continue making the molecules essential for regenerating cartilage. It also stimulates chondrocyte production of type II collagen and proteoglycans, protecting cartilage again. By contrast, Park contends, another form of collagen type II, the undenatured form, was shown in a German study not to stimulate chondrocytes in this way.

In terms of efficacy, earlier this year the company completed its largest human clinical study to date (to be published) demonstrating BioCell Collagen’s improvement of symptoms such as stiffness, pain, and mobility in 80 patients with moderate-to-severe osteoarthritis.

Another type of type II collagen comes from InterHealth Nutraceuticals (Benicia, CA). This is the undenatured, unhydrolyzed form and is branded by InterHealth as UC-II. UC-II addresses joint health in a unique way, the company says. Simply put, it breaks the destructive cycle of joint degeneration by stopping it at the inflammation stage. This gives the body the chance to rebuild cartilage and heal joints.

“UC-II helps slow down the release of collagen-specific T-cells that break down joint cartilage,” says Juliana Erickson, marketing manager. “This results in the production of anti-inflammatory cytokines and the reduction of inflammation, halting the erosion of joint cartilage. As inflammation subsides, the disequilibrium of cartilage turnover caused by arthritis shifts in favor of rebuilding. It appears that once the destructive cycle is broken, collagen-building activities that are part of the normal cartilage remodeling process resume.” She explains that UC-II’s mechanisms happen in the small intestine, where the collagen protein binds to Peyer’s patches and starts signaling to stop production of collagen-specific T-cells.

UC-II has many studies to its name, in both humans and in animals for pet-related joint health. Notable is a 2009 human study in the International Journal of Medical Sciences (Crowley et al.) concluding that UC-II was twice as effective as glucosamine and chondroitin in reducing joint pain and increasing joint mobility and flexibility in knee osteoarthritis.

Moreover, InterHealth says only a small dose is needed compared to glucosamine, chondroitin, and denatured, hydrolyzed type II collagen. The study mentioned above compared a daily 40 mg dose of UC-II with 1500 mg glucosamine and 1200 mg chondroitin.

In terms of comparisons to other forms of collagen type II, Erickson states, “Undenatured (UC-II) and denatured type II collagen are truly two different ingredients with two different mechanisms of actions and daily amounts. Denatured type II collagen from chicken sternum collagen basically serves as a source of joint-related nutrients such as collagen, chondroitin, and glucosamine and does not work to deactivate collagen-specific T-cells like UC-II does.”

Omega-3

Omega-3 fatty acids have a long history in reducing inflammation, making them a viable option for inflamed joints. Thus far, much research has focused on rheumatoid arthritis.

However, in 2009, a 177-subject study published in Advances in Therapy (Gruenwald J et al.) examined the potential of glucosamine sulfate paired with omega-3 fatty acids EPA and DHA on moderate-to-severe hip and knee osteoarthritis. When analyzing pain reduction equal to or greater than 80% on the WOMAC scale, the researchers concluded, “the combination product was statistically and clinically superior compared with glucosamine sulfate alone.” They posit that the two act synergistically, with glucosamine rebuilding lost cartilage and omega-3 inhibiting inflammation.
    

Eggshell Membrane

Among more-recent introductions to the joint-health market is ESM Technologies’ (Carthage, MO) NEM Natural Eggshell Membrane ingredient. As its name suggests, NEM is derived from eggshell membrane, a natural source of chondroitin sulfate, HA, and other naturally occurring glycosaminoglycans. NEM is also believed to offer anti-inflammatory benefits. (The company also offers ESC Eggshell Calcium for increasing bone mineral density.)

Kevin Ruff, PhD, MBA, ESM’s director of scientific and regulatory affairs, says a recent in vitro study (to be published) demonstrated NEM’s mode of action in significantly reducing a number of pro-inflammatory cytokines-most notably IFN-gamma and TNF-alpha. “The reduction in TNF-alpha was further enhanced by a simulated gastric digestion, likely giving insight into the compounds produced in the stomach following digestion of NEM,” Ruff adds.

