Supplying Cartilage Components
Big Fat Deal
Those aches and pains of aging, now the subject of television commercials and major pharmaceutical clinical trials, have always vexed humans. While the term arthritis is taken from the Greek, “arthro” meaning joint and “itis” for inflammation, its incidence dates back as far as 4500 BC. It can be seen in skeletal remains of Native Americans, mummies from Egypt, and the Iceman mummy Otzi, found along the border of modern Italy and Austria.
What these early ancestors share with today’s sufferers is the degeneration of the joints, points between the bones that are designed to provide shock absorption from movement. Cartilage is the primary joint tissue, produced by chondrocytes; the joints also contain a lubricant known as synovial fluid, which contains hyaluronic acid and glycoproteins to deliver nutrients to the cartilage.
Arthritis comprises more than 100 different diseases and conditions, affecting approximately 46 million U.S. adults. It is the most frequent cause of disability in the United States, limiting the activities of nearly 19 million adults, according to the Centers for Disease Control and Prevention (CDC). A study released in October 2007 by CDC reported work limitations due to arthritis in working-age adults range from 3.4 percent in Hawaii to a high of 15 percent in Kentucky, where more than 50 percent of adults with arthritis reported their condition was severe enough to limit their ability to work.
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. Osteoarthritis 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.
Fortunately, there are positive nutritional interventions and dietary considerations that can support the health of the joints, and even slow disease progression. As with many other degenerative conditions, oxidative stress appears to play a role. Patients with osteoarthritis have higher activity of antioxidant enzymes in response to increased oxidative stress,1 and such oxidative stress appears to be related to decreased collagen metabolism.2 In vitro work out of Marianna University, Kawasaki City, Japan, assessed oxidative damage and antioxidative capacity in osteoarthritis human cartilage, reporting presence of oxidative stress induced genomic instability and dysfunction of the chondrocytes.3 Similarly, a research team from the University of Iowa, Iowa City, exposed cartilage explants from human articular cartilage to stress compression, finding 30 percent of chondrocytes in the superficial zone died within 24 hours of exposure to the compression.4 In addition, preincubation of the explants to antioxidants such as superoxide dismutase (SOD), vitamin E and n-acetyl cysteine (NAC) blocked approximately 80 percent of such cell death, suggesting minimizing oxidative damage to chondrocytes could help prevent osteo arthritis progression.
However, researchers are not convinced antioxidants may be able to prevent disease progression. A review out of the University of Liege, Belgium, noted cartilage degradation does result from stress and free radical activity, which may be balanced by antioxidants; but, they found no consistent evidence that supplying additional antioxidants could relieve osteo arthritis symptoms or prevent structural changes to cartilage.5 Similarly, researchers from the Universities of Exeter and Plymouth recently released a systematic review of randomized clinical trials (RCTs) on the effectiveness of vitamins A, C and E or selenium, or a combination, in treating arthritis.6 They identified 20 studies, which they said were generally of poor quality, and concluded there was no convincing evidence of the efficacy of the antioxidants in treating any type of arthritis.
Their findings were in contrast to those from the University of Liverpool, England, which noted cartilage is critically dependent on a range of nutrients, including the antioxidant vitamin C and mineral co-factors, suggesting supplementation may benefit patients with joint disorders.7 In fact, a study out of Monash University, Melbourne, Australia, examined the intake of antioxidant vitamins among a cohort of 293 adults without knee osteo arthritis, who were followed for 10 years.8 Higher vitamin C intake was associated with a reduced risk of bone marrow lesions, which are linked to knee osteo arthritis pathogenesis, while lutein and zeaxanthin intake was associated with a decreased risk of cartilage defects. Similar findings were reported by researchers from the University of Manchester, England, in an eight-year dietary cohort, case-control study, in which adults with inflammatory polyarthritis (IP) consumed less fruit and vitamin C than matched controls; those in the lowest category of vitamin C intake, compared with the highest, had more than a three-fold risk of developing IP.9
The antioxidant alpha-lipoic acid may also play a role. Researchers from the University of Ulsan, Seoul, Korea, examined the ability of alpha-lipoic acid to attenuate the development of collagen-induced arthritis in mice, reporting the antioxidant was associated with a dosedependent reduction of arthritis, as well as preventing destructive changes; concurrent in vitro work found the compound could inhibit osteoclastogenesis.10 Turkish researchers reported similar findings in a rat arthritis model, with alpha-lipoic acid showing protective effects against oxidative damage.11
Supplying Cartilage Components
While antioxidants and basic nutrients support the body’s well-being, a great deal of research in the area of dietary supplements for joint health has revolved around providing compounds that are already found in the joints. The best-known of these would be glucosamine and chondroitin.
