Bone and Joint Health
Part 2: Dietary Supplements

By Stephen Holt MD

Stephen Holt MD is the President and CEO of BioTherapies Inc. is a company that is involved in the research and development of dietary supplements. He advises contact with a healthcare giver rather than self medication and makes no treatment recommendations.

Introduction.
In part one of this two part series on nutritional approaches to bone and joint health, many micro and macro nutrients with health giving benefits on skeletal function were identified. Several standard medical textbooks caution against food fads and what are described as unwarranted claims about the relationship between diet and osteoarthritis. However, nutritional approaches to the management of osteoarthritis and osteoporosis are used increasingly as it becomes clear that many conventional medical options have failed to prevent or treat these disorders of bones and joints1 in a safe manner2. Drug interventions for osteoarthritis and osteoporosis commonly cause iatrogenic problems and are sometimes dangerous or fatal.2,3 The objective of this article is to highlight evidence that exists to support the use of certain dietary supplements in the prevention and/or treatment of osteoporosis and common types of arthritis.

Failure of conventional therapy.
The management of osteoarthritis and osteoporosis in conventional medical practice has centered around interventions such as rehabilitation, patient education, exercise or physiotherapy and drug treatment. In more advanced cases of osteoarthritis surgical interventions are required, including the last resort of total joint replacement surgery4 . The principle indication for surgery in osteoarthritis is failure of conventional medical therapy. Frequent failure of conventional medical options result in frequent surgical interventions. Unfortunately, conventional medical therapy has not taken sufficient account of the many new nutritional options to prevent or treat common bone or joint disease. Therefore logic dictates that a more assertive use of nutritional interventions and selected dietary supplements may help reduce the need for surgical intervention. This point of view may not be a “voice in the wilderness”.

The limitations of non-steroidal anti-inflammatory drugs (NSAID).
The most commonly used medication for the treatment of osteoarthritis are non steroidal anti-inflammatory drugs (NSAID)2, including aspirin. Conventional medical text books often promote the use of aspirin as the drug of choice for arthritis because of its analgesic and anti-inflammatory properties. However, the use of other NSAID (e.g. ibuprofen, naproxen, suldinac etc.) by prescription or over the counter (O.T.C.) purchase has exceeded the general use of aspirin in many countries3 . NSAID work in arthritis by inhibiting the lipo-oxygenase conversion of lipids to prostaglandin precursors such as arachidonic acid2,3,5 .

Unfortunately NSAID therapy of osteoarthritis possesses many disadvantages and limitations1-3,5 . The improvement of pain and limitation of movement in arthritic joints is only relieved temporarily by the use of NSAID. Chronic dosing with these agents is necessary and they all share a potential for causing serious adverse effects such as peptic ulceration, bleeding from both the upper2 and lower digestive tract3, damage to the liver and promotion of renal impairment, especially in the elderly2 .

NSAID are the commonest reason for adverse event reporting to the Food and Drug Administration in the US. Clinical studies of admissions of patients to hospital with life-threatening gastrointestinal bleeding indicate that in more than 60% of circumstances, the individual has been taking aspirin or NSAID2. Follow up studies of patients who have been treated for NSAID related gastrointestinal hemorrhage show that a significant proportion of these patients continue to use NSAID in an inappropriate manner2,6-15. Studies which have attempted to assess the appropriateness of NSAID use by patients implied that in some circumstances these drugs are inappropriately self-administered and they may be over prescribed2,6-15 .

NSAID usage has been described as a focus of major public health concern2,3. Using drugs that lower gastric acid or protect the mucosa of the stomach or duodenum is common practice but this polypharmacy results in iatrogenic problems or intolerance of treatment3 It is very significant that recent studies imply that NSAID chronic usage may actually result in damage to joints which are already the seat of damage from osteoarthritis1
.
A recent study published in Annals of Internal Medicine by Dr Robyn Tamblyn PhD and her colleagues2 points out the dangers of NSAID use in the general population. This information is not new and Table 1 lists some of the many studies that show the monotonous reporting of life threatening diseases precipitated by NSAID and unfortunate but avoidable deaths. Dr Tamblyn and her colleagues2 report both unnecessary prescribing of NSAID and deficiencies n the management of adverse effects related to NSAID administered by prescription. These findings echo earlier studies6,7,9,15 that point out the dangers of NSAID, their misuse by patients and physicians and their contribution to avoidable morbidity and mortality.

Disadvantages of drug therapy of bone and joint disease.
Other pharmaceutical interventions for osteoarthritis include the use of muscle relaxants which may be habit forming and the taking of analgesic drugs. The American College of Rheumatology guidelines for the therapy of osteoarthritis recommend acetaminophen as a first-line option. However acetaminophen has suboptimal anti-inflammatory effects on joints and its analgesic actions are short lived. Many arthritis sufferers may take as much as 4 grams of acetaminophen per day to control pain and at these dosage levels the safety of this drug is in question, especially in chronic dosing schedules and if alcohol is consumed concomitantly.

Injections of steroids into joints may afford temporary relief in the presence of information but these agents have chemical characteristics that may even aggravate synovial inflammation, at least on a temporary basis. So disappointing has been standard pharmacological interventions for arthritis that several contemporary accounts of conventional medical therapy for this disorder characterize drug therapy as being one of the least important components of an effective management program for arthritis.

The desperation of some patients to achieve pain relief in the face of existing therapies is highlighted by the recent release in the US in 1997 of drugs that combine opioids with NSAID (hydrocodone and ibuprofen). These drugs are habit forming and may compound the problems of the affected arthritic who may become “a drug addicted arthritic”. A consideration of these limitations of conventional medical therapy for osteoarthritis have played a major role in producing disenchantment in both patients suffering from osteoarthritis and in healthcare givers who are charged with the responsibility of treating this apparently recalcitrant disease1 .

Osteoporosis treatment is disappointing
The treatment of established osteoporosis is even more disappointing in outcome than the treatment of osteoarthritis using conventional medical therapy. Not enough attention has been paid to the prevention of osteoporosis, despite the realization that its occurrence is universal in the elderly. Acute or chronic pain as a result of osteoporotic fractures is often treated by NSAID and adjunctive physical therapy or the application of cumbersome, orthopedic garments. These interventions are necessitated by repeated bone fractures or the common coexistence of osteoarthritis with osteoporosis. Calcium supplementation for men or women with osteoporosis with or without vitamin D supplements is commonly used to treat osteoporosis but it has questionable efficacy and the attendant risk of producing hypercalcemia.

