Oral Chondroprotective Agents.part I

Vol. 21, No. 7 July 1999

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FOCAL POINT ★Understanding joint physiology and oral chondroprotective agents may allow veterinarians to make an educated decision regarding the products available for use in treating osteoarthritis.

Oral Chondroprotective Agents. Part I. Common Compounds Veterinary Specialty Services, St. Louis, Missouri

Mark A. Anderson, DVM, MS

KEY FACTS ■ A synovial joint consists of the synovial membrane, synovial fluid, subchondral bone, surrounding supporting structures, and hyaline cartilage. ■ Chondroprotective agents alter cartilage metabolism, decrease destructive enzymes, and inhibit the formation of fibrin thrombi in periarticular tissue. ■ Although research is ongoing, much information about chondroprotective products is anecdotal. ■ Slow-acting, disease-modifying agents are a subset of chondroprotective agents that directly influence cartilage metabolism and improve joint function.

ABSTRACT: Joint structure and physiology may be modulated by some nondrug compounds. Categorizing these compounds as oral chondroprotective agents; nutraceuticals; or slow-acting, disease-modifying agents has produced confusion. This article provides descriptions and rationales for the use of some commonly marketed nondrug compounds used to treat osteoarthritis. Some form of combination therapy may be best for treating osteoarthritis in veterinary patients.

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hondroprotective agents enhance cartilage metabolism, decrease breakdown products, and prevent formation of periarticular fibrin thrombi. Oral chondroprotective agents have been confused with nutraceuticals, a group of nondrug substances that are constituents of normal body structure and are intended to improve animal health and well-being. To add to this confusion, oral chondroprotective agents are poorly regulated and the efficacy of many available products is uncertain. Several common oral chondroprotective agents have been described in the literature,1,2 although in many cases much research is needed to determine their merit. Part I of this two-part presentation reviews information designed to help veterinarians make educated decisions about oral chondroprotective products; Part II will provide criteria for evaluating product safety, efficacy, and purity and discuss compounds that may impact the marketplace in the future.

SYNOVIAL JOINT STRUCTURE Synovial joints comprise a complex arrangement of a variety of tissue. A thorough knowledge of joint anatomy and physiology is needed to understand how chondroprotective agents function; a brief discussion of pertinent tissues follows. A synovial joint generally consists of hyaline cartilage, a synovial membrane, synovial fluid, subchondral bone, and surrounding supporting structures (Figure 1). The majority of chondroprotective agents with slow-acting, disease-modifying ability appear to have an effect in hyaline cartilage. In addition, oral chondroprotective agents may have antiinflammatory capabilities and affect the structure and function of cartilage.

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physical therapy or antiinHyaline Cartilage flammatory agents (e.g., nonHyaline cartilage is comsteroidal antiinflammatory posed primarily (more than Bone drugs [NSAIDs] or cortico95%) of extracellular matrix steroids).1 plus a relatively small numIncreased knowledge about ber of chondrocytes, which Subchondral joint-tissue biochemistry maintain cartilage tissue by bone has recently fueled interest secreting collagen and proin the possibility of moduteoglycans that form the exSynovial Hyaline lating the metabolism of tracellular matrix. The mafluid cartilage joint tissue and actually trix, in turn, determines the managing disease processes type of cartilage formed and more consistently and more provides the environment the specifically than is possible chondrocytes require. The with existing therapies. The relationship between collaterm chondroprotective agents gen and proteoglycan aggreJoint capsule has been used to describe gates in the matrix is responand synovial compounds that could thesible for the slippery, resilient membrane Bone oretically function to (1) nature of hyaline cartilage. stimulate the synthetic caThe properties of hyaline pabilities of chondrocytes cartilage are fundamental to normal cartilage physiology. Figure 1—Cross-section through a normal synovial joint. and synoviocytes, (2) deChanges in the matrix, such Hyaline cartilage, synovial fluid, and the synovial membrane crease the action of degradative enzymes (e.g., metalloas degradation of proteogly- are the major features. proteases) in the joint, and cans and collagen, may be (3) inhibit fibrin and thrombi the initiating events in the formation in periarticular tissue.5 To date, no single pathogenesis of such joint disease as osteoarthritis.3 molecule has been able to meet all three criteria (particularly the first two criteria). However, combinations of Synovial Membrane and Fluid compounds have shown potential in meeting most, if The synovial membrane is the inner surface of the not all three, characteristics of a chondroprotective joint capsule. There are two types of synoviocytes in the agent.6 Many compounds involved in combinations are synovial membrane: Type-A cells are macrophage-like actually molecules that are endogenous to joint tissue, and have both secretory and phagocytic capabilities; and others have a similar molecular structure to entype-B cells are fibroblast-like and produce hyaluronan. dogenous molecules.7,8 Both cell types secrete specific cytokines. The synovial As mentioned, oral chondroprotective agents are membrane does not merely act as a barrier for synovial sometimes confused with nutraceuticals, but the two fluid but is also essential for normal fluid production terms are not synonymous. The North American Veteriand turnover. Synovial fluid functions in joint lubricanary Nutraceutical Association defines a nutraceutical as tion, nutrition, and protection and is thus a crucial faca nondrug substance that is produced in a purified or extor in joint health. The activity of most chondroprotectracted form and administered orally to provide comtive agents is directed toward the synovial membrane, pounds required for normal body structure and function synovial fluid, and/or hyaline cartilage.4 with the intent of improving health and well-being.9 Not all proposed chondroprotective agents are nutraceuticals CHONDROPROTECTIVE AGENTS because many do not meet the definition. For instance, Diseases of joint tissue, specifically the hyaline cartisome purported chondroprotective agents are not in a lage and synovial membrane, are major concerns in vetpurified or extracted form but are raw products. erinary medicine. Although seldom life-threatening, There is increasing interest in chondroprotective joint disease can cause significant economic losses for agents, but several issues have confounded efforts to cattle producers and horse owners and may greatly restudy these agents.2 First, there may be an abundance duce the quality of life for many companion animal of anecdotal evidence regarding a certain compound’s species. Conventional therapy for joint disorders has efficacy but a lack of published research substantiating been primarily symptomatic and has included medical its biochemistry, pharmacology, efficacy, and safety.10 and surgical intervention. Medical therapy can include EXTRACELLULAR MATRIX ■ JOINT DISEASE ■ NUTRACEUTICALS

