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The Great Glucosamine Wars

By

John C.  Cargill MA, MBA, MS and Susan Thorpe-Vargas PhD

Advertising hype, myth, tradition and a governmental hands-off approach have created a giant pseudo-pharmaceutical industry of diet and nutritional supplements.1,2  If one read the "fact" sheets at health, tack and feed stores, and pet shops--and believed them, there could only be one conclusion: herbal remedies and supplements can cure anything and everything.3  Nothing could be further from the truth.  However, amongst the "snake oil" products are some truly outstanding products with demonstrated safety, efficacy and good science to back them up.   We will describe the situation with glucosamine and chondroitin sulfate as they apply to the treatment of osteoarthritis, look at some of the products, examine the science and make some general recommendations. 

The process is something like this for most of us and for our animals: birth, aging, arthritis, eventual death.   These are the fundamental commonalities of life.   Arthritis, more correctly osteoarthritis, is a condition that affects virtually every older human and dog.   Possibly, the earliest fossil record of arthritis (or at least the earliest record the authors could find) is in a platycarpus (aquatic reptile) from 100 million years ago.4  Ape Man (2 million years ago), and Java and Lansing men (of 500,000 years ago) have been found with chronic arthritis of the spine5 and even Egyptian mummies have been found with arthritic joints6.   Despite man and beast having been troubled by arthritis, presumably since their respective beginnings, little is known about the etiology (causes of the disease) or what triggers its development. 

Arthritis is an idiopathic, slowly progressive disease of the synovial (diarthroidial) joints, generally occurring later in life.  Degeneration of articular (joint) cartilage, subchondral bone thickening (sclerosis), osteochondral outgrowths (osteophytes) and joint deformity and result in potentially debilitating pain.   Any synovial joint may be affected.   Those joints subjected to the greatest compression (stress), such as the lower spine, hip, elbow, stifle, hocks and joints of the foot, are especially vulnerable areas.   Old people and old dogs creak, ache and groan.   Such conditions heretofore have been accepted as part and parcel of old age with no hope of slowing down the progression or reversing the course of the disease process.  Arthritis has been a recognized veterinary problem for a very long time.   For the purpose of this article, let us conclude that arthritis is therefore universal.

The Role of Articular Cartilage

Articular cartilage, which covers the ends of long bones in synovial joints, is wonderfully adapted to its role as a hydrostatic, bearing, contact and gliding surface between bone surfaces in those joints.   In conjunction with synovial fluid, articular cartilage provides a near frictionless weight-bearing surface.   The frictional resistance of animal joints is twice as low as the rolling resistance of rubber on steel and one-tenth that of an ice-skate on ice7.   Articular cartilage functions by gently transmitting force to the underlying subchondral bone, which then deforms under load and provides for even distribution of stress in the joint.8

Unfortunately, articular cartilage is susceptible to use and aging degenerative processes that reduce cartilage resistance to compressive and tensile forces and ability to rebuild matrix.   Eventually, the results are fibrillations, deep clefts, shredding and even complete erosion of the cartilage down to the subchondral bone (bone beneath the cartilage).   Cartilage is “fatigue-prone,” i.e., overuse, without time to regenerate or without adequate nutrition, leads to breakdown of the articular cartilage.   Normal stresses may be amplified further by various congenital or trauma related deformities.  I n either case, excessive contact pressure results from excessive force applied over a small surface area progressing ultimately to damage and erosion.   Think of it as a “pounds per square inch” problem. 

Cartilage

Cartilage may be visualized structurally as a series of chondrocytes (cartilage cells) held in place by a systematically oriented hyperhydrated matrix of rope-strand-like fibrils.   The cell density of articular cartilage is low with water content ranging as high as 80 percent.  Nonetheless, the chondrocyte is a metabolically active cell that continually synthesizes matrix components, often at a rapid turnover rate.   This cartilage matrix is formed from collagen type II and glycosaminoglycans (GAGs, previously called mucopolysaccharides) derived mostly from glucosamine (an aminosugar), and comprises more than 90% of the cartilage. 