Glucosamine is a glucose derivative that naturally occurs in connective and cartilage tissues. It is a precursor of antioxidant-like glycosaminoglycan (GAG) and proteoglycans found in the body. Studies have shown glucosamine may affect subchondral bone turnover, structure and mineralization;12 inhibit COX-2 and inducible nitric oxide synthase (iNOS) activity;13,14 and decrease collagen degradation by inhibiting advanced lipoxidation reactions, thereby protecting the chondrocyte matrix.15 Such effects, coupled with clinical trials, have led researchers to conclude glucosamine may have positive effects on osteo arthritis symptoms and disease progression.16
However, there is not universal agreement, particularly after the high-profile release of results of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), a $12.5 million, multicenter clinical trial, supported by the National Institutes of Health (NIH).17 In the double blind GAIT study, 1,583 patients were divided into five treatment groups and given either: glucosamine alone, chondroitin sulfate alone, the two supplements in combination, celecoxib, a prescription drug to treat osteo arthritis pain, or placebo. The patients were monitored over 24 weeks and were separated into two pain subgroups—those with mild pain (78 percent) and those with moderate-to-severe pain (22 percent). The study’s primary outcome was defined as at least a 20-percent reduction in pain at 24 weeks.
At the study’s end, the study concluded glucosamine and chondroitin taken alone or in combination did not effectively reduce knee pain in osteo arthritis patients with mild pain. However, the researchers, led by Daniel O. Clegg, M.D., from the University of Utah, Salt Lake City, did find a significantly higher response rate to the nutrient combination in patients with moderate-to-severe pain at baseline, aiding almost 80 percent of study participants; the abstract further noted all treatments were well tolerated.
The GAIT trial was also the primary piece of evidence considered by reviewers from the U.S. Agency for Healthcare Research and Quality (AHRQ), which concluded there is no demonstrable clinical benefit to the use of oral glucosamine/chondroitin for knee osteo arthritis.18 They did note six study-level meta-analyses found statistically significant differences between treatment and placebo, but suggested more trials are necessary.
Such trials are underway, and have their own positive findings to build on. The Europeansponsored Glucosamine Unum In Die Efficacy (GUIDE) trial compared the effect of 1,500 mg/d glucosamine sulfate, 3,000 mg/d acetaminophen and placebo on various osteoarthritis pain and mobility indices in 318 osteo arthritis patients (88 percent women) over 24 weeks.19 Ibuprofen (400 mg/d) was permitted as a rescue medication. Glucosamine sulfate was efficacious in reducing scores on various osteo arthritis symptom indices. There were no differences in safety among treatments. The researchers concluded 1,500 mg/d glucosamine sulfate might be the preferred symptomatic medication in knee osteo arthritis. Similarly, researchers out of Poland reported 12 weeks of supplementation with glucosamine sulfate (500 mg tid) improved functional status and pain in patients with knee or hip osteo arthritis.20
There has been some recent controversy about whether glucosamine may impact insulin resistance in diabetics or overweight patients.21 While the majority of studies suggest no impact on glucose or insulin in healthy osteo arthritis patients,22 there is a possibility glucosamine could affect glucose uptake in patients with untreated diabetes,23 making it important that consumers talk with their health care providers about the use of dietary supplements for different health conditions.
