Nem136 365.374

Advance Access Publication 29 October 2007 eCAM 2009;6(3)365–373doi:10.1093/ecam/nem136 Evaluating Complementary Therapies for Canine OsteoarthritisPart I: Green-lipped Mussel (Perna canaliculus) Anna Hielm-Bjo¨rkman1, Riitta-Mari Tulamo1, Hanna Salonen2 and Marja Raekallio1 1Faculty of Veterinary Medicine, Department of Equine and Small Animal Medicine, University of Helsinki,PO Box 57, Fi-00014, Finland and 2Huhtakoukku 16, 02340, Espoo, Finland A green-lipped mussel (GLM) preparation was evaluated in a randomized, double-controlledand double-blinded clinical trial. It was hypothesized that the treatment effect would be less than that of the positive control (carprofen) but more than that of the negative control(placebo). Forty-five dogs with chronic pain and a radiographic diagnosis of osteoarthritisthat were randomly allocated into one of three groups completed the study. All dogs were fedthe test products or placebo for 8 weeks. The dogs were evaluated four times, at 4-weekintervals. Six different variables were assessed: veterinary-assessed mobility index, twoforce plate variables, owner-evaluated chronic pain index and pain as well as locomotionvisual analogue scales (VASs). Intake of extra carprofen was also evaluated. A chi-squared and a Mann–Whitney test were used to determine significance between groups. When changedto dichotomous variables, there were more dogs in the GLM than in the placebo groupthat improved, according to veterinary-assessed mobility, owner-evaluated chronic pain indexand pain VAS (P = 0.031, P = 0.025, P = 0.011, respectively). For the same three, theodds ratio and their confidence interval were over one. The extent of improvement wassignificantly different between the GLM and the control in veterinary-assessed mobility(P = 0.012) and pain VAS (P = 0.004). In conclusion, GLM alleviated chronic orthopedicpain in dogs although it was not as effective as carprofen. As no side-effects were detected,GLM may be beneficial in dogs e.g. when non-steroidal anti-inflammatory drugs cannotbe used.
Keywords: Controlled – dog – LyproflexÕ – nutraceutical – OA – placebo as naturally occurring, biologically effective nutritionalsupplements that can confer some degree of health Over the last few years, there has been a growing interest benefit and there is a whole new science referred to as in new treatment options for osteoarthritis (OA), both ‘bioprospecting’(3) that explores and introduces these for humans and pets, especially dogs. The so-called new herbs—or animal molecules or products. Currently, nutraceuticals have become available, since some patients several nutraceuticals on the market are claiming to cannot tolerate or do not want to take the risk of non- relieve arthritic symptoms. These products generally steroidal anti-inflammatory drugs (NSAIDs) because of fall mainly into two distinct product groups, including their side-effects (1,2). Nutraceuticals have been described or polyunsaturated fatty acids (PUFAs), particularly For reprints and all correspondence: Anna Hielm-Bjo¨rkman, DVM, CVA, Faculty of Veterinary Medicine, Department of Equine and Small Animal Medicine, University of Helsinki, PO Box 57, FI-00014, that may benefit OA is a product based on Perna Finland. Tel: +358-400885255; Fax: +358-9-19157298;E-mail: [email protected] canaliculus, or the green-lipped mussel (GLM) that ß 2007 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work isproperly cited.
Green-lipped mussel for canine osteoarthritis has been thoroughly examined by Halpern (4) [see walking up or down stairs, or definite lameness. Dogs were excluded from the study if they had had prior The early GLM-based products were often produced from rejected mussel meat from human food processing, symptoms, systemic or infectious disease, neurological which typically included steam processing as part of deficits, lameness from articular infection, or recent the manufacturing process and the early trials using these unstable GLMs, showed poor results. In the 1980s, Sixty-eight dogs were chosen based on 124 telephone a method of temperature-controlled cold processing interviews with owners. Of these, 51 dogs will be and stabilization of GLM by adding organic acids presented here and the remaining 17 constituted a to prevent oxidation and freeze-drying was patented treatment group for another study (17). Six dogs (6). After 1986, this new stabilized GLM has been in (two in each group) were excluded from the study at use and is documented to be efficacious in treating some point for the following reasons: having had a experimental arthritis in rats (7,8), clinical arthritis previous operation of the affected hip joint, having in humans (9,10) and more recently also in dogs (11,12).
