[Bone Health] Vol. 10 No. 11 October 2005

Better Bones and Joints

By Steve Myers, Managing Editor

Beyond injuries, bones and joints can be affected by numerous diseases and conditions, including inflammation, arthritis and osteoporosis. While bones can often regenerate and heal, age saps the ability to do so, and poor bone and joint health can devastate the body even further. However, bones are living tissue sensitive to diet and exercise; thus, certain , minerals and specialty supplement ingredients can be useful in both maintaining good general bone health and addressing specific aspects of bone and joint diseases.

A human adult is comprised of 206 bones and more than 230 moveable and semi-movable joints, all of which are a part of a musculoskeletal system that keeps a person vertical and mobile, and protects softer inner body parts. However, bones are more than just structural.

Inside bone is soft marrow, which is home to stem cells that produce the body's red blood cells and platelets. The periosteum, the outer membrane on bone, is dense with blood vessels and nerves that nourish and signal the bones for growth and repair. Three kinds of cells are special to bone. Osteocytes carry nutrients and waste to and from bone; osteoblasts help make new bone and repair damaged bone; and osteoclasts break down bone and reshape it.

Lifestyle factors prominently in bone health. Muscles attached to and surrounding bones move limbs, fingers and other body parts. Therefore, strong, healthy muscles contribute to bone health. Experts have advised weight-bearing exercise not only improves muscle, but it also promotes bone formation. A In a 2005 Swiss study, one year of regular weight bearing exercise increased bone density (BMD), a crucial marker in gauging bone strength and health.(1) Health officials also advise increased consumption of alcohol and caffeine can contribute to bone loss, as can long-term cigarette smoking. Beyond lifestyle factors, a 2005 study revealed chemotherapy treatments can cause decreased BMD.(2)

Bone is made mostly of calcium and protein collagen, as well as phosphorus, and other trace minerals. In fact, 99 percent of the body's calcium is in the bones, which store the mineral and release it into the bloodstream as it is needed in other parts of the body. In fact, if the body's calcium levels are not sufficient, the mineral is pulled from the bones. For these reasons, adequate dietary calcium intake has forever been linked to healthy bones.

A Cochrane Database System Review investigating data from 15 trials involving more than 1,800 people concluded calcium supplementation had a positive effect on bone density and reduced vertebral fractures.(3) Similarly, a controlled study of 200 Chinese postmenopausal women found consumption of high-calcium skim milk (providing 1,200 mg/d of calcium) led to reduced bone loss in the lumbar spine and hip.(4) According to a 2005 study conducted by Purdue University researchers, increased dietary calcium from dairy protected total hip BMD and spine BMD from loss in young healthy women who previously had low calcium intake and were taking oral contraceptives.(5)

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[Bone Health] Vol. 10 No. 11 October 2005

The Food and Drug Administration (FDA) recognized the importance of calcium intake and authorized a bone health claim for calcium-rich foods. The National Institutes of Health (NIH) reported high

Bone or Fat: The Role of Bone Marrow in Bone Health and Disease

Located in the cavities of bone is marrow, a soft tissue that is home to stem cells, which form a host of different blood cells, including white and red blood cells, and platelets. Over time, the blood cells in bone marrow, which starts as red marrow, turns into fat and is called yellow marrow. Bone marrow has very little fat content at birth, but it is half fat when a person is about 30 years old, and it is almost entirely fat by old age. Science has determined a stem cell present in bone marrow can turn into fat or bone, depending on the signals it receives. Furthermore, contrary to initial belief, bone cavities associated with osteoporosis are not empty, but are filled with this fatty yellow marrow. Studies have shown people with osteoporosis have more of this bone fat than do people of the same age without osteoporosis.

Scientists studying bone marrow stem cells in vitro reported stem cells subjected to glucocorticoids, drugs that cause bone loss, overwhelmingly turned into fat; conversely, stem cells subjected to D3 turned into bone.(1) How this would translate in vivo and how intake, plasma levels or supplementation would impact the conversion is still unknown. But it creates interesting possibilities. Recent research conducted at the Massachusetts Institute of Technology (MIT) has unveiled a gene called TAZ that is responsible for signaling adult bone marrow stem cells to turn into bone, fat or muscle.(2) Now the race is on to find substances that influence expression of the TAZ gene and, thus, could modulate bone formation and one aspect of osteoporosis.