Glucosamine is often paired with chondroitin, the most prevalent GAG found in joint cartilage, and research has shown the supplement might have long-term benefit to the symptoms and progression of osteo arthritis. Studies suggest it may reduce the activity and production of matrix metalloproteinases (MMPs), which play a key role in degradation of cartilage matrix.24 Russian researchers reported intervention with chondroitin sulfate in patients with hip osteo arthritis could protect cartilage, slow disease progression and aid in pain management.25
Pain management was also the primary efficacy criteria in a 24-week, randomized, placebocontrolled study conducted at Rangueil University Hospital, Toulouse, France, in which patients with knee osteo arthritis (n=307) received 1 g/d chondroitin sulfate for six months.26 While there was no significant difference in biomarkers between the groups, chondroitin was slightly more effective for pain management and quality of life scores. Another group of French researchers divided a crosssectional observational study, which found long-term users of chondroitin sulfate had a significantly lower current and long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics.27
Despite these findings, in early 2007, a meta-analysis concluded chondroitin supplementation has minimal to no effect on osteo arthritis.28 The authors narrowed the list of randomized or quasi-randomized controlled trials on chondroitin and osteo arthritis pain to 20 trials, involving a total of 3,846 patients. The smaller trials not employing an intent-to-treat protocol showed greater benefits from chondroitin than did the other trials reviewed. When the researchers narrowed the review to three large-scale trials—representing only 40 percent of the patients—they found symptomatic benefit of chondroitin was minimal or nonexistent, and concluded the use of chondroitin in routine clinical practice should be discouraged. Industry members took issue with the reviewers basing their decision on three trials, excluding 17 other trials selected and ignoring approximately 300 scientific reports on chondroitin. There was also a concern that the reviewers made no distinction between mild, moderate and severe osteo arthritis.
In fact, a 2007 risk assessment on the use of glucosamine and chondroitin sulfate noted: “A large body of human and animal research suggests that oral intakes of these ingredients, either alone or in combination, reduces joint pain and improves mobility in persons with osteoarthritis. ... The observed safe level (OSL) risk assessment method indicates that the evidence strongly supports safety at intakes up to 2,000 mg/d for glucosamine and 1,200 mg/d for chondroitin sulfate.”29
The organic compound MSM (methylsulfonylmethane) supplies the body with natural sulfur, which plays a major role in cartilage formation, and has been shown to have anti-inflammatory and antioxidant mechanisms.30 MSM (as OptiMSM®, from Bergstrom Nutrition) modified immune responses in mice that were induced with arthritis, diminishing the arthritic deformation and swelling induced by type II collagen injections.31 Animal trials have also confirmed the efficacy of MSM (as OptiMSM) in suppressing UV-induced skin inflammation and swelling reactions, suggesting it has anti-inflammatory activities and mitigates immune reactions that can contribute to inflammation.32
There have been a few clinical trials as well. An unpublished, double blind study using OptiMSM found patients with degenerative arthritis taking 750 mg/d showed an 80 percent improvement after six weeks. Follow-up work in a 12-week pilot clinical study found adults with mild to moderate knee osteo arthritis who took 3 g twice daily of MSM (as OptiMSM) had statistically significant reductions in pain and in difficulty performing activities of daily living.33 And research out of Nizam’s Institute of Medical Sciences, H yderabad, India, found combining 500 mg of MSM tid and 500 mg glucosamine tid for 12 weeks provided a significantly greater decrease in joint swelling and pain intensity among patients with mild to moderate osteo arthritis than either therapy alone; both MSM and glucosamine alone had greater effects than placebo.34
Hyaluronic acid (HA) plays a large part in synovial fluid where it is responsible for the fluid’s viscous and elastic properties, which are essential for healthy joint function. The majority of studies have examined intra-articular injections of HA; however, Fenchem Enterprises was set to present information at SupplySide West in November 2007 on a study conducted by Luke R. Bucci, Ph.D., vice president of research at Schiff Nutrition, examining the absorption and uptake of oral high-molecular weight hyaluronan.
Polish researchers reported in vitro, HA exerts a protective effect against interleukin-1-induced inhibition of collagen biosynthesis.35 A review from the Orthopedic Specialists of Louisiana, Shreveport, noted intra-articular HA viscosupplementation does appear to improve joint function and help relieve osteo arthritis-related pain.36 Further, it added, reduction of NSAID medication use and delayed need for surgical intervention could also mean total cost savings through the use of HA viscosupplementation. Similarly, Canadian researchers reported intraarticular HA injections can improve resting and walking pain in knee osteo arthritis patients, with symptom control lasting approximately six months.37 And the AHRQ review released in September 2007 stated results from 42 trials (n=5,843) generally showed positive effects on pain and function scores with HA viscosupplementation; however, it qualified the outcome, stating there is considerable uncertainty due to trial quality, publication bias and unclear clinical significance.38
HA is a component of collagen in the joints and in type II collagen or collagen hydrolysate supplements. Cartilage is also an important factor in the protection of joints, and one of its key components is collagen. Chicken collagen is a popular material because it provides chondroitin, HA and type II collagen, which is a rope-shaped, fiber-like protein that gives cartilage its structural strength. Researchers from the University of Illinois College of Medicine at Chicago reviewed medical literature on collagen hydrolysate, and found orally administered collagen hydrolysate is absorbed and accumulates in cartilage.39 Further, it appears to stimulate a significant increase in synthesis of extracellular matrix molecules by chondrocytes.