a transverse vertebra (n = 2), sustaining a cruciate The GLM product used in this study, which originates ligament injury (n = 2) and diagnosed with degenerative from mussel farms in the Pacific Ocean, has been myelopathy. There were 15 dogs in each group that harvested when the mussels are 12 to 18-months old, finished the study: 12 dogs with canine hip dysplasia and is stabilized, freeze-dried at À40C and packed (CHD) and three dogs with elbow OA in each group, all immediately thereafter. The GLM product is a rich confirmed by radiographs. Twenty-five dogs were male and 20 were female. The median age was 6 years (GAGs), such as chondroitin sulfates, vitamins, minerals (range 1–11) and the median body weight (BW) was and Omega-3 series PUFAs. It is not totally clear how 34 kg (range 18–56). There were both uni- and bi-laterally the products function (13) [this is not totally clear for affected dogs. All dogs had either moderate or severe NSAIDs either (14,15)], despite substantial research.
radiological changes in the worst-affected hip or elbow Although there has been only a few studies published on the use of stabilized GLM on dogs, it is already Owners were asked not to give the dogs NSAIDs or available for dogs with OA, as a powder, as capsules or corticosteroids for at least 30 days and no Na-pentosan The aim of this study was to evaluate a GLM Australia) for at least 90 days prior to the study.
product as an OA nutraceutical for dogs in a random- However, this proved not to be always the case, as some owners felt that their dogs were in such pain that We expected the positive control carprofen to signifi- they therefore gave them NSAIDs. The use of the cantly reduce pain and locomotion difficulties, and additional analgesic pre-trial was, however, recorded in the negative control (placebo) to have no such effect.
The effect of the nutraceutical was hypothesized to liesomewhere between those of the positive and negative.
Objective, semi-objective and subjective variables wereused for assessment. Since the GLM is also used in humans, the treatment outcome is of interest for many Cambridgeshire/Biofarm Oy, Finland). The capsules people as OA is becoming one of the most prevalent and costly diseases in our aging society. Due to the side-effects associated with NSAIDs, 60–90% of dissa- tisfied human arthritis patients are reported to seek eicosapentaenoic acid (EPA)/100 g and >400 mg docosa- complementary therapies for their disease (16).
hexaenoic acid (DHA)/100 g. The initial dose was4 (for dogs 40 kg BW) or 6 (for dogs > 40 kg BW)capsules/day for 10 days, then continuing with half of the loading dose (i.e. two or three capsules) for the rest ofthe study. This meant an initial dose of 20–49 mg/kg/day Inclusion criteria were that dogs had clinical signs and a Two control groups were included: the established radiographic diagnosis of OA, in either a hip joint or an positive control carprofen (RimadylÕ 50 mg; Pfizer, elbow joint. The owner had to have described at least two Helsinki, Finland) at a dose of 2 mg/kg twice a day and of the following signs as being frequent: difficulty in lying a negative control that received all products as placebos.
down and/or in getting up from a lying position, Carprofen was a white pill without the usual stamp difficulty in jumping or refusing to jump, difficulty in and its placebo an identical lactose tablet, GLM was a greenish capsule and its placebo a very similarly colored lactose capsule. In addition, all dogs were administered an ampoule of isotonic sodium chloride solution as a following evaluation, owners answered a three-part placebo for another study (17). The products were coded questionnaire. The first part used a descriptive scale of and organized by a research assistant who was not 0–4 and contained questions about attitude, behavior and locomotion. Of these, 11 questions were combined to For ethical reasons, all owners were also given a form a combined owner-assessed chronic pain index, as package of 50 mg carprofen in normal packaging and described previously (20). The second part contained two with the normal stamp on the tablet, at the start of the 10 cm visual analogue scales (VASs): one for pain and trial. This could be used as additional pain relief (dose of the other for locomotion. The end of the lines to the one tablet for a dog of 20–30 kg BW, two tablets for a left represented no pain or no difficulties in locomotion, dog of 31–40 kg and three tablets