Among skeptics, glucosamine, in the words of Rodney Dangerfield, just “can’t get no respect.” The most recent negative review in the human field ignited another round of debates concerning whether glucosamine supplementation has any value.1-2-3-4 After finding no clinically relevant effects on perceived joint pain or joint space narrowing, the authors wrote, “We are confident that neither of the preparations [glucosamine or chondroitin] is dangerous. Therefore, we see no harm in having patients continue these preparations as long as they perceive a benefit and cover the costs of treatment themselves.” From another glucosamine review, “[I]t is likely that most consumers find the presence or absence of clinical evidence demonstrating efficacy to be irrelevant.”5 Unsure of glucosamine’s benefits, many veterinarians nevertheless err on the side of hope and recommend products ranging from solo glucosamine to combinations containing chondroitin, avocado soy unsaponifiables, MSM and other chondroprotective agents. A recent evidence-based clinical vignette in JAVMA challenged this approach, stating: “[T]here is widespread belief in the safety and efficacy of this practice. However, it is important to base recommendations to clients on the best possible research evidence and not solely on the popularity of a practice or anecdotal reports of positive outcomes.”6 After analyzing three reports, the author decided to recommend only NSAID treatment without glucosamine, prompting this reader to ask, “Is it wrong to recommend glucosamine if we consider ourselves evidence-based?” What are the arguments against it, and what evidence supports it? Many of us are accustomed to hearing certain arguments against glucosamine but may not be aware of evidence-informed responses. For example: “Most of the glucosamine ingested doesn’t get absorbed; that’s why studies showing positive results needed extremely high doses.” Early studies did incorporate supra-physiologic concentrations, i.e., levels higher than those typically attained in synovial fluid following biologically relevant doses.7 More recent work found that clinically relevant doses led to levels measurable in both plasma and synovial fluid.8 Chemical makeup may influence absorption and bioavailability; significantly higher levels of glucosamine reached the synovial fluid after crystalline glucosamine sulfate than with glucosamine hydrochloride.9 “Even if it does reach the joint, it doesn’t build cartilage.” Glucosamine serves as a precursor for glycosaminoglycans, the main component of joint cartilage.10 Glucosamine supports cartilage regrowth by inhibiting cartilage degradation and stimulating proteoglycans synthesis.11 A 2010 rodent study confirmed that glucosamine inhibits type II collagen degradation (the collagen that forms articular and hyaline cartilage) and enhances type II collagen synthesis in articular cartilage.12 “It doesn’t reduce inflammation.” Glucosamine not only promotes cartilage health, it also reduces release of inflammatory mediators. Glucosamine appears to penetrate inflamed joints more readily than healthy ones, at up to quadruple amounts.13 “Glucosamine hasn’t shown benefits for small animals.”14 A 2007 randomized, double-blind, positive controlled, multicenter study on dogs demonstrated statistically significant improvements in scores pertaining to pain, weight-bearing and severity of the condition after day 70 of a glucosamine/chondroitin combination.15 A 2010 investigation of a glucosamine-containing therapeutic diet for arthritic cats demonstrated a significant increase in physical activity as well as weight loss compared to the control diet.16 “Glucosamine could harm diabetics.” Questions commonly arise about whether administration of glucosamine, an amino sugar, is safe for dogs and cats with diabetes mellitus.17-18 Clinicians express concern that glucosamine could either cause diabetes mellitus or make regulation more difficult in already diabetic patients by promoting insulin resistance via desensitization of the insulin-stimulated glucose transport system. In 2010, Lennox and Lunn examined whether glucosamine-chondroitin sulfate supplementation would affect serum fructosamine concentration in healthy dogs, finding no significant changes after either the supplement or the placebo.19 This indicated that oral glucosamine/chondroitin does not affect glycemic control or lead to diabetes in the short term. But this research does not answer the question of whether glucosamine is safe for diabetic dogs. On a positive note, a rodent study did find beneficial metabolic attributes of long-term administration of glucosamine for diabetic rats fed a high-fat diet.20 “One cannot rely on label claims for content.” True. A report in Equine Veterinary Journal found only 14 out of 23 evaluated products showed consistency between actual content and label claims, reflecting inadequate regulatory oversight.21 Research looking at whether glucosamine products are effective would obviously need to assess the content of the active agent