Joint Supplements: Potential for Harm
Written by: Dr Tom Shurlock for and on behalf of GWF Nutrition Limited.
Copyright GWF Nutrition Limited January 2020 - Not for reproduction.
Joint supplements can be extremely variable in their make-up. They can be a combination of NSAID, glycosaminoglycans, essential oils, minerals and antioxidants. Although all the components are safe when fed at recommended levels, there is evidence that some components, or combinations, may cause physiological damage when fed at elevated levels. Although not normally of concern, there can be situations when harm can occur.
A review by the American SPCA over 2008/9 reported a number of toxic occurrences of joint supplements, with and without NSAID, across a range of dog weights and ages. Poisoning was caused by dogs eating 20 – 240 tablets, the range of bioactive concentration being glucosamine hydrochloride (450 to 1,000 mg), methylsulfonylmethane -MSM- (400 to 600 mg), creatine monohydrate (250 to 400 mg), docosahexanoic acid (6 to 12 mg), eicosapentaenoic acid (9 to 18 mg), ascorbic acid (5 to 50 mg), vitamin E (25 to 50 U), thioctic acid (75 to 200 μg), and chondroitin (0 to 100 mg). Minor ingredients included zinc, manganese, selenium, glutathione, flavours, and fillers. Postmortem examination revealed severe histologic changes in the liver (centrilobular necrosis), kidneys (acute tubular necrosis and vascular thrombosis), pancreas (necrosis), and myocardium (necrosis).
In the case of NSAID, it has been shown that they impair the cyclooxygenase (COX 1&2) enzymes. These convert arachidonic acid into prostaglandin H, which is further converted into the PGE series. These are critical in maintaining cardio-renal function, and NSAID have been shown to affect various renal functions. Low COX2 has been associated with renal failure in dogs, whilst COX1 expression is noted in cardiac systems.
However, the main components of joint supplements are combinations of glucosamine, MSM and chondroitin. They can interact with other ingredients, as evidenced by interactions between these and manganese. Having consumed 100 joint supplement tablets (equivalent to 60 g of glucosamine hydrochloride (10.3 g/kg), 25 g of MSM (4.3 g/kg), 30 g of chondroitin sulfate (5.2 g/kg), and 500 mg of manganese ascorbate (86 mg/kg), a female pug suffered hepatic damage, and was euthanised. Although levels of 1g glucosamine a day has caused polyuria and polydipsia in retrievers, and MSM has hepatoprotective effects, higher levels of glucosamine had apparently no effect. As such it was concluded that elevated liver and renal manganese led to liver failure.
Another report showed that a Bernese Mountain dog, having ingested 200 joint supplement tablets (glucosamine and chondroitin sulfate ingested were 2173 mg/kg body weight (BW) and 217 mg/kg
BW, respectively.) suffered from vomiting, inappetence, and lethargy. And had elevated liver enzyme levels, including alkaline phosphatase, bilirubin, lipase and alanine aminotransferase. Associated with this were elevated manganese levels.
In those cases that are reported the toxicosis is obviously due to heavily overdosing dogs with joint supplements, possibly in conjunction with NSAID treatment. However, as dogs are opportunists, and supplement packages may contain up to 2 years supply, if access is available, a dog could easily overdose. Knowing, therefore, the components of a branded product, and how they act, will help shape recovery procedures.
Glucosamine has been shown to have a positive effect in the maintenance of cartilage, both through its role as a precursor of GAG, and also through mediation of inflammatory processes. However, these actions can be reversed if supplied at pharmacological levels.
The LD50 of oral glucosamine in animals is _8000 mg/kg with no adverse effects at 2700 mg/kg for 12 months. Altered glucose metabolism can be associated with parenteral administration of large doses of glucosamine in animals. This mechanism, the hexamine pathway, has been theorised as actively participating in the promotion of metabolic disorders such as diabetes as well as diabetic microvascular complications. However, in humans 200x the normal oral dose does not appear to affect kidney function. Elevated plasma levels of glucosamine result in the increase of the relative expression of both TGFβ1 and CTGF mRNA by up to 2.3-fold in liver, kidney and articular cartilage. Although these factors are part of the beneficial effect of cartilage protection, increased levels in the kidney can lead to sclerotic effects. Additionally, it has been reported that glucosamine can induce tubulointerstitial nephritis (TIN). Beyond this, early signs of glucosamine overdosing is vomiting, diarrhoea and gastric lesions.
