Osteoarthritis is the progressive degeneration of cartilage surrounding joints (Sandersoln et al, 2009). It can be painful and debilitating for an affected animal, worrying for an owner and can be a source of both emotional and financial stress. From the author's experience as a veterinary surgeon, osteoarthritis can pose certain unique challenges in management, relating to the identification of chronic pain, comorbidities (as 80% of osteoarthritis cases in canines over 8-years-old) and the longevity of the disease putting strain on owner financials and compliance. Many advocate for a holistic evidence-based multimodal approach to osteoarthritis management, as this is beneficial to the patient. As part of this management owners are oft en reaching for over-the-counter supplements believing them to be natural, side effect-free options.
Some owners may ask your opinion as a veterinary professional, whereas other will come to you already using certain products. It is therefore imperative that veterinary professionals are aware of the evidence behind the products so they can encourage good quality, evidence-based products as the first option. The aim is to avoid owners of arthritic dogs wasting precious finances buying multiple products with little or no evidence to back up their use, to be wary of bold unsubstantiated claims for improvements or health benefits, and to ensure that supplements are not used as a sole intervention for the management of arthritic pain as they are likely to not have the evidence base to support this claim.
What is the difference between a medication and a supplement?
Veterinary professionals are well aware of the differences between medications and supplements, but it may be important to highlight this to owners when having these discussions. It should not be as simple as a medication with negative side effects vs a supplement that is natural and safe, as there are many other factors to consider. A medication is a substance that has been shown to be medicinal by presentation and function. These are regulated by the Veterinary Medicines Directorate (VMD, 2021).
The VMD states that a product is medicinal by presentation if ‘it gives the averagely well informed person the impression that the product treats or prevents disease, or they gain that impression.’ In comparison, the definition for medicinal by function states: ‘A product is medicinal by function if it is used or administered to animals with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action or making a medical diagnosis. Risk to health is a factor that must be taken into account when classifying a product as medicinal by function’ (VMD, 2021).
In contrast, a supplement or nutraceutical is: ‘A food or naturally occurring food supplement marketed as having a beneficial effect on health and is treated like any other product. They require a marketing authorisation if medicinal claims are made or if they contain certain ingredients that exert a pharmacological effect on the target animal’ (VMD, 2021).
A good way to explain the difference to owners is by making reference to differences in the way the law treats these different products. A medication is regulated by law (Veterinary Medicines Regulations, 2013) and has a regulator to ensure that these laws are followed (the VMD). To be sold, a medication must have a ‘marketing authorisation’, and to get that, the manufacturer needs to have performed research to prove it is safe and effective. In comparison, nutraceuticals or supplements are far less controlled.
In line with its regulations, a medication has to be consistent in every batch and everything should be traceable, with a corresponding batch number present. They must also have safety data published about any possible adverse reactions or side-effects, indications, contraindications and dosages. This takes years of research and a lot of money to obtain. Once released, medications continue to be studied for many years in order to collect data from the wider field.
In contrast, with supplements, manufacturers can do their own research to say that their product could be of benefit – but they are under no obligation to do so. There are also external studies produced on supplements, that will be highlighted later. Owners should be made aware that the manufacturers have to be extremely careful when wording their advertising and packaging, to avoid making medicinal claims. As soon as the VMD decide a supplement manufacturer is claiming a medicinal effect (‘medicinal by presentation’), the manufacturer has to apply for a license as they would for any medication, or retract the claim.
The veterinary product market is crammed with false advertisements, unsubstantiated claims and fraudulent products, but among these are good companies that are trying to make sensible advertising, produce good quality supplements and back their product up with research and evidence. This can be extremely hard for owners to navigate and understand, so guidance, education and understanding from veterinary surgeons or registered veterinary nurses in osteoarthritis clinics will help to educate owners, maintain good client rapport, improve medication compliance and encourage the use of evidence-based interventions, in the interest of animal welfare.
What is there to consider when determining how effective supplements are?
