Can nutrition or supplements help in the treatment of joint disease?

Introduction

Osteoarthritis (OA) is the single most common cause of lameness in horses1 and in one survey, approximately 60% of lameness problems in horses were related to OA.2 Similarly OA is the most common form of human arthritis, affecting at least 20 million Americans and with its prevalence expected to double over the next two decades.3,4 OA involves a complex interaction of biologic and pathologic processes highlighted by eventual degradation of articular cartilage.5,6 With the US horse population currently estimated to be 7.3 million, this means millions of horses currently have this debilitating musculoskeletal condition. Multiple conventional therapies are available for treating OA with the goal of preventing further degradation while restoring function.6,7

For the purposes of these discussions the author is using the term oral joint supplements (OJSs) rather than nutrition and supplements or nutraceuticals as the talk is specific to joint disease with referencing to both equine and human data. Oral joint supplements are a common choice of clients, and have been perceived as a benign treatment for OA in horses.7 The high prevalence of OA in combination with the lack of a definitive cure for OA has probably contributed to the popularity of OJSs among owners, veterinarians, and trainers. These supplements, according to recent market surveys, are the most popular type of nutritional supplements for horses and account for approximately 1/3 (34%) of all equine supplement sales, 1/2 of all pet supplements sold in the US for equine consumption and it is estimated that 49% of all horse owners purchase and administer some form of dietary supplement for their horses (http://www.packagedfacts.com/pet-supplements-market-c1641). In a study of feeding practices in 3-day event horses, the authors found that horses were supplemented with an average of four different oral products daily including electrolytes, plain salt and OJSs.8

Indications for OJSs

Oral joint supplements are fed to horses for one of two purposes: (1) to treat lame horses or make chronically unsound horses sound or (2) to prevent or delay the development of joint problems. The first instance is flawed because often the source of lameness is never diagnosed when the owner or trainer elects to use these oral supplements without consulting a veterinarian. The second premise is hard to disprove but is the basis for high usage of both licensed drugs such as intramuscular AdequanTM and intravenous Legend TM, as well OJSs.

The osteoarthritic process is associated with multiple deleterious mediators released from inflamed synovial membrane or induced by trauma that initiate a cascade of degradation in the articular cartilage. Interleukin 1 (IL-1) is considered a major cytokine initiating this cascade and this can influence other cells to cause increased release of metalloproteinases, aggrecanase and prostaglandin E2 (PGE2). While this negative process can be influenced by certain nutraceuticals in vitro (Figure 1, Appendix) there is less certainty about their effects in vivo after undergoing digestion.

Terminology and regulatory issues in the use of OJSs (a US perspective)

The term nutraceutical was adopted in veterinary medicine from the medical profession and refers to compounds that are neither nutrients nor pharmaceuticals by combining the words ‘nutrients’ (nourishing food or food component) with ‘pharmaceuticals’ (medical drug).9 The nutraceutical category describes a broad list of products sold including nutrients, dietary supplements, functional foods and phytochemicals (including herbs) that are not recognized by the US FDA as food or drugs and are intended for the treatment or prevention of disease. The difference between a feed and a nutraceutical is that a nutraceutical is unlikely to have an established nutritive value. Feeds are required to have nutritive value and are accountable, by labeling, for these values. Oral joint supplements fall in between food and drugs and have advantages over either because they are not required to list ingredients or nutrient profiles as required by feeds, and in many cases, intended to treat or prevent disease without first undergoing proper drug approval.9

Manufacturers do not have to register themselves or their supplements with the FDA. In general a manufacturer has to comply with the FDA Ingredient Recognition Program, which entails applying for complete ingredient definitions as described by not-for-profit organization of state and federal feed regulators, the Association of American Feed Control Officials (AAFCO).10 There are no requirements of Good Manufacturing Practices (GMPs) for manufactures to guarantee high-quality and batch-to-batch consistency11 and because there is no post-production monitoring of veterinary nutritional supplements, a myriad of poor quality supplements are available.12