High levels of chondroitin sulphate (3000mg/day) have been shown to cause vomiting in dogs and an increase in gastric lesions. In conjunction with glucosamine early appearance of gastric lesions was observed. Beyond this there does not appear to a direct effect of chondroitin on hepato-renal function. There is however, evidence on the function of SLRP (small leucine-rich proteoglycans), where chondroitin can be incorporated into side chains of this molecule – mainly as biglycan and decorin. The interaction of these (biglycan having a pro-inflammatory function), can impact on fibrolytic renal diseases. There is also evidence that biglycan has pro-atherosclerotic effects.
MSM is reported as being extremely well tolerated. Safety data suggests acute dosages of 5g, in rats, did not cause physiological harm, although other data suggests lower levels of 1g are NOAEL. Beyond this toxicology data on MSM is scarce, and its potential effect in hepato-renal damage is therefore putative. There is more likelihood that additive effects of glucosamine and chondroitin are the probable perpetrators of observed non-NSAID toxicity.
Although data is limited, there is some information on combined effects of glucosamine & chondroitin (or through SLRP, hyaluron etc.). Feeding glucosamine & chondroitin at 2g & 1.6g daily for 120 days resulted in no change of various hepatic or renal factors (ALT, bilirubin). These values somewhat contraindicate those found in surveys in the introduction, although it must be assumed that the lower levels of intake correspond to smaller dogs. The range of “toxicity” were 183 – 6667 mg/kg liveweight for glucosamine, and up to 2000 mg/kg chondroitin. MSM levels of up to 4000mg/kg were also involved but, unless there is an unknown interaction between MSM and the GAG, this may be ignored. For the smallest animal toxicity was presumably achieved with 3000mg/kg bodyweight glucosamine (lowest intake of lowest concentration for a 2.7kg dog).
In terms of commercial products, some other observations should be made. Some brands market high levels of glucosamine & chondroitin but, without a competent delivery system, a proportion will not be absorbed. This could highlight the observation of diarrhoea in overdosed animals and may render high levels of intake “safe” in terms of physiological damage. However, with some supplements being packaged for up to 1 year of dosages, there is a real chance of the types of toxicosis described by the American SPCA.
For example, one brand of joint supplement delivers a daily dose of 2000mg and 800 mg of glucosamine and chondroitin respectively, for a medium sized (~25kg) dog. However, if the dog accidentally ate a whole tub, it could ingest in excess of 13000 mg/kg glucosamine and 5000 mg/kg chondroitin. Even assuming a 50% absorbability, this would equate to hepatic levels of 6500 mg/kg & 2500 mg/kg respectively – levels at the top end of those reported by the ASPCA. Conversely, for the same dog a 2kg tub of Joint Aid for Dogs would give 1600 mg/kg and 800 mg/kg respectively, even assuming 100% absorbability.
The actual level of bioactives in a dose of joint supplement are less relevant than their bioavailability and support and delivery mechanisms. The Oatinol Delivery System ensures maximum transition of active ingredients into the body, making good use of passive transport systems and lipid based transport that can distribute actives across the lymph system and so bypass degradation in the liver (also, in the case of excess, less negative effects on hepatic processes).
The efficacy of a joint supplement is not purely down to levels of active ingredients. High levels may, or may not, be beneficial and most data suggests a good tolerance to glucosamine and chondroitin, but an accidental large overdose – as evinced by concentration and pack size – can be dangerous. Even with the largest pack size, the overdosing of Joint Aid is within safe parameters.
It shouldn’t be that overdosing risks should be a factor in deciding which product to use. Joint Aid utilises a range of “protective” bioactives, support from natural antioxidants and anti-inflammatory markers, that allows modest levels of glucosamine, chondroitin, MSM & manganese to have a beneficial effect in joint support, without over-providing components.
