'Wise men' ingredients for joint health

'Wise men' ingredients for joint health

Delivering natural ingredients that are the building blocks of connective tissue in joint space and cartilage was the first step. Today's supply channel also features anti-inflammatory ingredients. For manufacturers looking to tweak joint-health formulations or offer something new and efficacious besides the near-commodity glucosamine and chondroitin, Science Editor Todd Runestad unveils what's new and validated.

It's December — when joints creak from the cold and tales swirl of three wise men delivering tidings of joy. So yeah, let's talk frankincense (Boswellia serrata). A December 2008 review published in the British Medical Journal assayed randomised clinical trials related to osteoarthritis (as well as asthma and colitis). The reviewer found frankincense evidence to be "encouraging but not compelling" in treating conditions caused or maintained by inflammatory processes, along with no serious safety issues.1 In particular, it cited a 2003 double-blind, placebo-controlled, crossover study conducted in India for eight weeks. Those receiving the frankincense extract reported decreased knee pain, increased knee flexion and increased walking distance, along with a decrease in frequency of swelling in the knee joint.2

But that's Old Testament frankincense. In the 21st century, Laila Nutraceuticals created a unique extraction process that standardises a frankincense extract to 30 per cent of what's seen as the most potent anti-inflammatory boswellic acid, AKBA. The result is a branded ingredient called 5-Loxin — so named for its ability to inhibit the 5-lipoxygenase enzyme, the enzyme that triggers the inflammatory response and breaks down protective joint tissues by ultimately producing pro-inflammatory leukotrienes. PL Thomas supplies the ingredient.

In 1997, Rexall Sundown launched the joint-health supplement formulation Osteo Bi-Flex. The glucosamine/chondroitin formulation quickly became one of the more successful product launches, and by 2004, it was the 34th-leading OTC product in America, and No. 1-selling joint-health supplement, according to Drug Store News, with sales north of $33 million and 10 per cent annual growth.

Not one to rest on its laurels, in 2006, Osteo Bi-Flex included the latest 'new and improved' joint-health ingredient: 5-Loxin. Its instincts were wise indeed, as a 2008 published study validated 5-Loxin's efficacy as an anti-inflammatory.

In the double-blind, randomised, placebo-controlled study, conducted in India, researchers gave 75 osteoarthritis patients either 100mg or 250mg 5-Loxin for 90 days. Both doses conferred clinically and statistically significant improvements in pain scores and physical function scores, though the 250mg dose was a bit more effective. Researchers noted improvements in as early as seven days for the 250mg group. They noted the ingredient worked not only by controlling pro-inflammatory modulators but also by reducing the enzymatic degradation of cartilage.3

"While a new ingredient, it is steeped in the historic roots of the Boswellia serrata plant, used in traditional Indian medicine for centuries," says Golakoti Trimurtulu, PhD, vice president of Laila Nutraceuticals. "Thus, 5-Loxin is the modern approach to tradition and history of Indian herbal therapy, being clinically proven for its effectiveness."

Researchers in India went so far as to put a Boswellia serrata extract in a head-to-head comparison study against valdexocib, a selective COX-2 inhibitor. The study was a six-month, randomised, prospective, open-label, comparative study in 66 patients with osteoarthritis of the knee. Researchers found that patients taking the boswellia extract showed statistically significant improvements with pain, stiffness and difficulty in performing daily activities after two months of taking the extract, with results that persisted for a month after the therapy was stopped.

The COX-2 inhibitor group, meanwhile, also experienced significant results in all parameters, with results occurring after only one month, but the results waned rapidly immediately after stopping the treatment.4


As India appears to be the nexus of boswellia research, it's no surprise that another major player in the boswellia world is Sabinsa, based in India with US offices in New Jersey and Utah. Sabinsa offers a composition branded Arthriblend-SR, which contains its branded Boswellin along with glucosamine sulphate and its branded Curcumin C3 Complex, which is composed of curcuminoids from Curcuma longa. Rounding out the composition it its Bioperine black-pepper extract, a patented bioavailability enhancer.

