Oral Chondroprotective Agents.part Ii

Vol. 21, No. 9 September 1999

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Refereed Peer Review

FOCAL POINT ★Lack of standardization for safety, efficacy, and truth in labeling of most nondrug oral compounds makes the decision-making process difficult for veterinarians choosing new products to treat osteoarthritis (OA).

KEY FACTS ■ Nondrug oral compounds cannot be sold with the claim that they treat OA, degenerative joint disease, or pain. ■ Quality, grade, and quantity must be carefully assessed when determining which nondrug oral compound to use. ■ The various unprocessed chondroitin sulfate products may not have equivalent results in the treatment of OA. ■ Glycosaminoglycans can be derived only from animal sources and not from sea algae, gelatin, or other plant sources. ■ No veterinary studies support or refute the efficacy of collagen type II, fatty acids, antioxidants, amino acids, proteolytic enzymes, and botanicals in the treatment of OA.

Oral Chondroprotective Agents. Part II. Evaluation of Products* Veterinary Specialty Services, St. Louis, Missouri

Mark A. Anderson, DVM, MS ABSTRACT: Many new chondroprotective products are becoming available on the veterinary market to treat osteoarthritis. Several of the new products on the horizon are discussed. These products must be used with some caution. Veterinarians should review all of the information about a product before deciding to recommend that owners purchase it for their pets.

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he number of the nondrug oral compounds known as chondroprotective agents has increased in recent years. However, lack of control by any government agency has led to poor regulation and contributed to veterinarians’ inability to decide which products are safe, effective, and have accurate labels. The lack of product standardization makes comparisons between similar products difficult if not impossible. New chondroprotective-agent candidates include such compounds as type II collagen, fatty acids, antioxidants, amino acids, proteolytic enzymes, and botanicals. However, until standardized methods for comparison are devised, none of these agents should be used as primary treatment of osteoarthritis (OA). Although many of these compounds have shown promise in treating arthritis in humans, veterinarians should evaluate products based on sound scientific findings and manufacturer reputations. Part I of this two-part series discussed nomenclature and the types of available chondroprotective agents. This article provides some parameters for evaluating many new chondroprotective products.

SAFETY, EFFICACY, AND TRUTH IN LABELING The confusion and occasional misinformation that surround the use of chondroprotective agents may be frustrating for veterinarians and clients alike. The list of compounds proposed as chondroprotective agents is long and expected to grow. Until chondroprotective agents are held to efficacy and safety standards similar to those of pharmaceuticals, veterinarians should approach newly proposed products with an open mind combined with healthy skepticism.1–3 Individuals in search of accurate information about chondroprotective agents are often thwarted by a lack of definite answers. Scientific veterinary information on most oral chondroprotective agents is limited.4 In most cases, this lack of accurate information is complicated by legal and economic, rather than purely scien*Part I of this two-part presentation appeared in the July 1999 (Vol. 21, No. 7) issue of Compendium.