Types of OJSs

The majority of joint supplements include glucosamine and/or chondroitin sulfate along with other added ingredients. Historically, the first products available for the horse included a chondroitin sulfate product from bovine trachea and a complex of glycosaminoglycans and other nutrients from the sea mussel, Perna canaliculus. Glucosamine (GU) is an amino monosaccharide and is the principal component of O-linked and N-linked glycosaminoglycans, and is produced in the body by the addition of amino groups to glucose; this molecule is subsequently acetylated to acetyl glucosamine. Hyaluronan (HA), keratan sulfate and heparan sulfate are composed in part of repeating units of acetyl glucosamine. Chondroitin sulfate (CS) consists of alternating disaccharide units of glucuronic acid and sulfated N-acetyl galactosamine molecules and is a principal glycosaminoglycan of aggregating proteoglycan (aggrecan).

Many OJSs have GU and CS as principal components, and may contain additional ingredients including manganese, vitamin C, hyaluronan (hyaluronic acid or HA), polyunsaturated fatty acids (PUFAs), rare earth mineral supplements, unsaponified avocado soy (ASU), extract of green-lipped mussel (Perna canaliculus), cetylmyristoleate, methylsulfonylmethane, and various herbs. With the exception of the latter two (no good equine documentation available), these various products will be discussed below.

Glucosamine and/or chondroitin sulfate

Mechanisms of action and in vitro studies
In vitro studies have investigated the effects of glucosamine and CS, individually or in combination, but of course, differ greatly in the source of products, as well as dosages used, in vitro study conditions and responses measured.13 Glucosamine and/or CS are thought to counteract cartilage degradation14-25 by inhibiting degradative enzymes such as collagenase and aggrecanase,19,21,23,26,27 and intermediary mediators, such as nitric oxide, PGE2 and nuclear factor kappa B.15,16,21,23,25,28-33 Synthesis of extracellular matrix (ECM) components is thought to be stimulated in the presence of GU and/or CS20,24,28,34-36 by provision of substrate, which may be deficient through dilution or hypermetabolic states;36 upregulation of gene expression;17,37 stimulation of cellular receptors and cellular signaling mechanisms, such as CD44 involved in positive feedback;28,38,39 and inhibition of negative intermediary messengers, such as nuclear factor kappa B, nitric oxide and PGE2.15,16,21,23,31,32-34

The Precursor Supply Theory is the most popular explanation regarding the apparent beneficial effects of GU in OA.40 In this theory, it is proposed that GU supplies excess basic building blocks for the synthesis of cartilage glycosaminoglycans (GAG)15,41,42 and/or bypasses rate-limiting steps in GAG synthesis.7,15 In addition, these structure-modifying agents appear to counteract inflammation primarily through their inhibition of intermediate messengers, such as nuclear factor kappa B, nitric oxide and PGE2,15,16,21,23,25,28,31-33 that mediate inflammatory responses, in addition to their previously described antianabolic and procatabolic effects. However, these structure-modifying agents have not been found to directly inhibit cyclooxygenase (COX) enzymes, in contrast to many antiarthritic medications.43 CS has also been shown to affect cell-based inflammatory events by inhibiting chemotaxis, reducing phagocytosis and lysozyme release, and protecting cell membranes from free radical injury.44

