Dis-Jointed

According to the U.S. Centers for Disease Control and Prevention (CDC), an estimated 50 million adults in the United States reported having been diagnosed with some form of arthritis, rheumatoid arthritis (RA), gout, lupus or fibromyalgia. Thane Slagowski, vice president of product development and quality at ISI Brands, recently told an INSIDER webinar audience that osteoarthritis (OA), also called degenerative joint disease due to the break down of cartilage from wear and tear, is the most common of the more than 100 different types of arthritic conditions and affects more than 20 million people in the United States. Another other common form is RA, an autoimmune disease whereby the body attacks the joint, resulting in chronic pain from inflammation and cartilage degradation.

 Age is an expected factor, with about 30 percent of those aged 45 to 65 receiving an arthritis diagnosis, while 50 percent of adults older than the age of 65 have arthritis. About 1 in every 250 children (under 18) has a form of arthritis or rheumatoid condition. Relative to gender, there is a slightly higher rate among women.

With a predicted 65 percent of American adults having some form of arthritis by 2030, the natural products industry has an ongoing opportunity ito address various aspects of joint health. Frost & Sullivan placed the total U.S. bone and joint health ingredients market in 2010 at $196 million, with expected growth in the total market at a compound annual growth rate (CAGR) of 4.7 percent in the next five years.

Reflecting what has become sound policy in the natural products industry, the ingredients with the most scientific support will likely go further in the market. The research on natural ingredients and arthritis highlights two general mechanisms: protecting and maintaining cartilage, and managing inflammation.

Some of the most-touted natural ingredients contain, mimic or affect compounds found in healthy joints, including cartilage and fluids. Arguably the most well-known joint health ingredient, glucosamine is naturally present in shells, bones and marrow of various sea creatures and other animals. Glucosamine helps produce glycosaminoglycans (GAGs), which are present in joint cartilage. The original theory was glucosamine may protect against cartilage damage, thereby relieving joint pain and arthritis.

Spanish scientists studied the effect of glucosamine sulfate treatment on K-trans, a biomarker of cartilage capillary permeability, in patients with patella degeneration.¹ They found glucosamine significantly increased K-trans after six months, improving pain scores and functional outcomes. Adding to the knowledge base, in vitro work has suggested glucosamine may stimulate synovial production of hyaluronic acid (HA),² and exert an antioxidant effect in chondrocytes by impacting genetic expression of inducible nitric oxide synthase (iNOS).³ Chondrocytes are cells found in the cartilage and consist of collagen and proteoglycans.

Chondroitin sulfate is a GAG found in the cartilage, where it contributes to resistance against compression of this cushioning membrane between the bone ends. Reviewers have reported chondroitin sulfates mechanism of action may include stimulating extracellular matrix production by chondrocytes, suppressing inflammatory mediators and inhibiting cartilage degeneration.^4,5 While on its own, chondroitin sulfate has demonstrated a significant effect on joint swelling, joint space narrowing and associated pain,^6,7 it is often used and studied in tandem with glucosamine.

Much attention on glucosamine and chondroitin sulfate in recent years has focused on the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT), a major multicenter trial funded by the National Institutes of Health (NIH). GAIT looked at the efficacy of glucosamine hydrochloride (HCL) and chondroitin sulfate in treating knee OA.

In the intervention part of GAIT, researchers from more than a dozen health care facilities across the United States compared the effects of 500 mg/tid glucosamine HCL, 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 for 24 weeks in 1,583 OA patients with knee pain.

Early results from GAIT indicated glucosamine-chondroitin supplementation did not lead to significant improvement in pain; however, a subset of patients with moderate-to-severe pain did experience significant relief from this ingredient tandem.⁸ Looking at joint-space narrowing, a follow-up publication found 24 months of intervention had no benefit to joint space in the overall study population, but there was another trend toward improvement in the moderate knee pain subjects.⁹

GAIT is only one part of the research canon on this supplement combination. A 2009 meta-analysis including six studies involving 1,502 casestwo studies on glucosamine sulfate and four studies on chondroitin sulfatefound glucosamine sulfate did not impact joint-space narrowing during the first year of treatment, compared to controls, but there was a small-to-moderate protective effect on minimum joint-space narrowing after three years of intervention.¹⁰ Similarly, chondroitin sulfate had a small, but significant protective effect on minimum joint-space narrowing after two years. The researchers noted daily administration of glucosamine and chondroitin sulfate for two to three years may delay radiological progression of knee OA.