in the product prior to testing clinical outcomes. “If glucosamine actually worked, we’d know it by now. With so many studies out there, the evidence would be clear.” In addition to confusion regarding the type of preparation used and doses administered, another reason clinical trials may have yielded conflicting results may pertain to population heterogeneity. For example, given that individuals with inflamed joints demonstrate higher intra-articular concentrations of glucosamine than do those with healthy joints, perhaps research subjects experiencing active inflammation derive greater benefits from supplemental glucosamine. Concomitant supplementation with other nutraceuticals such as probiotics might influence outcomes as well. Lactobacillus casei enhanced the type II collagen/glucosamine-mediated suppression of inflammation in experimental OA rats, possibly acting as a potent modulator that promoted analgesic, anti-inflammatory and anti-degradation effects.22 What to Do? Although the evidence on glucosamine remains contradictory, there does appear to be some value and little risk. Not ready to abandon a product that could very well help and likely not hurt, this evidence-based practitioner will continue to mention glucosamine as one of many options for multimodal analgesia for OA patients and potential disease modifying OA benefits as well. Dr. Robinson, DVM, DO, Dipl. ABMA, FAAMA, oversees complementary veterinary education at Colorado State University. <HOME> FOOTNOTES 1. Wandel S, Juni P, Tendal B, et al. Effectcs of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip of knee: network meta-analysis. BMJ 2010;341:c4675. doi:10.1136/bmj.c4675. 2..Pelletier J-P et al. Effect size is encouraging. BMJ 2010;341:c6328. 3. Giacovelli G and Rovati LC. Conclusions not supported by methods and results. BMJ 2010;341:c6338. 4. Reginster J-Y, Altman RD, and Hochberg MC. Prescribed regimen is effective. BMJ 2010;341:c6335. 5. Block JA, Oegema TR, Sandy JD, et al. Review. The effects of oral glucosamine on joint health: is a change in research approach needed? Osteoarthritis and Cartilage. 2010;18:5-11. 6. McKenzie BA. What is the evidence? JAVMA. 2010;237(12):1382-1383. 7. Meulyzer M, Vachon P, Beaudry F, et al. Joint inflammation increases glucosamine levels attained in synovial fluid following oral administration of glucosamine hydrochloride. Osteoarthritis and Cartilage. 2009;17:228-234. 8. Meulyzer M, Vachon P, Beaudry F, et al. Comparison of pharmacokinetics of glucosamine and synovial fluid levels following administration of glucosamine sulphate or glucosamine hydrochloride. Osteoarthritis and Cartilage. 2008;16:973-979. 9. Meulyzer M, Vachon P, Beaudry F, et al. Comparison of pharmacokinetics of glucosamine and synovial fluid levels following administration of glucosamine sulphate or glucosamine hydrochloride. Osteoarthritis and Cartilage. 2008;16:973-979. 10. Budsberg SC and Bartges JW. Nutrition and osteoarthritis in dogs: does it help? Vet Clin Small Anim. 2006;36:1307-1323. 11.Naito K, Watari T, Furuhata A, et al. Evaluation of the effect of glucosamine on an experimental rat osteoarthritis model. Life Sciences. 2010;86:538-543. 12. Naito K, Watari T, Furuhata A, et al. Evaluation of the effect of glucosamine on an experimental rat osteoarthritis model. Life Sciences. 2010;86:538-543. 13. Meulyzer M, Vachon P, Beaudry F, et al. Joint inflammation increases glucosamine levels attained in synovial fluid following oral administration of glucosamine hydrochloride. Osteoarthritis and Cartilage. 2009;17:228-234. 14. Block JA, Oegema TR, Sandy JD, et al. Review. The effects of oral glucosamine on joint health: is a change in research approach needed? Osteoarthritis and Cartilage. 2010;18:5-11. 15. 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;174:54-61. 16. Lascelles BDX, DePuy V, Thomson A, et al. Evaluation of a therapeutic diet for feline degenerative joint disease. J Vet Intern Med. 2010;24:487-495. 17. Buse MG. Hexosamines, insulin resistance and the complications of diabetes: current status. Am J Physiol Endocrinol Metab. 2006;290(1):E1-E8. 18.Lenox CE and Lunn KF. Effects of glucosamine-chondroitin sulfate supplementation on serum fructosamine concentration in healthy dogs. JAVMA. 2010;236;183-186. 19. Lenox CE and Lunn KF. Effects of glucosamine-chondroitin sulfate supplementation on serum fructosamine concentration in healthy dogs. JAVMA. 2010;236;183-186. 20. Barrientos C, Racotta R, and Quevedo L. Glucosamine attenuates increases of intraabdominal fat, serum leptin levels, and insulin resistance induced by a high-fat diet in rats. Nutrition Research. 2010;30:791-800. 21. Oke S, Aghazadeh-Habashi A, Weese JS, et al. Evaluation of glucosamine levels in commercial equine oral supplements for joints. Equine Veterinary Journal. 2006;38(1):93-95. 22 So J-S, et al, Lactobacillus casei enhances type II collagen/glucosamine-mediated suppression of inflammatory responses in experimental osteoarthritis, Life Sci (2010), doi:10.1016/j.lfs.2010.12.013. 2/14/2011 12:16 PM
