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Building better joint health supplements

Building better joint health supplements
Joint-health ingredients either maintain cartilage or alleviate inflammation and pain. A comprehensive therapy should use both avenues. Risa Schulman, Ph.D., details the functional ingredients that should be top of mind for any new product introduction.

Among the non-life-threatening health issues, joint health (or lack thereof) probably affects our quality of life the most. Like many things, until you lose the use of them, you don't appreciate just how much they do for you. A study published this August found that of the 27 million Americans with arthritis,1 40 percent of men and 56 percent of women with knee osteoarthritis (OA) are completely inactive.2 Those numbers were called by leaders in the field "sobering" and a "wake-up call" to both sufferers and their physicians—it's also just a downright shame.

So it really is fortuitous that there are so many supplement options to help support joint health. They do this in two main ways: cartilage maintenance (building on the one hand and preventing breakdown on the other) and alleviating inflammation and pain. Both of these factors are mechanisms in OA, the type of arthritis most studied with respect to supplements. Putting together ingredients from both of these categories therefore makes for a comprehensive therapy. In addition, some of the ingredients fall into both categories.

Before going into the supplements themselves, let's take a look at the nature of joints and how OA develops. The various components of joints serve as buffers between bones, providing cushioning and allowing flexibility. It consists of the cartilage, which covers the ends of the bones, the synovial membrane, which covers the cartilage, and the synovial fluid, which fills the space between the two bones and bathes the synovium and cartilage. In a healthy joint, there is a turnover of cartilage that is facilitated by, among other things, degradative enzymes called matrix metalloproteinases (MMP). This is countered by synthesis of new cartilage and inhibitors of the MMPs that strike a dynamic balance. In OA, that balance is disturbed such that breakdown processes are favored, leading to destruction of cartilage, friction between the bones, and pain and inflammation.3

Cartilage maintenance

This is the domain of several of the old standbys in the joint-health category. While consumers weigh in with their wallets, much of the study data are ambiguous. The strength of the data has at least as much to do with the insight, methodological rigor and standardization of materials that are brought to the study design as with the efficacy of the supplement itself.

Glucosamine and chondroitin

Glucosamine, which is synthesized from glucose in the body, is the limiting step in the synthesis of the glycosaminoglycans that make up cartilage, and of chondroitin sulfate and hyaluronic acid.4 Glucosamine is also thought to suppress mediators of cartilage destruction such as MMPs.3,5

Human studies using glucosamine have shown improvements in severity of disease and pain by 28 percent and 21 percent, respectively,6,7,8 compared to placebo, as shown in a 2005 Cochrane Database review of 20 randomized, controlled trials.9 One retrospective study in 340 OA patients showed that glucosamine obviated the need for joint replacement after supplementation of 12 months to three years, even five years after supplement discontinuation.10 However, more recent meta-analyses have not been able to recommend glucosamine on the strength of the combined data.11 Aside from the usual citations of heterogeneity, poor study quality and insufficient study duration, it has been suggested that the actual problems are under-dosing and inconsistencies in chemical potency and bioavailability of the material, and that if these are addressed the data would be strongly in favor of an effect.12 Glucosamine's Siamese twin chondroitin is also one of the glycosaminoglycan building blocks for cartilage and an important component of synovial fluid.

A recent meta-analysis focused on its ability to prevent joint narrowing and showed a small, positive result in the three pooled trials that were of two-year duration.13

A newly released multicenter, randomized, double-blind, controlled, pilot study in 69 patients with knee OA showed that cartilage loss decreased as early as six months into a 12-month regimen of 800 mg/day.14 However, other meta-analyses were unable to show an effect on function or pain reduction, with the same problems of study heterogeneity cited for glucosamine.15,16


Type II collagen is a primary component of cartilage and is a main target of the enzymes that degrade it. InterHealth Nutraceuticals, makers of UC-II, an undenatured type II collagen, has pioneered testing in people with OA; prior studies were limited to animals or rheumatoid arthritis patients. The 2009 90-day trial in 52 OA patients showed that compared to a glucosamine and chondroitin treatment (1,500 mg and 1,200 mg/day, respectively), UC-II (40 mg/day) showed a statistically significantly better response for pain reduction and physical function.17 Rather than a competitive approach, it would be more to the consumer's benefit to understand the additive effects of UC-II and glucosamine/chondroitin.


