Author Name: Charlotte Forkes; BSc (Hons) Bioveterinary Science
The oral supplementation of glucosamine (GS) and chondroitin (CS) in various mammalian species has been greatly discussed in literature over the last two decades, however comparatively little research relates to their use in horses. Studies regarding horses provide conflicting results as to their effectiveness in treating degenerative joint disease for a multitude of factors. Concerns revolve around poor consistency of nutraceutical products due to their unstable nature and poor legislation; undetermined mechanisms of action within the body, especially in horses; and lack of robust scientific research using objective assessments, controlled variables and appropriate time frames in a suitable equine population. Until further research is conducted that fulfils these criteria there is no definitive way of knowing the true efficacy of GS and CS. However, its current use alongside controlled exercise and other means of therapy should not be dismissed.
Degenerative joint disease (DJD), is a major cause of poor athletic performance, retirement and economic loss within the equine industry (Taintor et al, 2014; Broeckx et al, 2014; Clayton et al 2002; Hanson et al, 1997). DJD occurs due to mechanical stress, resulting in injury or instability of the joint and subsequent degradation of the articular cartilage, inflammation of the soft tissue and changes to subchondral bone (Taintor et al, 2014; McIlwraith and Trotter, 1996). There is no cure for DJD, however treatment aims to reduce clinical signs so as to improve quality of life (Taintor et al, 2014). Treatment can fall into two categories: physical or medical therapies (Duren, 2002). Physical therapies involve rest, cryotherapy, thermotherapy and controlled exercise (Duren, 2002), whereas medical therapies include the use of oral non-steroidal anti-inflammatory drugs (most commonly Phenylbutazone) (McIlwraith, 2010) and corticosteroids injected directly into the joint (Brommer et al, 2012; Richardson and Loinaz, 2007; Goodrich and Nixon, 2006).
Over recent years, oral supplements (nutraceuticals) containing ingredients found within healthy joints have been developed, with the theory that the nutrients can be absorbed and utilized by the body to maintain, or repair, joint tissues (Duren, 2002). These supplements are designed for both prophylactic and maintenance usage, many of which contain the supposedly beneficial ingredients glucosamine chloride and chondroitin sulphate (Goodrich and Nixon, 2006). However, claims made by joint supplements are often unsubstantiated and their efficacy undetermined, therefore they are potentially a controversial choice (Richardson and Loinaz, 2007).
Nutraceuticals is a term that combines the words ‘nutrition’ and ‘pharmaceuticals’ (Kalra, 2003). They can be defined as ‘a food (or part of a food) that provides medical or health benefits, including the prevention and/or treatment of a disease’ (Bauer, 2001). It is thought that conditions such as DJD in horses can be managed by the provision of certain nutrients within the diet (Collins et al, 2008), with Glucosamine and Chondroitin being frequently used for its chondroprotective properties (Hanson et al, 1997). Many equine veterinarians recommend supplements intended to treat or alter body function (such as joint supplements) containing similar ingredients as those found in prescription drugs (Collins et al, 2008). However, supplements often can be purchased ‘over the counter’ at feed stores (Ramey et al, 2002) due to the difference between drug and supplement legislation (Coppens, de Silva and Pettman, 2006). Drugs are required to conform to a certain standard for safety, consistency and quality assurance, whereas supplements only have to prove they are not harmful, not that they are safe (Collins et al, 2008). As supplements are not under such strict legislation and do not need veterinary prescription to be purchased, consumers are often influenced by branding associated with professional riders without having a sound understanding of what they are feeding nutritionally and whether there is a scientific basis for its use (Gemmill et al, 2014).
Ramey et al (2002) analyzed 11 joint supplements containing Glucosamine and/or Chondroitin available for sale for horses in feed stores and compared their results against the label claim. The results indicated that the amount of claimed active ingredient ranged from 63.6-112.2% (glucosamine) and 22.5-155.7% (chondroitin). Each sample was tested three times and an average value taken, with all identifiable branding removed so as to not influence the laboratory findings and increase the validity of the data collected. Russell, Aghazadeh-Habashi and Jamali (2002) in a similar study tested 14 glucosamine supplements, and equally found that each of them had varying consistency in product ingredients to label claim (59-138%). Although a limited number of products were tested in both studies, all of the supplements contained differing levels of active ingredients to the label claim. Ramey et al (2002) do not state whether multiple batches were tested, so it could be considered that there were individual problems with the supplement rather than overall product concerns, however, as Aghazadeh-Habashi and Jamalithis (2011) state this may be due to the instability of GS, which crystalizes with other molecules to form new compounds. Ramey et al (2002) do not state the label claims for dosage rates, so it is not possible to determine the dosage potency for the products, and thus whether the dosage recommended would be effective.