When considering the evidence there is a hierarchy, starting from weak opinionated or anecdotal evidence up to strong meta-analyses and systematic reviews. Veterinary professionals are all too aware that there are many anecdotal success stories on the internet. Clients should be given the tools to understand how to assess the authenticity of these claims, to help guide their decision making. Caregiver placebo is an extremely prevalent phenomenon where an owner or caregiver believes they are seeing a marked improvement of health and welfare based on the fact that they are giving a treatment, when in fact there is no marked change in the health of the animal. This could seriously impact an animal's welfare and delay the use of beneficial treatments. In one study, a caregiver placebo effect was observed 39.7% of the time in owners evaluating their dog's lameness (Conzemius and Evans, 2012). This highlights the need to educate clients on the need for independent and objective assessments of improvement when using new products.
Available supplements
The list of supplements advertised for osteoarthritis seems infinite, but there are some common ones that appear to feature regularly. Certain combinations of ingredients are also commonly combined in the supplements. Synergism has been noted in pharmacology and similar phenomena may translate to supplements, although this is not supported by evidence. For example, one study by the Royal College of Veterinary Surgeons, that is not available to view, of a common brand containing multiple ingredients (including glucosamine hydrochloride, green-lipped mussel, fish oil, vitamin C and E, n-acetyl d-glucosamine, manganese and hyaluronic acid), highlighted the importance of higher levels of essential fatty acids, such as eicosatetraenoic acid, eicosapentaenoic acid and docosahexaenoic acid, and claimed the dogs showed statistically significant improvements in activity after 6 weeks of taking the supplement (Guthrie, 2018; Vision Media, 2021). Synergism has been studied in few supplements, so common joint supplement ingredients should be investigated individually to assess their evidence base.
Anti-inflammatory claims
Omega-3 fatty acids
Omega-3 and omega-6 are both essential fatty acids. It is believed that the ratio of omega-3 to omega-6 is important to consider when giving supplements. However, a study by Hall et al (2006) stated that consideration of the absolute dose and source is more important. Omega-6s are pro-inflammatory, whereas omega-3s are not.
Anti-inflammatory action of omega-3s
There are a number of actions that are believed to cause the reduction in inflammation via omega-3 supplementation. One theory discusses arachidonic acid, which generates pro-inflammatory eicosanoids, a key mediator and regulator of inflammation, via a metabolic process. Eicosatetraenoic acid, eicosapentaenoic acid and docosahexaenoic acid, which are from marine-based sources such as fish oil, have been shown to be of significance in this process. The significance of the generation of eicosanoids from eicosapentaenoic acid is that its derived mediators are often much less biologically active than those produced from arachidonic acid, thus causing less of an inflammatory effect. Eicosapentaenoic acid and docosahexaenoic acid also have a role in resolvins as mediators, which have been demonstrated in in-vitro and animal feeding studies to be anti-inflammatory and inflammation resolving. There are a number of other fascinating modes of action suggested for marine-based omega-3 fatty acids, such as decreasing chemotactic responses of leukocytes, decreasing adhesion molecule expression and decreasing production of pro-inflammatory cytokines (Calder, 2010).
What is the evidence behind omega-3s?
There is good evidence to support the use of omega-3s in supplements and studies have shown statistically significant, mild improvements in owner perceptions of their pet's comfort and mobility.
In one study of 127 dogs with osteoarthritis, those fed a high omega-3 diet had improved ability to rise from a resting position and play over a period of 6 months, compared to dogs fed a control diet (Roush et al, 2010a). The importance of the length of this study should be highlighted, as many of these supplements' actions do not occur quickly or instantly. For this reason, they are not appropriate substitutes for medication if an animal is currently experiencing pain or discomfort associated with osteoarthritis, and this is a very important point to raise to owners.
In this study by Roush et al (2010a), dogs were fed a test food containing a 31-fold increase in total omega-3 fatty acid content and a 34-fold decrease in omega-6:omega-3 ratio, compared with the control food. This study concluded that ingestion of the test food raised blood concentrations of omega-3 fatty acids and appeared to improve the arthritic condition in pet dogs with osteoarthritis.
In a further study by Roush et al (2010b) of dogs fed a diet containing 3.5% omega-3 fatty acids for 90 days, it was reported that they had improved peak vertical force values and subjective improvement in lameness and weight-bearing when compared with dogs on a control diet (Roush et al, 2010b). This could suggest that supplementing an arthritic dog's diet with omega-3s, or feeding a high omega-3 diet, could be an appropriate intervention for an arthritic dog – although more objective data is warranted.
