Supplements for osteoarthritis: what’s the evidence?
Many dietary supplements are recommended for veterinary patients with osteoarthritis.1-14 Very few have been evaluated in a controlled manner, and even fewer have been evaluated in dogs with osteoarthritis. In the Fall 2015 issue of IVC Journal, we addressed food-derived supplements. In this issue, we will review the scientific evidence and research on other supplements recommended for dogs with osteoarthritis, including Omega-3 fatty acids, S-adenosylmethionine (SAMe), vitamin E, boswellia serrate, chondroprotectants, Zeel®, and Phycox®.
OMEGA-3 (N-3) FATTY ACIDS
These decrease inflammation and pain in dogs with osteoarthritis. They reduce expression of cyclooxygenase-2 (COX-2), lipoxygenase-5, aggrecanase, matrix metalloproteinase 3 and 13 (MMP-3, MMP-13), interleukin-1 and β (IL-1β, IL-1β), and tumor necrosis factor β (TNFβ).15-19 Novel oxygenated products, Resolvins (resolution phase interaction products) and docsatrienes, generated from n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), resolve inflammation.20-28 N-3 fatty acids support normal cartilage metabolism in the face of degradative enzymes, reducing inflammation and matrix degradative response elicited by chondrocytes during osteoarthritis progression.16-18,29 EPA appears to be more effective than DHA and-linolenic acid.15
There are several studies supporting use of n-3 fatty acids with osteoarthritis. An unpublished study performed in dogs showed lower serum concentrations of cholesterol, triglycerides, and phospholipids, lower synovial concentration of prostaglandin E2 (PGE2), better ground reaction forces, and less radiographic changes of osteoarthritis when dogs consumed a high n-3 diet than when dogs consumed a high n-6 diet.30,31 Owners perceive improvement in their pets’ arthritic symptoms when the animals are treated with fatty acids for various dermatologic problems.32
- In a study of 127 dogs with osteoarthritis, dogs fed a high n-3 diet had improved ability to rise from a resting position and play, over a period of six months, than dogs fed a control diet.33 Dogs fed a diet containing 3.5% n-3 fatty acids for 90 days had improved peak vertical force values (PVF) and subjective improvement in lameness and weight-bearing when compared with dogs on a control diet.34
- In a randomized, controlled clinical trial, dogs with stable chronic osteoarthritis treated with Carprofen could take a significantly decreased dosage when fed a diet supplemented with n-3 fatty acids, as compared to dogs on a control diet.35 Based on the results of these studies, there is a rationale for n-3 fatty acid supplementation, or feeding diets containing increased n-3 fatty acid levels to dogs with osteoarthritis.
- A placebo-controlled double-blind study of 77 osteoarthritic dogs involved randomly assigning a fish oil supplement or corn oil with fish smell (placebo) to the dogs (added to food). Primary variables were PVF and impulse, the validated Helsinki Chronic Pain Index (HCPI) and the use of rescue non-steroidal anti-inflammatory drugs (NSAIDS). Secondary outcome variables also assessed included locomotion visual analog scale (VAS), Quality of Life questionnaire, veterinary assessment, owner assessment of outcome, as well as guessing the product given. After 16 weeks, there was no significant difference in the primary outcome variables, but owners of dogs in the fish oil supplementation group reported positive outcomes and did significantly better at identifying the supplement as compared to the placebo group. Blood sampling confirmed owner compliance, with significant increases in EPA and DHA and a decrease in arachadonic acid (AA) in the fish oil group, as compared to a significant decrease in AA in the placebo group. Possible study limits were reported: the dosing at 90mg EPA, 20mg DHA, and 10mg eicosatetraenoic acid (ETA) per kg BW could have been too low for this population, and/or the 16-week study period too short. When baselines were compared to the study-end values within the fish oil group, a small but significant improvement was reported in outcomes. The authors concluded that for patients not taking NSAIDs for osteoarthritis, fish oil supplements may provide true but limited relief in pain symptoms.36
This co-substrate is involved in transmethylation, transsulfuration and aminopropylation reactions, which occur primarily in the liver. In controlled trials of humans with osteoarthritis, SAMe is as effective as NSAIDs and better than placebo in reducing pain and improving function, with a lower likelihood of side effects.37-44 However, no difference with an NSAID was found in one study.45 A systematic review was inconclusive and hampered by inclusion of small trials of questionable quality.46 No clinical trials of dogs have been published; however, an in vitro study showed SAMe adversely affected chondrocyte viability.47 SAMe may reduce inflammatory mediators, increase levels of the antioxidant glutathione, are chondroprotective, and maintain DNA methylation.48
- A double-blinded randomized pilot study evaluated vitamin E in a dog OA model. Fifteen adult crossbred dogs, one to four years old, weighing 23.6kg to 30.5kg, were randomly assigned to control with placebo and treated with vitamin E as a liquid-tocopherol acetate at 0.044 ml/kg body weight, equating to about 400 IU vitamin E per dog once a day. This is about ten times the daily amount recommended by the Association of American Control Officials (AAFCO), but considered safe and non-toxic. All dogs were maintained on the same diet starting two months before the study and until the end, with amounts adjusted to maintain optimal weights.
