Chondroprotective agents: Do they work? (Proceedings)

Regulation: Chondroprotective agents are available as injectable and oral formulations. The injectable formulations are classified as drugs and are regulated by the FDA. The present discussion will focus on the more nebulous branch of chondroprotective agents, the nutraceuticals. Oral formulations are considered to be nutraceuticals, a somewhat poorly-defined term used to describe compounds supplied exogenously to facilitate normal body functions and structures. Human and veterinary nutraceuticals are considered somewhat differently, as human compounds are classified as dietary supplements under the 1994 Dietary Supplement Health and Education Act (DSHEA), whereas veterinary formulations are excluded from DSHEA. As DSHEA clarified the regulation of human nutraceuticals, the lack of DSHEA coverage of veterinary products has left the regulatory status of veterinary nutraceuticals in limbo. State feed laws may govern the majority of products, but most products do not appear on Association of American Feed Control Officials (AAFCO) list of products that are "generally recognized as safe" (GRAS). As unregulated products, nutraceuticals are not required to meet U.S. Food and Drug Administration (FDA) guidelines for efficacy, purity, and potency. Similarly, supplement manufacturers are not required to follow Good Manufacturing Procedures (GMP), resulting in the sale of products that may differ from their stated ingredients are dose. Irregardless, both human and veterinary nutraceuticals are prohibited from making claims that would represent the supplement as a drug. Under The Food, Drug, and Cosmetic Act, a drug is "intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease". Thus, under DSHEA, nutraceutical products can claim on their labels that they support normal body structure and function but cannot make statements regarding mitigation or prevention of disease. This labeling requirement is somewhat at odds with how nutraceutical chondroprotective agents are most often used, where veterinary patients may receive these agents in an attempt to slow the progression of osteoarthritis and reduce pain.

Actions of Chondroprotective Agents: There are several different types and classes of nutraceutical agents purported to have actions in cartilage and joints. Chondroprotective agents are sometimes referred to as slow-acting, disease-modifying, osteoarthritis agents (SADMOAs). Numerous other agents, such as green-lipped muscle, avocado/soybean unsaponifiables, pentosan polysulphate, special milk protein concentrate, and elk velvet antler, have also been advanced as potential chondroprotective agents. However, due to limitations in space, the present discussion will be confined to the most commonly used agents, glucosamine and chondrotin sulfate. . The SADMOA agents are thought to act by promoting the synthesis of hyaline cartilage, which is a mixture of collagens, proteoglycans, and water. The water in the cartilage is an essential component of shock absorption during loading of the joint, and is attracted to cartilage by the proteoglycan macromolecules. The proteoglycan is actually a complex mixture of smaller constituents, such as multiple glycosaminoglycans, chondroitin sulfate, and keratin sulfate, attached to a protein and hyaluronic acid core. Glucosamine and chondroitin sulfate are two of the building blocks incorporated into the articular proteoglycans, and so are supplemented in hope that excess amounts of circulating precursors will encourage the net formation of hyaline cartilage. Other oral nutraceutical agents, such as manganese and ascorbate, are administered as cofactors for the synthesis of proteoglycans and collagen. As catabolism of hyaline cartilage has been implicated in the pathogenesis of osteoarthritis, a shift from catabolic to anabolic effects would be expected to improve joint function and decrease the pain associated with osteoarthritis. Although this line of reasoning provides a rational explanation for efficacy of oral chondroprotective agents, in vitro studies suggest that other mechanisms, such as scavenging of free radicals and direct anti-inflammatory effects, may also be involved in chrondroprotection. Numerous in vitro studies have detected positive anabolic and anti-inflammatory effects of glucosamine and chondroitin disaccharides on explants or cell cultures of chondrocytes. Anti-inflammatory effects include blockade of interleukins, decreased production of prostaglandins, inhibition of metalloproteinases, and a reduction in reactive oxygen species, perhaps moderated through inhibition of NF-kappa B nuclear translocation1 . These in vitro studies are largely impressive and demonstrate a rational mechanism of action of the SADMOAs in modulating osteoarthritis. However, most of the in vitro work has used much higher concentrations of glucosamine and chondroitin disaccharides than are found in the plasma after oral administration, complicating the direct applicability of these studies to clinical efficacy.