Science still has many questions to answer on bone formation, but it is clear bone marrow plays a role. Also, scientists from University of Vienna, Austria, studying animal models reported bone marrow actively participates in arthritis, particularly inflammatory arthritis.(3) They noted arthritis can destroy the cortical bone barrier, exposing bone marrow to synovial fluid and affecting the severity of rheumatoid arthritis. Therefore, in addition to its importance to blood cell production and the immune system, maintaining healthy bone marrow is vital to bone health.

Healthy bone marrow requires adequate nutrient intakes, especially such as B12, niacin, folic acid and biotin.

Natural ingredients can aid bone health in other ways. Studies show yeast-derived beta-glucans (as WGP 3-6® from Biothera) is taken up by gastrointestinal macrophage cells and broken down in the bone marrow to smaller parts that can enhance granulocyte activity.(3) Further research found WGP 3-6 improved recovery following bone marrow injury.(4)

References:

1. Gimble JM and Kelly KA. "1,25-Dihydroxy Vitamin D3 Inhibits Adipocyte Differentiation and Gene Expression in Murine Bone Marrow Stromal Cell Clones and Primary Cultures." Endocrinol. 139, 5:2622-8, 1998.

2. Yaffe MB et al. "TAZ, a transcriptional modulator of mesenchymal stem cell differentiation." Science 309, 5737:1074- 8, 2005.

3. Gortz B et al. "Arthritis induces lymphocytic bone marrow inflammation and endosteal bone formation." J Bone Mineral Res. 19, 6:990-8, 2004.

3.Hong F et al. "Mechanism by which orally administered beta-1,3-glucans enhance the tumoricidal activity of antitumor monoclonal antibodies in murine tumor models." J Immunol. 173:797-806, 2004.

4. Le Blanc, BW. "The effect of beta-glucan on cytokine transcription in the macrophages." Presented at Experimental Biology & the 35th International Congress of Physiological Sciences, April 2005.

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[Bone Health] Vol. 10 No. 11 October 2005 calcium intake reduces the risk of osteoporosis, a bone disease categorized by low bone mass and impaired bone structural integrity.

About 10 million Americans suffer from osteoporosis, with another 34 million people at risk for the disease. A whopping 68 percent of those inflicted or at risk are women, according to NIH, which also reported osteoporosis-related costs exceed $14 billion annually. Addressing these costs, a study commissioned by the Education Alliance (DSEA) and conducted by respected Washington-based research firm the Lewin Group found calcium supplements (1,200 mg/d) could prevent 734,000 hip fractures in people over 65, producing a net savings of $13.9 billion in the next five years.(6) Echoing the importance of such savings, top cancer prevention expert Harold Newmark advised the government in 2004 that vitamin D and calcium food fortification would lead to a 20- percent reduction in colon cancer and osteoporosis fractures.(7)

Calcium is often taken in combination with vitamin D, which promotes absorption in the gastrointestinal (GI) tract. While numerous studies have shown positive bone health benefits from this supplement combination, a recent study conducted in the United Kingdom and published in the Lancet and British Medical Journal questioned the efficacy of this vitamin-mineral tandem in preventing hip fractures in high-risk populations.(8) However, many experts noted a significantly low patient compliance issue threatened the accuracy of the studies results.

Vitamin D has stood on its own in various bone health study, as daily intake between 500 IU and 800 IU (with or without calcium) has been shown to increase BMD.(9) The body can produce vitamin D from sunlight absorbed through the skin, but people with limited sun exposure might need the help of supplements. In addition, the body's ability to produce vitamin D from sun exposure declines with age, making vitamin D supplements increasingly important for the elderly. An Australian study demonstrated cyclic variations in serum vitamin D levels corresponded to changes in ultraviolet light exposure; they also found an increase in bone resorption (process by which bone is destroyed and absorbed into the body) and bone fractures as vitamin D levels declined.(10) Vitamin D deficiency has also been linked to women who spend most of their time in the home, especially those suffering bone fractures.(11) In a 2005 Japanese study, ED-71, a new active form of vitamin D with improved binding to vitamin D binding protein (DBP), effectively and safely increased lumbar and hip BMD in osteoporotic patients who were under vitamin D supplementation.(12)