Hormone replacement therapy (HRT) has unquestionable benefit in preventing progression of osteoporosis in the postmenopausal female but it has risks including: the causation of endometrial cancer, the raising of blood lipids and an increase in the risks of coronary and cerebrovascular thrombosis5 . A real risk of breast cancer exists with HRT and common side effects of HRT such as weight gain, bloating and withdrawal bleeding limit its use.

The use of bisphosphonates that inhibit bone resorption has met with variable success in the treatment of osteoporosis. Alendronate sodium is a bisphosphonate. Clinical trials16,17 show that this drug has an ability to variably prevent osteoporotic fractures of the hip, vertebral column and wrist, with reductions of fracture incidence in these locations of 51%, 90% and 48%, respectively. However, the side effects and limitations of the use of alendronate may cast doubt on the overall therapeutic value of alendronate and other bisphosphonates (Table 2). The risk/benefit ratio of the use of bisphosphonates in the treatment of osteoporosis may require reappraisal. Unfortunately higher doses of biphosphonates can inhibit bone mineralization16 and long term safety information on the use of bisphosphonates is not available.

Calcitriol is an activated form of vitamin D that has produced variable benefits in patients with osteoporosis. Unfortunately, its use is limited by frequent side effects which may threaten renal function. To date, in the authors opinion, no effective conventional drug therapy has emerged for the treatment of osteoporosis. These circumstances prompt a review of several dietary supplements that have potential therapeutic benefit in the management of osteoarthritis and/or osteoporosis.

Soy Isoflavones
The soy isoflavones genistein, daidzein and glycetein have been shown in animal and human studies to prevent and reverse bone loss due to estrogen deficiency18,19 . These isoflavones are modulators of estrogenic activity and in states of estrogen deficiency, such as following the menopause, isoflavones are pro-estrogenic18. In menopausal and post-menopausal females, soy isoflavones have been demonstrated to reduce unpleasant menopausal symptoms, promote cardiovascular health and increase bone density in post menopausal subjects18,19 . Dr Gregory L. Burke, MD of Wake Forest School of Medicine in North Carolina has proposed that dietary soy supplements may be ideal alternatives to traditional hormone replacement therapy (HRT) with synthetic or animal derived estrogens20,21 . This is a timely proposal in view of doubts about the risk/benefit ratio of HRT19 .

Research supported by the Illinois Soy-bean Program Operating Board by Dr B. H. Arjmandi, MD and his colleagues20 suggest that diets supplemented with soy protein isolates containing isoflavones may be an effective way of preventing post menopausal bone loss. Several animal research studies show that genistein may be useful in retaining bone mass in the estrogen deprived state20 . Laboratory studies show that genistein and other compounds that inhibit key enzyme pathways in cell metabolism may surpress osteoclastic function, thereby reducing bone resorption20.

The mechanism of action of genistein in preventing osteoporosis may be non-estrogenic in some circumstances20 . The most compelling evidence that soy isoflavones may maintain bone health emanates from studies from Dr J.W. Erdman, MD and his colleagues20 at the University of Illinois. In one arm of a study that was designed to investigate the cholesterol lowering effects and other health benefits of supplementation of the diet with soy protein containing isoflavones in post menopausal women, Dr Erdman and his colleagues studied changes in bone density and bone mineral content in 66 post menopausal females over a period of 6 months20 . Among these 66 females one group received soy protein, with 1.39 mg of total isoflavones per gram of protein, a second group received soy protein, containing 2.25mg of total isoflavones per gram of protein and a third group received casein in a nonfat, dry-milk format8 . In this study, the soy protein supplementation of the diet was further supplemented with calcium to a level equivalent to that provided by the nonfat, dry-milk20.

Measurements of total and regional bone mineral content and density was assessed prior to the administration of the test diet and 6 months after the receipt of the diet20 . These measurements were made by dual-energy xray absorptiometry. Both bone density and mineral content were found to increase in the lumbar spine in the group that received soy protein containing 2.25mg of total isoflavones per gram of protein, delivered in an amount of 40g of protein per day in the diet. These findings are consistent with the opinion that isoflavones of soy origin are very useful in the maintenance of bone health and perhaps the treatment of osteoporosis20 .

Soy isoflavones, with or without accompanying soy protein are available as dietary supplements (Phyto-Est, Genista, Menobalance, Soy-Life, etc) and they have become first line choices for many menopausal females who have rejected HRT, cannot tolerate HRT or exhibit contra-indications to HRT18-20 . Several anecdotal reports have indicated that females receiving HRT have been able to lower the dose of HRT that they are taking or cease HRT supplements as a consequence of the self-administration of soy isoflavones in dietary supplement format22 .

Many, clinical gynecologists have recommended soy based diets to their patients in order to suppress menopausal symptoms and promote health in the post menopausal period. It has been argued that the best way to achieve the health giving benefit of soy is to eat tofu or drink soy milk. Unfortunately much commercially available tofu or soy milk is not standardized for its isoflavone content18,19 . Even when tofu contains isoflavones, at least one half a pound of tofu needs to be consumed daily to provide adequate isoflavones to obtain the desired health benefits in the menopausal or post menopausal female19 . For this reason, many healthcare givers and mature females have used the convenience of dietary supplements where as much as 50-60mg of total isoflavones can be taken in as little as 3 capsules daily19.

Individuals who have argued that isoflavones may be toxic have failed to acknowledge that dosage of isoflavones recommended in dietary supplements, such as Phyto-Est, is quite modest and it is well within the range of isoflavone intake in individuals who consume soy based diets18,19 . Soy-based diets have been consumed for centuries in South East Asia without any evidence whatsoever of any adverse effect18,19 . In fact, many Asian and Oriental females who consume soy based diets have been shown in well controlled epidemiological studies not to be as troubled by menopausal symptoms in comparison with females in Western Society18. In addition, epidemiological evidence supports that soy based diets containing isoflavones, may have the added benefit of reducing risks of coronary artery disease, hormone dependent cancer of the breast and notable reductions in the prevalence of osteoporosis and perhaps osteoarthritis18,19,21 .

Cartilage Supplements
Bovine, chicken and shark cartilage have been proposed as remedies of natural origin for osteoarthritis and osteoporosis23. In part one of this two part summary of a nutritional approach to bone and joint health several ingredients were identified in cartilage supplements that may exert health giving benefits for bones and joints23. Most evidence of a beneficial effect of cartilage supplements in osteoarthritis, sports injuries and osteoporosis has resulted from clinical studies in which shark cartilage was used23 . There are many shark cartilage supplements and these may differ in their origin, mode of manufacture and quality23 . Therefore, studies with one certain brand of shark cartilage can only be applied to the brand in question24,25 .