Curcumin C3 Complex was found to possess antioxidant and anti-inflammatory properties, and is also a COX-2 inhibitor.5 Curcuminoids also inhibit the enzymes that cause chondrocyte cells in the joint-cartilage matrix to degenerate. In an animal cell study, it suppressed enzymatic activity between eight and 100 per cent, depending on the enzyme.6

Sabinsa's Curcumin C3 Complex has enough promise to warrant its award of the Nutrition Business Journal (NBJ) Supplement Ingredient Product Merit Award of the Year at the NBJ Summit in the summer of 2009.

In a recent study that will help the joint-health category continue to make inroads into the 'healthy active ageing' demographic, researchers tested curcumin's effects on both inflammation and performance recovery following exercise-induced muscle damage. The mouse study found curcumin was able to decrease inflammation and some of the running deficits due to muscle trauma.7

In a notable achievement for suppliers — and manufacturers — who produce ingredient blends but don't research the finished formulation, Sabinsa conducted an unpublished study in India comparing its ArthriBlend complex to glucosamine sulphate on patients with osteoarthritis of the knee. After 90 days, the patients using the combination product experienced a more than five-fold decrease in pain on use and morning stiffness, and a 75 per cent decrease in swelling — all statistically significant.

"We're a science company that happens to sell products as well," says Sabinsa CEO Jeff Lind. "The reason is you can only separate yourself from the competition with real science. Our whole philosophy is efficacious doses with products that have been tested, substantiated, with a safety profile."

Enter the matrix

While manufacturers continue to tack on an increasing number of joint-health ingredients in order to cover all the bases of joint health, some suppliers are delivering compounds derived from sources that have a number of joint-aiding complexes in them — with hyaluronic acid being a common theme. Hyaluronic acid is seen as an important component of synovial fluid where it behaves as a viscous liquid to cushion the joints, thus allowing a soft and smooth movement of the joint.

Curiously, these all seem to be derived from barnyard animals. (Is it fair to ask: who dug around the barnyard and came up with these apps?)

Eggs: One new entrant to the field is Natural Eggshell Membrane (NEM), supplied by ESM Technologies. The name says much — it's derived from eggshells, and it contains naturally occurring glycosaminoglycans (GAGs) and proteins, including chondroitin and hyaluronic acid, collagen, and other proteins. These GAGs maintain healthy articular cartilage and the surrounding synovium. The company is aggressively publishing research to back its efficacy, with two studies published in 2009 alone.

In one double-blind, placebo-controlled clinical study carried out with 67 patients, half received 500mg/day NEM, the other 33 received placebo for eight weeks. Patients in the treatment group experienced a 16 per cent pain reduction and an average 13 per cent reduction in joint stiffness compared to placebo, with one fourth of these patients experiencing a more than 50 per cent reduction in stiffness in only 10 days. No side effects were reported by study participants.8

In another 2009 study, two 30-day open-label pilot studies were conducted to evaluate 500mg/day NEM as a treatment for general joint and connective tissue disorders. Results showed NEM produced an average 25 per cent reduction in pain (both studies) and an average 28 per cent increase in flexibility (study 1) in only seven days. No side effects were reported.9

The results are interesting not only for their time to treat but also for the amount needed. Compared to glucosamine, which studies show requires 1,500mg/day for roughly six weeks, formulators and marketers should like that ESM requires one third the dosage with positive results arriving in only one week's time.

"Consumers are tired of taking large quantities of supplements daily and suffering digestive discomforts," says Micah Osborne, president of ESM Technologies. "ESM's ingredients both offer distinct competitive advantages in dosing quantities and effectiveness that we believe will translate into much higher customer satisfaction and sell-through for our ingredient customers' finished products."

In late 2009, ESM entered an agreement with Novus International, which previously had played exclusively in the animal-nutrition world. Novus is helping with distribution in some international markets, and has select distribution rights in the US.