The effects of varying doses of GU and CS alone and in combination on cartilage metabolism in normal and recombinant IL-1α conditioned equine articular cartilage has been evaluated in the author’s laboratory using equine cartilage explants.24 Articular cartilage explants were allocated randomly to treatment with four doses of GU, CS, or GU + CS in the absence of IL-1 (normal explants) and in the presence of 40mg/mL recombinant IL-1α (Gibco- Light Technologies, Grand Island, NY, USA) (IL-1 conditioned explants). The patented joint supplements used were SCHG49GU and TRH122 low molecular weight sodium (Nutramax Laboratories, Edgewood, MD, USA). The treatment groups investigated for both normal and IL-1 conditioned explants were: treatment without GU or CS; four GU concentrations, 12.5, 25, 125 and 250μg/mL; four CS concentrations, 12.5, 25, 125 and 250μg/mL; and four GU + CS concentrations 12.5, 25, 125 and 250μg/mL each of GU and CS (in a 1:1 ratio by concentration). There was no significant negative effect of GU, CS, or GU + CS on normal cartilage explant metabolism. In normal (no IL-1) explants, the most substantial effects observed with the GU, CS and GU +CS treatment were in reducing GAG degradation, without evidence for an advantage of GU + CS compared to GU or CS alone. On the other hand, the highest dosage of GU + CS was more effective than all other treatments in reducing GAG degradation in IL-1 conditioned explants. The ability of GU and CS to protect against cartilage matrix degradation in osteoarthritic and stimulated chondrocytes in cartilage explants has been observed in other in vitro studies.14-21,29 It was also noted that the higher doses of test ingredients (125 and 250μg/mL) tended to be more effective than the lower dosages24 and these dosage ranges were within the ranges of other in vitro studies. It has been pointed out that high dosages of GU such as 6.5 and 25mg/mL have been shown to have detrimental effects on cartilage metabolism and chondrocyte viability in studies using bovine articular cartilage explants.45

In summary, purported mechanisms explaining the role for GU in osteoarthritis are: (1) provision of substrate for synthesis of cartilage glycosaminoglycans (Precursor Supply Theory); and (2) mediation of inflammatory responses. Chondroitin sulfate is thought to counteract cartilage inflammatory responses. In addition, there is in vitro evidence that GU and CS protect against cartilage matrix degradation.

Bioavailability and pharmacokinetics

The obvious flaw with in vitro studies of oral OJSs is that products are tested before undergoing any modification through digestion and absorption. In a relatively recent study a simulated digestion protocol with ultrafiltration has been described that was applied before testing the potential anti-inflammatory and chondroprotective properties of New Zealand green lipped mussel, abalone and shark cartilage.46 In this paper the authors showed that shark cartilage in New Zealand green lipped mussels significantly inhibited IL-1-induced PGE2 synthesis and IL-1-induced GAG release using this useful model for evaluating dietary nutraceuticals in vitro but having the components predigested before

testing. Inhorses,theoralabsorptionof8.0and16.9kDamolecularweightCS was compared because in vitro studies suggested that molecular weight of CS was negatively associated with its permeability across the gastrointestinal tract.47 The oral bioavailability of 8.0 kDa CS was 32% compared to 22% with 16.9 kDa CS.48,49 The oral bioavailability of GU hydrochloride in horses was found to be 2.5–5.9% with a large volume of distribution which indicates very poor absorption from the intestinal tract, but extensive tissue uptake.41,49 While serum levels of 4.5–6.5μg/mL for disaccharide fractions of CS48,49 and 10.6μg/mL for GU49 were attained, the dose was 5–10 times the typical labeled dose of GU to achieve these levels. Laverty et al. showed that maximum levels of GU serum reached 6μg/mL (about 1μg/mL) in the serum and about 0.3–0.7μM in the synovial fluid after clinically suggested doses of glucosamine hydrochloride were administered orally.41 It was also found that GU concentrations in the synovial fluid appeared to be relatively stable over time (remaining elevated at 0.1-0.7μM 12 hours after dosing) in that study41 and Dechant and Baxter suggested that this could indicate minimal utilization of GU by articular tissues.13 Based on these bioavailability studies it could be concluded that CS has increased potential for efficacy due to greater oral absorption,48,49 but it has been pointed out that the CS bioavailability study could be disputed because the assays measured disaccharide fractions of CS, which are not known to be biologically active.13

In summary, there is some controversy over which substances should be measured in studies on the bioavailability and pharmacokinetics of GU and CS. In general, the bioavailability of GU and CS appears to be low. In addition, molecular size of active ingredient, dose and joint inflammatory status may influence delivery to the target site of action.