Studies in animals and humans of the brand Cartilade (100% pure shark cartilage) have been recently reviewed in depth23,25 . Leading veterinarians have proposed that shark cartilage in the form of Carti-Vet (for small animals) and Cartequine (for horses) have stated that these dietary supplements have a role in the complementary therapy of chronic arthritis and acute joint or bone problems in animals23,25. The components of cartilage that may exert benefits in the management of osteoarthritis and osteoporosis are summarized in Table 3.

Cartilage supplements contain chondroitin, glucosamine-like compounds, calcium and phosphorus in a 2:1 ratio, anti-angiogenic proteins and Type II collagen2,3 . Each of these components has been shown in one or more studies in animals or humans to exert beneficial effects in arthritic disorders1,23,25 . Elegant research studies in animals show that the oral administration of foreign (derived from a different animal species) Type II collagen will prevent immune-induced arthritis that has been precipitated by the injection of the foreign Type II collagen into test animals26 .

The demonstrable anti-inflammatory effects of glucosamine and chondroitin are so important and plausible that these agents are being used alone or in combination to treat arthritis1 . Recommendations to use chondroitin and/or glucosamine are at the heart of the thesis proposed in the best selling book “The Arthritis Cure” by Dr Jason Theosadakis and his colleagues1 . These dietary supplements are being taken by to hundreds of thousands of arthritis sufferers in several countries, with increasing evidence of beneficial effects. This has occurred despite the availability of cartilage supplements which not only contain chondroitin and glucosamine-like compounds, but they are also composed of other substances that may promote bone and joint health1,23,25 . This has led to some health care givers using shark cartilage as a more holistic dietary supplement than chondroitin alone or in combination with glucosamine23,25 .

Dr Steven Levine PhD of the Allergy Research group (California) presented exciting information at the Collegum Humanum Symposium22 held in Burgenstock in Switzerland (June, 1997), on the potential benefit of shark cartilage in the management of Connective tissue disorders and autoimmune joint diseases caused by diseases such as scleroderma. Connective tissue diseases are a common cause of joint problems that are very resistant to standard medical therapy.

There are potential problems with the use of cartilage supplements of bovine or shark origin. Bovine cartilage may be obtained from locations in the world where transmissible sclerosing encephalopathy (mad cow disease) may occur25 . For this reason, it is better to select a bovine cartilage supplement that has been obtained from cows that are “certified free” of this disease that is universally fatal when contracted by humans.

Recent concerns about heavy metal contamination in certain shark cartilage products have been expressed. Products of marine origin may be contaminated with lead or mercury and these heavy metals may cause toxicity including irreversible damage to the brain or immune system. Only shark cartilage that is known to be free of unacceptable levels of heavy metals should be used as a dietary supplement.

Chondroitin Sulphate
The recognition that chondroitin is a natural substance that can potentially treat osteoarthritis1,27 caused a stampede for the purchase of chondroitin supplements in health food stores, a staggering increase in the price of this bulk commodity and even law suits in the dietary supplement industry concerning about combination products with this agent and glucosamine. Chondroitins are complex sugars that form an integral part of the matrix of cartilage1 . Chondroitins are components of complex molecules called proteoglycans and they serve to permit the hydration (attract water) of cartilage1 . Chondroitin sulphate is found in many tissues but they are particularly abundant in articular cartilage. These complex molecules facilitate the absorption of nutrients into cartilage and they inhibit the action of enzymes that may damage the matrix of cartilage. Chondroitins assist in stimulating the synthesis of several components of the cartilage matrix including collagen, glycosaminoglycans and proteoglycans. Therefore, chondroitin sulphate is chondroprotective and it is a natural anti-inflammatory agent1,27 .

Clinical trials using chondroitin sulphate1,28-32 by injection or by oral administration have shown benefits in the treatment of arthritis in terms of pain reduction and enhanced joint mobility1,27 . These studies1,27-32 were notable by the absence of side effects of patients who received chondroitin which in some circumstances was compared with the efficacy and tolerability of commonly used NSAID. Observations of the beneficial therapeutic effects of chondroitin were often equivalent and sometimes superior to those achieved with NSAID1,27-32 . Whilst not as many studies of the benefit of chondroitin sulphate administration in arthritis exist in comparison with studies reported with NSAID use, considerable benefit of chondroitin sulphate administration appears apparent and worthy of much further scientific exploration1,27-32 .

Glucosamine
Glucosamine and related compounds are major components of proteoglycans and they are vital for the synthesis of glycosaminoglycans, which are compounds that hold water in the supporting structure of cartilage1,27 . Glucosamine is composed of glucose and the amino-acid glutamine27. This compound stimulates chondrocytes to produce glycosaminoglycans and collagen1,27 . The stimulatory effect of glucosamine on the production of the supporting structures of cartilage and its protective effects may assist in repairing the damage that is present in cartilage in the osteoarthritic joint23,25 .

Several studies including double blind placebo control trials have shown that oral glucosamine administration may improve symptoms in osteoarthritis in a statistically significant manner compared with placebo34-42 (Table 4). Studies of glucosamine administration by injection or oral dosing in patients with arthritis have shown therapeutic equivalence with NSAID (Table 4). These studies support the notion that glucosamine has a chondro- protective effect and this compound may work synergistically with chondroitin sulphates1,27 .

The synergistic potential of chondroitin and glucosamine has been proposed as an ideal dietary supplement combination for the treatment of osteoarthritis1 . Combinations of chondroitin and glucosamine are rapidly gaining in popularity but consideration of accumulated evidence to date1,23,25,27,43 implies that their benefits in osteoarthritis are even more enhanced if they are cooadministered with antioxidants, such as vitamin C. More forward thinking formulators of dietary supplements have added essential trace minerals to chondroitin and glucosamine supplements (C-G Plus, BioTherapies Inc., Fairfield, NJ) in order to assist in the treatment of osteoporosis that almost invariably accompanies osteoarthritis especially in the elderly. More complex formulations of chondroitin, glucosamine, trace elements, and antioxidants such as vitamin C, will undoubtedly supersede the use of glucosamine or chondroitin alone as dietary supplements for the promotion of joint health. Management of osteoarthritis must take account of coexisting osteoporosis44.