According to studies, NEM also offers quick relief in a small dose (500 mg daily), in as few as 7 to 10 days.
 

Curcumin and Boswellia

Known for its anti-inflammatory effects, curcumin from turmeric (Curcuma longa) is increasingly being studied for joint health.

Earlier this year, Indena S.p.A. (Milan) announced the results of a 100-subject study published on Meriva in Alternative Medicine Review (Belcaro G et al.) on osteoarthritis, confirming the benefits seen in a previous 50-patient study. Meriva is the company’s proprietary formulation of curcumin with soy phospholipids. According to researchers in the 100-subject study, at 200 mg/day, Meriva not only relieved pain and increased mobility in patients; it also reduced inflammatory markers IL-1beta, IL-6, sCD40L, sVCAM-1, and ESR.

“This study represents the most ambitious attempt, to date, to evaluate the clinical efficacy and safety of curcumin as an anti-inflammatory agent,” stated Giovanni Appendino, Indena’s scientific advisor and professor of organic chemistry at the University of Eastern Piedmont, in a press release.

“Although no direct comparison study of Meriva versus NSAIDs has been conducted, the decreased use of these drugs observed in the treatment group provides a rationale for evaluating whether the biochemical improvement in the inflammatory status associated with Meriva could eventually translate to a phase-out of NSAIDs use, at least for mild-to-moderate [osteoarthritis],” Appendino added.

Curcumin expert Sabinsa (East Windsor, NJ) takes a well-rounded approach to joint health by pairing curcumin with other scientifically substantiated joint-health ingredients in several of its proprietary formulas.

One of those, Arthriblend-SR (Slow Release), was launched in 2007. It contains Sabinsa’s proprietary Curcumin C3 Complex (50 mg), glucosamine sulfate (375 mg), and its trademark Boswellin Boswellia serrata extract (100 mg) and bioavailability enhancer BioPerine.

The ingredients shore up joint health on several fronts. In addition to cartilage-synthesizing glucosamine sulfate, the curcuminoids in Curcumin C3 Complex (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) and the boswellic acids in Boswellin target inflammation.

As marketing director Shaheen Majeed explains, boswellic acids inhibit two pro-inflammatory enzymes: 5-lipoxygenase, which generates inflammatory molecules leukotrienes; and HLE, which can degrade tissue, triggering more inflammation. Curcuminoids may inhibit the pro-inflammatory COX-2 enzyme and matrix metalloproteinase enzymes that can accelerate cartilage degeneration. Additionally, curcuminoids work in an antioxidant capacity, preventing the free-radical formation associated with inflammation and resulting disease progression.

Sabinsa’s newest offering for joint health is Nilitis SR, part of its new bi-layer, multirelease tablet portfolio called Integrated Nutritional Composites (INC). Nilitis SR tablets combine Boswellin (272 mg), Curcumin C3 Complex (250 mg), and ginger (Zingiber officinale) (100 mg) extract. The gingerol in ginger works as an antioxidant and anti-inflammatory, inhibiting enzymes such as COX-2 and lipoxygenase.

Last year, Sabinsa conducted a clinical trial specifically examining the safety and efficacy of Nilitis SR on knee osteoarthritis, enrolling 32 patients. Results included a significant improvement in pain, stiffness, and mobility.
 

Other Possibilities

The botanical hops (Humulus lupulus L.) is also said to address joint inflammation. Soft Gel Technologies offers Perluxan, a proprietary standardized hops extract whose alpha acids (comprising 30%) are said to exhibit free radical–fighting antioxidant activity. Moreover, they may reduce pro-inflammatory enzymatic and non-enzymatic biomarkers, including PGE-2, COX-1 and -2, IL-1, TNF-alpha, and NF-kB.

“Recent research has demonstrated that up to 40% of pain-causing biochemicals (e.g., PGE-2) in the body come from a non-enzymatic pathway related to free radicals; it is now considered that a viable anti-inflammatory agent should also have antioxidative activity,” the company states on its website. Soft Gel says that a 36-subject human study investigating Perluxan on knee osteoarthritis found Perluxan to provide fast-acting pain relief.