After the two-month period, the dogs had transection of their cranial cruciate ligament and placebo and vitamin E treatment initiated next day. Lameness and pain were assessed on Days 0, 28 and 55 after CCL transection using the visual analog scale (VAS), numerical rating scale (NRS), and electrodermal activity (EDA). Blood vitamin E levels were measured at Days 0, 21, 42, 55 post-surgery. Synovial fluid and cartilage histological analysis was evaluated after the dogs were euthanized on day 56. VAS, NRS and EDA were lower in the test group and become statistically significant in the test group for VAS Day 55 and EDA Day 28. Concentrations of PGE2 and nitric oxides (NO) in the synovial fluid of the test group were lower and statistically significant as well as histological scoring and analysis of the cartilage. This study in dogs with OA suggests that higher doses of vitamin E may reduce inflammatory markers and histological expression as well as improve signs of pain.49
- In another study, large breed puppies fed a diet proportionately higher in protein, calcium, n-3 fatty acids and antioxidants had increased lean body mass and improved cartilage turnover as maturity was attained.50 In greyhounds and sled dogs, supplementation is associated with increased plasma levels; however, there was no difference in muscle damage with exercise.51-53 In dogs, vitamin C administration was found to increase vitamin C plasma levels, but was associated with decreased racing performance in greyhounds.54 In a study of antioxidant cocktail administration in 48 dogs over six weeks, subjects were assigned to four groups: untrained/not supplemented, untrained/supplemented, trained/not supplemented, trained/supplemented. Metabolomic profiling showed that dogs receiving the antioxidant cocktail recovered to baseline values at 24 hours after exercise, while dogs not receiving supplementation did not; therefore, administration of an antioxidant cocktail facilitates recovery from exercise.55
BOSWELLIA SERRATA (INDIAN FRANKINCENSE) Boswellia, also known as Boswellin or Indian frankincense, comes from the Indian Boswellia serrata tree. Resin from the bark of this tree is purported to have anti-inflammatory properties derived primarily from 3-O-acetyl-11-keto-βboswellic acid (AKBA), which inhibits 5-lipoxygenase and matrix metalloproteinases, and decreases tumor necrosis factor and interleukin 1β.56,57 Boswellia resin has been evaluated in 24 dogs in an open multi-center study.58 Improvement in clinical signs, lameness, and pain was found in 17 of 24 dogs. In five dogs, diarrhea and flatulence occurred.
CHONDROPROTECTANTS These are considered to be slow-acting drugs in osteoarthritis (SADOA) and can be subdivided into symptomatic slow-acting drugs (SYSADOA) and disease-modifying osteoarthritis drugs (DMOAD). Beneficial effects may include a positive effect on cartilage matrix synthesis and hyaluronan synthesis by synovial membrane, as well as an inhibitory effect on catabolic enzymes in osteoarthritis joints.59 Compounds fall under two different categories. One group includes agents approved by the US Food and Drug Administration and can have label claims of clinical effects such as polysulfated glycosaminoglycan (GAG). The second group includes products that are considered to be nutritional supplements, which are not regulated, and legally cannot claim any medical benefits. Examples of this group include glucosamine and chondroitin sulfate. While many of these products are administered as a supplement or alternative treatment, some, such as glucosamine and green-lipped mussels, are incorporated into pet foods.