A World Health Organization (WHO) research team published a review in 2007, citing the controversy surrounding glucosamine and chondroitin research in the area of joint health.¹¹ Referencing GAIT, they noted the use in that trial of glucosamine HCL, whereas glucosamine sulfate had been more recently discovered to have structure-modifying effects that may interfere with the progression of OA. They wrote, we can conclude that glucosamine sulfate (but not glucosamine hydrochloride) and chondroitin sulfate have small-to-moderate symptomatic efficacy in OA, although this is still debated. The WHO team later contacted knee OA patients who had participated in two previous randomized, placebo-controlled, double blind, three-year trials of glucosamine sulfate and received treatment for at least 12 months; they were asked to participate in a long-term, follow-up retrospective assessment of the incidence of total joint replacement (TJR).¹² In the 340 participants included in the follow-up assessment, TJR had occurred in more than twice as many patients from the placebo group than in those who had received glucosamine sulfate. They concluded glucosamine sulfate supplementation for one to three years may prevent TJR for an average of five years after drug discontinuation.

HA is uniquely a non-sulfated GAG that is a major component of synovial fluid, which is a viscous fluid that reduces friction in joints such as the knee. Synovial fluid also supplies nutrition to the cartilage, which has no dependable blood supply. While this ingredient continues to be a part of natural joint health products, most of the research to date involves viscosupplementation (injection into the joint). However, in 2008, Miami Research Associates conducted a trial on oral supplementation with a hyaluronic ingredient (as Hyal-Joint, from Bioiberica) on pain and quality of life in 20 subjects with knee OA.¹³ Subjects receiving 80 mg/d Hyal-Joint had a statistically significant reduction in body pain and improvements in quality of life.

Japan-based Kewpie Corp. had its Hyabest(J) HA ingredient studied for JKOM ( Japanese Knee Osteoarthritis Measurement) in OA patients in Japan, but decided the U.S. market would need a randomized, controlled trial using the Western Ontario and McMaster Osteoarthritis Index (WOMAC). The eight-week trial involved 37 patients with knee OA who received either 200 mg/d of Hyabest(J) or placebo.¹⁴ Using WOMAC scores to assess knee pain and blood tests to determine safety of the oral intervention, researchers found significant improvement of pain scores in the HA group subjects who had the most severe knee pain, compared to placebo. Otherwise, there were no statistical significant differences between the two groups.

The extracellular matrix produced by active chondrocytes and forms the mass of cartilage in the joints is comprised largely of collagen type II fibers, as well as proteoglycans and elastin. Type II collagen in various forms has been marketed as joint health ingredients backed by science. Hydrolyzed collagen, also known as collagen hydrosylate, is theorized to congregate in the cartilage and promote production of additional collagen fiber by chondrocytes.

Unpublished pilot research showed a patented type II collagen-based ingredient (as BioCell Collagen II®, from BioCell Technologies) reduced pain and improved quality of life in patients with knee OA. This ingredient contains mostly type II collagen proteins (60 to 65 percent), chondroitin sulfate (20 percent), hyaluronic acid (10 percent) and lower levels of glucosamine and assorted proteoglycans. It has demonstrated its safety and the ability to raise HA levels in the body.¹⁵

In 2010, Biocell reported a multi-center, double blind, placebo-controlled trial on the safety and efficacy of BioCell Collagen II in joint health generated positive results. In the yet unpublished study, BioCell Collagen II supplementation in 80 patients suffering from joint conditions associated with OA improved VAS (pain assessment) and WOMAC (OA assessment) scores.

