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Nutraceuticals for Joint HealthNutraceuticals for Joint Health

Heather Granato

December 1, 2009

34 Min Read
Nutraceuticals for Joint Health

When the Tin Mans joints lock up in the classic film, The Wizard of Oz, all it takes is a squirt from the oil can to get things back in working condition. In real life, getting frozen or inflamed joints to move smoothlyand without painis not quite so simple.

The National Center for Chronic Disease Prevention and Health Promotion reports 46 million Americansone in fivehave been diagnosed with arthritis or another rheumatic condition by a health care professional. In fact, the term arthritis describes more than 100 different conditions that affect joints and other parts of the body. It is one of the most chronic health problems, and one of the nations most common causes of disability, limiting the activities of nearly 19 million adults.

The most common form of the disease is osteoarthritis (OA), also called degenerative joint disease. It is caused by the breakdown of cartilage and bones from the wear and tear of life, resulting in pain and stiffness in joints such as the knees, hips, neck and fingers. As the cartilage degrades, the bones rub together, causing pain and limiting mobility. OA affects both men and women, and usually occurs after the age of 45, manifesting initially as general pain and stiffness in the joints. Treatments include medications, education, physical activity or exercise, heat or cold, joint protection, pacing activities, weight loss if overweight, self-care skills and sometimes surgery.

Rheumatoid arthritis (RA) is the other common form of arthritis. It is a chronic autoimmune disease that can impact any joint in the body. RA is found primarily in women, and usually strikes between the ages of 20 and 45. The condition is caused by a malfunctioning immune system that attacks healthy joints, inflames the lining of the joints and leads to cartilage degeneration and joint malformation that primarily affect the hands and feet. RA is a chronic condition and its presence ebbs and flows, which can make it hard to detect.

Other rheumatic conditions include lupus (chronic inflammatory disease that affects the skin, joints, blood and kidneys); gout (causes sudden, severe attacks of pain and tenderness and swelling joints, particularly the big toe); and fibromyalgia (characterized by generalized muscle pain and fatigue).

While there are certain contributing factors to development of arthritisincluding obesity and immune dysfunctionthe primary one is simple age; among adults older than 65, more than half are affected by some type of arthritis. Add to this the aging Baby Boomer population, and its no wonder that incidence of arthritis is on the rise. The Centers for Disease Control and Prevention (CDC) estimates by 2030, 67 million Americans aged 18 or older are projected to have doctor-diagnosed arthritis.

However, this expanded market, coupled with growing consumer awareness of the importance of preventive care and more research into the potential of nutraceutical compounds to address joint health, affords opportunity for marketers of joint health products. A recent report from market research firm Frost & Sullivan, U.S. Bone and Joint Health Ingredients Market, finds the market earned revenues of more than $178.4 million in 2008 and estimates to reach $246.4 million in 2015. There is growing interest in cutting-edge ingredients that can provide product differentiation and enhanced efficacy, although the bulk of attention has remained on established ingredients such as glucosamine, chondroitin sulfate and hyaluronic acid (HA).

One reason for the continued interest in glucosamine and chondroitin is the ongoing media attention on the results of the GAIT (Glucosamine/chondroitin Arthritis Intervention Trial) study. This large-scale, multicenter clinical trial was supported by the National Institutes of Health (NIH) and designed to test the efficacy of glucosamine hydrochloride and chondroitin sulfate in treating knee OA. In the active 24-week intervention portion, researchers from more than a dozen health care facilities across the United States compared the effects of 500 mg/tid glucosamine hydrochloride, 400 mg/tid sodium chondroitin sulfate (supplied by Bioiberica S.A.), both of these treatments administered simultaneously, 200 mg/d celecoxib (a drug used to relieve arthritis symptoms) and placebo, on patients with knee pain (n=1,583). The initial results, published in the New England Journal of Medicine in 2006, found the active glucosamine and chondroitin intervention did not provide significant pain relief in all participants; however, among subjects with moderate-to-severe pain, the combined supplement did have a significant effect.1 Follow-up work from the GAIT trial examined whether the interventions could prevent loss of joint space width (JSW) in patients with knee OA.2 After 24 months, none of the interventions showed a benefit to JSW loss, although there was a trend toward improvement in those subjects with moderate, not severe, knee OA.