Calcium and vitamin D certainly dominate bone health , but other micronutrients can improve various aspects of bone density and disease. Phosphorus is a mineral found in bone and is also a component of calcium phosphate, the most prevalent form of calcium found in bone. Researchers from Creighton University Medical Center, Omaha, Neb., concluded calcium phosphate is the preferred form of to increase phosphorus levels, especially in older women, who tend to consume 70-percent less than the recommended intake.(13) Japanese researchers explained phosphorus regulates bone formation and inhibits bone resorption, and concluded calcium phosphate should be 74 percent of total calcium supplementation to improve BMD, especially in women.(14)

Bone is mineral laden and, despite its comprising a mere fraction of bone composition, magnesium is vital to bone maintenance and strength. Magnesium deficiency has been shown to lead to bone loss in animals, due to increased bone resorption and inadequate bone formation.(15) An study of animals on a low magnesium diet revealed lower BMD and bone architecture among magnesium-deficient rats compared to rats given an adequate magnesium diet.(16) A research review from the University www.naturalproductsinsider.com Page 3

[Bone Health] Vol. 10 No. 11 October 2005 of Southern California, Los Angeles, investigating animal and human studies concluded magnesium deficiency results in bone loss possibly due to reduced bone magnesium content and increased osteoclast activity;(17) they further theorized such deficiency contributes to substance P-induced release of inflammatory cytokines and impaired parathyroid hormone production.

Dietary has been positively associated with bone mineral density in healthy, nonsmoking postmenopausal women receiving 800 mg/d of calcium along with hormone replacement therapy.(18)

Vitamins and minerals might also benefit bone health by acting as antioxidants, as plasma deficiencies of dietary antioxidants have been found in osteoporosis patients.(19) While researchers are still speculating on the mechanism behind antioxidant benefits to bone health, some have suggested the nutrients curb structural damage to bone. Turkish researchers studying osteoporotic rabbits discovered a combination of , and could slow progression of osteoporosis by preventing bone destruction and promoting normal bone structure.(20) However, a recent Columbia University, New York, trial based on the Women's Health Initiative concluded there is no link between vitamin and mineral antioxidants and BMD.(21) They did conclude the effect of vitamin C on BMD warrants further examination. Despite its antioxidant properties, an excess of might increase the risk of hip fracture by promoting bone loss, according to Swiss researchers.(22) They reported vitamin A increased subperiosteal bone resorption, reduced bone- forming surfaces below the periosteum, but not in cancellous bone, a mesh of tiny bone pieces inside compact bone.

B vitamins, primarily and vitamin B12 (cobalamin), have been studied for their benefit to risk of stroke, which is known to increase the risk of hip fracture by as much as four times. Research from Tokyo has demonstrated folate and B12 can significantly reduce the risk of such fractures following a stroke.(23)

Lesser known has been indicated as beneficial to a good bone health diet, especially in combination with vitamin D. Deficiencies of the these vitamins have been linked to development of osteoporosis and fracture, due to undercarboxylation of osteocalcin, a non-collagenous bone protein synthesized by osteoblasts.(24) The two vitamins combined in another study to inhibit the development of osteoporosis induced by a low protein diet.(25)

Protein intake walks a fine line between deficiency, which can cause osteoporotic developments, and excess, which can impair BMD. Results from a 2005 trial conducted in Australia positively associated dietary protein intake with BMD, suggesting protein intake above recommendations may help elderly women optimize bone mass.(26)

However, science is convincingly discovering the type of protein consumed might greatly affect its benefit to bone health and osteoporosis. When substituting soy protein for animal protein, researchers from Loma Linda University, Calif., found soy may improve bone strength and inhibit calcium excretion.(27) Data from the Shanghai Women's Health Study, a cohort of Chinese women aged 40 to 70, showed women in the highest quintile of soy consumption were 28 percent less likely to suffer fracture.(28)

Isoflavones from soy have produced similar research results, especially in hormone-related bone loss. A study conducted at University of Oklahoma, Stillwater, investigated selective estrogen www.naturalproductsinsider.com Page 4

[Bone Health] Vol. 10 No. 11 October 2005 receptor modulators raloxifene and soy isoflavones, finding the isoflavones stimulated bone formation while suppressing bone resorption.(29) Soy isoflavones (as SoyLife® from Acatris) have improved bone mineral concentration in postmenopausal women,(30) and are involved in a recently initiated trial funded by the U.S. Department of Agriculture (USDA) investigating the connection between soy isoflavones and prevention of osteoporosis.