In a clinical trial performed in dogs with stable chronic arthritis, who were already being treated with carprofen, feeding of a diet supplemented with omega-3 was found to decrease the necessary dosage of carprofen (Fritsch et al, 2010).
What other products that may be marketed as omega-3 fatty acids?
There are other products that contain omega-3s, such as flaxseed products, but as far as the author is aware it is not known how well this is metabolised by dogs. In one study by Bauer er al (1998) the flaxseed group showed no change in docosachexaenoic acid levels during the entire period, which could indicate dogs fed omega-3 fatty acids from a flaxseed source may not see the same benefits compared with a marine-based source.
Another common source of omega-3s is green-lipped mussel, which contains both glycosaminoglycans, which are structural components within cartilage, and high levels of omega-3s. From initial studies, the way the extract is produced could be critical to its effectiveness. There is evidence of it having a mild to moderately positive effect on mobility and pain in dogs with osteoarthritis, but the number of suitable trials is still limited. For instance, a study by Rialland et al (2013) concluded that a green-lipped mussel-enriched diet modified gait in dogs with arthritis, in that the peak vertical force significantly increased over a 60 day period when green-lipped mussel was introduced into a standardised control diet, suggesting its efficacy as a supplement. The study concluded that such diet should be proposed as an adjunctive treatment to conventional medication (Rialland et al, 2013). This is supported by a conclusion to a review by Bierer and Bui (2002) stating that ‘it is possible that the nutrients present in whole freeze-dried green-lipped mussel powder may act to reduce inflammation and pain, to limit further cartilage degeneration and, potentially, to support the regeneration of damaged joint cartilage and synovial fluid. The findings of the studies support the conclusion that dietary supplementation with green-lipped mussel may be of particular benefit in the management of dogs with arthritic signs’ (Bierer and Bui, 2002).
There are also studies available on PCSO-524, a patented marine oil lipid and omega-3 polyunsaturated fatty acid blend derived from the New Zealand green-lipped mussel. Soontornvipar et al (2015) conducted a single blinded study using 66 canine subjects with osteoarthritis of the hip and/or shoulder. Clinical outcomes and peak vertical force improved significantly within 2 weeks of administration of PCSO-524, and up to 88% of dogs improved their lameness scores in the PCSO-524 group compared to 32% of dogs in the fish oil group. In another study by Vijarnsorn et al (2019) firocoxib, PCSO-524 and combination of firocoxib and PCSO-524 was used orally for 4 weeks in a prospective, randomised, double-blinded study. Significant increases in peak vertical force were seen in all groups and orthopaedic assessment scores showed non-significant change in all treatment groups. Canine Brief Pain Inventory pain severity and pain interference scores showed no significant differences between the groups. Interestingly, serum biochemistry of PGE2, a prostaglandin, was assessed. There were no significant changes in serum PGE2 concentration for the firocoxib and PCSO-524 groups over the 4 weeks of study, however, serum PGE2 decreased significantly in the combination group, which could suggest some evidence for a synergistic effect between PCSO-524 and firocoxib in reducing elaboration of pro-inflammatory mediators. Further clinical studies into the use of these products as a standalone or combination, as well as to determine if there is any benefit of PCSO-524 over a placebo, are warranted.
Care must be taken to ensure clients do not turn to cod liver oils as an omega-3 source, as this could cause hypervitaminosis A (Lenox and Bauer, 2013).
Is there a suggested dose for omega-3s?
There are only guidelines for the correct dosing of omega-3s, (50–220 mg/kg eicosapentaenoic acid and docosahexaenoic acid with suggestion of higher doses for managing arthritis). The the duration of treatment until it takes effect is not known, but one study showed owner-assessed improvements 4 months after starting the supplement (Canine Arthritis Management, 2021). Again, this highlights that supplements are not an appropriate replacement for a veterinary consultation, examination or medication, as they can take an extremely long period of time to take effect, which is something clients should be made aware of.