The GAIT results added to the existing stable of research findings about glucosamine and chondroitin in treating OA. A 2009 meta-analysis reviewed studies on the effects of the nutraceutical ingredients in addressing JSW in knee OA, reporting long-term (two to three years) daily administration may delay the progression of knee OA, reducing narrowing of JSW.3 Similarly, a team from the World Health Organization (WHO) Collaborating Center for Public Health Aspect of Osteoarticular Disorders, University of Liège, Belgium, noted glucosamine sulfate and chondroitin sulfate may have a structure-modifying effect and exert small-to-moderate symptomatic efficacy.4 That research team further reported consumption of glucosamine sulfate may also prevent the need for knee replacement, with positive results seen even five years after discontinuing intervention.5

More recent studies focused on glucosamines mechanism of action. Spanish researchers investigated the effect of glucosamine sulfate treatment on cartilage capillary permeability (K(trans)) in patients with patella degeneration, and found the glucosamine significantly increased K(trans) after six months, improving pain scores and functional outcomes.6 In vitro work further suggests glucosamine may stimulate synovial production of HA,7 and also exert an antioxidant effect in chondrocytes by impacting genetic expression of inducible nitric oxide synthase (iNOS).8

Chondroitin sulfate has also been explored for its specific impact on OA. An exploratory post hoc analysis of the GAIT results, for example, revealed chondroitin sulfate had a statistically significant effect on joint swelling, particularly in subjects with milder pain.9 And a two-year randomized, double blind, placebo-controlled trial in France found 800 mg/d of chondroitin sulfate significantly reduced JSW loss and improved pain levels.10 Reviews suggest chondroitin sulfate may exert these effects by stimulating extracellular matrix production by chondrocytes, suppressing inflammatory mediators and inhibiting cartilage degeneration.11,12

The third major ingredient mentioned in the Frost & Sullivan report was HA. This compound is an unsulfated glycosaminoglycan with a high-molecular weight; it plays a key component in the extracellular matrix, particularly the synovial fluid, and is an important component in the articular cartilage. Injections of HA are commonly used in addressing knee OA; this viscosupplementation was found in a Cochrane Review to be both safe and efficacious in addressing pain and function.13 However, there is not much published research regarding the efficacy of oral consumption of HA. One pilot clinical trial conducted by Miami Research Associates examined the effect of oral supplementation with a natural extract of chicken combs with a high content of HA (as Hyal-Joint, from Bioiberica) on pain and quality of life in subjects with knee OA (n=20).14 Subjects receiving the active intervention (80 mg/d Hyal-Joint) had a statistically significant reduction in body pain and improvements in quality of life.

Similar results were reported in an eight-week intervention, in which patients with knee OA received placebo or 200 mg/d of high-purity HA (as Hyabest(J), from Q.P. Corp.).15 Western Ontario and McMaster Osteoarthritis Index (WOMAC) data showed a dose-related response in reduction of joint pain and stiffness. In addition, the impact was greater in the subgroup of subjects with moderate- to severe-OA. These findings echoed those in a Japanese trial, in which 240 mg/d of high-purity HA (as Hyabest(J)), taken orally, could reduce joint pain. Researchers suggest Hyabest(J) may work by activating anti-inflammatory cytokines and suppressing inflammatory cytokine activity.

Collagen is another important component of joint cartilage; hydrolyzed collagen, also known as collagen hydrolysate (CH), is produced through hydrolysis of collagen extracted from the bones and skin of animals, reducing the peptides to a smaller molecular weight. Reviews suggest orally administered CH is absorbed in the intestines and accumulates in cartilage, stimulating a statistically significant increase in chondrocyte synthesis of extracellular matrix molecules.16 A recent randomized, placebo-controlled, double blind study found administering 10 g/d of CH to athletes resulted in statistically significant improvements in joint pain, possibly reducing the risk of joint deterioration in a high-risk group.17 And Spanish researchers reported in subjects with primary knee OA, 10 g/d CH for six months significantly improved knee joint comfort and the WOMAC pain subscale, with the greatest improvements seen among the patients with the most joint deterioration.18