"Our core competency is in creating science-based nutritional solutions for the daily health and welfare concerns that farmers have for their animals," says Jeremy Moore, Director, Marketing and Strategic Development, Human Nutrition, Novus International. "We identified early on that joint health was a space that we wanted to participate in, and evaluated several technologies. Based on our evaluation, we felt ESM's NEM ingredient held the most promise for global human-nutrition use. NEM has a robust and highly scalable domestic supply chain, and a source material that is vegetarian friendly (although not vegan friendly) and is a trusted food that has been consumed for centuries. NEM also has a very mild flavour that we believe will help the ingredient translate well to food applications."

Chickens: Another ingredient that houses a multitide of GAGs and proteins is collagen, derived from the cockscombs of roosters. Collagen is the main protein present in joints and is the key to flexible and strong tissues. It is also a storehouse of GAGs.

One company, BioCell Technology, went through the trouble of conducting toxicity studies on its BioCell Collagen II ingredient, which contains collagen type II, chondroitin sulphate and hyaluronic acid. In this acute oral-toxicity study, five male and five female rats were given a single dose of 5,000mg/kg body weight and observed for 14 days. No gross pathological lesions were observed in any of the animals at the end of the study. In a subchronic study, 80 rats were separated into four groups and given either 0, 30, 300 or 1,000mg/kg body weight per day for 90 days. There were no significant changes seen in body weight or in microscopic examination of body tissues.10

"BioCell Collagen II is the only dietary ingredient of its kind to undergo the rigours of toxicity testing," says Suhail Ishaq, BioCell's vice president. "Consumers can be confident about the safety BioCell Collagen II, and it opens the door to new product development in the functional foods market."

In-house studies show it has significant peak absorption and steady-state bioavailability in normal volunteer subjects, which is notable because hyaluronic acid can have troublesome absorption issues due to its large molecular size. In the study, a 36-hour peak-absorption study using a single dose, BioCell Collagen II significantly increased hyaluronic acid levels in the blood in four hours, and peaked at a level 7,000 per cent above control in 12 hours. In the blood, hyaluronic acid was metabolised to two metabolites 1/600 the size of the ingested hyaluronic acid.11

The ingredient is GRAS and is marketed to new-product development formulators of vitamin waters, nutricosmetics, beauty-supplement drinks, fortified foods and juices, liquid joint-support beverages, chewable dietary supplements, and more.

A 2009 study went so far as to compare undenatured type II collagen (supplied by InterHealth Nutraceuticals) to standard-bearers glucosamine and chondroitin. For 90 days, 52 adults took either 40mg UC-II containing 10mg of bioactive undenatured type II collagen or the standard 1,500mg glucosamine and 1,200mg chondroitin. Both treatments reduced the WOMAC joint-comfort score — by 14 per cent in the glucosamine/chondroitin group, and by 33 per cent in the UC-II group. Using the visual analog scale (VAS), the glucosamine/chondroitin group scored a 15.4 per cent decline compared to a 40 per cent decline in the UC-II group. The Lequesne's functional index score was similarly reduced by six per cent in the glucosamine/chondroitin group, and 20 per cent in the undenatured UC-II group.12

"Even though glucosamine and chondroitin have become household names at the consumer level, many manufacturers and retailers are looking for ways to offer consumers a new generation of joint-health products that are proven safe and effective and based on solid science," says Paul Dijkstra, CEO of InterHealth Nutraceuticals. "This research has spurred interest at leading companies looking to include an efficacious joint-health ingredient with research demonstrating superiority over glucosamine plus chondroitin."

Sunshine: It probably shouldn't surprise anyone anymore that vitamin D is on this list. What list is the sunshine vitamin not on?

In vitamin D's case, it appears to relieve chronic pain. In a 2008 analysis of 22 clinical trials involving patients with chronic pain and fatigue, almost all patients were deficient in vitamin D. Nothing new there — it's now being discovered that most every demographic group is deficient. What is notable is that when the patients were supplemented with vitamin D, their pain symptoms improved significantly — in some cases, ameliorated completely.