Combining shark cartilage with chondroitin or glucosamine
Among the most difficult of joint disorders to treat are those that occur during sport or excessive exercise23,25,27 . The popularity of “working out” has resulted in thousands of “week-end warriors” who suffer varying degrees of joint discomfort as a consequence of sports injury. Sports injury bear much similarity to occupational joint injuries that result from repetitive movements of groups of joints and muscles. Evidence has accrued that shark cartilage supplements are useful in the management of sports injury23,25 , but more recently innovative trainers have recommended the addition of glucosamine and chondroitin supplements to the use of shark cartilage in sports injuries.

Ken Kaiser the renowned baseball umpire has claimed on TV and in the media that the Cartilade form of 100% pure shark cartilage has transformed his career by treating severe osteoarthritis in both his knees that occurred due to the repetitive stress of bending45. In a personal interview with the author46 , Mark Letendre, the head coach of the San Francisco Giants baseball team has reported success with the use of Cartilade combined with glucosamine supplements in the rehabilitation of professional athletes with bone and joint problems caused by sporting activities.

Essential Fatty Acids (EFA)
Essential fatty acids (EFA) have protean physiological functions47-51. Arthritis is listed among the symptoms and signs that may occur as a consequence as EFA deficiency47,48 . There are two principle classes of essential fatty aids that have received much attention as health giving dietary supplements47,48 . These include fatty acids of the omega-6 series which are found principally in vegetables and seeds and fatty acids of the omega-3 series which are found mainly in fish oil or in pre cursor formats in flax seed or soy bean oil49,50 . These classes of omega fatty acids are ideally given in ratios where preferential supplementation of omega-3 fatty acid intake (fish oil) is important in individuals consuming a typical Western diet49,50. The need for omega-3 supplementation is related to the observation that American and European diets are usually abundant, perhaps overabundant, in omega-6 fatty acids47-50.

Nutritionists often recommend that individuals take between 10% and 15% of their total daily calorie intake in the form of EFA48. The main way in which omega fatty acids promote health is believed to be related to their ability to influence the production of prostaglandins of various types which may have pro-inflammatory or anti-inflammatory or other actions46,48. The production of various series of prosta-glandins is quite dependent on the type and the quality of oil and fat that is present in the diet46,48. Thus the ratio between omega-6 and omega-3 fatty acids is important to maintain in health. It has been proposed that for optimal health maintenance the ratio between omega-6 and omega-3 fatty acids is approximately 4 to 1 in an optimal diet47,48. This may be the ratio at which essential fatty acids can exert their important functions in the formation of cell membranes and prostaglandin metabolism.

It is estimated that the average diet in Western Society may contain more than 10 times the amount of omega-6 fatty acids that are required for health because these fatty acids are contained in low quality oils that are purveyed “en masse” in the grocery industry. Fish oil contains two principle health giving omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA appears to have potent effects in suppressing inflammation47,48,51 .

Therapeutic uses of omega fatty acids in the treatment of arthritis has focused largely on the demonstrated value of omega-3 fatty acids of marine origin in the treatment of immune arthritis, especially rheumatoid disease47,48. Many clinical studies have shown the therapeutic effect of the use of dietary supplementation with fish oil in the treatment of a variety of acute and chronic inflammatory disorders such as rheumatoid arthritis, psoriasis and inflammatory bowel disease47,48,50. Several studies of the addition of fish oil to the diet in the treatment of rheumatoid arthritis have indicated quite consistent benefit48 . Double blind placebo controlled studies of the administration of EPA in the treatment of rheumatoid arthritis have shown reductions in joint pain and decrease in joint stiffness49.

Many other studies demonstrate health benefits of fish oil supplementation of the diet in the treatment of rheumatoid disease and osteoarthritis (Table 5). The mechanism of action of fish oil in the treatment of inflammatory arthritis is probably related to an ability of EPA and DHA to alter immune function. EPA is known to reduce the production of compounds that mediate inflammation in tissues such as leukotrienes48,50 . Leukotriene B4 has been implicated in the promotion of joint inflammation and this compound is synthesized from omega-6 fatty acids. It is proposed that supplementation with the Omega-3 fatty acid, EPA, will cause a preferential production of leukotriene B5, which is less likely to provoke of inflammation in joints48,50.

Studies in animals and humans have confirmed that the administration of fish oil will reduce leukotriene B4 production in association with a corresponding increase in leukotriene B5 production50. These changes in leukotriene production have been correlated with changes in measures of joint inflammation. The anti-inflammatory effects of fish oil may also be related to reductions in the production of thromboxane A2, inhibition of the synthesis of cytokines (e.g. interleukin-1-beta) and tumor necrosis factor48,50. Components of fish oil are effective scavengers of free radicals which are well recognized as playing a role in the causation of chronic degenerative disease such as osteoarthritis47,48,50.

The amount of fish oil required to suppress inflammation is much higher than the amount required for the promotion of general health such as promoting cardiovascular health47,48,50. It has been repeatedly demonstrated that fish oil given in crude liquid format or regular encapsulated products, produces common and unpleasant side effects including belching, indigestion, foul halitosis and altered bowel habit with diarrhea47-51. These side effects can be overcome to a major degree by presenting high concentrations of fish oil in delayed-release capsules51.

Dr A. Belluzzi MD and her colleagues51 have shown recently that enteric coated capsules of fish oil (delayed release) enhance the absorption, bioavailability and tolerability of high doses of fish oil that are needed to suppress inflammation. These researchers51 performed a one year, double blind placebo-controlled study to investigate the efficacy and tolerability of a delayed release fish oil preparation in the treatment of inflammatory bowel disease. This study concluded that enteric-coated fish oil preparations (delayed release) were effective and well tolerated in the treatment of inflammatory bowel disease51.

Thus, it is ideal to present fish oil in an enteric coated or delayed release format to enhance efficacy and reduce unpleasant side effects of the large doses of fish oil that may be necessary to treat chronic inflammatory disorders such as arthritis and inflammatory bowel disease51 . The only dietary supplement containing high concentrations of EPA and DHA (omega-3 fatty acids of fish oil) in a delayed release format available in the US market is the product Fisol (BioTherapies Inc., Fairfield NJ).