Six types of GAGs are found in the body, with chondroitin sulfate being the most abundant GAG found in articular cartilage.   Chondroitin sulfate, made from glucuronic acid and galatosamine when chondrocytes synthesize glucosamine, forms with proteins to create proteoglycans.   These proteoglycans then attach to hyaluronic acid molecules to form larger molecules called proteogylcan aggregates.  In a rather complex manner, collagen and the macromolecule proteoglycan aggregates entwine throughout the matrix binding to each other.  The hyperhydration gives the cartilage non-compressive and self-lubricating properties; the fibrils give cartilage the ability to deform under pressure and return to shape without damage when that pressure is released.   Tensile properties of articular cartilage are proportional to the structures as well as the amount of collagen in the matrix.   Compressive properties of the articular cartilage are proportional to the amount of proteoglycans in the matrix.  Without GAGs and their hydrostatic properties in cartilage, repeated compressive forces would soon break apart the cartilage.

Feeding the Joint

Except for the developing epiphysis (growing surface of the bone), articular cartilage is isolated from the vascular system.  Nutrients must pass through two diffusion barriers to reach the chondrocyte (cartilage cell).   First the nutrients must pass out of the synovial vascular plexus through the synovial membrane and into the synovial fluid and then pass through a dense matrix of hyaline cartilage to reach the chondrocyte.   This will be important to remember when we discuss the pharmacology and pharmacokinetics of glucosamine and chondroitin sulfate products

The turnover of rate of proteoglycans is probably controlled through a system of enzymes.  Unfortunately, cartilage regenerative properties in this system are limited and there is little spare capacity.  Thus, joints are especially vulnerable to insult and a general slow-down, characteristic of the aging process.  “Cartilage replenishes its major components by manufacturing and remodeling prodigious amounts of collagen and proteoglycans.   This constant and on-going synthesizing process often generates extremely large demands for building blocks of collagen and proteoglycans.   If the raw materials (nutrients) for these building blocks are not available in the amounts required, the synthesizing process is impaired and the cartilage loses its ability to replenish itself.”9  Take away from this article that it is not difficult to stress or age joints beyond their ability to compensate.   Result: arthritis. 

As early as the 1950's we knew that glucosamine hydrochloride and glucosamine sulfate were easily absorbed and could be used for GAG synthesis in the chondrocytes of the joints.10   Follow-on work showed that increased levels of glucosamine hydrochloride stimulated GAG and collagen synthesis in both chondrocytes and fibroblasts.11  A, now classic 1980 study12, using electron microscopy of cartilage biopsies, suggested the possibility of actual repair of damaged cartilage matrix, paving the way for the huge number of glucosamine and chondroitin products we see today.   Several studies determined chondroitin sulfate had a synergistic effect with glucosamine on the stimulation of cartilage matrix synthesis, thus achieving a disease modifying level of synergistic activity not otherwise reachable by providing the compounds separately in humans, horses and dogs.13,14,15   There has been some controversy concerning the efficacy of these nutraceutical agents and in particular their bioavailability given the oral route of administration.   From radiolabeled fecal excretion tests in man and in the dog, we know that both glucosamine and chondroitin sulfate are absorbed at significant levels.16  Thus, we conclude that "feeding the joint" not only prevents but also can slow or reverse the progress of osteoarthritis.

The Aging Joint

Chondrocytes either 1) acquire glucosamine preformed, or 2) synthesize it from glucose and amino acids and use it in the subsequent synthesis of glycosaminoglycans (GAGs, and in particular chondroitin sulfate).   As chondrocytes mature, they produce less chondroitin sulfate and more keratin sulfate than when they were young.   Keratin sulfate forms collagen linkages in the cartilage matrix having less tensile strength than the chondroitin sulfate-collagen linkages.  The cartilage therefore becomes softer as it matures.   As chondrocytes continue to age, they produce dermatan sulfate, which forms weaker collagen linkages than did keratin sulfate.  Aging cartilage becomes softer yet and thus more susceptible to long term wear from normal activities.   Thus, articular joints, even those not subjected to over-use, injury or infection, can be expected to eventually become arthritic with age unless the relative amounts and availability of chondroitin sulfate are increased. 