Methylsulfonylmethane is another staple in joint health,and is used based on its high sulfur content, which is important to form cross-linkages that strengthen the cartilage. Short-term (three month) studies have shown that MSM reduces pain in OA patients. In a randomized, double-blind, placebo-controlled trial in 50 subjects with OA, 3 g of MSM twice a day significantly decreased functional impairment and pain compared to placebo.18 A combined effect of MSM and glucosamine (both at an intake of 1,500 mg/day) was explored in a study with 118 OA patients and found that they were more efficacious in improving functionality and swelling together than separately.19 At the same time, a meta-analysis concluded that there was "positive but not definitive" evidence for the efficacy of MSM.20 Until now, the efficacy of DMSO (dimethylsulfoxide, the oxidized form of MSM), has not been well-elucidated as a result of poor quality studies.

Hyaluronic acid

This is a component of the synovial fluid that fills the cavity of the joint and gives the fluid its viscoelastic and lubricating properties. In OA, the amount of hyaluronic acid is reduced, compromising these properties. Injections of hyaluronic acid into the knee are sometimes used as therapy, but oral ingestion has been less well studied. Bioiberica, the makers of Hyal-Joint (60 percent hyaluronic acid), has made inroads by performing a pilot, randomized, double-blind, controlled trial using 80 mg/day in 20 knee OA patients, finding a significant improvement in physical and social functioning as well as pain, compared to placebo.21

Alleviation of pain and inflammation

New research reveals that inflammation is not just a symptom of joint degeneration, but is involved from the beginning. In fact, the level of inflammatory compounds is higher in early stage arthritis than late stage. In addition, the inflammatory mediators activate the cartilage degrading enzymes, amounting to a positive feedback loop.3 This makes an even more cogent argument for combining these ingredients with cartilage-building ones. Outlined below are several well-known anti-inflammatory joint health ingredients, as well as some up-and-comers that are well-founded development possibilities. Almost all act to inhibit either COX-2 (cyclooxygenase-2) or 5-LOX (5-lipoxygenase)—two of the key molecules that trigger the inflammatory cascade.

Frankincense is an old remedy that keeps serving up new tricks as knowledge develops. It is an herbal product, the sap of the plant Boswellia serata, also known as frankincense. The two main active ingredients are boswellic acids 11-keto-ß-boswellic acid (KBA) and acetyl-11-keto-ß-boswellic acid (AKBA).

Laila Nutraceuticals in partnership with P.L. Thomas has contributed to the science by testing their AKBA-standardized 5-Loxin ingredient in a randomized, double-blind, placebo-controlled trial showing reduced pain and stiffness and increased physical function in OA patients at the level of 100–250 mg/day in as little as seven days (at the 250 mg level). They also showed that it acts as an anti-inflammatory by inhibiting the enzyme 5-LOX. Lastly they documented a decrease in MMPs in the synovial fluid, suggesting that boswellia may also slow the degradation of the cartilage.22

Laila Nutraceuticals has also recently developed a new blend from the boswellia plant called Aflapin, which in a 2010 comparative study showed greater bioavailability and more efficacy as an anti-inflammatory and inhibitor of cartilage degrading enzymes than 5-Loxin when each was compared to placebo (however, statistics were not done to show whether the relative improvements were statistically significantly different from one another).23

Both branded products have good safety, tolerability and toxicology profiles.