Scientists from Purdue University, Lafayette, Ind., studied the effects of isoflavones and omega-3 essential fatty acids (EFAs) on bone conservation in ovariectomized animals; they found high intake of isoflavones and omega-3 EFAs correlated to positive bone mineral conservation.(31) According to a British review, a diet featuring a low ratio of omega-6-to-omega-3 EFAs may actually benefit bone health, most notably BMD.(32) In fact, EFAs have been found to inhibit osteoclast generation an activation in ovariectomized rats.(33)

OsteoSine Complex™ from NuLiv Science is a botanical blend from seeds of Cuscuta chinesis that contains many phenolic compounds, including isoflavones. The estrogenic flavones may stimulate osteoblasts,improve collagen synthesis and increase bone cell proliferation. Cuscuta, also called Tu Si Zi, was among four other Traditional Chinese Medicine (TCM) compounds studied by Taiwan researchers for their effects on bone cell regeneration.(34) When added to bone cell culture, Tu Si Zi clearly promoted the proliferation and differentiation of the osteoblasts from their precursor cells, according to the scientists. According to Michael Wang, president of NuLiv, subsequent in vitro and in vivo studies conducted at National Taiwan University Medical School, Tapei, and China Pharmaceutical University. Nanjing, have shown OsteoSine can reverse bone loss in both ovariectomized rats and retinoic-induced, acute osteoporosis rats.

Other herbal and specialty supplement ingredients can affect bone health factors, including nutrient absorption, BMD and fractures. In conjunction with USDA, researchers from Baylor College of Medicine and the Texas Children's Hospital, Houston, studied the effect of prebiotic short- and long- chain inulin-type fructans on the bone mineral content in pubertal adolescents.(35) They found 8 g/d of mixed fructans significantly increased calcium absorption and enhanced bone mineralization during pubertal growth.

Black tea and garlic have both demonstrated improvement of BMD. A study conducted at Presidency College, Calcutta, India, found significant improvements in BMD in ovariectomized rats given black tea compared to animals taking placebo;(36) the black tea deficient diet was further linked to significant decreases in bone levels of calcium and phosphate. Using the same study model, the researchers showed garlic extract mitigates low BMDs and prevents increased plasma markers of bone resorption.(37)

Comparing conventional drugs to a preparation of proteolytic enzymes (as Wobenzym™ from Naturally Vitamins), Czech researchers revealed patients with long bone fractures experienced significantly reduced postoperative swelling and faster recovery with the enzyme formula, compared to the drugs.(38)

Osteoarthritis

Joints help join two bones in a few different ways. Fibrous joints, such as those holding teeth in place or those of the skull, are comprised of fibrous tissue and are considered immoveable. Semi-moveable www.naturalproductsinsider.com Page 5

[Bone Health] Vol. 10 No. 11 October 2005 joints have some movement and are called cartilaginous, as they rely on cartilage to link bones, such as those in the spine. Freely moveable joints—such as those of the knee, hip, elbow, shoulder and wrist—can move in various directions and are called synovial joints, due to the fluid that protects the linked bones from rubbing against each other. These joints can swing like hinges, rotate like a pivot, or swirl around in a ball and socket manner.

Joints are susceptible to many different problems, including injuries, structural degradation and inflammation. While injuries can be a cause or result of joint problems, disease is one of the biggest long-term joint issues people face. The most common joint disease is arthritis.

Joint cartilage is a layer of connective tissue that protects the ends of bones. When osteoarthritis (OA) is present, degradation of the cartilage progressively erodes the protection of joined bones. Bones then rub together, causing pain and a variety of discomfort. This type of arthritis most commonly affects both the weight-bearing joints of the knee, hip and lower back, as well as small joints in the neck, fingers and toes.