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tific, reasons. For nondrug does not determine whether oral compounds, the FDA the product was properly does not legally allow claims manufactured. Practitioners to be made regarding the should choose products for treatment of arthritis, degenwhich research was conerative joint disease, or pain. ducted on the brand prodProducts should be suspectuct and not the raw comed if such claims are made pound; assumptions that on any label or literature.3 the brand product and raw Purity can also vary among compound have met similar nondrug products. A recent specifications are questionstudy found the content of able.10 For instance, manufacturers may only supply oral superoxide dismutase (SOD) to be no higher than Figure 1—Nondrug oral products should be validated by in- references for the raw compound and not for their prod5% of the label claim made dependent laboratory analysis. uct. Published studies may by six different manufacturevaluate a compound in pure ers.5 The low concentration of SOD may have been the result of the source not beform, whereas the product may not use this same pure ing purified to the labeled amounts or the SOD being compound. Finally, the study must be critically evaluatdestroyed in the manufacturing process or storage. Aned (e.g., information published on the treatment of other study showed that 70% of products analyzed for rheumatoid arthritis may not pertain to the treatment glucosamine and chondroitin sulfate (CS) did not meet of OA). label claims.6 Even when a product does contain the GLYCOSAMINOGLYCAN SOURCES stated amount, quality and grade of the labeled comThe efficacy of purified CS for treating OA has been pound may not be specified. For example, glucosamine well documented7,8,10–14; thus, certain whole animal tisand CS are available in a variety of grades of raw prodsues have been promoted to be beneficial primarily beuct. The studies that have evaluated the safety and efficause they are sources of glycosaminoglycan (GAG) or cacy of these two compounds used pharmaceutic-grade mucopolysaccharide and thus of CS. Because purified material7,8; products using lower-grade material may not achieve similar results. CS is expensive, alternative sources have been assumed When evaluating nondrug oral products, veterinarito be effective simply because GAG is present. Howevans must base their selection decisions on their knowler, that a product is a source of GAG does not ensure edge of the compound’s safety and efficacy and the the quality or milligram strength of CS. CS is often manufacturer’s reputation. One standard by which vetbound to aggrecan and is poorly available. erinarians can evaluate a manufacturer is whether the Sources of GAG proposed to have effects similar to product has been subjected to independent laboratory those of CS include cartilage powders of shark, chickanalysis (Figure 1) and clinical trials and has been made en, or bovine origin; sea cucumber; and Perna mussel. using good manufacturing practices.9 No study has proven these possible alternative sources Veterinarians should also study labels to ensure the of CS to be effective in treating OA. Theoretically, exact amounts of active ingredient are listed and the lasome alternative sources based on whole animal tissues bels are easy to understand. Labels that are not easy to could be beneficial if high enough doses are given, but read can often be deceptive if not examined closely.1,2 the absorption may still be poor. These products often Products that combine metric and apothecary systems provide a nonuniform and unstandardized mixture of should be questioned because calculating dosages beproteins, fats, carbohydrates, and minerals with uncomes difficult. In many instances, the milligram known and/or unpredictable effects. In addition, many strength may be listed but the sum of the listed ingrediGAG-source products contain absolutely no glucosaents is heavier than the final product. All products mine.6,15 Cartilage powders have been studied in wound healshould contain a specific dose. If a dose is not provided, ing,16 but no controlled studies on OA have been perit becomes difficult to determine how much to use formed in either human or veterinary medicine. There when treating patients. have been a few anecdotal reports showing that purified Veterinarians should also request a copy of the analyor raw shark cartilage administered at high doses is effisis of the finished product—not the raw material— cacious in dogs,17 but shark cartilage has been reported from the manufacturer because a raw product analysis PURITY ■ FINISHED-PRODUCT ANALYSIS ■ CHONDROITIN SULFATE

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to have a low percentage (18%) of GAG.15 A recent study using a purified, water-soluble protein fraction of shark cartilage showed an antiinflammatory effect in laboratory animals.18 However, this documented effect of the purified form of shark cartilage differs from that associated with feeding raw cartilage. Other research has shown shark cartilage to have an antiangiogenic effect.17 Perna mussel has been reported to be a source of GAG; however, the specific GAGs have never been identified.16 The analysis of Perna mussel has included proteins, amino acids, enzymes, carbohydrates, and fats; glucosamine, CS, and the specific GAGs are not listed on the label.19 Most research done on Perna mussel has been for the treatment of rheumatoid arthritis and is dated.16,17,20–22 Because Perna mussel lacks an identifiable active ingredient and a confirmed mechanism of action, research is limited on Perna mussel as a treatment of OA.16 In addition, although anecdotal reports exist, there are no good controlled studies that substantiate Perna mussel as a treatment of OA. Sea algae and gelatin are also proposed sources of raw GAG. However, GAGs can be derived only from animal sources and not from plants or algae.22 The only known exception is some bacteria (Streptococcus species) that can produce hyaluronic acid. As a result, it is impossible for algae to be a source of any GAG. Gelatin is mainly a conglomeration of water and soluble proteins. Based on this fact, GAGs should be either minimal or not present in gelatin. Veterinary studies have not been performed to confirm either algae or gelatin as an effective treatment for OA.

NEW CHONDROPROTECTIVE AGENTS In addition to the compounds discussed in Part I, there are a multitude of compounds that are marketed as being effective in the treatment of OA but have unsubstantiated efficacy. Some of these new chondroprotective agents will be discussed. The interaction caused by combining these new compounds with the previously mentioned products is unknown. Many of these compounds are added to numerous formulations that are sold in the veterinary market but in such small concentrations that they appear to have little or no effect in the treatment of OA. Type II Collagen Type II collagen is a molecule endogenous to the cartilage matrix that has been investigated as a potential treatment for OA.23 Hyaline cartilage is primarily composed of type II collagen and, to a lesser extent, types IX and XI. The random framework of type II collagen is essential to the normal function of the hyaline cartilage matrix. Derangement of the superficial zone of hya-

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line cartilage has been implicated as the initiating cause, and reason for progression, of OA.24 More recently, research on collagen as a therapy for joint disease has centered on oral administration of type II collagen for treating humans with rheumatoid arthritis.23,25 Two investigations have identified autoantibodies directed against type II collagen in dogs with naturally occurring joint disease.26,27 These facts may indicate that autoimmunity may be at least a part of the disease progression in certain humans and animals with joint disease. The potential for collagen-based therapies to contribute to the management of joint diseases is novel; however, more research needs to be performed before collagen can be recommended for treatment of joint disease.