GLUCOSAMINE AND CHONDROITIN
Glucosamine is a precursor for glycosaminoglycans and a major component of joint cartilage; supplemental glucosamine may help rebuild cartilage.60-66
- In a randomized, double-blind, positive-controlled clinical trial comparing glucosamine hydrochloride and chondroitin sulfate to Carprofen in dogs with osteoarthritis, Carprofen-treated dogs had improvement in five subjective measures while dogs treated with glucosamine-chondroitin sulfate had improvement in three of five measures but only at the final assessment point.67
- A 60-day, prospective, randomized, double-blinded, placebo-controlled trial of 71 dogs with osteoarthritis assessed subjective and objective measures comparing Carprofen, Meloxicam, glucosamine/chondroitin, and placebo. Results indicated that objectively measured variables improved significantly with Carprofen and Meloxicam, but not with glucosamine/chondroitin or placebo. Subjective findings of veterinarians agreed with the results of objective evaluation, but subjective assessment by owners identified improvement only with Meloxicam.68 Based on these results, there is weak clinical evidence of the benefits of glucosamine/chondroitin in dogs with osteoarthritis.69-71
This over-the-counter homeopathic preparation is based on highly diluted extracts from plants, animals, and minerals (sulfur) as well as defined biochemical substances including coenzyme A, DL-alphalipoic acid, sodium diethyl oxalate, and nicotinamide adenine dinucleotide.72,73 In one study in dogs aged >1 year diagnosed with osteoarthritis, Zeel was compared with Carprofen in a multi-center, prospective, observational open-label cohort study in 12 German veterinary clinics.93 In another study in dogs (n=44), aged >1 year diagnosed with osteoarthritis, it was compared with Carprofen and a placebo.73 Clinical signs and several measures of osteoarthritis improved significantly in both studies; however, in one study73, Zeel was not as effective as Carprofen. The composition of the products and the dosage of Zeel differed between the two studies, which confounds interpretation of results.
A study of the commercially available C-phycocyanin-based (CPC) nutraceutical (Phycox®), its individual constituents, and Carprofen was performed using an in-vitro model of canine osteoarthritis. CPC is a biliprotein containing chromophore derived from cyanobacteria, also known as blue-green algae. Inflammatory conditions were induced using IL-1β in normal canine articular chondrocytes, and 0 to 250 µg/ml concentrations of the nutraceutical, constituents, and Carprofen were evaluated for any reduction in inflammatory mediators and markers of catabolism of the extracellular matrix: PGE2, TNFβ, IL-6, MMP-3, nitric oxide and GAGs. Inhibition of COX1, COX-2 and LOX pathways were assessed using assay kits.
No statistical difference was seen in the nutraceutical as compared to Carprofen, in the inhibition of TNFβ, IL-6, MMP-3, nitrate, nitrite and GAGs production in the OA in-vitro canine model across the concentration ranges tested. Both the nutraceutical and Carprofen failed to significantly decrease the following mediators at the 0.1 to 10 mg/ml: TNF-a, IL-6, MMP-3, nitrate and nitrite.
The nutraceutical did significantly reduce the concentration of PGE2 and GAG from the positive control. It was noted that the nutraceutical and many of its constituents appear to display selectivity for COX-2 inhibition and were poor LOX inhibitors. A multi-center in-vivo efficacy study has been undertaken by this laboratories.74
The pharmacological management of OA in dogs is dominated by NSAIDs, but adverse side effects can occur and there is concern over long-term administration of these drugs. NSAIDs have not been shown to slow the progression of the disease or to have a positive impact on joint degradation. Dietary supplements are being increasingly studied as the economics of osteoarthritis in the aging human population is a growing concern. This review is not exhaustive as there are many supplements being evaluated for the treatment of OA.
Translational research, new study methodology (nutrogenomics and metabololomics), and well-designed non-inferiority study design may open new horizons for the management of osteoarthritis in dogs. Practitioners need conclusive data to know how to select and integrate supplements into the multimodality management of their patients with osteoarthritis.
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