Glucosamine is available in several forms, the most common used being Glucosamine Sulphate (GS) (Gregory, Sperry and Wilson, 2008). The recommended dosage for adult horses is 20mg/kg per day (Laverty et al, 2005). Early research indicated that GS was a small, hydrophilic molecule and therefore could be absorbed through the gut wall and circulate via the bloodstream to the target tissues (Aghazadeh-Habashi et al, 2002). However, Qian et al (2013) indicated that GS is a similar molecule to glucose, therefore cannot readily pass through intestinal membranes and instead requires transport via transcellular pathways and uses glucose facilitative transporters. This leaves their absorption susceptible to inhibition and saturation, therefore preventing their uptake. The saturation level has yet to be determined, however it may be lower than the required levels to show clinical improvements in horses, therefore the efficacy of the supplement may be altered due to the inability of the body to fully orally absorb them rather than the active ingredients being ineffective.
The use of surfactants in conjunction with small hydrophilic drugs (similar in size and structure to GS) is commonly used so as to increase the paracellular permeability across the mucosal epithelia of the upper small intestine (Qian et al, 2013). A common surfactant used in the pharmaceutical industry is microcrystalline cellulose (Kamel et al, 2008), however cellulose was found in rats to reduce the absorption rate of GS (Qian et al, 2013). Qian et al, (2013) found that when chitosan (a polymer found in the shells of crustaceans) was added to GS there was increased bioavailability in in-vitro and in-vivo tests involving rats and Beagles. Hejazi and Amiji (2003) indicated that when chitosan is exposed to acidic conditions, such as gastric juices, it becomes buoyant and increases the duration of gastric residence. This aids the absorption of drugs in the upper gastrointestinal tract by prolonging their controlled release in target areas that otherwise would not be achieved, such as if the drug is insoluble in intestinal fluid. The addition of chitosan to GS therefore aids absorption and increases the chance for the supplement to have its intended effect. The applicability of surfactant use in horses is yet to be investigated. Although it has shown promise in monogastric species, horses are hind gut fermenters and have varying gastric pH. Additionally stomach emptying can take up to 24hrs, therefore their potential use may be limited in horses as there is already an increased gastric residence compared to monogastric species.
Determination of the true availability of GS in horses is not fully know, as currently it is unclear as to how much reaches the systemic circulation unchanged (Persiani et al, 2005). Aghazadeh-Habashi et al (2002) found that in rats 82% of radiolabeled GS was systemically available, while only 21% of that was bioavailable following dosage with GS at 350mg/kg (greater than the recommended 20mg/kg used in other clinical studies). Higher dosages were used in the rats due to their fast metabolism and excretion of GS, and the inability to test for concentrations below the detectable level of 0.63 g.mL. Oral and intravenous administration routes were analysed with no significant differences in results, and findings showed that GS was rapidly absorbed, metabolized and excreted by the body via either method of administration. However, as GS is present in the extracellular matrix of mammalian cartilage and synovial fluid, it exists naturally in the blood due to cellular turnover. Blood serum testing may therefore give unrepresentative results as to its systemic availability as currently studies have been unable to differentiate between metabolites, waste products and unchanged GS circulating in the blood (Persiani et al, 2005).
Chondroitin sulphate (CS) is a complex sugar and primary component in proteoglycan, an important structural component of cartilage providing resistance to compression (Hanson et al, 1997). When cartilage is damaged or inflamed, the level of proteoglycan is reduced (Zwerina et al, 2004). The supplementation of chondroitin in the diet is thought to replace the damaged proteoglycan and so repair the joint, as well as inhibit the action of enzymes associated with cartilage breakdown (Hanson et al, 1997).