for a dog of 41–60 kg) and to the right, the worst possible pain or the most if they felt the dog was in considerable pain. The number severe difficulties in locomotion. The third part consisted of additional carprofen doses used was recorded in the of questions about possible adverse reactions to treat- ment, including change in appetite, vomiting, diarrheaand atopic skin reactions. The question about additional analgesics was not a continuous variable but used the following scale: ‘during the last four weeks additional The study was designed as a randomized double- carprofen was given 1 = not at all, 2 = 1–2 times, 3 = about once a week, 4 = about 3–5 times a week, CONSORT guidelines (19). A secretary made the first appointments, and at this first visit (W0), the dogs were assigned into groups, in order of arrival using a computer-generated random list. Only the location ofthe diseased (hip or elbow OA) was stratified for in the randomization. Initial clinical, orthopedic and neurologi- (Kistler forceplate, Type 9286, Kistler Instrumente AG cal examinations were performed and diagnostic criteria Winterhur, CH-8408, Switzerland), which assesses weight included decreased range of motion and pain on bearing of limbs. The force plate was submerged into the stretching the hip or flexing the elbow. Radiographs concrete floor so that the plate and floor surfaces were on were taken of the dogs’ hips and/or elbows and other the same level. The floor was then covered with a 2 mm thick rubber mat that extended from 7 m before to 7 m was set as baseline, except for pre-trial analgesic after the plate, forming a 14 m walkway. A hole was cut medication, where the assessment was made at W in the mat over the force plate and a 3–4 mm gap was the owners were told not to use them anymore between left between the force plate mat and the rest of the mat.
The signal from the plate was processed and stored using À4 and W0. Follow-up visits with questionnaires for reassessment were at 4, 8 and 12 weeks (W a computer-based software program, and velocities and acceleration were determined by three photoelectric The dogs were given the products orally for cells placed exactly 1 m apart and a start-interrupt off all medication for 4 weeks and were evaluated to determine long-term effects of the different treatments as follow up. All evaluators (veterinarians and owners) Dogs guided by their owners trotted over the walkway and all technical assistants were blinded. Owners of from left to right. The speed was one comfortable the dogs were required to sign informed consent forms.
for each dog in trot and had to be in the same range Committee of the University of Helsinki.
performed (at W0, W4, W8 and W12). The accelerationwas < 0.5 m/s/s and contact had to be made with theplate first by the forelimb and shortly after with the hindlimb of the same side for the evaluation to be valid. The test was repeated until sufficient valid results were Two veterinarians subjectively assessed three parameters obtained for both left and right limbs.
at W0, W4, W8 and W12: locomotion, jumping and Three valid measurements for each side and for each walking stairs using 0–4 descriptive scales. The three visit were then chosen by a blinded assistant (one scores assigned by the two veterinarians were summed to not otherwise participating in the study) according to form a veterinary-assessed mobility index, with a possible speed, acceleration and with no interferences, such as minimum score of 0 and a maximum of 24 (2 Â 3 Â 0–4).
gait abnormalities or extra body movements. The mean Green-lipped mussel for canine osteoarthritis of these three measurements was used for analysis.
The ground reaction forces were normalized for eachdog’s BW and mean peak vertical force (PVF) and mean vertical impulse were used as variables. Only measure- Baseline variable median (range) values were: for the ments from the most severely affected leg at time veterinary-assessed mobility index: 6 (0–18), PVF: 71.21 (54.7–135.25), vertical impulse: 9.11 (6.02–19.9), owner-evaluated chronic pain index: 16 (4–25), pain VAS: 3.55 (0–8.4) and locomotion VAS: 4.8 (0–8.3). There was nostatistical bias between the groups at baseline. The Blood samples were collected from the dogs at each visit.
evaluations of the two veterinarians correlated well Blood urea nitrogen (BUN), creatinine, serum alanine aminotransferase (ALAT), alkaline phosphatase (AFOS),total protein and albumin were analyzed.