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This situation is changing rapidly as more basic research is being devoted to the mechanisms of action and clinical responses to some chondroprotective agents, especially the combination of glucosamine hydrochloride and chondroitin sulfate.1 Second, chondroprotective agents are grouped on the basis of proposed effects rather than on molecular structure or mechanism of action; therefore, chondroprotective agents are a heterogeneous group of compounds. Substances that have been considered chondroprotective agents include glycosaminoglycans (GAGs), amino sugars, structural proteins, enzymes, minerals, preparations of whole tissue, and semisynthetic compounds.11 To further confound things, some veterinary chondroprotective compounds are classified as drugs under FDA regulations, whereas others are considered food.9 All injectable agents are classified as drugs because of the route of administration, although the same or similar substance given orally may sometimes be considered a food.9 The injectable agents (polysulfated GAGs, hyaluronic acid, and superoxide dismutase) will not be discussed at length in this article because they have already been evaluated by the FDA for efficacy and safety and have clear and concise label information. However, the same is not true for veterinary nondrug oral agents because the manufacturing and labeling of these products are not closely regulated. As a result of poor regulation and lack of manufacturing standards, inaccurate labeling and packaging can often occur.12–14 Manufacturers of these agents cannot legally claim that their products can treat, prevent, or cure disease.9,15,16

NOMENCLATURE The term chondroprotective agent is currently used loosely in veterinary medicine and has been applied to compounds that have not been proven by consistent research to affect cartilage metabolism. As a result, some investigators have suggested that chondroprotective agent be replaced by the term slow-acting, disease-modifying agent.10 For the purpose of this article, chondroprotective agent will include the broad scope of all agents that have been proposed to modify cartilage structure; slowacting, disease-modifying agents will represent a subset of agents that have been documented to slow or reverse the progression of osteoarthritis. GLUCOSAMINE HYDROCHLORIDE/CHONDROITIN SULFATE/MANGANESE ASCORBATE The most common oral chondroprotective agent in veterinary medicine (and one of the only agents that has been studied) is a patented combination of glucosamine hydrochloride, chondroitin sulfate, and manganese ascorbate (Cosequin®; Nutramax Laboratories,

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Baltimore, MD). This chondroprotective combination has been studied in humans with osteoarthritis in the knee and been proven effective.17,18