Another combination of type II collagen (55 percent), chondroitin (12 percent) and HA (~1 percent) is a patented chicken cartilage extract powder (as ChondrActiv, from Diana Naturals). An unpublished clinical trial involving 37 adults with joint pain given 1,500 mg/d of ChondrActiv or placebo resulted in decreased consumption of non-steroidal anti-inflammatory drugs (NSAIDs) by 73 percent in the active intervention group; there was also a three-fold increase in the number of ChondrActiv patients perceiving improvements in mobility, compared to the placebo group.

Undenatured type II collagen (as UC-II®, from InterHealth Nutraceuticals) has turned in some published results, featuring both animal and human subjects. As joint health and arthritis are common issues in aging dogs, research on arthritic dogs taking UC-II alone or in combination with glucosamine and chondroitin sulfate showed significantly reduced pain and lameness.¹⁶ UC-II alone given for 120 days decreased overall pain by 62 percent. A similar study in horses with OA showed 320 or 480 mg/d of UC-II reduced overall pain by 79 percent and 88 percent, respectively, while increasing mobility and joint flexibility.¹⁷

Human trials have strengthened these results, including a pilot study in which 40 mg/d of UC-II significantly reduced pain, morning stiffness and stiffness following periods of rest.¹⁸ A broader double blind study featured 52 patients with knee OA who were randomized to receive 40 mg/d of UC-II or glucosamine/chondroitin.¹⁹ After 90 days, those taking UC-II experienced a 33-percent reduction in WOMAC index scores, compared to a 14-percent score reduction in those on the glucosamine/chondroitin; subjects taking UC-II also reported significantly reduced pain when walking, climbing stairs or at rest.

Naturally occurring glycosaminoglycans and proteins essential to maintain healthy joints and connective tissues can also be found in eggshell membrane. Two single-center, open-label pilot clinical studies evaluated the safety and efficacy of Natural Eggshell Membrane (NEM®, from ESM Technologies) as a treatment for pain and inflexibility associated with joint and connective tissue disorders.²⁰ Patients received oral NEM 500 mg/d for four weeks, and researchers assessed pain and range of motion (ROM). In the single-arm and double-arm trials, supplementation significantly reduced pain measures at seven days and 30 days, and also increased flexibility and reduced ROM-associated pain. A follow-up, randomized, multicenter, double blind, placebo-controlled study confirmed these results, as 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.²¹

Fired Up Joints

The most active area of joint health research of late has been in reducing inflammation, thereby reducing pain and improving mobility in both OA and RA. Essential fatty acids (EFAs) play a crucial role in the inflammatory cascade, a mechanism targeted in joint health research. Omega-3s, particularly eicosapentaenoic acid (EPA), 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.²² A York University, Toronto, review of studies on omega-3s and inflammatory conditions such as RA found supplementation for three to four months reduced joint pain intensity, number of painful and/or tender joints and NSAID consumption.²³ Fish oil (as EPAX 5500 TG, from EPAX) containing 55-percent EPA and DHA (docosahexaenoic acid) relieved symptoms and reduced disease activity in patients suffering from akylosing spondolitis, a chronic rheumatic disease mainly affecting the joints of the spine.²⁴

Cetylated fatty acids are derived from esterfying oils and are known to lubricate cell membranes including those that pad the joints. Orally, a study of 64 chronic knee OA patients who took 350 mg/d cetylated fatty acids (as Celadrin®, from Pharmachem Laboratories) for 68 days found significant improvement in knee flexion and overall joint function in the intervention group, compared to placebo.²⁵ An unpublished study released in 2007 furthered these benefits, as 93 subjects with knee pain randomized to take 894 mg/d of Celadrin in a crossover, washout design significantly increased their walking distance by 45 percent after two months.