Avocado and soybean unsaponifiables
An interesting addition to the array of supplements is avocado and soybean unsaponifiables. Canine Arthritis Management (2019) states that these are relatively new supplements, made from a specific part of the oil of avocados and soybeans. They are believed to promote cartilage repair and reduce inflammation within the joint, and have been shown to reduce pain in human osteoarthritis and improve joint health in horses. However, there are no clinical trials looking into the use of these supplements in dogs with established naturally occurring arthritis. Although, a study by Boileau et al (2009) explored the effects of these supplements in an anterior cruciate ligament dog model of osteoarthritis. As the aetiologies of human and canine osteoarthritis may have very similar pathways, reference can be made to human evidence. However, this may not translate to canine patients as its bioavailability via oral administration is not yet known.
One human study by Christiansen et al (2015) concluded that at a clinical level, avocado and soybean unsaponifiables reduce pain and stiffness while improving joint function. It also stated that they address acute pain and actively prevent progression of osteoarthritis symptoms. However, it does state that further studies are required to determine the specific mechanisms and target molecules of avocado and soybean unsaponifiable function on osteoarthritis at the cellular and metabolic level. Trials in dogs are limited, but one study demonstrated that treatment with avocado/soybean unsaponifiables can reduce the development of early osteoarthritic cartilage and subchondral bone lesions in the anterior cruciate ligament dog model of osteoarthritis (Boileau et al, 2009). Another small study, using artificially stimulated arthritis, concluded that morphometric analysis of cartilage tissue revealed more immature repair tissue with greater collagen and chondral tissue content in the regenerated tissue in the avocado and soybean unsaponifiable-treated dogs as compared to the untreated dogs (Altinel et al, 2011). As there is limited data in naturally occurring osteoarthritis models in dogs, it could be suggested that more substantial evidence is needed before the full extent of avocado and soybean unsaponifiable use in osteoarthritis management is understood, although initial suggestions are intriguing.
Turmeric
Turmeric has gained much popularity as a natural anti-inflammatory. There have been in vitro studies regarding this claim, which suggest antioxidant, anti-inflammatory, and anti-cancer activity for curcumin and other constituents of turmeric. However, it must be highlighted to owners that in vitro studies can never prove a clinical benefit for patients (McKenzie, 2013). A lot of focus is directed towards circumin, one of its active ingredients. However, there are other ingredients and there is some evidence that these possess anti-inflammatory properties. The most studied in terms of medical applications are the curcuminoids. In humans it has been suggested that there is little reliable evidence to support the use of turmeric for any health condition because so few clinical trials have been conducted (National Center for Complementary and Integrative Health, 2020). Many of the studies that have been done in humans have focused on curcumin and highlight that a major barrier to curcumin's clinical efficacy is its poor bioavailability (Lopresti, 2018). When looking at objective measures, one study found no statistical significance when assessing peak vertical force of the affected limb, but there was some improvement in subjective indicators from the assessors (Innes et al, 2003). This outcome is particularly important when considering the impact of care-giver placebo. Objectively there was no benefit, but from a subjective viewpoint there was. If the patient did indeed not experience any positive effects but the owners believed there was, then this could result in the dog not receiving adequate pain control in a timely fashion.
A common brand of turmeric-based supplement sold in the UK discusses the ingredients turmeric, coconut oil, apple cider vinegar, Ceylon cinnamon, black pepper, citric acid and potassium sorbate. The black pepper and coconut oil are reported to aid in ‘bioactive absorption’ of turmeric, which is understood to have poor absorption, biodistribution, metabolism, and bioavailability (Prasad et al, 2014). In one study comparing human and rat subjects, the addition of piperine (black pepper), a known inhibitor of hepatic and intestinal glucuronidation, with turmeric, did show a significant increase in bioavailability of turmeric in humans. The results in rats however, were much less drastic (Shoba et al, 1998). In relation to coconut oil, curcumin has a low solubility in water, so the addition of oil to the ingredients aims to mitigate this problem. Evidence for this theory is somewhat lacking in animal studies, but one review did look at liposomal encapsulation. Liposomes are considered as effective drug carriers because of their ability to solubilise hydrophobic compounds. This in theory could suggest that the use of oil alongside turmeric could aid in increased bioavailability and absorption (Prasad et al, 2014). However, the evidence base does not yet allow us to draw conclusions as to the in vivo efficacy of this combination. Hopefully future studies will shed further light on the proposed interaction between the specific components in this formulation.