Clinical trials and experimental studies

Horses
Clinical trials and in vivo experimental studies in horses are limited and the results are variable. This was highlighted in a recent review article of 15 in vivo papers published in the equine literature in which the authors signaled an encouraging trend of manufacturers of these products investing in research, but most not meeting a quality standard that provided sufficient confidence in the results reported.50 Consequently, the overall level of evidence for in vivo demonstration of efficacy is weak. Administration of CosequinTM (Nutramax Laboratories, Wedgewood, MD) in horses with OA in the distal interphalangeal, metacarpophalangeal, tarsometatarsal, or carpal joints resulted in improvement in lameness grade, flexion test grade and stride length within 2 weeks; however, no further improvement in lameness grade and no significant changes in other variables were seen after 4 weeks.51 Twenty-five horses were in the study and there was no placebo group. It has been pointed out by others that although the lack of continued improvement may be attributable to the return of most of the horses in the study to exercise and competition after an initial 2 weeks of treatment. Return to previously obtainable performance levels and continuation in a competition career is necessary for a treatment to be considered successful, as well as fulfilling the expectation of the owners of the affected horses.52

A recent placebo-controlled study investigating the effect of 3 months’ oral supplementation with a compound containing glucosamine, chondroitin sulfate and methyl sulfonyl methane in a group of geriatric horses (age 29 ± 4 years) used kinematic outcome criteria (primary: stride length; secondary: carpal flexion, fore fetlock extension and tarsal range of motion). In the study no effect of the supplement on these gait parameters could be demonstrated, leading to the conclusion that the use of a glucosamine/chondroitin sulfate/methyl sulfonyl methane supplement to improve stiff gait in geriatric horses could not be supported because of the lack of a sizeable effect (Higler et al. 2014). More recent studies with specific nutraceuticals are detailed further in this manuscript.

Humans

Numerous clinical studies have been done with human OA patients. The Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) is the best known and was a multicenter trial that assigned 1583 patients to randomly receive 1500mg of glucosamine; 1200mg of CS; both GU and CS; 200mg of celecoxib (Celebrex, Pfizer, New York, NY) or placebo for 24 weeks. Patients randomized to celecoxib had significant improvement in knee pain compared to those randomized to placebo. No statistically significant improvement in knee pain compared to placebo was seen among patients randomized by dietary supplements, although a subset of patients with moderate to severe knee pain at entry who were assigned to the combination of GU and CS seemed to experience some improvement and patients taking CS were found to have statistically significant decrease in knee joint swelling.53 A major limitation of the study noted by the authors was the high rate of response to placebo (60%) and the relatively mild degree of OA among the participants. A post-hoc analysis was then undertaken to further assess the observation that patients receiving CS compared to patients who received placebo had improvement in joint swelling.54 The results of this analysis suggested that patients with Kellgren and Lawrence grade II radiographic changes were substantially more responsive to CS than those with Kellgren and Lawrence grade III changes. Also, improvement was more likely to occur in the CS-treated patients with lower WOMAC Function and Stiffness Scores and a numerical trend was seen also in patients with WOMAC Pain Scores.

In another study as part of the GAIT study, progressive loss of joint space width (JSW) in patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence grade II or III and JSW of at least 2mm at baseline) were studied. The mean JSW loss of 2 years in knees with OA in the placebo group, adjusted for design and clinical factors, was 0.166mm. No statistically significant difference in mean JSW loss was observed in any treatment group compared with the placebo group. There was a trend towards improvement in the grade II knees. The authors concluded that the power of the study was diminished by the limited sample size, variance of JSW treatment and a smaller than expected loss of JSW.55

Wandel and colleagues performed a meta-analysis of studies examining the effect of GU, CS or the two in combination on joint pain and on radiological progression of disease in OA of the hip or knee.56 Ten trials involving a total of 3803 patients were included in the analysis. It was concluded that, compared to placebo, GU, CS, and their combination do not reduce joint pain or have an impact on narrowing of joint space, and the authors recommended that use of GU and CS for treatment of hip or knee OA should be discouraged.