The Treatments

Throughout history, there have been many proposed cures and remedies for arthritis.  At best, they have done no harm; at worst, they have killed.   Arthritis has been treated with almost everything from Chinese herbal medicine17, acupuncture18, glandular therapy19, homeopathic medicine20, low-level laser therapy21, magnetic field therapy22 to perna mussel formulations23.   The outcomes have been variable.   Since the 1960's, starting with the work of Dr.  John Prudden24, interest in therapeutic properties of bovine cartilage has intensified.   In particular, research concerning glucosamine compounds and chondroitin sulfate has given birth to a major worldwide disease-modifying anti-arthritis industry. 

The Products

While the human nutraceutical industry is marketing new products at an ever-expanding rate, the veterinary and companion animal nutraceutical industry is not far behind.   As we researched this article, products kept popping into and out of the market.  Many manufacturers we wished to contact could not be reached at their advertised locations or telephone numbers.   Nutraceuticals are a "wild cat" market, which is expected to reach US$500 billion worldwide by the year 2010.   The chondroprotective products generally fall into the following categories:

• Perna Mussels:  The GlycoFlex® perna mussel formulation was one of the first anti-arthritic nutraceuticals on the market.  Although there are no recent published veterinary trials, anecdotal evidence does exist to suggest that perna mussel formulations may have anti-inflammatory properties, especially in rheumatoid arthritis conditions.  The original New Zealand studies25,26 have not been updated and lack the sophistication and scope of the more recent studies involving glucosamine or glucosamine and chondroitin sulfate.  Nonetheless, many practitioners, especially those in equine practice, swear by GlycoFlex®, having had many anecdotal successes with it in their patients.  Interestingly, the active component(s) has not been identified, but GlycoFlex® is purported to contain minerals, vitamins, unknown fats and proteins.

• Glucosamine salts:  A large body of scientific literature strongly suggests that glucosamine, whether glucosamine sulfate or glucosamine hydrochloride, as long as it is in a pure form, is efficacious in the treatment of degenerative joint disease.  In one 1998 study, glucosamine was concluded to be similar in efficacy in relieving joint pain to ibuprofen, but was without the deleterious side effects of chronic ibuprofen use.27  However, a disease modifying effect has not been well shown with glucosamine alone.  The most recent study, reported in Boston at the November 1999 annual meeting of the American College of Rheumatology showed an annual increase in human knee joint space (purportedly with corresponding increase in thickness of cartilage) of 0.08 to 0.1mm.28  To our way of thinking, and to that of other researchers, this does not constitute a disease modifying growth or regrowth of cartilage. 

• Glucosamine salt with vitamins, minerals and herbals:  It is well known that certain vitamins, minerals and proteins are necessary for synthesis of cartilage matrix, thus some manufacturers add such vitamins and minerals to cover all bases in all patients.  Various herbal compounds have anti-inflammatory properties and may also be included.  Unfortunately, little research has been published concerning the efficacy of minerals, herbs and vitamins in conjunction with glucosamine or chondroitin sulfate.  Separately, however, grapeseed extract, turmeric, Devil's Claw root and other herbal/botanicals show promise as anti-inflammatory agents.

• Chondroitin sulfate:  Numerous clinical studies document the therapeutic effects of orally administered chondroitin sulfate.  However, unlike glucosamine alone, recent and emerging literature strongly suggests that chondroitin sulfate has true disease modifying properties.  One recent study (1999) concludes that the chondroprotective effects of chondroitin sulfate in OA may be related to the inhibition of NO synthesis."29   Chondroitin sulfate molecules vary in size.  There is a good likelihood that the varying molecular sizes have different pharmacokinetics and pharmacology.  On the other hand, there are claims that these chains are broken down during the digestive process and there is little or no therapeutic difference.  Even if the chains are broken down during the metabolic process, purity seems to be the key.  Ground up cartilage products would not have free chains to break up for significant amounts.  The conclusive studies demonstrating efficacy were done with highly purified low molecular weight chondroitin sulfate.  Until more research is done, the pharmacokinetics and pharmacology of the more common (less expensive) heavier molecular weight chondroitin sulfate ingredients are relatively unknown.