Topically, Celadrin cream administered to knee OA patients for 30 days in a placebo-controlled design improved range of motion, balance and stair- and chair-climbing performance.²⁶ In another study, the use of a topical cream containing Celadrin and menthol in subjects with either knee, elbow or wrist OA for only one week resulted in similar positive effects on stair climbing, while also reducing pain.²⁷ Another study from the same University of Connecticut scientists found among 40 patients with knee OA who were randomly assigned to receive a Celadrin or placebo cream twice daily and tested for static postural stability and plantar pressures, those applying Celadrin showed improved static postural stability in patients with knee OA presumably due to pain relief during quiet standing.²⁸

A combination of cetylated fatty acids and creatine (as Kre-Celazine®, from All American Pharmaceuticals) has also reduced site-specific, chronic joint- and muscle-related inflammation and pain.²⁹ In the trial, 35 subjects who had experienced one or more areas of muscle and/or joint inflammation and pain were randomized to take oral capsules of Kre-Celazine or placebo for 30 days and were assessed for pain and inflammation at the beginning and end of the study period. Results indicated subjects receiving the Kre-Celazine 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.

These benefits were confirmed in follow-up studies, including two unpublished trials conducted by BioCeutical Research & Development Laboratory, Billings, MT. In one study, the researchers 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. All subjects reported some level of benefit, including increased mobility, daily routines and energy levels, from taking the test product, with no side effects. Their other study found oral administration of buffered creatine (as Kre-Alkalyn®, from All American Pharmaceuticals) in professional football players decreased joint pain due to inflammation and direct bruising, while increasing endurance and stamina.

Marine fatty acid ingredient krill oil has also generated positive results in joint research. In a Canadian trial, 90 subjects with confirmed cardiovascular disease (CVD) and/or RA and/or OA, as well as increased C-reactive protein (CRP) levels, took either placebo or 300 mg/d of krill oil (as Neptune Krill Oil, NKO, from Neptune Technologies & Bioressources).³⁰ In the intervention group, CRP levels fell by 19.3 percent after seven days, by 29.7 percent after 14 days, and by 30.9 percent after 30 days; 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 after seven days of intervention.

Yet another marine source of omega-3s for anti-inflammatory use is green-lipped mussel extract (GLE), an ingredient derived from mussels (Perna canaliculus) harvested off the coasts of New Zealand and packed with EPA and DHA, glycosaminoglycans and phosphorylated glycogen.³¹ A 2008 meta-analysis found four randomized clinical trials on GLE as an adjunct treatment to conventional medical in patients with mild-to-moderate OA demonstrated clinical benefits from GLE, although the reviewers noted a lack of research on optimal dosage.³² The ability of GLE (as Lyprinol®, from Pharmalink) to decrease the production of inflammatory cytokines and improve both the mobility and clinical signs of degenerative joint disease was further elucidated in animal trials.^33,34

Going from sea to land, and animal to plant, a seaweed-sourced mineral supplement (Aquamin, supplied in the United States by GTC Nutrition) has shown anti-inflammatory benefits that can improve joint health. In a trial on 29 adults with moderate to severe knee OA, those taking 2,400 mg/d of Aquamin for 12 weeks significantly improved passive and active extension ROM and reduced the use of NSAIDs, compared to those taking a placebo.³⁵ In another trial, 70 subjects with moderate to severe knee OA randomized to either 1,500 mg/d of glucosamine sulfate, 2,400 mg/d of Aquamin, a combination of glucosamine and Aquamin, or placebo for 12 weeks resulted in the Aquamin and glucosamine interventions positively impacting pain and stiffness scores; however, the two combined did not appear to influence WOMAC measurements.³⁶

Many plant-based ingredients have dipped their roots into the fertile joint health grounds. Among such botanicals, curcumin has drawn much attention for its anti-inflammatory actions in cartilage. In vitro work has shown curcumin can inhibit the production of inflammatory and catabolic mediators by chondrocytes, as well as suppress NF-kappaB-mediated inflammatory signaling pathways in chondrocytes.^37,38 In another in vitro study, explants made from normal horse articular cartilage, which mimics OA inflammation, were provoked with pro-inflammatory cytokines to induce cartilage degradation, then treated with 100 micromol/L curcumin, which reduced the inflammatory cytokines.³⁹