CS is utilized as a symptomatic slow acting drug (SYSADOA), whereby its full effect is only apparent following multiple administrations in horses (Adebowale et al, 2002; Volpi, 2002). The absorption rates and bioavailability is variable depending on molecular weight (ranging from 6-50 kda), sulfonation pattern and dosage (Igarashi et al, 2013; Neil, Caron and Orth, 2005). High molecular weights are associated with poor absorption rates, whereas low molecular weights (LMW) have an increased absorption and significant accumulation effect following multiple dosing (Niel, Caron and Orth, 2005; Adebowale et al, 2002). Adebowale et al (2002) research found that when 1600mg of LMWCS was administered either as a single dose or multiple doses in Beagles, bioavailability was significantly increased from 4.8-5%, to 200-278% respectively (Adebowale et al, 2002). The results appear convincing, however the study only dosed the participants for 14 days, therefore the long term effect of CS has not been identified. The ability to generalize the results to horses (which require a longer dosing periods) is therefore questionable.
Kahan et al (2009) investigated the long term effects of CS (800mg) in humans with osteoarthritis (OA) of the knee over a two year period. The conclusions reached were that CS provided sufficient structural and symptomatic modification to OA. However, the main limitation for projecting these results for its use to horses is that CS used in the study was approved as a prescription drug. The results may therefore not be representative of all CS supplements available for use in horses due to differing regulations regarding quality assurance of drugs and supplements.
2.3 Glucosamine and Chondroitin
Research has indicated that glucosamine and chondroitin used in conjunction have the ability to improve pain scores and weight bearing capabilities, as well as protect and reduce degradation of cartilage in horses (Chan et al, 2005). However, nutraceutical studies in horses are limited, and largely use subjective assessment rather than objective assessment with control groups thereby limiting the validity of the results.
Forsyth, Brigden and Northrop (2006) conducted an assessment on chondroprotective supplements (GS and CS) in an attempt to quantify their effectiveness on veteran horses. Gait analysis and stride length were taken prior to random treatment assignment (n=15) or placebo (n= 5). Following 12 weeks of manufacturers recommended dosing, there was a significant improvement of range of motion, and increased stride length in the treated horses compared with the placebo group, with greatest results shown when GS and CS were used synergistically. Subjects were selected by age rather than veterinary history of DJD, and were kept in differing routines therefore the validity of the results are questionable as additional variables could have influenced the results.
In opposition to this, Higler et al (2014) in a similar duration of study combining exercise and the use of GS, CS and methyl sulfonyl methane synergistically (n= 12) at manufacturers guidelines found no significant difference in stride length to the control group (n=12) when using gait analysis techniques. Their conclusions were that exercise habituation influences stride length to a greater effect then the use of oral supplementation of GS and CS. Like Forsyth, Brigden and Northrop’s (2006) study, the subjects selected were based on age rather than veterinary history of DJD, therefore the results have limited validity for dismissing the use of GS and CS as a treatment for DJD.
Although the equine studies give conflicting results, they cannot be directly compared due to variation in the products studied. Forsyth, Brigden and Northrop (2006) were analyzing the efficacy of Cosequin powder, whereas Higler et al (2014) used an unnamed liquid supplement. The difference between liquid and powder supplement may have affected the overall results due to differing absorption rates alongside differing supplement composition. The study by Ronca et al (1998) found that when CS is dissolved in water, the time taken to reach maximum serum concentration was a quarter of the time compared to gastroresistant capsules (powder) (1.0 hours± 0.3 : 4.0 hours ± 1.0), with maximum serum concentration three times greater (6.6 µg/ml ± 0.7 : 2.4µg/ml ± 0.5). This variation in supplement administration may result in increased metabolism of the supplement, and therefore lead to faster excretion of metabolites. As Higler et al (2014) only dosed once per day, it may have reduced the effect of multiple dosages required by horses to result in improved clinical signs.
Degenerative joint disease (DJD) is a major factor influencing economic loss and poor performance in the equine industry. Due to this fact, research has been conducted to look at ways of managing this condition through the use of oral supplementation of glucosamine (GS) and chondroitin (CS). However, their effectiveness in horses is questioned due to limited numbers of studies currently being available.
Poor regulation and legislation of nutraceuticals has been shown to result in varying standards of products. The difference in product content to label claims in commonly available joint supplements highlights the importance of ensuring product standardisation, consistency and quality assurance prior to denouncing efficacy of GS and CS in treating DJD.
Lack of external and internal validity and reliability from studies in humans, rats and dogs restrict the application of results to horses, largely due to subjective assessment techniques and variation in products being tested. Due to this fact, further robust scientific research is required to either confirm or deny the efficacy of GS and CS as a holistic treatment of DJD in horses.
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