There are four main types of collagen in the human body; type II collagen is the main one found in cartilage. Hydrolyzed type II collagen has been studied for its ability to positively impact joint health. An unpublished, pilot clinical trial conducted by Miami Research Associates examined the effect of a patented hydrolyzed type II collagen ingredient (as BioCell Collagen II®, from BioCell Technologies) on 16 adults with knee OA. The intervention reduced pain and improved quality of life parameters. Additional studies have also shown the ability of the ingredient to increase the bodys levels of HA. Its safety was affirmed in acute and subchronic tests, which showed BioCell Collagen II was safe, even at levels well above recommended dosage.19

Diana Naturals supplies ChondrActiv, a patented chicken cartilage extract powder that contains high levels of type II collagen as well as chondroitin sulfate and HA. An unpublished, in vitro bioavailability study found the ingredients bioavailability was approximately three times greater than native cartilage. Positive results were also seen in an unpublished clinical trial, in which 37 adults with joint pain received 1,500 mg/d of ChondrActiv or placebo. Consumption of non-steroidal anti-inflammatory drugs (NSAIDs) decreased by 73 percent in the active intervention group, and there was a three-fold increase in the number of patients perceiving improvements in mobility, compared to the placebo group.

Studies have also looked at the efficacy of an undenatured type II collagen ingredient (as UC-II®, from InterHealth Nutraceuticals). In two canine studies, providing arthritic dogs with UC-II alone or in combination with glucosamine and chondroitin sulfate, significantly reduced pain and lameness, with UC-II alone given for 120 days decreasing overall pain by 62 percent.20,21 Similar results were reported in a study of horses with OA, in which 320 or 480 mg/d of UC-II reduced overall pain by 79 percent and 88 percent, respectively, while increasing mobility and joint flexibility.22

These results have been echoed in clinical trials. A human pilot study found 40 mg/d of UC-II significantly reduced pain, morning stiffness and stiffness following periods of rest.23 A broader double blind study included 52 patients with knee OA, who were randomized to receive 40 mg of UC-II or glucosamine/chondroitin.24 UC-II reduced WOMAC index scores by 33 percent, compared to a 14-percent reduction on the glucosamine/chondroitin. Further, subjects taking UC-II reported significantly reduced pain when walking, climbing stairs or at rest.

Natural Eggshell Membrane (NEM®, from ESM Technologies) is a novel dietary supplement that contains naturally occurring glycosaminoglycans and proteins essential to maintain healthy joints and connective tissues. Two single-center, open-label pilot clinical studies were conducted to evaluate the safety and efficacy of NEM as a treatment for pain and inflexibility associated with joint and connective tissue disorders.25 Patients received oral NEM 500 mg/d for four weeks, with general pain as primary outcome; the single-arm pilot trial also examined range of motion (ROM). In the single-arm and double-arm trials, supplementation significantly reduced pain measures at seven days and 30 days. Intervention also increased flexibility and reduced ROM-associated pain. These positive results were echoed in a follow-up, randomized, multicenter, double blind, placebo-controlled study.26 Supplementation with 500 mg/d of NEM for eight weeks produced a statistically significant reduction in pain and stiffness and trended toward improvement for function and WOMAC scores.

Another ingredient commonly found in combination with glucosamine and chondroitin is methylsulfonylmethane (MSM), an organic sulfur-containing compound that appears to exert anti-inflammatory and antioxidant effects in the body.27 A systematic review out of the University of Southampton, England, examined six trialstwo for MSM and four for the related compound dimethyl sulfoxide (DMSO)and found the MSM trials and two DMSO trials reported significant improvements in pain outcomes in OA patients.28 They concluded the data from the more rigorous MSM trials provided positive evidence regarding MSMs ability to treat mild to moderate knee OA. One such trial found 3 g tid of MSM produced significant decreases in WOMAC pain and physical function impairment in adults with knee OA.29

A recently completed, unpublished clinical trial found MSM (as ActivMSM, from TandemRain Innovations) was rapidly absorbed, modified sulfur metabolism and was retained in the body for an extended period of time. The study, conducted by Miami Research Associates, examined the absorption and excretion of MSM, and impact on sulfate and homocysteine metabolism, following a single dose of 1, 2 or 3 g. The 3 g dose peaked MSM levels in the blood within 90 minutes; MSM blood concentrations remained higher than baseline for up to one week.