In humans, a 2009 trial involving 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, showed reduced mean scores for knee function and pain levels in both groups, with no significant difference in adverse events.⁴⁰ In 2010, Italian researchers reported a complex of curcumin with soy phosphatidylcholine (as Meriva®, from Indena SpA) improved WOMAC scores and mobility at a dosage of 200 mg/d, which is much lower than the doses used in previous trials.⁴¹ They noted global WOMAC score decreased by 58 percent after three months of treatment, while walking distance in the treadmill test was prolonged from 76 m to 332 m in the same time frame. CRP levels decreased from 168 (± 18) to 11.3 (±. 4.1) mg/L in the subpopulation with high CRP, while the control group experienced only a modest 2-percent increase in WOMAC score, a slight improvement in mobility and a modest drop in CRP. Also the treatment costs (use of anti-inflammatory drugs, treatment and hospitalization) were reduced significantly in the treatment group.

In a 32-week randomized controlled trial, researchers provided 90 subjects with knee OA with placebo or RA-11, an Ayurvedic combination product containing C. longa, Withania somnifera, Zingiber officinale and Boswellia serrata.⁴² The intervention group experienced significantly reduced pain at 16 and 32 weeks, and improved WOMAC scores at the same time points.

Boswellia has also performed well in its own joint health trials, demonstrating anti-inflammatory actions, primarily by inhibiting 5-lipoxygenase (5-LOX), but also by affecting TNF-alpha and interleukin activity.⁴³ In animal and human trials, boswellia extract has reduced lameness and joint pain, with researchers suggesting the use of a standardized preparation would best ensure quality and stability of the extract.^44,45

An in vitro study conducted at The Ohio State University Medical Center, Columbus, gave teeth to this recommendation, as a standardized boswellia extract (as 5-Loxin®, from PL Thomas) showed it could inhibit TNF-alpha-induced expression of matrix metalloproteinase-3 (MMP-3) and inducible expression of apoptosis mediators.⁴⁶ A follow-up study examining the effect of different percentages of acetyl-11-keto-beta-boswellic acid (AKBA), one of the active principles in boswellia, on inflammatory markers found the extract with 30-percent AKBA was significantly more effectiveboth in vitro and in vivothan a 3-percent AKBA extract.⁴⁷ Further, 5-Loxin has demonstrated broad spectrum safety in acute oral and dermal, as well as sub-chronic studies.⁴⁸

Additional support for 5-Loxins benefits were delivered in a 90-day, double blind, randomized, placebo-controlled study of 75 OA patients who received 100 mg or 250 mg of 5-Loxin daily, or a placebo.⁴⁹ Utilizing the WOMAC scoring system and Lequesnes Functional Index, researchers discovered both doses of 5-Loxin led to clinically and statistically significant improvements in pain scores and physical function scores, with subjects in the 250 mg/d group showed significant improvements after seven days. The intervention also significantly reduced MMP-3 levels in synovial fluid.

Another herb used in the Ayurveda system, Bacopa monnieri, displayed anti-arthritic effects based on anti-inflammatory actions in a 2010 study from the University of Kerala, India.⁵⁰ Researchers administered bacopa extract to rats for a total of 60 days and assessed paw swelling; arthritic index; and inflammatory mediators such as cyclooxygenase (COX), lipoxygenase (LOX), myeloperoxidase and serum anti-collagen IgG, and IgM levels in control and experimental rats. Results revealed significantly inhibited footpad swelling and arthritic symptoms in bacopa-treated animals. Bacopa also inhibited COX and LOX activities, in addition to reducing neutrophil infiltration and serum anti-collagen IgM and IgG levels in the arthritic rats.