Glucosamine Hydrochloride Glucosamine is an amino sugar—not a GAG, which has different physical and biochemical properties. A decrease in the chondrocytes’ synthesis of glucosamine has been implicated in the decline in matrix GAGs in early osteoarthritis.19 Cell culture studies have confirmed that glucosamine has a stimulatory effect on chondrocytes, causing them to secrete increased amounts of normal collagen and proteoglycans.20 Oral availability is excellent when glucosamine is presented in the form of a salt, such as a sulfate or hydrochloride.21 Glucosamine sulfate and glucosamine hydrochloride are both efficacious when given in a pure form. However, N-acetylglucosamine in cell culture was shown to be less efficacious compared with other glucosamine products.22 All of glucosamine’s functions appear to stimulate metabolism in hyaline cartilage, and it has no apparent catabolic effect on the cartilage matrix.23 Chondroitin Sulfate Chondroitin sulfate, a GAG present in several body tissues, has been shown to inhibit cartilage breakdown in vitro and in vivo.24,25 A specific purified formulation of chondroitin sulfate has been used in research. Two types of chondroitin sulfate exist. Chondroitin-4-sulfate, which is sulfated on the fourth carbon of the Nacetylgalactosamine residue, is derived primarily from mammalian tissue. Chondroitin-6-sulfate, which is sulfated on the sixth carbon, is derived primarily from shark cartilage. These two types of chondroitin sulfate are not the same and may vary greatly in molecular weight, potentially influencing bioavailability and purity.17 Chondroitin-4-sulfate is the most abundant GAG in growing mammalian hyaline cartilage. This form of chondroitin sulfate is structurally important because it binds to collagen in the cartilage matrix, thereby contributing to the resiliency and water-holding properties of cartilage. As animals age, chondrocytes secrete decreased amounts of chondroitin-4-sulfate and increased amounts of other GAGs (e.g., keratin sulfate); this change in the type of GAG in the cartilage matrix has been implicated in the initiation and progression of degenerative processes within cartilage. Cell culture studies have shown that exogenously supplied chondroitin sulfate competitively inhibits the action of metalloproteases in the cartilage matrix,26 decreasing the degradation of collagen and proteoglycans. In addition, chondroitin sulfate was shown to be clinically effective in decreasing NSAID use in human trials.27–29

GLYCOSAMINOGLYCANS ■ SLOW-ACTING, DISEASE-MODIFYING AGENT

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Chondroitin sulfate is a large molecule, and oral absorption has been questioned by some researchers.30 However, administered orally, radiolabeled chondroitin sulfate is more than 70% absorbed unchanged.31,32 Ex vivo experiments have shown a significant rise in serum GAGs after oral administration of high-grade sodium chondroitin sulfate in dogs.10 Chondroitin sulfate plays a role in many body tissues and has been investigated for its effects on the cardiovascular system. Chondroitin sulfate is released by platelets as a part of normal control of blood coagulation. There is evidence that disease- or age-related decreases in endogenous chondroitin sulfate levels are involved in the pathologic formation of occlusive thrombi in the microvasculature. Prevention of thrombi formation in the microvasculature may be beneficial to the synovial membrane and subchondral bone.33,34 This effect on the microvasculature along with inhibition of metalloproteases via the modulation of interleukin-3 meet part of the definition of a chondroprotective agent not met by glucosamine alone.17

Manganese Ascorbate Manganese ascorbate is an essential trace element that affects the growth and development of several connective tissues. Manganese ascorbate is an essential cofactor in the synthesis of GAGs and, when added to glucosamine, efficient GAG production is stimulated.35 In addition, manganese deficiency is a limiting factor in the synthesis of cartilage and synovial fluid.36 An antioxidant effect has been proposed for manganese ascorbate as well. As a salt (e.g., ascorbate), manganese ascorbate is well absorbed from the digestive tract. No toxic side effects have been reported.37 Clinical Effects and Efficacy Neither glucosamine, chondroitin sulfate, nor manganese ascorbate alone satisfies all three criteria of a proposed chondroprotective agent. However, the concurrent use of glucosamine and chondroitin sulfate combines the anabolic effects of the former with the anticatabolic effects of the latter, resulting in a net increase in the amount of healthy cartilage and normal synovial fluid.17,22,38 The differing mechanisms of action of glucosamine and chondroitin sulfate provide a synergistic rather than an additive effect because both agents are endogenous to chondrocytes.17,23 In addition, chondroitin sulfate possesses extracellular properties not found in glucosamine.17,23 The possible synergistic effect was documented in radiolabeled cartilage cell culture studies using serum of dogs given glucosamine hydrochloride, chondroitin sulfate, and manganese ascorbate in capsule form for 1 month.39

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This combination has been used in veterinary medicine for the past 5 years, primarily to treat degenerative joint disease. Although clinical data are limited, preliminary results show the formulation to be safe and possibly efficacious. 2,40,41 Although a mild and clinically insignificant decrease in platelet numbers was documented,42 no clinical evidence of bleeding has been documented to my knowledge. The lethal dose has been assessed to be higher than 5 g/kg in rats; however, no histologic lesions have been identified at extreme dosages.43 A disease-modifying effect in dogs with cranial cruciate disease was recently identified.44 In this model, the severity of degenerative joint disease was reduced and the stifle joints returned to a more normal physiologic state in treated dogs compared with untreated dogs.44 The same disease-modifying effect was reported in a meniscectomized rabbit model in which a significant decrease in moderate to severe osteoarthritic changes in the stifle was identified.45 In another study, dogs pretreated with the combination of glucosamine hydrochloride, chondroitin sulfate, and manganese ascorbate followed by induced synovitis showed decreased inflammation and reduced lameness.46 Finally, perceived safety and efficacy were confirmed in a survey of more than 3000 small animal practitioners, who reported that the combination improved mobility, alleviated pain, and improved attitude in small animal patients.47 The most common adverse side effect was gastrointestinal upset, which occurred in 2% of patients.47 This combination of compounds is also reportedly safe and efficacious in horses and cats48–50 and may be effective in treating immune-mediated arthritis in rats.51