According to the Arthritis Foundation (AF), OA affects around 21 million Americans, especially women over the age of 45, and many more are at risk. However, the disease is not an inevitable consequence of aging; obesity, sports injuries and work-related accidents can be potent risk factors, as can dietary deficiencies.

Adequate intakes of vitamins and minerals are crucial to ensuring good bone health and lowering risk of OA. Antioxidants are especially important, as oxidative stress can increase the risk of the disease. While high antioxidant intake was found to reduce risk of cartilage loss and slow OA progression,(39) vitamin C has been specifically noted for its role in collagen production—type II collagen is found in articular cartilage. An animal study showed vitamin C stimulates collagen synthesis as well as synthesis of aggrecan, an aggregating proteoglycan that comprises 10 percent of cartilage weight.(40) Fellow antioxidants selenium and vitamins E, C, A, B6 and B2 have been indicated as preventive against OA. In another animal study, a combination of these antioxidants decreased OA incidence, due to their effects on reactive oxygen species (ROS).(41) In addition to antioxidants, vitamin D deficiency has been linked to increased risk of OA of the knee(42) and the hip.(43) Low vitamin D levels were also present in women with advanced OA of the hip.(44)

Glucosamine hydrochloride (HCL), a precursor of glycosaminoglycans (GAG) and proteoglycans found in the body, has long been a popular dietary supplement ingredient for joint health. Despite the positive benefits suggested by early studies of and OA, recent research has been mixed. Study results published in the journal Lancet indicated long-term glucosamine use delivers combined structure- and symptom-modifying effects, including inhibition of joint space narrowing.(45) This particular research generated much expert commentary and debate, as well as follow-up investigation.(46) World Health Organization (WHO) researchers found similar results, showing postmenopausal women taking glucosamine experienced no joint space narrowing and suggesting the supplement is the first disease-modifying pharmaceutical intervention for OA.(47) Also confirming the positive benefits, an Eastern European study concluded glucosamine retarded the progression of knee OA, significantly modifying symptoms such as joint narrowing, pain, function and stiffness.(48) Glucosamine also compared favorably to ibuprofen on anti-inflammatory reduction of pain and outmatched the drug in reducing pain associated with daily activities.(49) www.naturalproductsinsider.com Page 6

[Bone Health] Vol. 10 No. 11 October 2005

Chondroitin sulfate (CS), the most prevalent GAG in joint cartilage, has also demonstrated long term benefit to symptoms and progression of OA. CS significantly decreased pain during both daily activity and rest, with the effect lasting for more than a month.(50) Swiss trials confirmed CS helps relieve knee OA by inhibiting joint space narrowing, reducing pain and improving overall mobility.(51)

Glucosamine and chondroitin have developed into a popular combination product. In fact, the National Institutes of Health (NIH) is conducting a major trial, the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), which will use CS Bioactive, Bioiberica's chondroitin sulfate product. Other studies have shown the ingredient tandem reduces pain at rest, improves mobility and limits tenderness better in tandem than individually.(52)

MSM (methylsulfonylmethane) is a compound that contributes to the health of joint cartilage by supplying nutritional sulfur, which is a vital constituent of cartilage. While research on MSM specific to OA has been scant, Jeremy Appleton, N.D., director of scientific affairs for Cardinal Nutrition, which makes OptiMSM®, reported a recent trial of OptiMSM and knee OA has been completed and submitted for journal publication. "This is the best controlled study of MSM ever conducted, and it showed statistically significant reductions in joint pain, as well as improvements in performing activities of daily living," he said.

Sulfur plays an interesting role in joint health and arthritis. Keratin (as Cytadine FLX™ from Keratec), an animal-based protein matrix, is a good source of sulfur and cysteine, which promotes proteoglycan sulphation. Proteoglycans, sugar-protein polymers found in chondrocytes (cartilage cells), are necessary for joint strength and mobility, as well as resistance to compression. Heavy sulphation of joint proteoglycans is a natural occurrence, without which joints will deteriorate.(53)

Hyaluronic acid (HA) is a primary component of synovial fluid and has been studied for its effect on OA. Research has shown injection of HA, especially from non-animal sources, directly into the joint is a safe and effective treatment for knee OA.(54) These injections improve pain and stiffness by reducing levels of certain inflammatory cytokines in synovial fluid.(55) However, scientific evidence for a similar effect from oral HA supplementation is still in early stages.