Ayurveda is not the only traditional medical system contributing to inflammation control in joint health. In 2010, researchers from China Pharmaceutical University and the Shanghai University of TCM investigated the Traditional Chinese Medicine (TCM) herb Radix linderae, reporting an alkaloid fraction from the herb demonstrated anti-inflammatory, analgesic and antimicrobial activities helpful to managing arthritis and protecting the affected joint.⁵¹ After inducing arthritis using chicken type II collagen (II), they treated mice with different doses of the alkaloid norisoboldine (10, 20, 40 mg/kg) for 20 consecutive days and then monitored body weight changes and joint histopathology, in addition to assessing and recording clinical scores. The alkaloid significantly reduced clinical scores and body weight, in addition to dose-dependently inhibiting inflammatory cells and synovial hyperplasia (extra cell growth), while protecting the joint from damage. Norisoboldine also significantly suppressed Th1 response in the mice.

In another 2010 study, oral administration of a compound from magnolia, which is used in TCM, inhibited type II collagen-induced arthritis development by reducing the production of pro-inflammatory cytokines, MMP expressions and oxidative stress.⁵² According to the Korean researchers, clinical arthritis scores and paw swelling were reduced in arthritic mice treated with magnolia phenolic compound honokiol, which was also credited with preserved joint space and suppression of interleukin (IL)-17, matrix metalloproteinase (MMP)-3, MMP-9, MMP-13 and receptor activator for nuclear factor-kappaB ligand, as well as nitrotyrosine formation.

Fellow TCM herb thunder god vine (Tripterygium wilfordii) also contains compounds shown to remedy inflammatory factors in autoimmune diseases such as RA. In 2010, Chinese scientists published results exhibiting the pharmacological actions of the herbs glycosides, including glycoside wilforde A and trptolide, on inflammation in rats.⁵³ They induced various swelling and immune dysfunction in the rats, then administered the test preparations; there was no benefit from wilforde A administration, but triptolide significantly improved the study parameters.

African botanicals are also in the joint health mix and have posted some recent positive research results. Extracts from the seed of the African shea tree (Vitellaria paradoxa) appear to inhibit OA by targeting inflammation and cartilage degradation, according to studies. A 2010 single-site, 15-week randomized, double blind, parallel, placebo-controlled study examined a range of biomarkers in 89 patients with OA of the knees and/or hips to determine potential modes of action of a triterpene-rich shea nut extract (as SheaFlex70, from BSP Pharma).⁵⁴ In participants who had OA biomarker levels in the upper quartile at baseline, SheaFlex supplementation led to significant decreases in inflammation and cartilage breakdown, as well as trend level decreases in bone remodeling, compared to placebo. The data revealed inflammation marker TNF-alpha fell 23.9 percent in the treatment group, with only a 6-percent drop for placebo, while cartilage degradation marker CTX-II fell 28.7 percent for treated subjects, but increased 17.6 percent for placebo subjects. Also, osteocalcin levels fell 9.2 percent in the shea group and 1.2 percent in the placebo group.

Japanese researchers also published results in 2010, featuring tests on eight triterpene esters from shea fat in an inflammatory mouse model.⁵⁵ All of the compounds tested exhibited marked anti-inflammatory activity, with lupeol cinnamate having the highest anti-inflammatory action.

The gnarly-named devils claw (Harpagophytum procumbens) is another native African botanical whose compounds may deliver anti-inflammatory and analgesic effects. According to a monograph published in Alternative Medicine Review, studies have shown the plants harpagosides may inhibit COX-2 expression and the release of other inflammatory mediators, as well as inhibit certain compounds involved in cartilage degradation.⁵⁶ In an eight-week open study, a standardized devils claw extract (from Bioforce) significantly improved quality of life, global pain measures and mean pain scores.⁵⁷ 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.