Boswelia
Boswelia is extracted from the bark and resin of the Indian Boswelia tree. Interestingly, Boswelia resin has been evaluated in 24 dogs in an open multi-centre study. Improvement in clinical signs, lameness and pain was found in 17/24 dogs (Reichling et al, 2004). This suggests that more research is necessary in order to confirm that Boswelia would be a truly beneficial addition to a regime, as although positive results are initially being reported, the study size is extremely small.
Devil's claw and cat's claw
This is a supplement heard of less commonly, but that may be brought up by those looking into herbal options. It has been discussed that ‘the anti-inflammatory activity of the devil's claw may be critical in the symptomatic treatment of osteoarthritis’ (Musco et al, 2019). However, it was concluded in a review that ‘limited evidence was found for… plant extracts from Harpagophytum procumbens’ otherwise known as devil's claw (Ameye and Chee, 2006). Furthermore, it has been concluded that ‘the methodological quality of the existing clinical trials is generally poor… the clinical evidence to date cannot provide a definitive answer whether it is effective or safe to use (Brien et al, 2006). Therefore, further evidence is warranted before suggesting devil's claw as an evidence-based intervention. Evidence for cat's claw (Uncaria tomentosa and U. guyanensis) being trialled successfully in dogs is distinctly lacking. Although, an extremely small study in humans by Piscoya et al (2001) did show pain associated with activity, medical and patient assessment scores were all significantly reduced. Knee pain at rest or at night, and knee circumference were not significantly reduced. Cat's claw was also found to have no effect on basal PGE2 production. This study alone is not enough to warrant advising cats claw as a suitable treatment option for osteoarthritis in canines and further studies are required. Humans studies show there are few high quality clinical trials of cat's claw, and that there's no conclusive scientific evidence based on studies in people that supports using cat's claw for any health purpose (National Center for Complementary and Integrative Health, 2016).
Disease modifying claims
Glucosamine
This is an extremely commonly marketed arthritis supplement for both humans and animals. The theory is that it helps repair joints, as glucosamine is an important basic component of articular cartilage. In in-vitro studies, glucosamine was shown to enhance the production of cartilage matrix components in chondrocyte culture, but there is still much debate as to what concentration will actually reach the joint via oral ingestion.
Evidence for the use of glucosamine
The 2006 Glucosamine Arthritis Intervention Trial study (Clegg et al, 2006) suggested that glucosamine alone or with chondroitin sulphate did not perform better than placebo. Since, this has evolved into a long term study, concluding that ‘over 2 years, no treatment achieved a clinically important difference in Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain or function as compared with placebo’ (Sawitzke et al, 2010). Although the Mayo Clinic (2020) suggests that ‘oral use of glucosamine sulphate might provide some pain relief for people with osteoarthritis of the knee, hip or spine’, the NHS will no longer prescribe it following a study that looked at evidence in a number of clinical trials (Canine Arthritis Management, 2019), suggesting its use in arthritis management may be very limited.
A study into the synergism of glucosamine and chondroitin stated that the outcome seen was not caused by a synergistic effect of both agents during intestinal absorption, but as an indirect effect of these two agents (Bhathal et al, 2017). In a review on glucosamine and chondroitin combined, it was concluded that ‘although glucosamine and chondroitin have benign adverse effect profiles, the clinical benefit of using these agents remains questionable. The available evidence is difficult to interpret due to the use of different manufacturers, salt forms, compositions, sources, strengths, regimens, therapy durations and combinations of active ingredients (Bhathal et al, 2017).’
This review suggested that based on the available literature for the use and potential benefits of glucosamine and chondroitin in osteoarthritic canines, its effectiveness can neither be confirmed nor denied. It was concluded that further clinical studies, using improved methodologies, are required. The review stated that trials conducted to date have yielded mixed results, which could be down to shortcomings in the clinical trials. This highlights that these supplements may not be beneficial, and there may be better options and interventions for owners of arthritic dogs to channel their efforts and finances.
The studies and trials highlight the questionable usefulness of this particular supplement, suggesting the evidence is not enough to recommend it as a clinically effective anti-inflammatory, pain-relieving, joint-disease modifier. If a patient is showing any signs of pain or discomfort, bearing in mind that owner and veterinary perception and detection of chronic pain is very difficult, then supplements alone are not adequate.