Keratin may also modify sulfur metabolism in the body. The protein serves an important structural role in the body and has one of the highest proportions of the amino acid cysteine, a natural sulfur reservoir. Keratec developed a patented process to enable the intact keratin molecule to be solubilized; the branded ingredient Cynatine FLX is a functional keratin with a four-fold mechanism supporting joint health. According to the company, its research shows Cynatine FLX increases sulfated joint polymers, increases the bodys anti-inflammatory action, increases endogenous levels of glutathione peroxidase and superoxide dismutase (SOD), and protects against free radical damage. Specifically, the active cysteine in the compound appears to stimulate proteoglycan synthesis to prevent joint breakdown and build joint polymers.

A proprietary blend of cetylated fatty acids (as Celadrin®, from Pharmachem Laboratories), as oral supplements or topical creams, may also support joint health. In an initial study, 40 patients with knee OA used a Celadrin cream or placebo for 30 days; assessments included range of motion, up-and-go from a chair and stair climbing.30 Significant decreases in time were seen at 30 minutes after initial treatment and at studys end for stair climbing and up-and-go. The cream also improved knee range of motion and balance. These findings were confirmed in a second study involving 28 individuals with knee, elbow or wrist OA.31 Use of a topical cream containing Celadrin and menthol, applied twice daily for one week, improved stair climbing and up-and-go ability, and significantly reduced pain.

Studies on oral administration of Celadrin have also reported positive results. A study conducted in 64 patients with chronic knee OA who took Celadrin (350 mg/d) for 68 days showed significant increases in knee flexion and a shift toward functional improvement.32 In a 2007 unpublished, randomized study, 93 participants experiencing knee pain were given 894 mg/d of Celadrin in a crossover, washout study. Participants who at baseline walked an average distance of 1,183 feet walked an average distance of 1,720 feet after interventionan increase of 45 percent from two months earlier.

Studies have also examined the impact of a cetylated fatty acid-creatine compound (as Kre-Celazine®, from All American Pharmaceuticals) in joint health. One recent clinical trial determined the ability of the compound to reduce site-specific chronic joint and muscle-related inflammation and pain.33 Researchers randomized 35 subjects to receive placebo or test compound for 30 days. At studys end, the subjects receiving the active intervention reported improvements in ankle/foot pain (100 percent response), neck/shoulder/elbow/wrist/hand pain (85 percent) and knee pain (71 percent). Members in this group also experienced a modest increase in mobility. The compound appeared most effective at reducing inflammation/pain in extremities, as well as the neck and shoulder region.

Follow-up work has yielded similarly positive results. An unpublished trial conducted by BioCeutical Research & Development Laboratory, Billings, MT, examined the short-term benefits and side effects of an oral dose and topical application of Kre-Celazine in subjects with OA or joint pain/inflammation. At the studys conclusion, all subjects reported some to significant benefit from taking the test product, with no side effects. Intervention also increased mobility, daily routines and energy levels. Another unpublished trial conducted by the same team reported oral administration of buffered creatine (as Kre-Alkalyn®, from All American Pharmaceuticals) by professional football players decreased joint pain due to inflammation and direct bruising, while increasing endurance and stamina. Additionally, acute oral toxicity studies in animals support the safety of Kre-Celazine.

Essential fatty acids (EFAs), particularly the omega-3s, appear to exert beneficial anti-inflammatory effects. A meta-analysis out of York University, Toronto, examined the effects of omega-3 EFAs in patients with RA and other inflammatory conditions.34 Supplementation for three to four months reduced joint pain intensity, number of painful and/or tender joints and NSAID consumption. Omega-3s, particularly eicosapentaenoic acid (EPA), may inhibit the formation of inflammatory cytokines and degrading enzymes, including cycloxygenase-2 (COX-2), possibly by balancing the bodys ratio of omega-3s to pro-inflammatory arachidonic acid.35

A clinical study in patients suffering from akylosing spondolitis, a chronic rheumatic disease mainly affecting the joints of the spine, found providing 4.5 g/d of omega-3 (as EPAX 5500 TG, from EPAX), delivering 55 percent EPA and docosahexaenoic acid (DHA), significantly reduced disease activity and relieved symptoms.36