In 2002, German researchers reported an eight-week course of Doloteffin in 250 patients suffering from non-specific low back pain (n=104) or OA pain in the knee (n=85) or hip (n=61) resulted in improved generic and disease-specific outcome measures by week four, with additional benefits by week eight.⁵⁸ There were differences between the back, knee and hip groups, as well as between the different ages and genders, but the researchers noted between 50 and 70 percent of patients benefited from the intervention with few adverse effects. Subsequent studies by the German researchers confirmed these results in similar OA populations.^59,60

A similarly occult-sounding herbal compound, decursinol is a coumarin compound isolated from the roots of Angelica gigas Nakai, also known as Korean angelica, and it also possesses analgesic and anti-inflammatory properties. Animal studies have shown a methanolic extract of decursinol (as Decursinol-50, from SunBio) produces an antinociception (pain relieving) effect on the central nervous system and is especially active in inflammatory pain.⁶¹ The same team discovered decursinols antinociception may be mediated by noradrenergic, serotenergic, adenosine A (2), histamine H(1)   and H(2) receptors.⁶² Korean researchers published in vitro research in 2006 that suggested 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.⁶³

The anti-inflammatory actions of hops (Humulus lupulus L.) may be due to its alpha and beta acids (humulone and lupulone), which have been credited with inhibiting pro-inflammatory PGE2, according to unpublished research supplied by Pharmachem Laboratories. In 2006, Dutch researchers released results from their investigation of a standardized CO2 extract of hops and its ability to selectively inhibit COX-1 and -2 in a mouse model of arthritis.⁶⁴ The effect of hop extract on healthy and arthritic cartilage was investigated as well as effects on inflammatory joint swelling. The extract inhibited COX-2 by limiting PGE2 production. The scientists reported their tests showed the hops extract was bioavailable, but oral administration of the extract showed no negative or positive effects on healthy cartilage proteoglycan synthesis or on zymosan-induced arthritic cartilage proteoglycan synthesis. They concluded the hops extracts could be a useful intervention in inflammation management and pain.

A six-week, open-label trial of human subjects published in 2008 revealed 1,000 mg/day of mixed rho iso-alpha-acids from hops produced a 54-percent reduction in WOMAC Global scores in exhibiting knee OA.⁶⁵ In the same report, researchers detailed how this modified hops extract inhibited inducible, but not constitutive COX-2, and exhibited only minimal PGE2 inhibition in a mouse model, compared to several NSAIDs that showed better PGE2 inhibition.

Known for its antioxidant flavonoids, French maritime pine bark extract might also possess anti-inflammatory properties, as an study of OA patients with elevated CRP and plasma free radicals linked treatment to a statistically significant reduction in levels of CRP and fibrinogen.⁶⁶ The Italian researchers had already published a prior evaluation of 100 mg/d of pine bark extract (as Pycnogenol®, supplied in the United States by Natural Health Science) given to 77 OA patients for three months who were then assessed using the WOMAC index.⁶⁷ Subjects taking Pycnogenol saw a 50-percent reduction in their global WOMAC scores and significantly increased walking distance on a treadmill test. Supplementation also reduced food edema, GI complications and usage of OA drugs.

In a 2007 study, Iranian researchers enrolled 37 patients with OA to receive either placebo or pine bark extract in a blinded fashion for three months and evaluated OA symptoms via WOMAC Index, as well as usage of NSAIDs and COX-2 inhibitors.⁶⁸ After 90 days, subjects taking Pycnogenol reported significant reductions in pain, stiffness and physical function, and their WOMAC scores also decreased. Dosage and frequency of NSAIDs and COX-2 inhibitors was increased in the placebo group, but dropped in the active intervention. Slovakian researchers found similar results after giving 150 mg/d of Pycnogenol to patients with knee OA for three months; WOMAC scores improved and pain was significantly alleviated by the intervention.⁶⁹

There may be more bite to bark, as Citrofen®, 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, generated positive results in an eight-week, placebo-controlled, double blind study comparing 80 overweight and normal weight subjects with knee OA.⁷⁰ Citrofen intervention reduced CRP levels and significantly improved LAI (Lequesne Algofunction Index) scores; subjects taking Citrofen also showed statistically significant weight loss.