• Glucosamine salt with chondroitin sulfate:  While it has been known for some time that both glucosamine salts and chondroitin sulfate independently have beneficial properties resulting from two different mechanisms of operation, it is a relatively recent discovery that chondroitin sulfate has a synergistic effect with glucosamine.30,31  Given the slow disease-modifying effect of either glucosamine or chondroitin sulfate, to find that together their effect is much more rapid, this is, indeed, a welcome finding.  A second recent finding is that manganese further potentiates this effect and is a limiting factor in the synthesis of cartilage and synovial fluid.32   Chondroitin sulfate has been shown to lessen the destructive effect on of degradative enzymes on cartilage.33  Therefore, the state of the art formulation in arthritis modifying nutraceuticals is glucosamine HCL with chondroitin sulfate and manganese.  All of the large scale U.S.  veterinary trials have been done using this specific combination (Cosequin®).  Interestingly, this glucosamine-chondroitin-manganese product has now been shown efficacious as a pre-treatment before stressful activity to preclude or reduce bony and soft tissue changes when joints are stressed.34  All of you with performance animals should take note of this brand new study and discontinue the traditional practice of pre-treating with NSAID's before hunting, sledding and other performance events. 

Not All Formulations Are the Same

The human nutraceutical industry got a great boost when Congress ended the FDA's absolute control over nutritional supplements.  Passage of the Dietary Supplement Health and Education Act of 1994 (DSHEA) opened the floodgates of pent-up consumer demand to take immediate advantage of the good science, new science, bad science and everything in between.  “Nutraceuticals, one of the medical buzz-words of the decade, are revolutionizing the medical community.”35  Note, however, that DSHEA applies only to human products and not to livestock and pet food products.36  This interpretation has been tested in court, with the determination that FDA, indeed, does have control over dietary supplements for animals (nutraceuticals).  One of the results of the deregulation of the nutraceutical industry has been the proliferation of products purporting to be what they are not.  We would like to use D.M.  Boothe's view of the industry, whereby he characterizes the range of nutraceutical products as "The good, the bad, and the ugly."37  The University of MD School of Pharmacy analyzed thirty (30) human glucosamine-chondroitin products and found at least 50 percent did not meet label claims.38  It has become common for veterinary publications to caution against using products that were not specifically used in live animal trials and to favor those which were used in trials.  A recent continuing education piece for physicians recommended that they use the "brand name used in the trials."39  It is generally unknown what molecular weights chondroitin sulfate are optimal for nutritional support of cartilage synthesis; however, it is known what weights worked in the few rigorously controlled clinical trials that exist.  We caution the reader that with these unknowns, we agree with researchers who say that results are likely to be more consistent with formulations that have been subjected to rigorous trials than those formulations comprised of unknown or mixed molecular weights and purities.  Products that say "source of" or "fortified with" should be looked at with caution as exact ingredient levels and purity are unknown.  Few of the products on the market are supported with clinical trials.  See Figure 1 for the products whose manufacturers responded to a questionnaire asking about ingredient sources, grade, product assays and clinical trials.  Note that many manufacturers advertising in magazines and on the Internet failed to respond to return receipt requested mail.  To date, only one of the glucosamine nutraceuticals containing glucosamine, chondroitin sulfate and manganese (Cosequin® DS) has been subjected to numerous independent, peer-reviewed, published, randomized, double-blind, placebo-controlled in vivo studies with their exact product in humans, dogs, cats, rabbits and rats.40,41,42  This does not mean, however, that other products are without merit, just that their claims are not as well substantiated.  On the other hand, many veterinarians feel that your dog is better off with products that have actually been used in clinical trials.  Note that some veterinary products, such as Cosequin® DS, have human exact equivalents.43 