BioCell Collagen II®, from BioCell Technologies, is 70-percent collagen hydrolysate, 20-percent chondroitin sulfate and 10-percent HA. Collagen hydrolysate has been shown to protect against articular cartilage degradation and boost collagen synthesis,40 as well as alleviate pain in osteo arthritis of the knee and hip.41 In other research, a 1,000 mg/d dose of BioCell Collagen II proved safe and effective in decreasing joint pain and stiffness in patients with osteo arthritis of the knees, hips or hands.42
InterHealth’s UC-II®, derived from chicken sternum cartilage, consists of undenatured (native) type II collagen that works with the immune system to promote healthy joints and increase joint mobility and flexibility. A study presented in mid-October 2007 examined the impact of UC-II on arthritis in horses.43 There was a significant doserelated response, with the horses receiving 80, 120 and 160 mg/d UCII showing significant and marked improvement in arthritic signs, including overall pain, pain upon limb manipulation and pain after physical exertion. These findings support those found in a study presented in early 2007 in which horses receiving 320 or 480 mg/d had significant reductions in pain.44 The 320 mg/d group had a 79 percent reduction in overall pain, while the horses receiving 480 mg/d had an 88 percent reduction in overall pain.
Previous work in arthritic dogs has netted similar results. Supplementation for 120 days with 10 mg/d alone or with glucosamine and chondroitin decreased overall pain by 62 percent or 57 percent, respectively, in a group of arthritic dogs.45 And providing 10 mg/d of UC-II to a group of overweight arthritic dogs reduced lameness and pain after physical activity; the dogs also lost weight as a result of becoming more physically active.46 Preliminary human studies have also shown promise. A pilot clinical study in five older women with RA suffering significant joint pain were given 10 mg/d of UC-II for 42 days; supplementation reduced pain and morning stiffness and improved joint flexibility.47
Big Fat Deal
Increasing the intake of beneficial fats may also support joint health, as essential fatty acids (EFAs) impact production of inflammatory prostaglandins (PGs) and cytokines. A review from the Center for Genetics, Nutrition and Health, Washington, D.C., noted the omega-3 polyunsaturated fatty acids (n-3 PUFA) possess immunomodulatory and anti-inflammatory activities, with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) helping modulate the types of eicosanoids made, preferentially making anti-inflammatory PGs and cytokines.48 Further, n-3 PUFAs reduce the release of proteoglycan metabolites from articular cartilage and abolish expression of mRNA for COX-2, 5-lipoxygenase and tumor necrosis factor-alpha (TNFalpha), among other inflammatory mediators.49
Researchers from Mahidol University, Bangkok, Thailand, investigated the effects of diets low in n-6 and n-3 EFAs on proinflammatory cytokines among RA patients (n=60).50 Those on the diet who also received n-3 PUFA fish oil supplement had significant reductions in linoleic acid, C-reactive protein (CRP), TNF-alpha and TNF-receptor p55, as well as elevated EPA and DHA plasma levels.
One specialty source of n-3 EFAs is Neptune Krill Oil™ from Neptune Technologies & Bioressources Inc., which can inhibit inflammation and reduce arthritic symptoms within a short treatment period, according to a 2007 study published in the Journal of the American College of Nutrition.51 The randomized, double blind, placebo-controlled study included 90 patients with a confirmed diagnosis of cardiovascular disease (CVD) and/or RA and/or osteo arthritis, and with increased levels of CRP.
After seven days of NKO treatment (300 mg/d), CRP was reduced by 19.3 percent—compared to an increase of 15.7 percent observed in the placebo group. After 14 and 30 days of treatment, NKO further decreased CRP by 29.7 percent and 30.9 percent, respectively. In addition, NKO reduced pain scores by 28.9 percent, reduced stiffness by 20.3 percent and reduced functional impairment by 22.8 percent.