Another source of beneficial fatty acids, krill oil, was studied in a Canadian trial, in which 90 subjects with confirmed cardiovascular disease (CVD) and/or RA and/or OA, and with increased CRP levels, received placebo or 300 mg/d of krill oil (as Neptune Krill Oil, NKO, from Neptune Technologies & Bioressources).37 NKO intervention reduced CRP levels by 19.3 percent after only seven days; after 14 and 30 days, NKO treatment further decreased CRP by 29.7 percent and 30.9 percent, while CRP levels in the placebo group rose over time. NKO intervention also reduced pain scores by 28.9 percent, reduced stiffness by 20.3 percent and reduced functional impairment by 22.8 percent, all within the first week of treatment.

Also from the sea comes greenlipped mussel extract (GLE), produced from mussels (Perna canaliculus) harvested off the coasts of New Zealand. It contains novel omega-3 fatty acids, including EPA and DHA, glycosaminoglycans and phosphorylated glycogen, which act to combat inflammation.38 A meta-analysis out of the University of Southampton, England, included four randomized clinical trials, in which GLE was assessed as an adjunct treatment to conventional medical in patients with mild-to-moderate OA, and found all trials reported clinical benefits, although the research team suggested further studies are necessary to assess efficacy and optimal dosage.39 Animal trials further support the ability of GLE (as Lyprinol) to decrease the production of inflammatory cytokines,40 and improve mobility and clinical signs of degenerative joint disease.41

Waitaki Biosciences developed its Pernatec stabilized GLE ingredient with the addition of a special antioxidant blend to fight oxidative degradation.

Seaweed also yields beneficial compounds for the body. A natural, multi-mineral supplement from seaweed (as Aquamin, supplied in the United States by GTC Nutrition) has been tested for its ability to relieve joint pain and stiffness. In one trial, subjects (n=70) with moderate to severe knee OA were randomized to four double blinded treatments for 12 weeks: 1,500 mg/d of glucosamine sulfate; 2,400 mg/d of Aquamin; combination of glucosamine and Aquamin; or placebo.42 There were significant differences between the groups for changes in WOMAC pain scores over time, with the Aquamin and glucosamine interventions positively impacting pain and stiffness scores; the combination did not appear to influence WOMAC measurements. A second trial included 29 adults with moderate to severe knee OA who received 2,400 mg/d of  Aquamin or placebo for 12 weeks.43 Intervention did significantly improve passive and active extension ROM, and subjects taking Aquamin reduced their usage of NSAIDs.

Botanicals from the land yield a number of active ingredients with the ability to address inflammation. Curcumin, from turmeric (Curcuma longa), has been high profile in the nutraceutical market of late, and new in vitro and clinical work is focusing on its application in the joint health area. An in vitro trial from the University of Nottingham, England, used normal articular cartilage from horses to establish an explants model mimicking OA inflammation.44 After stimulation with proinflammatory cytokines to induce cartilage degradation, some explants were treated with curcumin at varying levels; adding curcumin at 100 micromol/L significantly reduced release of inflammatory cytokines. Further in vitro trials have found curcumin can inhibit the production of inflammatory and catabolic mediators by chondrocytes,45 and suppress NF-kappaB-mediated inflammatory signaling pathways in chondrocytes.46

A recent trial at Mahidol University, Bangkok, involved 107 patients with knee OA who were randomized to receive 800 mg/d of ibuprofen or 2 g/d of curcumin extract for six weeks.47 Mean scores for knee function and pain levels were reduced similarly in both groups, with no significant difference of adverse events (33 percent in curcumin, 44 percent in ibuprofen). In another 32-week randomized controlled trial, researchers provided subjects with knee OA (n=90) with placebo or an Ayurvedic combination product, RA-11, containing C. longa, Withania somnifera, Zingiber officinale and Boswellia serrata.48 Active intervention significantly reduced pain at 16 and 32 weeks, and improved WOMAC scores at the same time points.

On its own, boswellia has been shown to exert anti-inflammatory actions, primarily by inhibiting 5-lipoxygenase (5-LOX), but also by affecting TNF-alpha and interleukin activity.49 Animal and human trials have shown the ability of boswellia extract to reduce lameness and joint pain;50,51 however, researchers noted the use of a standardized preparation would be best to ensure quality and stability of the extract.