Not all Trials Are the Same

Nutritional studies are notoriously difficult, lengthy and expensive to conduct.  Many researchers attempt leaps of faith from in vitro (outside the animal) studies and extrapolate to what would occur in an animal.  A second extrapolation is often made from one species to another.  Thus, an in vitro study on mouse cartilage may not be reproducible in an in vivo (in the animal) study in a dog.  In vivo in the species of interest carries more weight than in vitro with another species.  Results published in peer reviewed journals carry more weight than results from unpublished non-peer reviewed studies.  Long-term large-scale studies are far more convincing than short-term small-scale studies.  It is not uncommon for nutraceutical advertisers to support their products with references to inappropriate studies.  Few advertisers are able to reference studies conducted with their own formulation.  To our way of thinking, this would be a third and fatal leap of faith given the different pharmacology and pharmacokinetics of not only differing formulations, but also of differing purities and molecular weights.  With that said, we must not fully discount anecdotal evidence and these leaps of faith.  Many successful treatment protocols, eventually supported with the full weight of science, originally started with an in vitro finding followed by what was probably at the time an over-optimistic leap of faith, often to a hoped for effect in another species. 

Market Demand

Is there demand for such "combo" products.  You bet there is! In their 1st quarter 1999 financial report, Rexall Sundown, Inc.  (NASDAQ: RXSD) proudly announced "Osteo Bi-Flex® (a glucosamine-chondroitin product) remained the number two supplement in the country."44 What people take for themselves, they will also want for their dogs. 

Even dog food manufacturers are getting into the combo act.  Iams Large Breed Adult Formula45 and Natura Pet Products Innova Senior46 both contain glucosamine and chondroitin "ingredients", however, purity is not listed, nor is a minimal beneficial level determined.  We expect to see more dog food companies joining the Great Glucosamine Wars fray.  A question that needs to be answered is: "What are the therapeutic levels?  We know from the famous Kealey, Lawler et al studies at Ralston Purina that restricted diets help prevent joint problems,47,48,49 but the true impact of restricting diets, feeding chondroprotective agents and treating with disease modifying agents is not yet known.  We look forward to disease preventing dog foods in the future.

Not only are the many recent scientific studies encouraging, but so too, are the results of a 1999 study random sampling US veterinary practices questioning the perceived clinical efficacy of oral combination of glucosamine and chondroitin sulfate.  More than 2,500 veterinarians responded reporting “good” or “excellent outcomes” of 89%, 83% and 85% in the areas of “improved mobility”, “alleviating pain”, and “improved attitude”.50  So positive are the results with chondro-protective nutraceuticals that many veterinary practitioners have concluded that “...chrondro-protective agents...will remain the preferred drug therapy for...DJD.”51

We conclude, along with many researchers, from the various scientific studies that "Glucosamine products can be used for many cartilage and disc degeneration conditions, including osteoarthritis, hip dysplasia, and nonspecific arthritic conditions.  The direct benefit appears to be protective and restorative, leading to less pain and inflammation and greater mobility."52  Until the Great Glucosamine Wars shake out the marginal players, or until the FDA develops post DSHEA authority, clout and resources to force control of nutraceuticals, there will be many questionable products available.  Those manufacturers willing to present assays of their formulations, manufacture to close tolerances to ensure the uniformity of their products, and conduct appropriate studies using those very same brand name formulations, should have an attractiveness to the consumers that the others may lack. 

As more and more veterinarians are being taught nutrition and are turning to a more holistic approach, we expect more recommendations being made to veterinary clients for the use of glucosamine and chondroitin products.  Given the number of unsubstantiated claims for human nutraceuticals, and their use with pets, we feel moved to quote Ms.  Christa Vecchi of the Federal Trade Commission: "A smart consumer is the best protection against fraud."53  Follow that piece of wisdom with these cautions from the Arthritis Foundation:54

• "Begin by asking your doctor or other health (veterinary) professionals what they recommend."

• "Don't buy through the mail or over the Internet unless you know the vendor is reputable…"

• "Avoid products that are backed only with testimonials."

• "When a company advertises that a supplement has been 'scientifically studied' or 'scientifically proven,' contact them and ask to receive copies of the studies.  If they can't or won't send them, don't buy this brand."

• "When a supplement has been studied with good results, find out which brand was used in the study, and buy that."

In summary, we have the technology to treat arthritis.  With this article in hand, you have the knowledge to better understand and ask the necessary questions as you search through the increasing number of dietary supplements touted as capable of preventing, alleviating or curing arthritis in your dog.  Many of these products are bogus, but among them are some truly amazing products that can be scientifically shown to do just what they say they do.  After that, it remains "caveat emptor."