A May 2009 study found an association between serum levels of vitamin D and knee-cartilage loss and joint-space narrowing. The study, conducted in Africa, found these results in women with osteoarthritis, but not in men or in those without knee pain.13

An August 2009 study found an association between vitamin D intake and osteoarthritis among 1,248 subjects in the so-called Rotterdam study, conducted in The Netherlands. Those with the highest baseline vitamin D levels experienced osteoarthritis in 5.1 per cent of participants, vs 2.6 per cent of those with the lowest vitamin D levels.14 In Massachusetts, similar results were found in the Framingham Study. Here, among 556 participants, those with the highest serum vitamin D levels had three times fewer incidents of osteoarthritis compared with those with the lowest vitamin D levels. Low serum levels of vitamin D also predicted loss of cartilage.15

These associations are important. Less well known is exactly how vitamin D works to these effects. Some evidence suggests that physiologic processes in bone are important determinants of osteoarthritis, and vitamin D has well-known positive effects on bone by promoting the absorption of calcium and phosphorus needed for bone mineralization, growth and repair. Or, cumulative damage to tissues, mediated by oxidative stress, could also be a pathway to osteoarthritis, as this certainly appears to be a mechanism in other degenerative conditions.16

When all else fails…

Finally, not that ethical supplements makers should think about going this route, but a December 2008 review of 198 trials covering more than 17,000 patients found one ingredient to be effective at relieving osteoarthritis pain, improving function and ameliorating stiffness. This ingredient: placebo.17

Select suppliers: get wise to joint-health ingredient sources

Biocell Technology
BioCell Collagen II is a natural hydrolysed type 2 collagen composed of collagen, chondroitin sulphate and hyaluronic acid. Its low molecular-weight ingredient is easily absorbed.

This Spanish company provides the glucosamine and the chondroitin sulphate used in the landmark GAIT study of glucosamine and chondroitin.

Hydro5 is a patent-pending hydrolysation process for making eggshell membrane soluble. Ovacore eggshell membrane is standardised at not less than 85 per cent protein.

Regenasure vegetarian-sourced glucosamine is US produced, GRAS for foods and beverages, kosher, halal, and produced in accordance to GMPs.

BioAstin astaxanthin is produced from micro-algae on the Big Island of Hawaii. The world's best-selling brand of astaxanthin for humans, it relieves joint pain via natural anti-inflammatory response.

Cyvex Nutrition
AvoVida avocado/soy unsaponifiables is a natural extract of phytosterols from avocado and soy, including beta-sitosterol, campesterol and stigmasterol, so it's effective for joints and cholesterol.

ESM Technologies
NEM — Natural Eggshell Membrane — is a complex ingredient matrix composed of naturally occurring glucosamine, chondroitin, hyaluronic acid, collagen and other proteins. It is suitable for foods and supplements. ESM is being helped with distribution by Stratum Nutrition.

InterHealth Nutraceuticals
UC-II is undenatured native type 2 collagen derived from chicken-sternum cartilage. It is supported by six human clinical trials and has four US patents and international patents pending to benefit those with osteoarthritis, as well as rheumatoid arthritis.

Natural Health Science
Pycnogenol-brand French maritime pine bark extract had three published studies in 2008 for osteoarthritis. The ingredient decreased the use of anti-inflammatory drugs by 58 per cent, lowered CRP levels (a marker for inflammation), and cut patient pain.

PLX is NDN's lemon verbena extract 10 per cent oligosaccharides with anti-inflammatory and antioxidant properties demonstrated in clinical trials. A PLX formula can be provided with collagen, chondroitin sulphate, gluocosamine, omega-3s and more.

Neptune Technologies & Bioressources
NKO krill oil has been licensed to Valensa International for eye and joint-health applications. NKO is the only krill tested in a published human clinical trial for chronic inflammation and arthritic symptoms, where it significantly reduced pain, stiffness and impairment.

Perluxan is a proprietary extract of hops cones (Humulus lupulus) that reduces joint discomfort via various anti-inflammatory mechanisms.

Proprietary Nutritionals
Celadrin topical cream is a natural blend of special fatty acids that can reduce pain and improve mobility in joint-, muscle-, and tendon-related ailments. It boasts four published clinicals.