Chondroitin sulphate
Chondroitin sulphate is extracted from mammalian cartilage. In a similar way to glucosamine, it is believed to provide structural components for helping to repair the articular cartilage.
Evidence base for chondroitin
There is only weak evidence of its effectiveness both structurally and in improving clinical condition of arthritis in dogs. It is often paired with glucosamine or green-lipped mussel. One review stated that several in-vitro studies have shown beneficial effects, supporting the chondroprotective effect. This study stated that some in-vivo evidence suggest that diets supplemented with glucosamine hydrochloride and chondroitin sulphate together improve mobility in cats with joint disease. It also states that data on bioavailablity and pharmacokinetic are limited, but suggest that when combined, the compounds are absorbed to some extent in dogs and that there is accumulation after multiple dosing, indicating a possible residual effect. However as most evidence is in-vitro despite the initial suggestions of their benefit, after looking at the data, they concluded ‘the benefits of using a combination of glucosamine hydrochloride and chondroitin sulphate nutraceuticals to improve symptoms associated with canine and feline joint disease has yet to be determined’(Bhere, 2021).
How to pick a supplement
Given the accessibility of osteoarthritis supplements and the variety in product quality, it may be difficult to give advice to clients if they wish to pursue them as an extra intervention. A few considerations can be followed to advise of which product may be superior.
First, choosing a product that contains ingredients that have an evidence base is important to ensure the animal is likely to see some benefit to its use, even if only minor. Use a product that is marketed as working in unison with veterinary professionals and medicine, not against them. Look for a product that makes sensible and evidence-based claims, any bold medicinal claims are both illegal and unethical. A product that lists its ingredients and amounts of each are important.
Second, use products that are quality checked, have batch numbers and contain good quality, sustainable ingredients. This is especially pertinent when considering the sustainability of marine-based omega-3 fatty acids. As global population increases, the opportunities to increase seafood harvest are limited, so new alternate sources for omega-3 fatty acids are being considered for sustainability purposes. These include substances such as microalgae, although the evidence of their bioavailability in dogs is not yet known (Nichols et al, 2010). Beynen (2019) stated that supplements, treats and complete foods featuring docosahexaeonic acid-rich algae promise improvements in joint health but is no evidence that extra intake, as a sole omega-3 polyunsaturated fatty acid, meets the claims (Beynen, 2019).
Conclusions
Clients must be made aware that supplements should only be used in conjunction with other evidence-based interventions and can only be assessed fully following a substantial trial period of at least 2–3 months, using objective measures. Many of these supplements have conflicting evidence for their effectiveness, so should not be used as the only modality of treatment. Clients should also be made aware of the care-giver placebo effect, to allow them to objectively measure their dog's pain.
Clients are commonly under the illusion that supplements are an appropriate replacement for conventional analgesia and anti-inflammatory medication prescribed by a veterinary surgeon, but there is no evidence to support that misconception. Some supplements or combinations of supplements may certainly be beneficial as one part of the multimodal approach to osteoarthritis management. Although, some owners seem to have developed a unsubstantiated fear of medication, especially when considering it on a long term basis, so it is important to educate them on quality of life, safety data for medications, availability of biochemistry monitoring and the vast array of prescription medications that are available for osteoarthritis pain. If one medication causes an undesirable side effect, the likelihood is another can be used that suits the patient well.
Clearly there is still a huge amount to learn about the extent of usefulness of supplements in osteoarthritis management. There are interesting prospects and literature emerging that will guide decisions on how to educate and guide owners to making informed choices about which products are supported by evidence and which are not. Hopefully in the coming years more evidence will emerge and give a clearer picture on these products. In the meantime, veterinary professionals need to be guiding owners to make good financial choices, to direct finances to interventions with good evidence, and support them to implement a multimodal protocol that will hopefully greatly benefit the nation's arthritic pets.
KEY POINTS
- Supplements are a popular choice for owners wanting to aid in the management of canine osteoarthritis.
- For many supplements, the evidence base is too weak to suggest they will have a real benefit for the patient.
- We must be aware of caregiver placebo and ensure owners are equipped to objectively assess their dog's condition.