In fact, there have been several positive studies conducted using a standardized boswellia extract (as 5-Loxin®, from PL Thomas). An in vitro study conducted at The Ohio State University Medical Center, Columbus, examined the genetic and anti-inflammatory effects of 5-Loxin, and found it could prevent TNF-alpha-induced expression of matrix metalloproteinase-3 (MMP-3) and inducible expression of apoptosis mediators.52 In a follow-up study, the team examined the effect of different percentages of acetyl-11-keto-beta-boswellic acid (AKBA), one of the active principles in boswellia, on inflammatory markers.53 In vitro and in vivo, the extract with 30 percent AKBA was significantly more effective than a 3-percent level. Additional research has supported the broad spectrum safety of 5-Loxin, showing no adverse effects in acute oral and dermal studies, as well as subchronic toxicity studies.54

These results were validated in a 90-day, double blind, randomized, placebo-controlled study, in which 75 OA patients received 100 mg or 250 mg of 5-Loxin daily, or a placebo.55 Patients were evaluated on the WOMAC and Lequesnes Functional Index, and the synovial fluid was evaluated for levels of MMP-3. Both doses of 5-Loxin yielded clinically and statistically significant improvements in pain scores and physical function scores; subjects in the 250 mg/d group showed significant improvements after seven days. Additionally, intervention significantly reduced MMP-3 levels in synovial fluid.

Also in the botanical arena is devils claw (Harpagophytum procumbens), which contains certain iridoid glycosides that appear to exert analgesic and anti-inflammatory effects. A monograph published in Alternative Medicine Review noted studies have shown harpagoside may inhibit COX-2 expression and the release of other inflammatory mediators, and also inhibit certain compounds liked to cartilage degradation.56 A standardized devils claw extract (from Bioforce) was shown in an eight-week open study to significantly improve quality of life, global pain measures and mean pain scores.57 Further, clinical trials in patients with knee and hip OA suggest a specialized extract of devils claw (as Doloteffin®, from Ardeypharm GmbH) can significantly reduce pain indices.58,59

Pain relief is also a major effect exerted by decursinol, a coumarin compound isolated from the roots of Angelica gigas Nakai, also known as Korean angelica. It appears to exert analgesic effects, while also affecting the release of inflammatory cytokines. A series of animal experiments found a methanolic extract of decursinol (as Decursinol-50, from JLM Industries) enhanced the latency of the pain response.60 The response was dose-dependent, starting at an oral dose of 100 mg/kg body weight. Further, decursinol attenuated production of inflammatory cytokines TNF-alpha and IFN-gamma, while also diminishing pain sensation in treated mice.61 In vitro research suggests the decursinol may suppress the induction of MMP-9 by macrophages in a dose-dependent manner, and also suppress production of certain cytokines and inflammatory markers.62 An unpublished clinical trial conducted in South Korea on adults with chronic pain (n=40) reported 500 mg/d of decursinol (as Decursinol-50) reduced average pain scores by an average of 68 percent after two weeks.

An extract of hops (Humulus lupulus L.) may also aid in controlling inflammation. Its alpha and beta acids (humulone and lupulone) have the ability to inhibit pro-inflammatory PGE2, according to unpublished research supplied by Pharmachem Laboratories. Follow-up work using a proprietary hops extract (as Perluxan, from Pharmachem Laboratories) found human oral consumption of the extract inhibited inflammation via the COX-2 pathway, with a nine-hour potency comparable to a 400-mg dose of ibuprofen and more favorable selectivity.