In addition to synovial fluid, cartilage is an important protective structure in joints. Collagen, which is available as dietary ingredient in many forms, is a key component of cartilage, as well as tendons and ligaments crucial to joint protection and operation. Collagen derived from chicken sternum provides chondroitin, HA and type II collagen. 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,(56) as well as alleviate pain in OA of the knee and hip.(57) 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 OA of the knees, hips or hands.(58)

A different form of collagen, undenatured (native or unaltered) collagen type II (as UC-II® from InterHealth Nutraceuticals), reduced lameness and pain in study involving arthritic dogs.(59) A similar study on dogs with OA showed UC-II combined with glucosamine and chondroitin produced better improvements to pain and lameness than glucosamine-chondroitin alone.(60)

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Velvet antler, cartilage regrown on deer and elk antlers every year, is another animal source of collagen. In a study involving dogs with OA given either placebo or elk velvet antler (as Qeva, from Qeva Corp.) for two months, Qeva reduced pain and improved gait, performance and vitality.(61)

Various herbs have demonstrated safety and efficacy in symptomatic treatment of OA. Boswellia extract has been shown to decrease pain, extend walking distance and increase flexion in patients with OA of the knees.(62) Guggul, an oleoresin of the herb Commiphora mukul, has also reduced pain and stiffness, in addition to improving function and tolerability in older patients with OA of the knee.(63) Research has demonstrated Devil's claw (Harpagophytum procumbens), containing 60 mg harpagosides, is effective against OA of the spine, knee and hip;(64) various doses, of as much as 100 mg, of the herb have alleviated pain and other symptoms of acute and chronic arthritis in a rat study.(65) In a German study, white willow bark given to OA patients who experienced improved symptoms—including joint function, pain and stiffness—exhibited an analgesic effect.(66) Curcumin, the active compound in turmeric, produced mixed results in a study on OA of the canine hip or elbow.(67) According to the researchers, pain and lameness scores significantly favored dogs taking turmeric over dogs taking a placebo. Scientists have concluded Tripterygium wilfordii, also known as thunder god vine, can protect against degeneration of cartilage and aggrecan by inhibiting certain cytokine and gene expression associated in primary OA chondrocytes and synovial fluid.(68)

Among specialty joint supplement ingredients, enzymes have demonstrated beneficial effects on symptoms of OA. Bromelain reduced mild acute pain and stiffness, and improved joint function and overall well-being in one study of knee OA,(69) while improving pain and tolerability in knee OA in another study comparing the enzyme to conventional OA drug diclofenac.(70)

Research has also concluded cetylated fatty acid esters (as Celadrin® from Imaginetix) improve symptoms of chronic OA of the knee, including range of motion and overall function.(71) Early results from another study of knee OA patients, Celadrin topical cream led to significant improvement to quality of life, such as stair climbing and rising from a sitting position.(72) Another recent study, involving patients with OA in one or both knees, discovered topical Celadrin use for 30 days improved static postural stability and exercise trainability.(73)

Milk protein concentrate (as MicroLactin™ from Humanetics Corp) has also addressed OA joint pain and inflammation. According to Scott Steil, vice president of sales and marketing for Humanetics, MicroLactin reduces the build-up of neutrophils (inflammatory cells) in areas of soreness. MicroLactin helped relieve temporary pain, stiffness, inflammation and functionality of arthritic joints in two separate studies involving OA patients.(74)

Rheumatoid Arthritis

Swelling in the synovium can cause thickening of the synovial lining and subsequent release of enzymes that erode adjacent bone and cartilage. This is the pathology of rheumatoid arthritis (RA), a debilitating form of arthritis that affects 2.1 million Americans--again, mostly women. Pain is the primary symptom of RA, which is also characterized by swelling, stiffness, joint damage and lack of mobility.