Cetylated fatty acids may be another joint option. Proprietary Nutritionals Inc.’s (PNI; Kearny, NJ) Celadrin ingredient is a proprietary blend of specialized fatty acids said to work against inflammation. (The company also offers VegeCeladrin, a veggie version.)

“The special fatty acids found in Celadrin have also been shown to reduce the production of the negative immune factor IL-6 and to control other immune factors responsible for inflammation,” states PNI’s president, Dean Mosca. “This alone could explain some of the effects of Celadrin, such as reduction of discomfort [as well as subsequent damage to joints from inflammation] in joints affected by osteoarthritis.” Decreases in knee osteoarthritis discomfort and mobility were noted in a double-blind, placebo-controlled study.

“The immediate concern of most people who suffer from [poor] joint health is relief from the discomfort it causes,” Mosca adds. “Celadrin can effectively address that problem.” Following that, he says, other restorative ingredients like glucosamine can be applied.
 

A Joint Approach

Many companies interviewed say their ingredients may work synergistically with others.

“Treatment of most ailments should be approached from as many aspects as possible-and joint health is no exception,” says ESM Technologies’ Ruff.

Sidebar: Bone Health: Solid on Calcium

No conversation about joint health would be complete without talking bone health. The two-pardon the pun-are inextricably connected. Calcium remains a mainstay here, with developments including:

DimaCal:
Albion Human Nutrition (St. Clair Shores, MI) says its patented form of calcium, DimaCal, has two moles of calcium attached to one mole of malic acid and that DimaCal is a better alternative to calcium carbonate and other calcium salt forms, offering a much higher elemental calcium content (29% elemental calcium). Two bioavailability studies indicated that DimaCal was significantly better absorbed compared to calcium carbonate and that it maintained an elevation in serum calcium for a much longer period of time. Moreover, the company says that unlike calcium carbonate and some of the other alkali calcium forms, DimaCal does not cause the formation of gas when subjected to stomach acid and does not cause the acid rebound seen with other calcium forms. Recently, Albion announced it has obtained a Chemical Abstracts Service (CAS) number for DimaCal.

VersaCAL Clear:
Taking calcium into new waters, Innophos (Cranbury, NJ) this year launched VersaCAL Clear, a highly soluble calcium phosphate ingredient specifically designed to go into clear beverages, without causing cloudiness or off-taste. “I think the interesting thing about VersaCAL Clear is that it lets a beverage formulator use a calcium ingredient at 20% of the daily value, so it becomes an excellent source of calcium in a beverage,” says Larry Esposito, business director. “You can’t really do that with any other calcium ingredient today. There are other calcium ingredients that are used in fortified clear beverages; however, the problem is they can’t be included in a dose high enough to be considered a good source of calcium. And even if they get close, their negative organoleptic results make them hard to use.”

HuberCal:
Derived from natural limestone sources, Huber Engineered Materials’ (Atlanta) HuberCal pure calcium carbonate is touted by the company as a higher-purity source compared to synthetic calcium carbonate ingredients. In fact, says Nick Kalfas, global sales director, demand for HuberCal is up-so much so that the company is expanding operations at its Quincy, IL, facility to increase production capacity (up to 10,000 metric tons).

KoACT:
Instead of simply focusing on calcium to build bone mineral density, AIDP Inc. (City of Industry, CA) is going a step further by also focusing on bone flexibility. As director of research and development, Jennifer Gu, PhD, explains, 90% of the bone’s matrix comprises collagen. (Picture this matrix as the steel framework of a skyscraper, to which calcium attaches to form bone mineral density.) The bone matrix itself must be kept strong and flexible in order for bones to absorb impact. AIDP’s unique, triple-patented KoACT calcium collagen chelate ingredient has calcium chelated to bone collagen “in a very biological way, mimicking the bone structure to deliver both components at the same time,” Gu says. Because it mimics the bone’s natural structure, KoACT is better absorbed, she adds.