French maritime pine bark extract exerts beneficial antioxidant effects that benefit the body in many ways; however, it also appears the botanical extract can specifically address joint dysfunction. In a study out of Iran, researchers enrolled 37 OA patients to receive either placebo or pine bark extract (as Pycnogenol®, supplied in the United States by Natural Health Science) in a blinded fashion for three months.63 OA symptoms were evaluated on the WOMAC Index, and usage of NSAIDs and COX-2 inhibitors was assessed. After 90 days, subjects taking Pycnogenol reported significant reductions in pain, stiffness and physical function, and their WOMAC score was also decreased. Also, dosage and frequency of NSAIDs and COX-2 inhibitors was increased in the placebo group, and dropped in the active intervention. Similar findings were published by Slovakian researchers, who found 150 mg/d of Pycnogenol given to patients with knee OA for three months could improve the WOMAC index and significantly alleviate pain.64

Positive results were also reported by an Italian team, which evaluated the impact of 100 mg/d of Pycnogenol given to OA patients for three months.65 Subjects in the treatment group (n=77) halved their global WOMAC score, and significantly increased walking distance in a treadmill test; intervention also reduced food edema, gastrointestinal complications and usage of OA drugs. A follow-up trial in a subset of OA patients with elevated CRP and plasma free radicals found Pycnogenol treatment netted a statistically significant reduction in levels of CRP and fibrinogen; the researchers concluded Pycnogenol exerts systemic anti-inflammatory effects.66

Citrofen® is a proprietary blend from Next Pharmaceuticals that includes bark of Phellodendron amurense and a patented (U.S. Patent No. 6,184,246) formulation of polymethoxylated flavones extracted from Citrus sinenis. Its effects were tested in an eight-week, placebo-controlled, double blind study comparing Citrofen to placebo in overweight and normal weight subjects (n=80) with knee OA.67 Intervention reduced CRP levels and significantly improved LAI (Lequesne Algofunction Index) scores; subjects taking Citrofen also showed statistically significant weight loss.

There are other specialty ingredients that may benefit joint health. Humanetics branded ingredient MicroLactin® is composed of milk protein concentrate (MPC), comprising unique antibodies and other bioactive nutrients. Two published clinical trials support the efficacy and safety of MicroLactin in addressing joint pain and stiffness and improving mobility in OA patients. In a six-week, randomized, double blind, placebo-controlled trial, participants (n=42) received placebo, 500 mg tid of glucosamine sulfate or 2,000 mg BID milk protein concentrate (as MicroLactin).68 The results showed significant improvement from baseline to studys end for the MPC-treated group for pain, stiffness, activities and total WOMAC index scores. Similar results were reported in a six-week, double blind, placebo-controlled study involving subjects (n=31) with OA in both knees.69 Active intervention included 12 oz./d of a beverage containing MPC (as MicroLactin) or placebo. All KOOS (Knee Injury and Osteoarthritis Outcome Score) scores improved significantly over time in the MPC group, as did overall treatment effect, based on changes in the WOMAC composite score.

BIO SERAE also developed a natural ingredient from bio-active milk proteins, Osteol, to preserve chondrocytes, exert an anti-inflammatory effect and reduce cartilage degeneration. Unpublished research conducted by BIO SERAE found adding Osteol to a glucosamine/chondroitin formula significantly increased chondrocyte protection against inflammatory markers in vitro and boosted the combinations anti-inflammatory effects in animals. The company also reported in vitro studies found Osteol could significantly increase the expression of genes involved in cartilage preservation, and reduce the expression of MMP. Further, an unpublished clinical trial in 57 subjects with knee OA found providing a mix of glucosamine, chondroitin and Osteol for three months could significantly reduce pain sensations.

Finally, systemic enzymes also show possible efficacy in treating arthritic conditions, working actively within the body to break down proteases that can impact rheumatic pathology.70 An open study conducted in Pakistan investigated the efficacy and safety of a combination of rutosid, bromelain and trypsin in patients with knee OA (n=103).71 Enzyme therapy improved functionality and decreased pain at rest and on motion. German researchers also found a specialty enzyme therapy (Phlogenzym) decreased pain and stiffness measures in patients with hip OA with a high-pain level.72 Similar results were reported in a study from India using Phlogenzym, in which patients with knee OA had reduced pain and joint tenderness and swelling after taking the enzyme therapy for three weeks.73

With formulations incorporating synergistic nutraceutical ingredients for joint health, marketers can truly deliver consumers joint health products to take them over the rainbow.


References on the next page...