Scientists are thus far unsure of the exact cause of RA and have few clues on how to prevent the disease. While RA is not curable, it can be controlled with proper treatment, including dietary www.naturalproductsinsider.com Page 8

[Bone Health] Vol. 10 No. 11 October 2005 intervention. Epidemiological evidence has highlighted numerous nutrients as keys to reducing incidence of RA. Deficiencies of certain vitamins, including antioxidant vitamins A, C D and E and beta-carotene, have been found in RA patients,(75) as were intakes of (76) and CuZnSOD.(77)

In addition to beta-carotene, the carotenoid astaxanthin has proven useful in RA as both an antioxidant and anti-inflammatory supplement ingredient. Scientists investigating astaxanthin's antioxidant mechanism of action demonstrated the non-vitamin A carotenoid inhibits nitric oxide production and suppresses gene expression associated with inflammatory diseases.(78) Acting as an anti-inflammatory in another trial, astaxanthin (as BioAstin® from Cyanotech) improved pain and mobility scores after four and eight weeks of supplementation in RA patients, compared to placebo.(79)

Inflammation is the hallmark of RA, thus scientists have focused on anti-inflammatory compounds in search of RA management tools that can inhibit various genes and antibodies, as well as cytokines and other pro-inflammatory immune cells.

Polyunsaturated fatty acids (PUFAs) have demonstrated significant anti-inflammatory effects in RA trials. Research has suggested the primary protective action of gamma linolenic acid (GLA) is inhibition of pro-inflammatory IL-1 and TNFalpha.(80) Benefits have been found using a variety of GLA sources. In one study, evening primrose oil addressed inflammation causes of RA, thereby reducing pain and morning stiffness.(81) Borage seed oil has produced similar results, reducing certain prostaglandins and leukotreines, as well as reducing generation of arachidonic acid oxygenation products in RA research.(82) RA study subjects taking black currant oil, which contains both GLA and alpha linolenic acid (ALA), also experienced cytokine and prostaglandin activity.(83) While ALA alone failed to suppress inflammation and joint tissue injury in one study,(84) this benefit was achieved by combined supplementation of GLA and ALA in another study.(85)

A popular anti-inflammatory ingredient, essential fatty acids (EFAs) in have been shown to control parameters of pro-inflammatory prostaglandins, cytokines and chemokines in RA patients.(86) Fish oil EFAs have also suppressed production of degradative enzymes and impacted intracellular signaling pathways, transcription factor activity and gene expression.(87) On the strength of this immune-modulating activity, fish oil supplementation has resulted in significant improvements to RA symptoms, including tender and swollen joints, morning stiffness, joint pain, fatigue and grip strength.(88) A 2005 research review of human studies revealed fish oil is more effective alone than combined with conventional drugs.(89)

A study combining eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), key components in fish oil, with New Zealand green-lipped mussel, an omega-3 EFA ingredient, (as Lyprinol® from Pharmalink) lead to reduced RA symptoms and dependency on drug therapy in a study involving men and women with RA.(90)

In another study, Lyprinol alone inhibited production of certain prostaglandins; researchers linked the benefit to the supplement's content of omega-3 EFAs and assorted antioxidants.(91)

There is some overlap of OA and RA supplementation. While useful against OA, type II collagen is also anti-inflammatory and can inhibit T-cell activity, alleviating RA symptoms. Undenatured type II collagen (as UC-II) improved joint pain, morning stiffness, swelling, flare duration, range of motion in www.naturalproductsinsider.com Page 9

[Bone Health] Vol. 10 No. 11 October 2005 one study of women with RA.(92) Similarly, hydrolyzed type II collagen significantly reduced tender and swollen joints in patients suffering severe, active RA.(93) Other research has shown bovine tracheal type II collagen can reduce rheumatoid factor and TNFalpha, which helps reduce swollen and tender joints and duration morning stiffness in RA patients;(94) the researchers noted this effect can sometimes result in remission.