Oral Absorption of Chondroprotective Agents: Pharmacokinetic and efficacy studies have been reported in both the human and veterinary peer-reviewed literature for several of these agents, demonstrating absorption and activity. The SADMOAs generally have limited oral absorption as an intact molecule as a consequence of their structure. For example, chondroitin sulfate and proteoglycans are large, charged macromolecules, so they are not absorbed intact. However, chondroitin sulfate is readily cleaved to distinct disaccharides that can be found at elevated concentrations in the plasma after oral administration in dogs. The elimination of chondroitin disaccharides appears to be slower than that of glucosamine, with accumulation occurring with the administration of multiple doses. Although the slow accumulation of chondroitin may partially explain the delayed onset of action of the SADMOAs, the proposed mechanism of cartilage synthesis suggested by in vitro studies would also support a slow onset of action. Indeed, significant improvements in dogs with osteoarthritis that were administered glucosamine and chondroitin were reported at 70 days after beginning supplementation.2 Additional studies with radiolabeled compounds have revealed that fragments of chondroitin are absorbed from the gastrointestinal tract and can be found in synovial fluid and hyaline cartilage, demonstrating both absorption and a tropism for joints. Glucosamine is a much smaller molecule than is chondroitin and is better absorbed intact from the gastrointestinal tract in the species that have been studied, including in dogs. In one formulation of glucosamine HCl administered orally to dogs, the bioavailability was low (12%), but the glucosamine was rapidly absorbed, with a maximum plasma concentration achieved in 1.5 hours. Although glucosamine is rapidly metabolized to simple sugars, exongenously administered glucosamine also exhibits a tropism for articular cartilage, which may offset its rapid metabolism.

Efficacy Studies: The chondroprotective agents are probably the best studied of all of the oral nutraceutical agents. Although the majority of these studies were funded by the product manufacturers, numerous studies have demonstrated a positive, if often mild, effect in patients with osteoarthritis. Unfortunately, the efficacy studies for orally administered agents that have been performed in veterinary medicine tend to have small numbers of subjects and flaws in study design. The slow-acting nature of the SADMOAs further complicates their definitive study. Most studies have focused on the co-administration of glucosamine and chondroitin sulfate, often with other cofactors, such as methylsulfonylmethane (MSM). Glucosamine is an ionic molecule, so is formulated as a salt of either HCl or sulfate. Although most empirical evidence suggests that the identity of the salt is not clinically important, there is some controversy regarding this point and few direct comparisons of the effect of formulation on outcome. Studies have utilized both objective evidence of efficacy, such as scintigraphic improvement in induced inflammatory joint disease using a synovitis model, and subjective effect on osteoarthritis, as judged by veterinarians and owners. The results of the efficacy of glucosamine/chondroitin supplementation on osteoarthritis in dogs are somewhat mixed, with systemtic reviews themselves differing in whether the available evidence is strong enough to recommend supplementation.

Several studies have compared the efficacy of glucosamine/chondroitin supplementation for amelioration of osteoarthritis in dogs with that of non-steroidal anti-inflammatory drugs (NSAIDs), such as carprofen and meloxicam.2 The results of these limited studies are variable, with one study finding positive effects associated with nutraceutical use and one reporting no benefit. However, in both studies, the NSAIDs were superior for relief of pain and lameness in both studies. This result suggests that the administration of glucosamine/chondroitin alone to noticeably painful dogs with osteoarthritis should probably be avoided. Although studies evaluating the efficacy of co-administration of an NSAID and SADMOA are lacking, empirical evidence suggests that such a combination would be warranted in painful dogs, with possible weaning of the NSAID after several months of co-administration. The safety of such a combination has not been assessed. However, the SADMOAs have demonstrated a very low proclivity for producing side effects, mainly confined to minor gastrointestinal irritation. Given the different mechanisms of action of the SADMOAs and the NSAIDs, co-administration of the two for symptomatic pain relief and chrondroprotection is unlikely to cause side effects beyond the familiar toxicities associated with NSAID use alone in dogs. However, studies investigating the efficacy and safety of a combined approach would be helpful.