"Nutraceuticals for Joint Health" References

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3. Lee YH et al. Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis. Rheumatol Int. 2009 Jun 21. [Epub ahead of print]

4. Bruyere O, Reginster JY. Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis. Drugs Aging. 2007;24(7):573-80.

5. Bruyere O et al. Total joint replacement after glucosamine sulphate treatment in knee osteoarthritis: results of a mean 8-year observation of patients from two previous 3-year, randomised, placebo-controlled trials. Osteoarthritis Cartilage. 2008 Feb;16(2):254-60. Epub 2007 Jul 27.

6. Martí-Bonmatí L et al. Glucosamine sulfate effect on the degenerated patellar cartilage: preliminary findings by pharmacokinetic magnetic resonance modeling. Eur Radiol. 2009 Jun;19(6):1512-8. Epub 2009 Feb 13.

7. Uitterlinden EJ et al. Glucosamine increases hyaluronic acid production in human osteoarthritic synovium explants. BMC Musculoskelet Disord. 2008 Sep 11;9:120.

8. Valvason C et al. Influence of glucosamine sulphate on oxidative stress in human osteoarthritic chondrocytes: effects on HO-1, p22(Phox) and iNOS expression. Rheumatology (Oxford). 2008 Jan;47(1):31-5.

9. Hochberg MC, Clegg DO. Potential effects of chondroitin sulfate on joint swelling: a GAIT report. Osteoarthritis Cartilage. 2008;16 Suppl 3:S22-4. Epub 2008 Sep 2.

10. Kahan A et al. Long-term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: the study on osteoarthritis progression prevention, a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2009 Feb;60(2):524-33.

11. Kubo M et al. Chondroitin sulfate for the treatment of hip and knee osteoarthritis: current status and future trends. Life Sci. 2009 Sep 23;85(13-14):477-83. Epub 2009 Aug 18.

12. Uebelhart D. Clinical review of chondroitin sulfate in osteoarthritis. Osteoarthritis Cartilage. 2008;16 Suppl 3:S19-21. Epub 2008 Jul 31.

13. Bellamy N et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD005321.

14. Kalman DS et al. Effect of a natural extract of chicken combs with a high content of hyaluronic acid (Hyal-Joint) on pain relief and quality of life in subjects with knee osteoarthritis: a pilot randomized double-blind placebo-controlled trial. Nutr J. 2008 Jan 21;7:3.

15. Sato T, Iwaso H. An effectiveness study of hyaluronic acid [Hyabest®(J)] in the treatment of osteoarthritis of the knee on the patients in the United States. J New Rem Clin. 2009;58(3).

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17. Clark KL et al. 24-Week study on the use of collagen hydrolysate as a dietary supplement in athletes with activity-related joint pain. Curr Med Res Opin. 2008 May;24(5):1485-96. Epub 2008 Apr 15.

18. Benito-Ruiz P et al. A randomized controlled trial on the efficacy and safety of a food ingredient, collagen hydrolysate, for improving joint comfort. Int J Food Sci Nutr. 2009;60 Suppl 2:99-113. Epub 2009 Feb 11.

19. Schauss AG et al. Acute and subchronic oral toxicity studies in rats of a hydrolyzed chicken sternal collagen preparation. Food Chem Toxicol. 2007;45(2):315-21.

20. Deparle LA et al. Efficacy and safety of glycosylated undenatured type-II collagen (UC-II) in therapy of arthritic dogs. J Vet Pharmacol Therap. 2005;28:385-90.

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About the Author(s)

Heather Granato

vice president, content, Informa Markets, Food EMEA division

Heather Granato is a 25-year veteran of the natural products industry, currently serving as the Vice President, Content, in Informa Exhibitions’ Global Health & Nutrition Network. She has been a presenter at events including SupplySide, Vitafoods, Natural Products Expo, the Natural Gourmet Show and the Folio: Show. Her publishing experience includes Natural Products INSIDER, Food Product Design, Country Living's Healthy Living, Natural Foods Merchandiser, Delicious Magazine and WomenOf.com. She was named a 2015 Top Woman in Media by Folio:; received the 2014 Visionary Award from the American Herbal Products Association (AHPA); and was awarded the CEO Merit Award for Content from Informa in 2014. Granato graduated magna cum laude from the University of Richmond, Virginia, in 1992 with a bachelor’s degree in journalism; she currently serves as a national vice president for Kappa Alpha Theta women's fraternity.

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