It has been recently reported that there is a convergent body of evidence saying that glucosamine sulfate given at a daily oral dose of 1,500mg is able to significantly reduce the symptoms of OA in people and also there are two independent studies showing that there is a reduction in joint space narrowing in patients with mild to moderate knee OA and this translates into a 50% reduction in the incidence of OA-related surgery of the lower limbs during a 5 year period following the withdrawal of treatment.57 Specifically, in one paper 106 patients on placebo had a mean joint space loss after 3 years of -0.31mm (95% confidence interval [CI] -0.48 to -0.13) and there was no significant joint space loss in the 106 patients on glucosamine sulfate -0.06mm (-0.22 to 0.09).58 In a second study, in patients of mild to moderate severity and average joint space widths of slightly less than 4mm, progressive joint space narrowing with placebo was -0.19mm (95% CI -0.29 to -0.09mm) and with no change in the glucosamine sulfate treated group (0.04mm; 95% CI -0.06 to 0.14) (P=0.001).59

Despite this, Towheed et al recently updated the Cochrane Review of available data with the intent of investigating what might predicate differences in glucosamine trial results.60 An analysis restricted to the eight studies that reported adequate allocation concealment showed no benefit of glucosamine for pain and WOMAC function. Collectively, however, the pooled data from 20 eligible studies favored glucosamine over placebo with a 28% improvement in pain and a 21% improvement in function according to the Lequesne index.60 It should be noted that there are a number of positive studies since publication of this study. There was also a difference in the quality of preparation of glucosamine and specific higher quality glucosamine had superior results.61 In a clinical review of chondroitin sulfate in OA, it was classified as a symptomatic, slow-acting drug for the treatment of OA (SYSADOA) and it was also commented that two pivotal studies provided evidence that oral CS does have structure modifying effects in knee OA patients.62

Sasha’s Blend

Sasha’s Blend (New Zealand green lipped mussel, shark cartilage, abalone and Biota orientalis lipid extract) is a proprietary mixture of bioactive lipids obtained from New Zealand green lipped mussel (NZGLM) (Perna canaliculus), abalone (Haliotis sp.), and SKC (Galorhinus galeus) and a lipid extract from Biota orientalis (Sasha’s EQ powder, Interpath Pty Ltd, Australia). Raw ingredients are manufactured in New Zealand with the four constituents being artificially digested in vitro, and an extract of each simulated digest has been evaluated by use of a cartilage explant model of inflammation.46 Each constituent has been shown to exert unique effects on the formation of rh-IL-1β- induced PGE2, GAG and on chondrocyte viability in equine cartilage explants. More recently the product has been tested in 22 healthy horses. Twelve horses were fed 0, 15, 45 or 75g of Sasha’s Equine Powder (SEQ) (3 horses per treatment) daily for 84 days. Ten other horses received 0 or 15g of SEQ per day (5 horses per treatment) for 29 days (beginning day −14). One middle carpal joint in each horse was injected twice with IL-1β (10 and 100ng on day 0 and 1, respectively) and the contralateral joint similarly injected with saline (0.9% NaCl solution). In this study, administration of the SEQ (up to 75g/day) to horses for 84 days did not induce any adverse effects.63 Synovial fluid PGE2, GAG and protein concentration as well as leukocyte count increased after intraarticular injection of IL-1β (compared to saline injection) in horses that received no SEQ but in horses that were fed SEQ intraarticular IL-1β injections did not induce significant increases in synovial fluid PGE2 and GAG concentrations. These results suggested that SEQ could be useful in preventing inflammation associated with synovitis and OA in horses.

Hyaluronan (Hyaluronic Acid)

Intra-articular HA has been used in the horse for many years.64 Oral HA formulated for the horse has been available for 7–8 years and anecdotal reports have suggested that its use has been effective in treating lameness associated with synovial effusion and OA. Hyaluronan has been shown to be absorbed by rats and beagles when administered orally65 but there are no published data from equine studies. Other GAG products such as chondroitin, dermatan and heparan sulfates have also been shown to be absorbed orally in rats and man.66-69