 

References:

[1] FDA traditionally considered dietary supplements to be composed only of essential nutrients, such as vitamins, minerals and proteins.  The Nutrition Labeling and Education Act of 1990 added "herbs, or similar nutritional substances," to the term "dietary supplement." Through the DSHEA, Congress expanded the meaning of the term "dietary supplements" beyond essential nutrients to include such substances as ginseng, garlic, fish oils, psyllium, enzymes, glandulars, and mixtures of these.  The DSHEA established a formal definition of "dietary supplement."

[2] http://vm.cfsan.fda.gov/~dms/dietsupp.html

[3] The DSHEA 1994 provides that retail outlets may make available "third-party" material so to help inform consumers about any health-related benefits of dietary supplements. 

[4] F.M.  Ahern, R.C.  Johnson, G.C.  Ashton, “Family Resemblances in Serum Uric Acid Level,” Behavior Genetics, Vol.  10 No.  3, May 1980, pp.  303-307.

[5] J.  Ahlqvist, “Endocrine Influences on Lymphatic Organs, Immune Responses, Inflammation and Autoimmunity,” Acta Endocrinologica Supplement (Copenhagen), Vol.  83 No.  206, 1976, p.3. 

[6] J.H.  Kellgren, Osteoarthrosis in Patients and Populations, British Medical Journal, July 1961, p.5243.

[7] E.L.  Radin and I.L.  Paul, “Response of joints to impact loading.  I.  In vitro wear." Arthritis and Rheumatism, Vol.  14, No.  3, May-June 1971, pp.  356-362.

[8] D.J.  McCarty (ed.), Arthritis and Allied Conditions: a Textbook of Rheumatology, Lea & Febiger, Philadelphia, 1992, p.  188.

[9] R.R.  Hanson, “Mode of Action of Oral Chondroprotective Agents”, in Round Table discussion: Degenerative Joint Disease in Dogs, Canine Practice: The Journal of Canine Medicine and Surgery for the Practictioner, Vol.221, Nos.  1-4, Jan/Feb-July/Aug 1996, p.9.

[10] L.  Roden, Effect of hexosamines on the synthesis of chondroitin sulfate, Ark Kami 1956, 10:345.

[11] Grevenstein J; Michiels I; Arens-Corell M; Stofft E.  "Cartilage changes in rates induces by papain and the influence of treatment with N-acetylglucosamine," Acta Orthopaedica Belgica, 1991, Vol.  57 No.2, pp.157-61.

[12] A.  Drovanti, A.  Bignamini, A.  Rovati, "Therapeutic activity of oral glucosamine sulfate in osteoarthritis: a placebo-controlled double blind study," Clinical Terapeutics, March, 1980, p.260.

[13] David S.  Hungerford, Treating Osteoarthritis with Chondroprotective Agents, Orthopedic Special Edition: A Compendium of Educational Reviews, Vol.  4, No.  1, Jan-Apr 1998.  (no page number in reprint)

[14] R.  Reid Hanson, Lowell R.  Smailey, Gerald Huff, S.  White, Tarek A.  Hammad, "Oral Treatment with a Glucosamine-Chondroitin Sulfate Compound for Degenerative Joint Disease in Horses: 25 Cases," Equine Practice, Vol.  19 No.9, October 1997, pp16-22.

[15] D.S.  Hulse, D.  Hart, M.  Slatter, B.S.  Beale, The Effect of Cosequin in cranial cruciate deficient and reconstructed stiffle joints in dogs, Proceedings, 26th Annual Surgical Forum, 33 Annual Scientific Meeting (Small Animal), American College of Veterinary Surgeons, Chicago, IL, October 8-11, 1998.

[16] P.S.  McNamara, S.A.  Johnston, Rory J.  Todhunter, “Slow-acting Disease-Modifying Osteoarthritis Agents” Veterinary Clinics of North America: Small Animal Practice Vol.27 No.4 July, 1997, p.864.

[17] Azadirachata indica, Commiphora wightii and Curcuma longa.