S-ADENOSYLMETHIONINE S-adenosylmethionine (SAMe) is synthesized from methionine and is involved in several biologic reactions. Large doses of methionine are toxic and thus cannot be given to increase endogenous levels of SAMe. Therefore, SAMe must be supplemented by either injection or oral administration. The high reactivity of SAMe makes the compound unstable, but the synthesis of stable salts has enabled SAMe to be administered and researched.52 In human clinical trials, SAMe was shown to be effective in treating symptoms associated with osteoarthritis via a potent antiinflammatory action similar to that of most NSAIDs.53,54 SAMe was also shown to directly affect chondrocytes by increasing proteoglycan synthesis and protecting cartilage in several in vivo studies.55–57 The chondroprotective effects of SAMe partially result from the compound’s capability as a methyl donor and ability to transsulfate the GAG.52

THROMBI FORMATION ■ CRANIAL CRUCIATE DISEASE ■ METHIONINE

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Oral pharmacokinetics have been studied in dogs. Plasma levels have been documented; however, absorption was better when dogs were fasted overnight before administration.52 The recommended dose in humans is 600 mg/day for the first 2 weeks, followed by 400 mg/day. Clinical response was present at 1 month and was still present after 2 years of treatment.58 Veterinary studies need to be completed before recommendations can be made regarding the use of SAMe in animals.

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SUPEROXIDE DISMUTASE Superoxide dismutase (SOD) is the enzyme that converts superoxide formed in phagocytes during the respiratory burst into hydrogen peroxide.57 Hydrogen peroxide is potentially harmful, and it is neutralized in the body by catalase or glutathione peroxidase. SOD has a potent modifying effect on the inflammatory process that, unlike the effect of corticosteroids, does not delay healing or produce any observable side effects.59 SOD is extracted from bovine liver cells. Oral SOD has been advocated by some manufacturers but has not been shown to be absorbable. 60 As a result, only the injectable formulation, which has been thoroughly studied in mice,60 appears to be effective.61 Oral SOD recently has become more popular in veterinary medicine because of the increasing knowledge of its mechanism of action. Previous information indicated that SOD is beneficial in treating acute injury. New research, however, has shown a profound effect in the treatment of chronic osteoarthritis.62,63 SOD’s effect on chronic osteoarthritis appears to be related to decreasing the amount of superoxide that would react with nitric acid to produce peroxynitrite. Peroxynitrite is a long-lasting free radical that can cause injury to DNA and ENDIU MP intracellular proteins, resulting in chondrocyte death. Information from reANNIVERSARY search in several species indicates that both acute and chronic effects of SOD are possible treatments for joint Oral chondroprotective agents disease.64–67 SOD has been have emerged as a new shown to disrupt chemotaxis treatment modality for of phagocytic cells and stabinumerous conditions over the lize lysosomal membranes.60 past 20 years. Although
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information regarding the efficacy of many of these products is limited, new research has documented their effectiveness in treating osteoarthritis.

COMBINATION THERAPY There is increasing evidence to support the combination of chondroprotective agents.40 For example,

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degenerative joint disease is difficult to treat because its severity varies; thus it becomes rational to combine agents to achieve a quick and more complete response. Many practitioners will begin a course of treatment with an injectable agent, such as SOD or a polysulfated GAG, because these agents have rapid antiinflammatory action. For a sustained treatment, an oral combination of glucosamine hydrochloride, chondroitin sulfate, and manganese ascorbate could be used.40 Another option would be to use an NSAID for immediate relief followed by a long-term oral chondroprotective combination; however, it seems more synergistic to use chondroprotective combinations with differing mechanisms.9 The haphazard combination of numerous agents should only be used with caution unless a well-recognized synergism exists.12 There is often little scientific evidence that mixing unstandardized plant products, whole animal tissue, minerals, and vitamins will work and thus should not be recommended. A true therapeutic agent, regardless of origin, should be given serious consideration.12,15 However, the benefits of any chondroprotective agent must be weighed against its risk. It must be emphasized that neither risk nor benefits have been established for many of the cartilagesparing agents.15 ACKNOWLEDGMENT

The author thanks all of the manufacturers that provided information for this paper.

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About the Author Dr. Anderson is affiliated with Veterinary Specialty Services, St. Louis, Missouri, and is a Diplomate of the American College of Veterinary Surgeons.