Another marine-sourced ingredient is green-lipped mussel (Perna canaliculus). A review out of the Universities of Exeter and Plymouth reported there is little consistent evidence to support the use of freezedried green-lipped mussel powder for osteo arthritis or RA treatment; however, they suggested further research is necessary, as some studies have shown benefits.52 For example, in vitro research has found mussel extract (as Lyprinol) could inhibit COX-1 and COX-2,53 while studies in rats found Lyprinol could prevent induced polyarthritis and exerted significant anti-inflammatory activity.54 And a two-month trial conducted at Yonsei Medical Clinic, Seoul, on 60 patients with knee and hip osteo arthritis found Lyprinol treatment for four and eight weeks reduced pain and improved joint function in 53 and 80 percent (respectively) of patients.55
A proprietary blend of cetylated fatty acids (as Celadrin®), as oral supplements or topical creams, may also support joint health. In an initial study, 40 patients with knee osteo arthritis used a Celadrin cream or placebo for 30 days; assessments included range of motion, “up-and-go” from a chair and stair climbing.56 Significant decreases in time were seen at 30 minutes after initial treatment and at study’s 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 osteo arthritis.57 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 osteo arthritis who took Celadrin (350 mg/d) for 68 days showed significant increases in knee flexion and a shift toward functional improvement.58 In a 2007 unpublished, randomized study, 93 participants experiencing knee pain were given 894 mg/d 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 intervention—an increase of 45 percent from two months earlier.
There are also numerous botanical extracts with activities that benefit the body’s shock absorbers. A review out of the University of Cincinnati noted plant-derived compounds offer a “gold mine” of treatments for arthritis, with the ability to modulate inflammatory responses without side effects.59 Among the cited compounds were boswellic acid, ashwaghandha, curcumin and tea polyphenols.
In vitro studies have explored the anti-inflammatory activities of boswellic acids (BAs), sourced from Boswellia serrata. German researchers reported BAs directly interfere with COX-1 and suppress lipoxygenases, with less effect on COX-2 or leukotriene biosyntheses.60 Diterpenoids isolated from boswellia resin have been shown to inhibit NF-kappaB,61 while the methanolic extract of boswellia switches off pro-inflammatory cytokines and mediators at the sites of chronic inflammation.62 Additionally, preclinical animal studies have found a synergistic effect between BAs and glucosamine, helping to reduce carrageenan-induced edema and swelling in rats.63
In a recent clinical trial, a specialty Boswellia serrata extract (as WOKVEL®, from Verdure Sciences Corp.) decreased arthritis pain and inflammation scores compared to the NSAID valdecoxib over a sevenmonth period.64 Overall increases in joint health and function were observed each month—through six months after baseline for both WOKVEL and valdecoxib. After the one-month washout, scores for the WOKVEL Extract group remained low—while scores for valdecoxib increased back to near-baseline values.
Another Indian botanical, Withania somnifera, also known as ashwaghandha, also has anti-inflammatory activity. In vitro research has shown an ethanol extract of the botanical can inhibit inflammatory transcription factors and suppress the production of pro-inflammatory molecules.65 Indian researchers have also examined the effect of ashwaghandha against induced arthritis in rats, administering root powder to the animals orally after adjuvant injection.66 Ashwaghandha significantly ameliorated increases in lipid peroxides and glycoproteins, and depletion of bone collagen seen in control animals.
Turmeric (Curcuma longa), the source of the anti-inflammatory active curcumin, also has a role to play in this area. A German study using cultures of human articular chondrocytes found curcumin could suppress induced NF-kappaB activation, downregulating COX-2 and MMP-9 expression.67 Similar findings were reported in a Korean study, in which curcumin decreased COX-2 expression without impacting COX-1 levels.68 And Israeli scientists found curcumin worked synergistically with the pharmaceutical COX-2 inhibitor celecoxib to inhibit cell growth, suggesting the botanical could enable the use of the drug at lower dosages.69
The botanical ginger (Zingiber officinale) also has strong antiinflammatory and antioxidant properties, working to prevent generation of free radicals.70 A review from RMG Biosciences noted ginger works to inhibit prostaglandin biosynthesis by inhibiting COX-1, COX-2 and 5-lipoxygenase.71 The review added ginger extract may also modulate biochemical pathways activated in chronic inflammation. In vitro, it has been shown to inhibit nitric oxide and PGE production in osteoarthrotic chondrocytes,72 while also protecting normal chondrocytes.73
These exotic botanicals may also work synergistically, according to a study from Deemed University, Pune, India, which examined the effect of a combination of boswellia, ashwaghandha, ginger and curcumin (as RA-11, from BIO-VED Pharmaceuticals) in 90 patients with knee osteo arthritis.74 The randomized, double blind, placebo-controlled, parallel efficacy, 32-week trial evaluated pain scores as the primary efficacy variable. Compared with placebo, RA-11 significantly reduced pain scores compared to patients on placebo, with no differences in adverse events reported between groups.