A 2011 study has called into question whether KBA and AKBA are the active ingredients, arguing that their poor bioavailability results in serum levels that are too low to inhibit 5-LOX. The authors instead note that ß-boswellic acid is found in the serum in concentrations 100 times higher, and that it inhibits inflammatory compounds prostaglandin E synthase-1 and the serine protease cathepsin G, which perhaps should be considered the mechanism of action.24 If this were in fact the case, it would change how products should be processed and standardized.

Glucosamine and chondroitin

There's a reason these two are almost always the foundation of a joint-health formula. In addition to being cartilage and synovial fluid builders, they have also been shown to suppress many inflammatory mediators, and to reduce the synthesis of COX-2.3


Curcumin (diferuloylmethane) is the main component of the spice turmeric and is responsible for its color and flavor. While numerous in vitro and in vivo studies in the last 20 years have shown its effects as an inhibitor of COX-2, 5-LOX, and many of their downstream products,25 a short serum half-life, conjugation, and low bioavailability have hampered strong results in humans.25,26 Improvements in bioavailability may be key to advancing research and efficacy for this ingredient.


Part of the omega-3 magic is due to its anti-inflammatory properties, so it's only natural that at some point omega-3s would be explored for joint health. Recently, the combination of omega-3s (DHA and EPA) together with glucosamine was compared to glucosamine alone in a randomized, double-blind study with 177 OA patients. There was a therapeutically meaningful additional improvement in morning stiffness and pain when omega-3s were added to glucosamine.27 In vitro and animal studies show that not only do the omega-3s decrease COX-2, but they also are one of the ingredients with a dual action, helping to build cartilage and suppress cartilage-degrading enzymes, making them an excellent candidate for formulations as well as additional research.28,29


The longstanding story of resveratrol's heart-health benefits overshadows some of its other effects. In vitro studies in the '90s showed that resveratrol had a potent inhibition of both COX-2 and many of its downstream inflammatory modulators.30,31 It was also shown on a molecular level that resveratrol shuts off COX-2 synthesis.30 The most recent research in this area has focused on the implications of this property in conditions such as cancer and diabetes, but not joint conditions. Given that the same inflammatory pathways operate in OA as in these other diseases, resveratrol is worthy of more attention for an OA application in research and development circles.

Avocado Soy Unsaponifiables

ASU are made from the natural oil of avocado and soybeans and have been shown to be an inhibitor of COX-2 and other inflammatory compounds.32 Consumption of avocado and soy alone cannot deliver the amount needed for efficacy. Four randomized, placebo-controlled trials have been done to assess the efficacy of ASU as an anti-inflammatory in OA patients. A meta-analysis of these trials, which included 664 subjects taking 300 mg of ASU for an average of six months, found that it significantly reduced pain and improved physical functionality compared to placebo.33

In Europe, ASU is available as the prescription drug Piascledine 300, which was tested in an efficacy trial in 364 OA patients. It compared 300 mg of Piascledine to 1,200 mg of chondroitin sulfate and showed that both improved pain, stiffness and physical function to the same significant degree according to a standard index, and that both were well tolerated.34

Risa Schulman, PhD, president of New York City-based consulting firm Tap~Root, has 13 years of science and regulatory experience developing functional foods and dietary supplements with great stories.

Capturing your science in a claims substantiation dossier

  • Relevant papers have already been reviewed and gathered to present to the FDA if necessary—no frantic scramble
  • Can serve as a reference for PR and marketing strategy development, sales and other educational presentations
  • If used as such a reference document, provides uniformity in communications
  • Can help identify gaps in research
    The dossier structure should contain:
  • Intake level to which claims apply: This should correspond to the levels that are supported by clinical trials.
  • Date and version number
  • List of claims using the exact wording that will be used on labeling: This will often be the result of a collaborative effort between R&D, marketing, sales and legal to arrive at a regulation-compliant, scientifically accurate and compelling wording.
  • Full citations of the papers used to substantiate the claims: These should ideally be accompanied with summaries of the specific evidence each paper brings. Taking this extra step is the added value that can make the dossier a reference for internal staff.
  • Human studies with details of the study provided in the short summaries. These can be ordered according to the level of cogency as specified by the FDA: randomized controlled trials, epidemiological studies, case studies, meta-analyses, review articles, followed by animal and meaningful in vitro studies.
  • A summary of the evidence for the claim
  • Updates as they occur: The dossier should be periodically updated and reissued as new research is added to the body of evidence.