Boswellia: An Ayurvedic, Anti-inflammatory, Phytonutrient
Boswellia is extracted from gum resins that are derived from the tree Boswellia serrata52 . It belongs to a class of compounds called guggals which have been described in ancient Ayurvedic medicine as possessing potent, anti-rheumatic properties52,53 . The active ingredients of boswellia extract are beta-boswellic acid and other similar triterpene acids. Boswellic acids and related compounds appear to be inhibitors of leukotriene production and they directly inhibit the 5-lipoxygenase enzyme without affecting the activity of cyclooxygenase enzyme activities52,54. This means that boswellic acids and associated compounds may be specific inhibitors of the inflammatory mediating leukotrienes but they do not exert significant effects on prosta-glandin synthesis52.

Many studies have confirmed the benefit of standardized Boswellia extract in the treatment of osteoarthritis and rheumatoid arthritis52 . Boswellic acids can protect against artificially induced arthritis in animals and anti-inflammatory actions have been well documented in soft tissue inflammation52,53 . Detailed laboratory experiments have shown that extracts of Boswellia serrata resin exert a chondroprotective function by reducing the activity of several enzymes that degrade important structural components of cartilage, such as glycosaminoglycans52.
Some scientists have referred to Boswellia as a non-steroidal anti-inflammatory agent54 but this is not to be confused with standard non-steroidal anti-inflammatory drugs (NSAID), such as ibuprofen and naproxen, which often cause stomach upset and may produce stomach or duodenal ulcers52 . It is notable that Boswellia exhibits anti-ulcerogenic activity52 in contrast to the ulcerogenic potential of NSAID3 .

Dietary supplements containing standardized extracts of Boswellia have been reported repeatedly to produce reduction in joint swelling, increase in joint mobility, reduction in morning stiffness, corticosteroid sparing activity and overall improvements in quality of life in patients with a variety of rheumatological disorders such as: osteoarthritis, gouty arthritis, rheumatoid disease, nonspecific rheumatism, fibrositis, myositis, cervical spondylosis and back-ache due to vertebral disorders52-54. Boswellia is finding an increasing role as a dietary supplement or in topical format in the treatment of arthritis in humans, dogs with hip dysplasia and lame horses52 . The importance of standardization of Boswellia products for their content of boswellic acids and pentacyclic triterpene acids should not be underestimated52.

Combining Dietary Supplements with Drugs or Each Other?
Little research exists on the safety or efficacy of the co-administration of synthetic, anti-arthritic drugs used in the treatment of arthritis with remedies of natural origin used for the same purpose. Apart from drug interaction potential, there may be benefits or disadvantages of combining natural or synthetic remedies in the treatment of bone and joint disease. For example, fish oil in high doses has a natural anti-coagulant effect which would be unwanted in a patient who is taking an NSAID that could cause gastrointestinal ulceration and bleeding.
Shark cartilage, chondroitin or glucosamine supplements appear to be quite compatible with conventional medical therapy for arthritis25 . Such remedies of natural origin may result in an ability of a patient to reduce their dosage of standard synthetic, antirheumatic medications. The side effects of NSAID may be dose related3 and the application of a dietary supplement that would spare the need for chronic dosing with dangerous drugs such as NSAID or corticosteroids would be a valuable option. In this regard, the steroid sparing effect of the Boswellia52 is of particular interest and much further research in combining natural and synthetic therapies is required. Anti-arthritic therapies of the future may result from combinations of synthetic and natural treatment agents.

The knowledge that remedies of natural origin may be synergistic in their beneficial effects is deeply rooted in traditional medical systems, such as Ayurvedic55 and traditional Chinese medicine56 . In Ayurvedic medicine Boswellia has been combined with other botanical agents in effective treatment regemes52. Traditional Chinese medicine has proposed herbal formulas for the treatment of arthritis but a clear understanding of the reason for the Chinese habit of combining multiple botanical agents in Chinese remedies has not been clear in either traditional medical writings or in modern research56. In fact, modern biotechnology research, using signal transduction technology57 , seems to question the need for complex botanical mixtures because single extracts of herbs have been shown to have potent biological effects that can be inferred to be health giving.

The author believes, based on his experience of studying traditional Chinese medicine during academic visits to Chinese Universities, that the art of formulation of complex herbal remedies in traditional Chinese medicine occurred as a consequence of the need for Chinese physicians to promote their remedies as unique and proprietary to their own practice. This is not necessarily a criticism of Chinese herbal formulations because almost all contain one or more active botanical ingredients for a specific health purpose56.

There are many commonly used formulations of Chinese herbs that have been used in the treatment of acute and chronic arthritis56. Treatment of the early phases of rheumatoid disease by Chinese herbalists often involves the use of two herbal concoctions known as Ma-huang-chia-chu-tang and Ma-hsing-i-kan-tang56 . These two traditional Chinese remedies have been reported to be quite effective in reducing inflammation and they have in common the inclusion of Ma-huang, apricot seed and liquorice. However, one of these mixtures is more complex in formulation than the other but evidence for the difference in formulations as a function of efficacy remains unclear. Many traditional Chinese medical formulas have been approved by regulatory affairs bureaus in South East Asia. In fact, more than 20 herbal formulas are commonly used in Japan for chronic rheumatoid arthritis or osteoarthritis and some have been approved by the Japanese Food and Drug Administration for general use in clinics56.

Conclusion.
Evidence is mounting that remedies of natural origin, as found in dietary supplement format, are safe and often apparently efficacious in the management of many rheumatological disorders. Several conventional, medical interventions for diseases such as osteoporosis, osteoarthritis and rheumatoid disease have fallen into disrepute. However, some healthcare givers have proposed that the use of dietary supplements to promote bone and joint health has occurred without adequate scientific foundation to support their use.

It has been stated that medicine is at the “cross-roads” and this is very apparent in looking at existing treatment options for common bone and joint diseases. The modern physician is now engaged in the practice of pluralistic medicine where the over riding obsession is with treatments that work regardless of their source of origin, be it conventional or alternative. The modern proposal of integrated medicine is rejected by the author because it highlights the contentious dichotomy that exists in medical practice. An “open- minded” look at existing medical options (conventional or alternative or complementary or integrated or whatever) for the management of bone and joint disease should serve to dispel the dichotomy and redirect the enthusiasm of the healthcare giver to select from potentially effective drug therapies and natural treatment agents. The obsession must now be “what works” in the face of the recalcitrance of osteoarthritis and osteoporosis to make existing common medical interventions.

Abbas F, Trapp R, Lai G, kolm P, ColliverJ, Vasudeva R, Holt S. Sequential observations of symptoms and gastroduodenal damage due to non-steroidal anti-inflammatory drugs (NSAIDS). American Journal of Gastroenterology, 83, 9:1028, 1988.