- Ali AA, Lewis, HSM, Badgley L, Allaben WT, Leakey JEA. Oral glucosamine increases expression of transforming growth factor β1 (TGFβ1) and connective tissue growth factor (CTGF) mRNA in rat cartilage and kidney: Implications for human efficacy and toxicity. Archives of Biochemistry and Biophysics Volume 510, Issue 1, 1 June 2011, Pages 11-18
- Anderson JW, Nicolosi RJ, Borzelleca JF: 2005, Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy. Food Chem Toxicol 43:187–201.
- Audimoolam VK, Bhandari S. Acute interstitial nephritis induced by glucosamine. Nephrol Dial Transplant (2006) 21: 2031
- Borchers A, Epstein SE, Gindiciosi B, Cartoceti A, Puschner B. Acute enteral manganese intoxication with hepatic failure due to ingestion of a joint supplement overdose. Journal of Veterinary Diagnostic Investigation 2014, Vol. 26(5) 658– 663.
- Breese McCoy SJ, Bryson JC: 2003, High-dose glucosamine associated with polyuria and polydipsia in a dog. J Am Vet Med Assoc 222:431–432.
- Butawan M, Benjamin RL, Bloomer RJ. Methylsulfonylmethane: Applications and Safety of a Novel Dietary Supplement. Nutrients 2017, 9, 290
- D’Altilio M, Peal A, Alvey M, Simms C, Curtsinger A, Gupta RC, Canerdy TD, Goad JT. Therapeutic Efficacy and Safety of Undenatured Type II Collagen Singly or in Combination with Glucosamine and
- Chondroitin in Arthritic Dogs. Toxicology Mechanisms and Methods, 17:189–196, 2007
- Hsieh LT, Nastase M, Zeng-Brouwers J, Iozzo RV, Schaefer L. a Soluble biglycan as a biomarker of inflammatory renal diseases. Int J Biochem Cell Biol. 2014 September; 0: 223–235
- Khan SA, McLean MK, Gwaltney-Brant S. Accidental overdosage of joint supplements in dogs. JAVMA, Vol 236, No. 5, March 1, 2010. 510
- Magnuson BA, Appleton J, Ryan B, Matulka RA. Oral developmental toxicity study of methylsulfonylmethane in rats. Food and Chemical Toxicology Volume 45, Issue 6, June 2007, Pages 977-984
- De Mattei M, Pellati A, Pasello H, de Terlizzi F, Massari L, Gemmati D, Caruso A. High doses of glucosamine-HCl have detrimental effects on bovine articular cartilage explants cultured in vitro. Osteoarthritis and Cartilage (2002) 10, 816–825.
- Nganvongpanit K, Kungprathum K, Yano T, Soontornvipart K. Endoscopic Evaluation of Gastric Mucosa to Determine Safety of Three Chondroprotective Drugs in Healthy Dogs. Thai J Vet Med. 2013. 43(3): 439-443
- Nobles IJ, Khan S. Multiorgan dysfunction syndrome secondary to joint supplement overdosage in a dog. Can Vet J 2015;56:361–364
- Radi ZA, Khan KN. Cardio-renal safety of non-steroidal anti-inflammatory drugs. J. Toxicolk Sci. 2019. 44:6. 373 – 391.
- Schaefer L. Small Leucine-Rich Proteoglycans in Kidney Disease. J Am Soc Nephrol 22: 1200–1207, 2011
- Scuruchi M, Potì F, Rodríguez-Carrio J, MaurizioCampo G, Mandraffino G, Biglycan and atherosclerosis: Lessons from high cardiovascular risk conditions. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. Volume 1865, Issue 2, February 2020,
- Theriault J, Pittman D. Glucosamine-Induced Endoplasmic Reticulum Stress Response in Kidney Cells: Potential Role in Diabetic Nephropathy. Diabetes. Jun2007 Supplement 1, Vol. 56, pA609-A609. 1/4p.