Dimethylsulfoxide (DMSO), a precursor to MSM, has antiphlogistic and analgesic properties and has been shown to improve RA symptoms, including morning stiffness and hand strength.(95) Researchers have also reported DMSO impacts microcirculation and fibrin formation associated with inflammation.(96)

While the sulfur and cysteine in Cytadine FLX can help cartilage health in OA, the cysteine alone can address inflammation in RA. Researchers from the Institute of Rheumatology, Warsaw, Poland, discovered deteriorated joints, such as those in RA patients, exhibit defective cysteine metabolism;(97) they further noted RA patients are deficient in -CL, which has anti- inflammatory properties. British researchers reported cysteine can contribute to increased presence of taurine by increasing levels of a crucial catalyst.(98) Keratin also contains building blocks for antioxidant proteins, such as glutathione, that can defend against radical oxygen species (ROS) in RA.(99) Furthermore, the cysteine and essential amino acids in keratin help produce new joint proteins crucial to joint health.(100)

As in OA, herbs can improve RA symptoms, primarily due to anti-inflammatory effects. Studies have shown ginger can relieve RA symptoms by impairing prostaglandin and leukotriene production spurred by increased arachidonic acid oxygenation.(101) Similar relief was also linked to supplementation with guggul, which decreased joint swelling in an animal RA model,(102) and cat's claw, which delivers antioxidant protection and inhibits pro-inflammatory producing NFkappaB gene expression.(103) Further in vitro study revealed cat's claw (as Vincaria® from Rainforest Nutritionals) combined with a mineral complex (as SierraSil® from Sierra Mountain Minerals) can suppress cartilage degradation and inflammation.(104) According to Mark Miller, Ph.D., lead study researcher, the herb-mineral combination appeared to have potent anti-inflammatory effects on joint pain, probably due to suppression of gene expression. SierraSil, a blend of 65 naturally occurring macro and trace minerals, has also improved joint flexibility and quality of life in arthritis patients in a study expected to be published in 2005. Anti-inflammatory activity useful in RA was also exhibited by novel stinging nettle extract Hox alpha, which suppressed IL-1 pro-inflammatory actions in a 2002 German study.(105) In the same year, the researchers reported the hox alpha extract altered the T-cell response that often leads to dendritic cell maturation—a possible component of RA development.(106)

Andrographolide, a lactone from Andrographis paniculta, is theorized to down-modulate both humoral and cellular adaptive autoimmune responses, which can possibly translate to RA activities. Chilean researchers concluded andrographolide (as Paractin™ from HP Ingredients) interfered with T cell proliferation and cytokine release in response to allergenic stimulation in both laboratory and animal autoimmune models.(107) Boswellia has also exhibited autoimmune-related anti- inflammatory effects that can carryover to RA treatment. Researchers from Ohio State University Medical Center, Columbus, recently investigated boswellia's actions at the genetic level.(108) They identified 522 genes induced by TNFalpha and found 113 of those genes are sensitive to boswellia (as 5-Loxin® from Laila Nutraceuticals). The scientists made special note of the regulatory effect of www.naturalproductsinsider.com Page 10

[Bone Health] Vol. 10 No. 11 October 2005 boswellia on TNFalpha-inducible of VCAM-1 and ICAM-1 gene expression. Other research has shown various Boswellia preparations can inhibit leukotriene activity and reduce inflammation in RA patients.(109)

The structures of bones and joints are more complex than they may initially appear, and the molecular level of bone disease, including osteoporosis and various forms of arthritis, is even more complex. The research into the biochemical actions of numerous natural product ingredients is challenged to keep pace with the continuous findings on nutritional deficiencies and cellular mechanisms of action associated with these bone problems. If success can be measured in increments, the supplement industry has triumphantly built up an abundant number of natural options that are being increasingly proven to help manage the development, progression and symptoms of these bone diseases. Such a broad spectrum of researched ingredient choices has allowed manufacturers to formulate bone and joint health products that combine benefits, such as anti- inflammatory actions for RA or bone forming actions for OA. Future positive, quality trials will only strengthen this roster of bone and joint healthy ingredients, and promote greater product development.

References:

1. Englund U et al. “A 1-year combined weight-bearing training program is beneficial for bone mineral density and neuromuscular function in older women.” Osteoporos Int. 16, 9:1117-23, 2005. http://www.springeronline.com/sgw/cda/frontpage/0,11855,5-10054-70-1102329-0,00.html

2. Swenson KK et al. “Interventions to prevent loss of bone mineral density in women receiving chemotherapy for breast cancer.” Clin J Oncol Nurs. 9, 2:177-84, 2005.

3. Shea B et al. "Calcium supplementation on bone loss in postmenopausal women." Cochrane Database Syst Rev. 1:CD004526, 2004. www.medlib.com/spi/cdsr.htm

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