A double-blinded, controlled study has been reported in 48 yearlings which were operated arthroscopically for unilateral or bilateral osteochondritis dissecans (OCD) of the tarsus (yearlings were included only if they had mild or no synovial effusion pre-surgery).70 Twenty-four of the yearlings (27 joints) were treated with 100mg of HA orally for 30 days postoperatively and 24 (30 joints) with a placebo orally for 30 days. Thirty days post-arthroscopic surgery, a blinded examiner scored the effusion of the dorsomedial tarsocrural joint individually using a scale of 0 to 5 (0 = no effusion, 1 = barely palpable, 2 = palpable effusion (without plantar effusion), 3 = golf ball size effusion with plantar effusion, 4 = tennis ball size effusion with plantar effusion, 5 = greater than tennis ball size effusion with plantar effusion). The mean 30 day effusion score of the HA-treated group (27 joints) was 0.7 while the mean of the 30 day placebo group (30 joints) was 2.05 (P ≤ 0.0001). Similar results were noted when comparing treated versus placebo for each lesion location, as well as for lesion size. This author feels the results speak for themselves; however, the mechanism of action is certainly less obvious. In a recently conducted survey using the Colorado State University (CSU) osteochondral fragment model, there was a significant reduction in the PGE2 levels of the OA joints in horses treated with oral HA compared to both the OA joints of the placebo horses (Frisbie, McIlwraith & Kawcak unpublished data).

Extract of Green-Lipped Mussel (Perna canaliculus)

As mentioned previously, one of the first products made available for the horse was a complex of glycosaminoglycans and other nutrients from the sea mussel, Perna canaliculus. Since then clinical trials in man and dogs have demonstrated the efficacy of lyophilized products from Perna canaliculus (LPPC) in treating osteoarthritic conditions71-73 and more recently in horses.74 In vitro data shows that LPPC has a range of antiinflammatory activities including inhibition of tumor necrosis factor alpha (TNFα), COX-2 expression, PGE2, phospholipase A2 (PLA2), oxygen radical absorbance capacity (ORAC), antioxidant capacity, lipolytic and fibrinolytic activities.75,76

A randomized double-blinded, placebo controlled study on the efficacy of a unique extract of green-lipped mussel (Perna canaliculus) in horses with chronic fetlock lameness attributed to OA was recently reported. This study was performed in New Zealand and data was analyzed from 26 horses with primary fetlock lameness in a multicenter trial. The study design was a partial crossover with a washout period and consisted of 19 horses treated with LPPC and 20 with a placebo. Horses were dosed orally with 25mg/kg bwt per day LPPC or placebo for 56 days. Efficacy was evaluated by clinical assessment of lameness, passive flexion, pain, swelling and heat in the affected joint.74 Relationships between variables were analyzed using an ordinal logistic model with random effects for horse and X treatment according to a modified-intention-to-treat analysis. Clinical evaluation of horses with a fetlock lameness treated with LPPC showed a significant reduction in severity of lameness (P<0.001), and proved response to joint flexion (P<0.001) and reduced joint pain (P=0.014) when compared with horses treated with placebo. It was concluded that LPPC significantly alleviated the severity of lameness and joint pain and improved response to joint flexion in horses with lameness attributable to OA in the fetlock.

Avocado Soy Unsaponified (ASU)

Avocado/soy bean unsaponifiable (ASU) extracts are produced by extracting the oils from avocados and soy beans, collecting the unsaponifiable fractions (i.e. the oil that remains after hydrolysis and do not form soaps) and combining these in various ratios. This product has been reported to be beneficial in randomized, placebo controlled human trials.77-79 In vitro studies have displayed anabolic, anticatabolic and anti-inflammatory effects on human chondrocytes. ASU increased the basal synthesis of aggrecan and reversed the IL-1β-induced reduction of aggrecan synthesis by human chondrocytes in alginate beads.80 It also decreased the spontaneous and IL-1 beta-induced production of matrix metalloproteinase (MMP)-3, IL-6 and -8 and PGE2, while it weakly reversed the IL-1-induced inhibition of tissue inhibitor of metalloproteinase-1 TIMP-1 production.80,81