Bloom BS. Cross-national changes in the effects of peptic ulcer disease. Ann Intern Med. 1991;114:558-62.

Bloom BS. Direct medical costs of disease and gastrointestinal side effects during treatment of arthritis. Am J Med. 1988;84:20-4.

Gabriel SE, Jakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann intern Med. 1991;448:787-96

Garcia Rodriguez LA, Walker AM, Perez Gutthann S. Nonsteroidal anti-inflammatory drugs and gastrointestinal hospitalization in Saskatchewan: a cohort study. Epidemiology. 1992;3:337-42.

Greene JM, Winickoff RN. Cost-conscious prescribing of nonsteroidal anti-inflammatory drugs for adults with arthritis. A review and suggestions. Arch Intern Med. 1992;152:1995-2002.

Griffin MR, piper JM, Daugherty JR, Snowden M, Ray WA. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med. 1991;114:257-63.

Guess HA, West R, Strand LM, Helston D, Lydick EG, Bergman U, et al. Fatal upper gastrointestinal hemorrage or perforation among users and non-users of nonsteroidal anti-inflammatory drugs in Saskatchewan, Canada, 1983. J Clin Epidemiol. 1988;41:35-45.
Henry DA, Johnston A, Dobson A, Duggan J. Fatal peptic ulcer complications and the use of non-steroidal anti-inflammatory drugs, aspirin and coticosteroids. Br Med J (Clin Red Ed). 1987;295:1227-9.

Henry D, Lim LL, Garcia Rodriguez LA, Perez Gutthann S, Carson JL, Savage R, et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. NMJ. 1996;312:1563-6.

Hochberg MC. Association of nonsteroidal anti-inflammatory drugs with upper gastrointestinal disease: epidemiologic and economic considerations. J. Rheumatol. 1992;19:63-7.

Holt S, Irshad M, Howlen CW, Maneiro m. Nonsteroidal anti-inflammatory drugs and lower gastrointestinal bleeding. Dig Dis Sci 38:1619-1623, 1993.
Holt S, Saleeby G. Gastric mucosal injury induced by anti-inflammatory drugs (NSAIDs). Southern medical Journal 84, 3:355-360,1991.

Holt L, Holt S, Saleeby G, Todd M. Gastroduodenal injury from non-steroidal anti-inflammatory drugs: risk management issues. Gastroenterology Nursing 14(3):124-126,1991.

Howden CW, Saleeby G, Holt L, Holt S. Follow-up of patients with NSAID-related complicated peptic ulcer disease (CPUD). The American Journal of Gastroenterology 86, 9:1313,1991.

Howden CW, Holt S. Acid suppression as treatment for NSAID-related peptic ulcers. American Journal of Gastroenterology 86([email protected]):1720-2, 1991.

Irshad M, gopal A, Saleeby G, Holt S, Howden CW. NSAID use as a conributory factor in lower GI tract bleeding. The American Journal of Gastroenterology 86, 9:1312,1991.

Langman MJ, Weil J, Wainwright P, lawson DH, Rawlins MD, Logan RF, et al. Risks of bleeding peptic ulcer associated with individual, non-steroidal anti-inflammatory drugs. Lancet. 1994;343:1075-8.

Laporte JR, Carne X, Vidal X, Moreno V, Juan J. Upper gastrointestinal bleeding in relation to previous use of analgesics and non-steroidal anti-inflammatory drugs. Catalan Countries Study on Upper Gastrointestinal Bleeding, Lancet. 1991;337:85-9.

Saleeby G, Howden CW, Holt S. Over the counter (OTC) non-steroidal anti-inflammatory drug (NSAID) use may be an important determinant of complicated peptic ulcer disease (CPUD). The American Journal of Gastroenterology 86, 9: 1375,1991.

Saleeby G, Holt S. Why do patients with life threatening complications of peptic ulcer (PU) take nonsyteroidal anti-inflammatory drugs (NSAID) ? The American Journal of Gastroenterology 85, 9:1294,1990.

Saleeby G, Holt S. An alarming association between nonsteroidal anti-inflammatory drug (NSAID) use and complicated peptic ulcer (PU). The American Journal of Gastroenterology, 85, 9:1294,1990.

Saleeby G, Howden CW, Holt S. Patient understanding of NSAIDs and ulcer complications: a need for improvment. Proceedings of the Annual Meeting of the British Society of Gastroenterology, 1991.

Saleeby G, Holt S, Holt L, Eleazor P. Pattern and prevalence of non-steroidal anti-inflammatory drug use in elderly patients with complicated peptic ulcer disease. Clinical Research 39, 2:594A 1991.

Smalley WE, Ray WA, Daugherty JR, Griffin MR. Nonsteroidal anti-inflammatory drugs and the incidence of hospitalizations for peptic ulcer disease in elderly persons. Am J Epidemiol. 1995;141:539-45.

Wong S, Gilrane T, Holt S. Pattern and determinants of peptic ulcer and veterans administration endoscopic practice. The American Journal of Gastroenterology 85, 9:1299, 1990.

Table 1: In the US, UK and Canada there are 70,20 and 10 million prescriptions or dispensations of NSAID. This table lists studies from these countries and Australia that show the risk of gastrointestinal bleeding perforation and deaths associated with NSAID use. Up to 3% of users of NSAID will bleed from their gut and more than ¼ will require medications that are used to treat peptic ulceration. As staggering as this information is, the real danger of NSAID use remains underestimated because over the counter use of NSAID may be likely to cause significant gastrointestinal and other problems.

Problem Comment

Erosion and ulceration of the Oropharyngeal ulceration, Esophageal erosions, lining of the upper gastrointestinal esophagitis, ulceration and bleeding are reported.
Tract. Sometimes severe requiring hospitalization.
Gastric and duodenal ulcers sometimes severe with complications. Anastomotic ulcers following gastric surgery reported. Contraindication in case of upper gastrointestinal disease e.g. stricture.

Critical Dosing Requirements Must stand up for 30 minutes after taking with 8 oz of water – cannot take orange juice or coffee because reduces absorption. Cannot take in bed or retiring to bed.

Supplements Required Hypocalccemia must be corrected, Vitamin D and calcium is often given but calcium interferes with absorption of the bisphosphonate.