Many more publications of nutraceutical efficacy have been published in people, but the same study design flaws that plague veterinary studies are often present in the human literature. Metanalyses and systematic reviews, where numerous smaller studies are pooled and compared, have found a modest treatment effect for glucosamine and chondroitin administration. Unfortunately, metanalysis also demonstrates considerable heterogeneity between study outcomes, perhaps due to factors like publication bias that exist in these industry funded studies. Despite these shortcomings, several publicly funded, large, well-designed studies have been performed in humans. For example, the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) study was funded by the National Institutes of Health, enrolled 1,583 subjects, and was designed to definitively determine whether glucosamine HCl, chondroitin sulfate, or a combination of glucosamine HCl and chondroitin sulfate, alleviated joint pain better than did a placebo.10 Subjects were enrolled with osteoarthritis of the knee and received the randomized treatment for six months. Interesting, this study demonstrated an unusually high placebo effect, where 60% of subjects receiving a placebo reported 20% improvement in joint pain. In people with mild to moderate pain, the findings from the GAIT study were negative regarding the primary endpoints studied, although there were differences between treatment groups for some of the smaller subsets of patients. For example, 79% of patients in the glucosamine combined with chondroitin group who started with moderate to severe pain experienced at least a 20% reduction in pain, as compared to 54% of those in this higher pain category that received placebo. The finding that glucosamine + chondroitin was more effective in patients with greater pain as compared to those starting with lower pain scores runs counter to expectations regarding this group of nutraceuticals, which are expected to be more effective in countering milder, early osteroarthritis than more progressive, severe disease. When comparing the conduct of the GAIT trial to studies performed in veterinary medicine, it is sobering to note that the positive findings for the moderate to severe pain group are viewed as preliminary, due to the small number of patients (354!) enrolled in this section of the study.

REFERENCES

1. Iovu M, Dumais G, du Souich P. Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage 2008;16 Suppl 3:S14-8.

2. McCarthy G, O'Donovan J, Jones B, et al. Randomised double-blind, positive-controlled trial to assess the efficacy of glucosamine/chondroitin sulfate for the treatment of dogs with osteoarthritis. Vet J 2007;174(1):54-61.

3. Reginster JY. The efficacy of glucosamine sulfate in osteoarthritis: financial and nonfinancial conflict of interest. Arthritis Rheum 2007;56(7):2105-10.

4. Black C, Clar C, Henderson R, et al. The clinical effectiveness of glucosamine and chondroitin supplements in slowing or arresting progression of osteoarthritis of the knee: a systematic review and economic evaluation. Health Technol Assess 2009;13(52):1-148.

5. Vlad SC, LaValley MP, McAlindon TE, et al. Glucosamine for pain in osteoarthritis: why do trial results differ? Arthritis Rheum 2007;56(7):2267-77.

6. Moreau M, Dupuis J, Bonneau NH, et al. Clinical evaluation of a nutraceutical, carprofen and meloxicam for the treatment of dogs with osteoarthritis. Vet Rec 2003;152(11):323-9.

7. Canapp SO, Jr., McLaughlin RM, Jr., Hoskinson JJ, et al. Scintigraphic evaluation of dogs with acute synovitis after treatment with glucosamine hydrochloride and chondroitin sulfate. Am J Vet Res 1999;60(12):1552-7.

8. Aragon CL, Hofmeister EH, Budsberg SC. Systematic review of clinical trials of treatments for osteoarthritis in dogs. J Am Vet Med Assoc 2007;230(4):514-21.

9. Sanderson RO, Beata C, Flipo RM, et al. Systematic review of the management of canine osteoarthritis. Vet Rec 2009;164(14):418-24.

10. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354(8):795-808.