Fatty Acids Omega-3 and omega-6 fatty acids have occasionally been successful at modulating joint disease in humans,28 but there are no controlled veterinary studies that evaluate these compounds in treating joint disease. These fatty acids are essential for health and have been used successfully to treat other inflammatory diseases in veterinary patients (e.g., skin disorders).29 Fatty acids, as well as other endogenous molecules, are being investigated for their role in modulating rheumatoid arthritis and OA in humans.28 Current human research uses high doses (ranging from 2 to 5 g/day) to obtain clinical results30; it seems questionable that lower amounts added to a combination product would be of any value in either humans or animals. Although fatty acids may be valuable in managing joint disease in animals, little is known regarding their specific role. Many fatty acids have been implicated as antiinflammatory agents in certain disease conditions (e.g., autoimmune arthritis, skin disease); however, potential interactions with current therapies are unknown.28–30 Many questions regarding this group of compounds and their use in the treatment of OA remain unanswered. Antioxidants Antioxidants (e.g., vitamins E and C, selenium) may have some effect in decreasing joint disease in humans, but no veterinary studies have evaluated the efficacy of any of these compounds. In humans, the dose for vitamin E is 400 to 800 IU/day for musculoskeletal disease, with minimal effects being observed; however, vitamin E is oil soluble, and overdose is possible.31 Other antioxidants, such as selenium, have not shown a significant decrease in pain scores in humans with OA, although using selenium to treat rheumatoid arthritis is promising.32 Vitamin C has been proposed as a treatment for many musculoskeletal diseases because of the

PERNA MUSSEL ■ HYALINE CARTILAGE ■ VITAMIN E

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crucial role it plays in collagen synthesis.33,34 However, because dogs make vitamin C endogenously, the role of additional vitamin C in the diet has been questioned. In addition, very high doses of vitamin C would be required to increase the tissue levels of vitamin C. A dose of 90 mg/kg was required to clinically improve OA in dogs,17 but these results have not been repeatable. If large doses of vitamin C are used, gastrointestinal side effects may occur.17

and composition of the marketed product may not be the same as those that were proven effective in the research. In addition, calculating the amount of compound to administer may be difficult because most compounds are unstandardized.1 As more is learned about the mechanism of action of these botanicals, plant-derived compounds can be expected to become increasingly important as therapeutic agents.

Amino Acids and Proteolytic Enzymes Creatine is an amino acid thought to modify musculoskeletal activity in humans. Creatine’s benefit in the treatment of OA is questionable; it has been documented that large doses help muscle function in humans.35 The dose used in some veterinary products is extremely small, making any potential benefit unlikely. Bromelain is a proteolytic enzyme that reportedly decreases acute swelling from sport injuries in humans when taken in high doses every 4 hours.36,37 However, to be effective, most proteolytic enzymes must be given prior to the insult.36,37 Because bromelain appears to be most effective when given before acute injuries, its use is unlikely to be beneficial in the treatment of OA.

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

ACKNOWLEDGMENT

Botanicals Botanicals that have been proposed as potentially chondroprotective include the yucca (several species of the Agavaceae family), boswellia (Boswellia serrata), and tumeric (Curcuma longa) plants. Substances derived from these plants have been used for years to treat a variety of human ailments. However, no veterinary studies have documented or refuted the use of these botanicals in the treatment of OA. Many of these plants or herbs appear to have some unknown antiinflammatory effect but do not meet any of the criteria for the definition of a chondroprotective agent. Although it is entirely reasonable that plant-derived agents may be beneficial in treating OA, research is required to standardize the plant extracts, determine the pharmacologic principles and mechanism of activity, and document the proposed effects. Because not all plant-derived substances are harmless or beneficial, these substances should meet the same standardization rigors as do pharmaceuticals before any conclusions regarding safety or efficacy can be made.1,3 Even if the substances are found to be safe and effective, interactions with other compounds must be considered before using them in a combined therapy. Currently, the labeling of herbal products is often vague, incorrect, and misleading, and thus purity and dosing must be questioned. Even when a botanical has been shown to have an antiinflammatory effect for a given condition, the dose

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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.