Beyond herbal remedies, specialty ingredients have made their mark on inflammation and pain in joint health research, although much of the science is unpublished. Methylsulfonylmethane (MSM) is an organic sulfur-containing compound offering anti-inflammatory and antioxidant benfits.⁷¹ In 2008, a systematic review highlighted six trialstwo for MSM and four for the related compound dimethyl sulfoxide (DMSO)and found the MSM trials and two DMSO trials resulted in significant improvements in pain outcomes in patients with mild to moderate OA of the knee.⁷² One such trial found 3 g tid  of MSM produced significant decreases in WOMAC pain and physical function impairment in adults with knee OA.⁷³

A unpublished clinical trial conducted by Miami Research Associates 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 researchers examined the absorption and excretion of MSM, and its impact on sulfate and homocysteine metabolism following a single dose of 1, 2 or 3 g. They noted the 3-g dose peaked MSM levels in the blood within 90 minutes, and MSM blood concentrations remained higher than baseline for up to one week.

Another modifier of sulfur metabolism is keratin, a complex of fibrous proteins that has one of the highest proportions of the amino acid cysteine, a natural sulfur reservoir. Keratec, which makes a patented keratin ingredient (Cynatine FLX ), reported its research shows Cynatine FLX increases sulfated joint polymers, the bodys anti-inflammatory action and endogenous levels of glutathione peroxidase and superoxide dismutase (SOD), in addition to protecting against free radical damage. The active cysteine in the compound may stimulate proteoglycan synthesis to prevent joint breakdown and build joint polymers.

Other types and sources of proteins have also generated positive results in joint health research. Milk protein concentrate (MPC) contains unique antibodies and other bioactive nutrients that may contribute to the ingredients ability to relieve pain and improve joint function in OA patients. In a six-week, randomized, double blind, placebo-controlled trial, 42 participants received placebo, 500 mg tid of glucosamine sulfate or 2,000 mg BID of MPC (as MicroLactin®, from Humanetics).⁷4 The MPC-treated group had significant improvement in pain, stiffness, activities and total WOMAC index scores throughout the study duration. Similar results occurred in a six-week, double blind, placebo-controlled study involving 31 subjects with OA in both knees who were given either 12 oz/d of a beverage containing MPC (as MicroLactin) or placebo.⁷⁵ Knee Injury and Osteoarthritis Outcome Scores improved significantly over time in the MPC group, as did overall treatment effect as reflected by changes in the WOMAC composite score.

A natural ingredient from bio-active milk proteins (as Osteol, from BIOSERAE) is theorized to protect chondrocytes, inhibit inflammation and reduce cartilage degeneration. The company has noted its unpublished research shows adding Osteol to a glucosamine/chondroitin formula can significantly increase chondrocyte protection against inflammatory markers in vitro and boost the combinations anti-inflammatory effects in animals. It further referenced in vitro studies showing Osteol could significantly increase the expression of genes involved in cartilage preservation and reduce the expression of MMP. An unpublished clinical trial in 57 subjects with knee OA revealed a mix of glucosamine, chondroitin and Osteol taken for three months could result in significantly reduced pain sensations.

No stranger to dairy proteins are probiotics, which count anti-inflammatory actions among their immunomodulating benefits. A pilot study suggested Bacillus coagulans GBI-30, 6086 (from Ganeden Labs) might have potential as an adjunctive therapy with pharmacological anti-arthritic medications, and the probiotic strain appeared to be safe and effective for patients suffering from RA.⁷⁶ The randomized, double blind, placebo-controlled, parallel-design, clinical study involved 45 adult men and women with symptoms of RA who were randomly assigned to receive B. coagulans GBI-30, 6086 or placebo once a day for 60 days, in addition to their standard anti-arthritic medications. Using American College of Rheumatology (ACR) criteria, the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI), and laboratory tests for erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), researchers found the intervention was linked to improved pain scores and joint function/mobility, and reduced CRP.

Maintaining the health of cartilage and fluid in the knee is a key first step in addressing joint health, while managing inflammation can reduce pain and increase functionality of a joint affected with a form of arthritis or other joint condition. Natural ingredients have been researched for both methods of joint support, although much more research is needed to clarify mechanisms and populations, and to strengthen the existing results that show significant benefits from supplementation.

References are on the next page...

References for "Dis-Jointed"

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