Similarly, Sabinsa Corp. developed a combination formula (ArthriBlend-SR®) that is a sustained release composition including glucosamine sulfate (375 mg), Boswellin® (patented boswellia extract, 100 mg) and CurcuminC3Complex® (curcuminoids, 50 mg). A company-sponsored, unpublished study in 50 patients with knee osteo arthritis found taking ArthriBlend for 90 days significantly reduced pain and stiffness.
Another botanical investigated for its efficacy in reducing inflammatory mediators is cat’s claw (Uncariatomentosao rU. guianensis), a plant from the Amazon that appears to inhibit TNF-alpha production and serve as an antioxidant.75 It contains a number of proanthocyanidins and phenolic acids, suggesting an antioxidant mechanism underlies its anti-inflammatory activity.76 A study from Universidad Nactional Mayor de San Marcos, Lima, Peru, evaluated the efficacy of cat’s claw extract in controlling pain among patients with knee osteo arthritis (n=45).77 Pain associated with activity was significantly reduced in patients taking cat’s claw, with benefits occurring with the first week of therapy; it also inhibited TNF-alpha and PGE2 production.
Devil’s claw (Harpagophytum procumbens) may also serve as an effective general therapy for rheumatic disorders, working to serve as an anti-inflammatory and analgesic to help treat acute and subacute inflammation.78 In vitro studies have shown devil’s claw can inhibit the expression of COX-2 and iNOS by suppressing NF-kappaB activation;79 it may also decrease production of MMPs.80 An open clinical study conducted by Consulting Herbal Medicinal Products, Rheda-Wiedenbrueck, Germany, assessed the efficacy of devil’s claw on patients with hip or knee osteo arthritis, finding the extract could reduce pain and improve mobility.81 Another open study performed in the United Kingdom assessed the efficacy of devil’s claw on 259 patients with arthritis and other rheumatic conditions, reporting there were statistically significant improvements in assessment of global pain, stiffness and function, with improvements in quality of life measurements.82
Andrographis paniculata is an herb commonly used in China, India and other countries in subtropical and Southeast Asia. Both the fresh and dried leaves, as well as the fresh juice of the whole plant, have been used in a variety of cultures for purposes including cardiovascular health, immune support and digestion. Its active compounds are suspected to be the diterpene lactones.
More recent research has explored the possibility that these diterpene lactones may impact inflammation. Researchers from Shanghai University of Traditional Chinese Medicine tested neoandrographolide, a diterpene lactone from Andrographis, in vitro and in vivo for anti-inflammatory activity. Oral administration of neoandrographolide (150 mg/kg) significantly suppressed induced ear edema in mice. In vitro, the extract worked to reduce production of inflammatory cytokines.83
Further research out of China found neoandrographolide could inhibit COX-2 expression.84 And Indian researchers reported methanolic extract of Andrographis paniculata could inhibit formation of oxygenderived free radicals such as superoxide (32%) hydroxyl radicals (80%) lipid peroxidation (80%) and nitric oxide (42.8%) in vitro and in vivo; further the extract completely inhibited carrageen-induced inflammation in an animal model compared to control.85
HP Ingredients developed a patented extract of Andrographis paniculata, ParActin®, which has been researched for its ability to impact immune function and inflammation. Company-sponsored research suggests the compound can activate PPAR-gamma, inhibiting the production of pro-inflammatory cytokines. In vitro work found ParActin could inhibit NFkappaB activation, reducing COX-2 expression;86 additional animal research concluded ParActin interfered with the function of inflammatory cells, and showed anti-apoptotic activity.87 Further, unpublished work in RA patients supports the idea that ParActin may act on both immune and inflammatory pathways. Two studies (n=10, n=14) involved early stage RA patients who received 200 mg/d ParActin. Supplementation decreased pain indices and normalized inflammatory markers in the blood.