Boswellin is an anti-inflammatory botanical (Boswellia serrata). Curcumin C3 Complex is a complex of three curcuminoids that act as anti-inflammatories — as well as offer a host of other benefits including anti-cancer potential.

Soft Gel Technologies
Injuv contains nine per cent low molecular-weight hyaluronic acid, which is believed to help body tissues retain moisture and keep joints lubricated.

TandemRain Innovations
ActivMSM is the only GRAS and US-manufactured version of MSM. It is the subject of three published human clinicals, and appears to work by staying in the body for an extended time in uniquely modifying sulphur metabolism.

TSI Health Sciences
Pureflex chondroitin sulphate and glucosamine comes in a variety of salts and sources, and in supplement grade as well as pharma/OTC grade.

Univestin has three patents for its mixture of free-B-ring flavonoids and flavans as therapeutic agents for alleviating joint discomfort and stiffness, improving mobility, flexibility and physical comfort. Patents also cover formulations of bioflavonoid extracts from Scutellaria and acadia in combination with other joint-care ingredients.



1. Ernst E. Frankincense: systematic review. BMJ 2008 Dec 17;337:a2813.
2. Kimmatkar N, et al. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee--a randomized double blind placebo controlled trial. Phytomedicine 2003 Jan;10(1):3-7.
3. Sengupta K, et al. A double-blind, randomized, placebo-controlled study of the efficacy and safety of 5-Loxin for treatment of osteoarthritis of the knee. Arthritits Res Ther 2008;10(4):R85.
4. Sontakke S, et al. Open, randomized, controlled clinical trial of Boswellia serrata extract as compared to valdecoxib in osteoarthritis of knee. Indian J Pharmacol 2007 Feb;39(1):27-9.
5. Majeed M, et al. Curcuminoids: antioxidant phytonutrients. NutriScience Publishers Inc. Piscataway, New Jersey. See also www.curcuminoids.com
6. Liacini A, et al. Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes. Matrix Biol 2002 Apri;21(3):251-62.
7. Davis JM, et al. Curcumin effects on inflammation and perforamnce recovery following eccentric exercise-induced muscle damage. Am J Physiol Regul Integr Comp Physiol 2007 Jun;292(6):R2168-73.
8. Ruff KJ, et al. Eggshell membrane in the treatment of pain and stiffness from osteoarthritis of the knee: a randomized, multicenter, double-blind, placebo-controlled clinical study. Clin Rheumatol 2009 Aug;28(8):907-14.
9. Ruff KJ, et al. Eggshell membrane: A possible new natural therapeutic for joint and connective tissue disorders. Results from two open-label human clinical studies. Clin Interv Aging 2009;4(1):235-40.
10. Schauss AG, et al. Acute and subchronic oral toxicity studies in rats of a hydrolyzed chicken sternal cartilage preparation. Food Chem Toxicol 2007 Feb;45(1)@:315-21.
11. www.npicenter.com/anm/templates/newsATemp.aspx?articleid=5574
12. Crowley DC, Lau FC, Sharma P, et al. Safety and efficacy of undenatured type II collagen in the treatment of osteoarthritis of the knee: a clinical trial. Int J Med Sci. 2009;6:312-321.
13. Ding C, et al. Serum levels of vitamin D, sunlight exposure, and knee cartilage loss in older adults: the Tasmanian older adult cohort study. Arthritis Rheum 2009 May;60(5):1381-9.
14. Bergink AP, et al. Vitamin D status, bone mineral density, and the development of radiographic osteoarthritis of the knee: The Rotterdam Study. J Clin Rheumatol 2009 Aug;15(5):230-7.
15. McAlindon TE, et al. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med 1996 Sep 1;125(5):353-9.
16. McAlindon TE, et al. Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum 1996 Apr;39(4):648-56.
17. Zhang W, et al. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis 2008 Dec;67(12):1726-23.


Hide comments


  • Allowed HTML tags: <em> <strong> <blockquote> <br> <p>

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.