Select suppliers: joints

Aker BioMarine
Provides krill oil and meal through an optimized value chain, from raw materials to customer.

Bulk manufacturer of pharmaceutical grade omega-3 ingredients, offering up to 85 percent DHA and 95 percent EPA in capsule, powder and emulsion form.

Bergstrom Nutrition
This family-owned nutrition ingredient company is dedicated to supplying methylsulfonylmethane (MSM).

BioCell Technology, LLC
The exclusive supplier of BioCell Collagen II—a patented dietary ingredient containing highly bioavailable hydrolyzed collagen, low molecular weight (MW) hyaluronic acid and chondroitin sulphate.

Bioiberica, S.A.
Specializes in research, manufacture and marketing of biomolecules for the pharmaceutical and nutrition industries, especially chondroitin sulfate, hyaluronic acid and glucosamine.

Bio Serae Laboratories SAS
Specializing in the manufacture and the supply of original, active ingredients for the nutraceuticals and industries. Creator of Osteol, a natural ingredient that optimizes the activity of standard D-glucosamine and chondroitin in joint formulas.

Croda Inc.
Supplier of nutraceutical and pharmaceutical ingredients excipients, solubilisers, plant and marine lipid concentrates, proteins and biopolymers.

Cyanotech Corp.
A producer of branded functional microalgae ingredients BioAstin Natural Astaxanthin and Hawaiin Spirulina Pacifica.

Provides gelatin, collagen peptides and collagen used in the production of functional foods and nutritional products that enhance bone and joint health, calorie management and protein enrichment.

Helios Corp.
Develop and market new ingredients for the functional foods and nutrition community, utilizing Phase I and Phase II human clinical studies.

Humanetics Corp.
A science-based company providing nutritional supplement-based solutions for weight- and glucose-management, joint health, and sports performance.

Indena USA Inc.
Concentrating its efforts on the industrial production of standardized extracts derived from plants for use in health food products.

National Enzyme Co.
Specializes in product formulation and patented, branded ingredients, particularly unique enzyme blends for everything from digestive aids to energy supplements.

Nutra Bridge Corp.
Focused on patented, branded ingredients such as 7-Keto for weight loss, MicroLactin joint health solution, and InSea2, the first dual-action starch- and sugar-blocker for blood sugar management.

Nutraceutix Inc.
Delivers probiotics in bulk powder, capsules and tablets using processes and delivery technology that extend shelf-life and protect probiotic organisms from stomach acid en route to the intestines.

P.L. Thomas
Supplies a wide variety of joint-health ingredients aimed at improving joint integrity, comfort, and mobility including 5-Loxin and Après Flex.

Proprietary Nutritionals Inc.
A division of Pharmachem Labs, PNI is a global marketer and distributer of nutraceutical ingredients such as Celadrin for joint health and Perluxan for pain management.

TSI Health Sciences Inc.
Suppliers of chondroitin and glucosamine that meet or exceed the highest quality and regulatory standards in the world.

Sabinsa Corp.
Manufactures ArthriBlend SR, a sustained-release formula of herbal extracts and nutrients to support healthy joints and connective tissues.

Soft Gel Technologies Inc.
Provides contract manufacturing of soft gel caps for the dietary supplements industry.

Stratum Nutrition
Provides safe and reliable ingredients that support cardiovascular, structural, digestive and immune health.

Research and development in the natural products industry for functional foods, dietary supplements, cosmeceuticals.

Vitaco Health (NZ) Ltd.
One of Australasia's largest health and wellness manufacturers producing health foods, supplements and nutritional products.


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