Another patented ingredient features extracts from orange peel and phellodendron tree (Citrofen™, from Next Pharmaceuticals) A double blind, placebo-controlled, unpublished trial with 80 overweight adults found Citrofen could reduce arthritis pain and improve mobility for those suffering from knee osteo arthritis. Over the eight week trial period, Citrofen showed a highly significant reduction in measures of pain and inflammation.
Angelica gigas Nakai, or Korean angelica, has also been investigated for its impact on arthritis. A specialty extract (Durcsinol- 50™, from JLM Industries) was developed to standardize the decursin level. Company-sponsored studies have shown oral administration of the extract can reduce paw swelling in a dose-dependent fashion in animals induced with inflammation. Orally administered Decursinol-50 was found in another animal study to reduced response times of nociceptive behavior induced by pro-inflammatory cytokines.88 There has also been some initial human clinical work. In an unpublished study conducted at Mapo Pain Clinic in Mapo, South Korea, osteo arthritis patients were given 250 mg twice daily of Decursinol-50 to control joint and blunt trauma pain. It is suggested the compound works on the neural pathways to reduce pain sensations and inhibits COX-1 and COX-2 at receptor sites.
Arnica montana, in the form of a full-potency herbal, not homeopathic, product (A. Vogel Arnica Rub, from Bioforce USA) has also been researched for its role in osteo arthritis, and found to be equal to ibuprofen in treating osteoporosis of the hands.89 Researchers randomly assigned 204 participants from 20 clinics to receive ibuprofen gel or the arnica gel. Pain intensity and hand function improved in both treatment groups; there was a 23.9 percent reduction in pain for those using ibuprofen and 26.5 percent in the arnica group.
The study supported previous results from an open, multicenter trial on arnica montana rub on 26 men and 53 women with mild to moderate knee osteo arthritis, which found significant reductions in pain and stiffness, and improvements in overall function.90 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.
The Mediterranean diet, which is rich in olive oil, has also been linked to lower incidence of several degenerative conditions, including inflammatory diseases.91 Further research has examined the role of the polyphenols, including hydroxytyrosol, found in the aqueous fraction of olive pulp, for its antioxidant and anti-inflammatory effects. 92 In fact, researchers from CreAgri Inc. reported olive vegetation water could inhibit the production of inflammatory cytokines in an animal system of inflammation.93 When the olive water extract was combined with glucosamine, the two acted synergistically to further reduce TNF-alpha levels.
In mid-2007, researchers from Arizona State University, Tempe, released results of a clinical study that found a polyphenolicrich olive extract (as HIDROX®, from DSM Nutritional Products) could reduce pain and improve activities of daily living in patients with osteo arthritis and RA.94 Patients with a diagnosis of osteo arthritis or RA were enrolled in the eight-week, randomized, double blind study; the treatment group received 400mg/ doffreeze-driede xtract. Statistically significant differences were seen in the osteo arthritis and RA patients compared to control, with improvements in pain, inflammation and movement reported, and decreased markers of disease activity.
Milk protein concentrate (MPC) may also have anti-inflammatory qualities. Stolle Milk Biologics Inc. used proprietary methods to develop SMBI milk, and provided the milk free to people living near Cincinnati between 1960 through 1996. Anecdotal reports of relief from muscles orenessled to further investigation. A six-month study period in which highly-trained runners took SMBI milk (n=10) or control milk (n=8) found 70 percent of runners taking the SMBI product had improved training and recovery times, compared to only 20 percent of runners on the control product.
In a related study, researchers from the Minnesota Applied Research Center in Chanhassen studied osteo arthritis patients (n=42) in a six-week, double blind, placebo-controlled study to assess the impact of MPC(2,000mg bi d, as Microlactin™, from Humanetics Corp.), glucosamine sulfate (500 mg tid) or placebo.95 The results showed significant improvement from baseline to week six for the MPCtreated group for pain, stiffness and daily activity index.
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.96 An open study conducted in Pakistan investigated the efficacy and safety of a combination of rutosid, bromelain and trypsin in patients with knee osteo arthritis (n=103).97 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 osteo arthritis with a high pain level.98 Similar results were reported in a study from India using Phlogenzym, in which patients with knee osteo arthritis had reduced pain and joint tenderness and swelling after taking the enzyme therapy for three weeks.99
By addressing the myriad symptoms that comprise arthritis—whether collagen degradation, inflammation, pain or oxidative damage—it is certain these nutritional joint chiefs will ensure the readiness of the body’s shock absorbers to handle life’s bumpy road ahead.
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