[18] Acupuncture is often used to reduce chronic pain.

[19] Glandular therapy was practiced by early Egyptians and Indians.  The Hindu physician Susrata prescribed animal tissues as early as 1600 B.C., and was especially popular during the 1920's and 30's. 

[20] Common veterinary homeopathic arthritis medications: Apis mellifica, Bryonia, Calc.  Fluor., Causticum, Ledum, Rhus tox, Ruta grav.

[21] Low energy photon therapy (LEPT).  Helium-Neon and infra-red irradiation of joints.

[22] Magnetism has been used to treat a variety of illnesses with reports as far back as 2800 BC.  Pulsed electromagnetic field therapy (PEMF) gained popularity it Germany in the 1970's.  Today it is used widely in the equine field and is making in roads into small animal practice. 

[23] T.E.  Hill, D.  Ormrod.  “The Anti-inflammatory activity of Perna canaliculus (NZ green lipped mussel)”, New Zealand Medical Journal, Vol.  92, 1980, pp.187-193.

[24] J.  Prudden, L.  Balassa.  The biological activity of bovine cartilage preparations, Seminars in Arthritis and Rheumatism, Vol.3 No.  4, Summer, 1974, pp.287-321.

[25] S.  McFarlane, Green mussel and rheumatoid arthritis, New Zealand Medical Journal, Vol.25 No.81, June, 1975, p.569.

[26] T.  Miller, Anti-inflammatory effects of mussel extract, New Zealand Medical Journal, Vol.  14 No.93, January, 1981, p.23.

[27] T.E.  Towheed, Glucosamine sulphate in osteoarthritis: A systematic review.  Abstract 995, Abstract Supplement, 19998 National Scientific Meeting, Nov 8-12, 1998, American College of Rheumatology, Arthritis & Rheumatism, Vol 41 No.  9 (Supplement) September 1998. 

[28] J.Y.  Reginster, R.  Deroisy, I.  Paul, R.  L.  Lee, Y.  Henrotin, G.  Giacovelli, J.  Dacre, L.C.  Rovatti, C.  Gosset, "Glucosamine Sulfate Significantly Reduces Progression of Knee Ostheoarthritis Over 3 Years: A Large Randomized, Placebo-Controlled, Double-Blind Prospective Trial."Arthritis & Rheumatism, Abstract Supplement, American College of Rheumatology 1999 Annual Scientific Meeting, Nov 13-17, 1999, Boston Massachusetts, Vol 42 No.  9, September 1999, p.  S400. 

[29] F.J.  Blanco, E.  Maniero, F.J.  de Toro, J.  Veges, F.  Galdo, "Effect of Different Extracelluar Matrix Components on Nitric Oxide Production by Human Osteoarthritic Chondrocytes," Osteoarthritis Research Society International, 4th World Congress on Osteoarthritis and Satelite Symposia, September 16-19, 1999, Vienna, Austria.

[30] D.S.  Hungerford, "Treating osteoarthritis with chondroprotective agents," Orthopedics, Special Edition, Vol.  4 No 1, 1998, pp.39-42.

[31] L.  Lippiello, A.  Idouraine, P.S.  McNamara et al, "Cartilage stimulation and antiproteolytic activity is present in sera of dogs treated with a chondroprotective agent," Canine Practice, Vol.  23, No 6, 1998, pp.10-12.

[32] R.M.  Leach, "Role of manganese in mucopolysaccharide metabolism," Federal Proceedings, Vol 30, 1971, pp.991-994.

[33] M.A.  Anderson, D.P.  Beaver, “Glycosaminoglycans in the Treatment of Degenerative Joint Disease in Small Animals” Emerging Science & Technology, Summer, 1996, p.38.

[34] Sherman O.  Canapp Jr., Ronald M.  McLaughlin Jr., James J.  Hoskinson, James K.  Roush, Michael D.  Butine, "Scintigraphic evaluation of dogs with acute sinovitis after treatment with glucosamine hydrochloride and chondroitin sulfate," American Journal of Veterinary Research, Vol.  60 No.  12, December 1999, pp.  1550-1556.