In a blinded and placebo-controlled study using the CSU osteochondral chip fragment model, horses were randomly assigned to two groups with the ASU extract group receiving the supplement mixed with molasses while the placebo group only received molasses from days 0–70. The ASU supplementation did not have a significant effect on pain or lameness, but there was a significant reduction on the degree of macroscopic cartilage erosion and synovial hemorrhage scores in the OA joints compared to placebo controlled joints, as well as s significant decrease in intimal hyperplasia (inflammation) in the synovial membrane. There was also a decrease in the cartilage disease score.82 A significant decrease in cartilage disease indicates that this product could be classified as a disease-modifying osteoarthritic drug (DMOAD). Although the improvements were modest, they were more significant than those seen with other parenteral polysulfated GAG, IV HA and oral HA products tested using the same model of equine OA, at least at the level of articular cartilage change. Unfortunately the ASU extract product used in the CSU equine study cannot be made available in the United States. At present the only ASU product available in North America is sold in combination with GU and CS (Cosequin ASUTM, Nutramax Laboratories, Edgewood, MD, USA). Considerable in vitro work has been done with this product, but, as yet, no in vivo efficacy has been reported.

Polyunsaturated Fatty Acids (PUFAs)

Polyunsaturated fatty acids (PUFAs), at sufficiently high intakes as found in oily fish and fish oils, decrease production of inflammatory cytokines, arachidonic acid-derived eicosanoids (prostaglandins, thromboxanes, leukotrienes, and other oxidized derivatives), other inflammatory agents such as reactive oxygen species and adhesion molecules.83 Omega-3 (n-3) PUFAs contain α-linolenic acid that is desaturated in the body to produce eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) analogs of arachidonic acid.7 There is some evidence that n-3 PUFA can be beneficial in humans84 and dogs85,86 with OA, and in vitro studies have demonstrated positive outcomes.87,88 An in vivo study in a spontaneous guinea pig model showed that dietary n-3 PUFAs reduced disease in OA prone animals.89

Although there is currently no evidence of efficacy in the horse, the potential for usefulness of PUFAs in equine OA has led to it being incorporated into some OJSs.

Cetyl Myristoleate

Cetyl myristoleate (CM) is another fatty acid that is being used in equine joint supplements. CM is an ester of cis-9-tetradecenoic acid (myristoleic acid) and 1- hexadecanol (cetyl alcohol) and is a 14-carbon monounsaturated omega-5 fatty acid.7 CM may act by inhibition of the 5-lipooxygenase pathway, which is responsible for the metabolism of leukotrienes, potent inflammatory mediators, from the arachidonic acid cascade.90 Studies in adjuvant-induced arthritis and collagen-induced arthritis in rats respectively have demonstrated that CM can confer protection and reduce severity of the disease respectively.91,92 A study in human knee OA has been reported where CM showed improvement in knee flexion and function.93

A product containing CM, glucosamine hydrochloride, methylsulfonylmethane and hydrolyzed collagen (MyristolTM) was investigated in a blinded-controlled clinical trial with 39 horses. Each horse was scored using American Association of Equine Practitioners (AAEP) guidelines for lameness, as well as a 0–10cm Visual Analog Scale (VAS) for lameness at walk, lameness at trot, response to joint flexion, lameness after flexion and quality of life.94 Horses were assessed on day 0, 14, 28 and 42 days after treatment. A responder was defined as improving one grade on the AAEP Lameness Scale or 2cm on the VAS. The MyristolTM treatment group improved significantly more than the placebo group in AAEP Lameness Score, lameness at walk, response to joint flexion, lameness after flexion and quality of life.

Conclusions

Use of OJSs in horses is prevalent worldwide. Although data from in vitro studies suggest mitigation of joint diseae, evidence regarding the in vivo efficacy of OJSs is still limited, in part due to a lack of well-designed clinical trials. However, more recently some randomized, placebo controlled studies are emerging.74

*The author wishes to acknowledge that most of this information has been previously published in McIlwraith CW (2013) Oral Joint Supplements in the Management of Osteoarthritis. In: Equine Applied and Clinical Nutrition, Geor RJ, Harris PA, & Coenen M (eds). Saunders-Elsevier, pp549-557 and McIlwraith CW (2016) Use of Oral Joint Supplements in Equine Joint Disease. In: Joint Disease in the Horse, 2nd ed., McIlwraith CW, Frisbie DD, Kawcak CE, van Weerren R (eds). Elsevier, St, Louis, MO, pp270-280.

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