Significant, miscellaneous problems Increased risk of ulceration and erosion in the upper gastrointestinal tract with aspirin use. Not known to be safe or effective in men, only for women. Unknown effects of an age on safety and efficacy of bisphosphonates. Hypersensitivoty reactions e.g. urticaria and angioedema. Discontinuation due to intolerance or adverse event in 1 in 20 users. Causes muscle, bone and joint pain in some patients.

Table 2: Disadvantages and limitations of the use of bisphosphonates (e.g. alendronate sodium) in the treatment of osteoporosis. The major drawback of the use of bisphosphonates appears to be frequent and sometimes serious adverse effects on the upper gastrointestinal tract.

Component Therapeutic Potential

• Calcium and Phosphorus Ideal, balanced, bioavailable mineral in a 2:1 ratio supplement for bones (prevents osteoporosis)

• Collagen, Type 2 A nutrient with potential for the development of the immune tolerance phenomenon (e.g. rheumatoid and connective tissue disease).

• Glycosaminoglycams Anti-inflammatory and immunomodulating agents (suppress inflammation , enhance immune function with T cell and natural killer cell modulating activity).

• Antiangiogenic Protein Varying molecular weight antiangiogenic proteins have been repeatedly demonstrated in shark cartilage. The molecular weight of some of these proteins is such that they may cross the intestinal mucosal barrier. Potential action in many angiogenesis-dependent diseases, e.g. cancer, arthritis, skin disease, proliferative retinopathy, Kaposis sarcoma.

• Chondroitin sulfate, Regarded as potential therapy for arthritis. Heparan sulfate, Dermatan sulfate, Keratan sulfate

Table 3: Constituents of shark cartilage that may confer a health benefit in several disease states. Potential mechanisms of actions and applications are summarized.

Study Comment

Dovianti, A et. al. Double-blind placebo-controlled study showed (1980) improved symptoms with glucosamine in patients with OA.
Pujalte, JM et. al. Double-blind placebo-controlled study showed (1980) reduction in joint pain and swelling in patients with OA of the knee.
Vajaradul, Y Injectable glucosamine sulfate compared with (1980) placebo showed benefits for glucosamine in OA of knee.
Crolle, G et. al. Oral and injectable glucosamine was effective in (1980) OA in a blinded study with patients with severe co- existing illnesses.
Tapadinhas, MJ et. al. Multi-center study of glucosamine in OA showed it (1982) to be beneficial and well tolerated.
Vaz, A.L. Comparison of glucosamine with ibuprofen showed (1982) benefit from both but slower improvement with glucosamine which eventually surpassed the benefits seen with ibuprofen in symptom reduction.
Fabender, H.M. et. al. Glucosamine as effective as ibuprofen and better (1994) tolerated in OA.
D’Ambrosio, E. et. al. Injected and oral glucosamine better than placebo (1981) in reducing symptoms of arthritis.

Table 4: Studies of glucosamine in arthritis.

References

1. Theodosakis, J., Adderly, B., Fox, B., The Arthritis Cure. St Martins Press, NY, 1997.

2. Tamblyn, R., Berkson, L., Dauphinee, D., Gayton, D., Grad, R., Huang, A., Isaac, L., McLeod, P., Snell, L., Unnecessary Prescribing of NSAIDs and the Management of NSAID-Related Gastropathy in Medical Practice Annals of Internal Medicine, Volume 127, No 6, 429-43,1997.

3. Holt, S., Saleeby, G., Gastric mucosal injury induced by anti-inflammatory drugs (NSAIDS). Southern Medical Journal 84, 3:335-360,1991.

4. Harris, W.H., Total joint replacement. N Engl J Med 297:650-654, 1977.

5. Amadio, P.J. Jr, Cummings D.M., Amadio P., Nonsteroidal anti-inflammatory drugs; tailoring therapy to achieve results and avoid toxicity. Postgrad Med 93:73, 1993.

6. Saleeby, G., Howden, C.W., Holt, S., Over the counter (OTC) non-steroidal anti-inflammatory drug (NSAID) uses may be an important determinant of complicated peptic ulcer disease (CPUD). The American Journal of Gastroenterology 86, 9:1375,1991.

7. Howden, C.W., Saleeby, G., Holt, L., Holt, S., Follow-up of patients with NSAID-related complicated peptic ulcer disease (CPUD). The American Journal of Gastroenterology 86, 9:1313,1991

8. Saleeby, G., Howden, CW., Holt, S., Patient understanding of NSAIDs and ulcer complications: a need for improvvement. Proceedings of the
Annual Meeting of the British Society of gastroenterology, 1991.

9. Saleeby, G., Holt, S.,Holt, L., Eleazor P., Pattern and prevalence of non- steroidal anti-inflammatory drug use in elderly patients with complicated peptic ulcer disease. Clinical Research 39, 2:594A, 1991.

10. Irshad, M., Gopal, A., Saleeby, G., Holt, S., Howden, C.W., NSAID use as a contributory factor in lower GI tract bleeding. The american Journal of Gastroenterology 86, 9:1312, 1991.

11. Holt, S., Irshad, M., Howlen, C.W., Maneiro, M., Nonsteroidal anti- inflammatory drugs and lower gastrointestinal bleeding. Dig Dis Sci
38:1619-1623, 1993.

12. Holt, S., Howden, C.W., Omeprazole; overview and opinion. Digestive Diseases and Sciences 36(4):385-93, 1991.

13. Howden, C.W., Holt, S., Acid suppression as treatment for NSAID- related peptic ulcers. American Journal od Gastroenterology 86(12):1720- 2,1991.

14. Holt, S., Proton-pump inhibition for acid-related disease. Southern Medical journal 84(9):1078-87, 1991.

15. Holt, L., Holt, S., Saleeby G., Todd, M. Gastroduodenal injury from non- steroidal anti-inflammatory drugs: risk management issues.
Gastroenterology Nursing 14(3):124-126,1991.

16. Riggs, B.L., Melton, L.J., The Worldwide problem of osteoporosis: Insights afforded by epidemiology, bone 17(5) (Suppl.):505S-511S,
November 1995.

17. Black, D.M. et.al. for the Fracture Intervention trial Research Group:
Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures, Lancet 348:1535-1541, December 7,
1996.

18. Holt, S., Soya for Health, The Definitive Medical Guide. Mary Ann Liebert Inc., Larchmont, NY, 1996.

19. Holt, S., Phytoestrogens for a Healthier Menopause. Alternative and Complementary Therapies, April, 1997, 1-5.

20. Second International Symposium on the Role of Soy in Preventing and treating Chronic Disease, Brussels, Belgium, September 15-18, 1996.
Program and Abstract Book; proceedings to be published in J Coll Nutr 1997-8.