[35] D.M.  Boothe, “Nutraceuticals in Veterinary Medicine.  Part 1.  Definitions and Regulations”, The Compendium, November 1997, p.1248.

[36] Federal register, 4/22/96.

[37] D.M.  Boothe, "Pharmacology: Nutraceuticals: The good, the bad, and the ugly," 1998 Proceedings, American Animal Hospital Association, pp.292-295.

[38] Dr.  Natalie Eddington, University of Maryland School of Pharmacology.  Unpublished study.  Personal communication, November, 1999. 

[39] Amal K.  Das, The Biochemistry of Cartilage and Osteoarthritis Treatment Options, Retail Pharmacy News, Special Report, January 1999, p.3. 

[40] Amal K.  Das, The Biochemistry of Cartilage and Osteoarthritis Treatment Options, Retail Pharmacy News, Special Report, January 1999, pp.  1-4. 

[41] Patrick McGee, Study indicates efficacy of glucosamine and chondroitin sulfate for OA symptoms, Alternative Therapies, Orthopedics Today, Vol 19 No 1, January 1999, pp.  15.

[42] Alan F.  Philippi, Navy Special Warfare Group Two, Naval Amphibious Base Little Creek, VA, Glucosamine, Chondroitin, and Manganese Ascorbate for Degenerative Joint Disease of the Knee or Low Back: A Randomized, Double-Blind, Placebo-Controlled Pilot Study, Military Medicine, Vol 64 No 2, February, 1999, pp.  85-91.

[43] Cosequin® DS is essentially the same formulation as Cosamin ® DS Nutramax Laboratories Inc.  (1-800-925-5187) which is available for people at the pharmacy counter without a prescription.

[44] Rexall Sundown, Inc., (Nasdaq: RXSD), 6111 Broken Sound Parkway, NW Boca Raton, FL 33487, (561) 241-9400.

[45] Iams Eukanuba Large Breed Adult Formula guarantees 400 ppm of glucosamine HCL and chondroitin sulfate.

[46] Natura Pet Products, 1171 Homestead Road, #275, Santa Clara, CA 95050, 800-532-7261.

[47] R.D.  Kealy, D.F.  Lawler, J.M.  Ballam, et al, "5-year longitudinal study on limited food consumption and development of osteoarthritis in coxofemoral joints of dogs," Journal of the American Veterinary Medical Association, Vol.  210 No.  2 February, 1993, pp.222-7.

[48] R.D.  Kealy, D.F.  Lawler, K.L.  Monti et al, "Effects of dietary electrolyte balance on subluxation of the femoral head in growing dogs," American Journal of Veterinary Research, Vol.  54 No.  4, 1992, pp.555-62.

[49] R.D.  Kealy, D.F.  Lawler, K.L.  Monti et al, "Effects of limited food consumption on the incidence of hip dysplasia in growing dogs," Journal of the American Veterinary Association, Vol.  201 N0 6, 1992, pp.857-63.

[50] M.A.  Anderson, M.  Slater, “Results of a Survey of Small Animal Practioners on the perceived efficacy and safety of an oral nutraceutical” Preventative Veterinary Medicine, Vol 38, 1999, pp.65-73.

[51] L.  Gelfand, in RoundTable discussion: Degenerative Joint Disease in Dogs, Canine Practice: The Journal of Canine Medicine and Surgery for the Practictioner, Vol.221, Nos 1-4, Jan/Feb-July/Aug 1996.

[52] Roger V.  Kendall, Therapeutic Nutrition for the Cat, Dog, and Horse, in Complimentary and Alternative Medicine, Eds.  Allen M.  Schoen, Susan G.  Wynn, Mosby, St.Louis, 1998, p65.

[53] "Federal Trade Commission Fighting Internet Fraud", Proceedings Fifth Workshop in Pet Food Labeling and Regulations, Nov 11-14, 1999, St.  Louis, Association of American Feed Control Officials.

[54] Judith Horstman, "The Arthritis Foundation's Guide To Alternative Therapies," 1999, The Arthritis Foundation, Atlanta, Georgia, pp.  179-180.

 

Thank you to Susan for permission to post this informative article which was originally published in Dog World magazine, 2000.