21. Burke, G., Phytoestrogens as an alternative to conventional hormone replacement therapy. Proceedings of the First World Conference on
Nutrition in Medicine, held at Pennsylvania Hotel, NY, NY, October 1997.

22. Holt, S., Soy for Health. Proceedings of the First World Conference on High Technology Medicine, Collegum Humanum, Burgenstock,
Switzerland, June, 1997
.
23. Holt, S., Gagliardi, G., Fuerst, M., The Shark Cartilage Alternative For Bone and Joint Health. Keats Publishing, New Canaan, Connecticut,
1997.

24. Holt, S. Shark Cartilage and Nutriceutical Update. Alternative and Complementary Therapies – November/December, 30-34, 1995.

25. Holt, S., Barilla, J.R., The Power of Cartilage, Kensington Publishers, NY, NY (in press) 1998.

26. Staines, N.A., Suppression of collagen induced arthritis by oral administration of type II collagen: Changes in immune and arthritic responses mediated by active peripheral suppression. Autoimmunity; 16:189-199 1993.

27. Brown, S.E., Better Bones, Better Body. Keats Publishing Inc., New Canaan, CT.1996.

28. Rovetta, G., Galactosaminoglycuronoglycan Sulfate (Matrix) in Therapy of Tibiofibular Osteoarthritis of the Knee. Drugs in Experimental and
Clinical research 18(1):53-57,1991.

29. Pipitone, V.R., Chondroprotection with Chondroitin Sulfate. Drugs in Experimental and Clinical Research 18(1):53-57, 1991.

30. Oliviero, U., et al. Effects of the Treatment with Matrix on Elderly People with Chronic Articlular Degeneration. Drugs in Experimental and
Clinical research 17(1):45-51,1991.

31. Mazieres, B., et al. Le Chondroitin Sulfate Dayns le Traitement de la Gonarthrose et de la Coxarthrose. Rev. Rheum. Mal. Osteoartic 59(7-
8):466-472,1992.

32. Kerzberg, E.M. et al. Combination of Glycosaminoglycans and Acetylsalicylic Acid in Knee Osteoarthrosis. Scandinavian Journal of
Rheumatology 16:377-380,1987.

33. Mueller-Fabender, H., et al., Glucosamine Sulfate Compared to Ibuprofen in Osteoarthritis of the Knee. Osteoarthritis and Cartilage 2:61-
69, 1994.

34. Crolle, G., D’Este, E., Glucosamine Sulphate for the Management of Arthrosis: A Controlled Clinical Investigation. Current medical research
and Opinion, 7(2):104-109,1980.

35. Dovanti, A., Bignamini, A.A., Rovati, A.L., therapeutic Activity of Oral Glucosamine Sulphate in Osteoarthrosis: A Placebo-Controlled Double-Blind Investigation. Clinical therapeutics 3(4):266-272,1980.

36. Pujalte, J.M., Lavore, E.P., Ylescupidez, F.R., Double-blind Clinincal Evaluation of Oral Glucosamine Sulphate in the Basic treatment of
Osteoarthrosis. Current Medical Research and Opinion 7(2):110-114, 1980.

37. Vajaradul, Y., Double-blind Clinical Evaluation of Intra-articular Glucosamine in Outpatients with Gonarthrosis. Clinical Therapeutics 3
(5):260+, 1980.

38. Crolle, G., D’Este, E., Glucosamine Sulphate for the Management of Arthrosis: A Controlled Clinical Investigation. Current Medical Research and Opinion 7(2):104-109, 1980.

39. Tapadinhas, M. J., Rivera, I.C., Bignamini, A.A., Oral Glucosamine Sulphate in the Management of Arthrosis: Report on a Multicentre Open
Investigation in Portugal. Pharmatherapeutica 3(3):157-168, 1982.

40. Vaz, A.L., Double-blind Clinical Evaluation of the Relative Efficacy of Ibuprofen and glucosamine Sulphate in the management of Osteoarthritis of the Knee in Out-patients. Current Medical research and Opinion 8(3):145-149, 1982.

43. Gaby, A.R., Wright, J.V., Nutrients and Bone Health. Health World, 1988, 29-31.

44. National Osteoporosis Foundation, National Objectives for Disease Prevention and Health Promotion for the year 2000. National Osteoporosis Foundation, Washington D.C., 1988.

45. Ken Kaiser. Television interview on New York Cable Sports Channel 1, Wednesday May 21st 1997.

46. Personal interview with Mark Letendre. Head Trainer. San Francisco Giants. Shea Stadium. August. 1997.

47. Erasmus, U., Fats that Heal, Fats that Kill. Alive Books, Burnaby BC, Canada, 1993.

48. Murray, T.M., Beutler, J., Understanding Fats and Oils. Progressive Health publishing, Encinitas, CA.1996.

49. Kremer, J.M., Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Arthritis Rheum 33:810-20. 1990.

50. Passwater, R.A., Fish Oil Update. Keats Publishing Inc., New Canaan, Connecticut, 1987.

51. Belluzzi, A., Brignola, C., Campieri, M., Pera, A., Boschi, S., Migoli, M., Effect of an enteric-coated fish oil preperation on relapses in Crohn’s
disease. N Engl J Med 1996:334:1557-60.

52. Majeed, M., Badmaev, V., Gopinathan, S., Rajendran, M.S., Norton, T., Boswellin The Anti-inflammatory Phytonutrient. Nutriscience Publishers, Inc., Piscataway, NJ, 1996.

53. Singh, G.B., Atal, C.K. Pharmacology of an extract of salai guggal ex-Boswellia serrata, a new non-steroidal anti-inflammatory agent. Agents and Actions, 18(3/4), 407-411, 1986.

54. Kakrani, H.K., Guggal – a review. Indian Drugs, 18,417-425, 1981.

54. Shanbhag, V., A Beginner’s Introduction to Ayurvedic Medicine. Keats Publishing, New Canaan, Connecticut, 1994.

55. Tsung, P., Hong-yen, H., Arthritis and Chinese Herbal Medicine. Keats Publishing, New Canaan, Conecticut, 1987.

56. Sedlak, B.J. Signal Transduction Companies, Genetic Engineering News, 16, 1:10-12, 1996.

Spread the word. Share this post!

Leave A Reply