There were four dogs (all from the placebo group) that had used extra carprofen more than three times per week The number of dogs needed in each group was at W8. For three of the variables [veterinary-assessed calculated for a two-tailed test (Fisher). The sample size (n = 15/group) was sufficiently large to detect a 47% (P = 0.028) and pain VAS (P = 0.011)] there were difference (11) in treatment outcome (effective versus not significantly more improved dogs in the GLM group effective) with a statistical power of 0.8 and allowing for compared to the placebo group (Table 1). The odds ratio for the veterinary-assessed mobility index was 5.5 To counteract the effect of the extra NSAID on dogs (95% CI 1.14–26.41) indicating that a dog that had received the GLM product was 5.5 times more likely to 8 had used extra carprofen more than three have a positive response compared to a dog that had most negative value measured for any dog at that time.
received the placebo. The odds ratio for the force plate This enabled us to use the whole data in the statistical PVF was 2.50 (95% CI 0.52–11.93), for the force plate impulse 2.40 (95% CI 0.52–10.99), for the owner- assessed chronic pain index was 6.0 (95% CI 1.17–30.72), for the pain VAS 8.0 (95% CI 1.52–42.04) and for the ratio, the results of each variable were converted into locomotion VAS 4.12 (95% CI 0.88–19.27).
dichotomous responses of ‘improved’ and ‘not improved’.
Dogs that deteriorated and dogs with no change in the evaluated variable were considered ‘not improved’.
The difference between the treatment groups and the All variables showed a similar trend of improvement, placebo was calculated using a chi-squared test. The odds with carprofen being the most efficient, placebo the ratio was calculated using the common Mantel–Haenszel least and GLM being between these two (Table 1). There odds ratio estimate and the confidence interval (CI) was was a significant difference between the GLM and the set to 95%. An odds ratio more than 1.0 indicated a placebo in two variables [veterinary-assessed mobility beneficial effect of the test treatments.
index (P = 0.012) and pain VAS (P = 0.004)] and a The changes from baseline to W8 were also calculated third variable was close to significant [locomotion VAS for each variable. The difference between the GLM and placebo group was analyzed using the Mann–Whitneytest. The changes from W0 to W8 in the force plate variables were proportional in the front and hind legs,although the values were different. Therefore, force plate At WÀ4, before the owners were requested to stop all data of all four legs were analyzed together. The dogs, for medication, 14% of the carprofen group, 13% of the which no force plate results could be registered, were GLM group and 8% of the placebo group were given considered ‘not improved’ in the dichotomous evalua- NSAIDs once a week or more. At W8, (Fig. 1) 0, 7 and tions and excluded in the median analyses. A correlation 27% of the respective groups were given additional test was used to evaluate the association between carprofen once a week or more. At follow-up (W12), the assessments of the two veterinarians. Statistical the respective numbers were 33, 14 and 29%. The differences between both GLM and carprofen compared were preformed using SPSS 12.0 for Windows (SPSS to the placebo group at time W8 were significant (P = 0.021 and P = 0.008, respectively).
Table 1. Percentage of improved dogs and median (range) of improvement for evaluated variables, per group from W0 to W8 For each treatment group: First column: Percentage of dogs in the group that improved. Below: P = Difference in percentage of improved betweentreatment groups and placebo. Second column: Median (with range) of change from W0 to W8 [(+), improvement; (À), deterioration] in evaluatedvariables for the carprofen-, GLM- and placebo-groups. P = Difference in improvement between treatment groups and placebo (the force platevalues do not include three dogs for whom no results were obtained). n, number of patients per group; GLM, green-lipped mussel; PVF, peakvertical force; VAS, visual analogue scale.
euthanized between W8 and W12 due to severe pain.
In populations, neither our findings of clinical side- Additional
carprofen given
effects nor clinical chemistry in any of the blood parameters were severe or related to any particular group. Palatability was never a concern.
In our study, dogs showed a beneficial clinical response to treating OA-induced pain and locomotion difficultieswith GLM. More dogs improved in the GLM group compared to the placebo group and the extent oftreatment effects was between that of our two control n of dogs per group
groups, as can be seen from the median values in Table 1.
The carprofen had in previous studies shown 56–80%of improvement in dogs with OA (graded by veterinar- ians and owners) whereas the placebo in the samestudies showed improvement in only 23–38% of thecases (21, 22). As these numbers are close to the resultswe obtained in our study for the two control groups carprofen
(Table 1), they indicate that our cohort reflects realitywell and that we can trust the results of our treatmentgroup. The fact that extra carprofen was used signifi- Figure 1. At the end of the treatment period (W8), there was 4/15 dogsin the placebo group given extra carprofen 3–7 days/week (n = number cantly more often in the placebo group at W8 is also a positive result for the tested product.
This positive outcome opens a discussion about possible working mechanisms of the GLM (Fig. 2).
In the early GLM clinical trials on human patients, the Three dogs (one in the GLM group, two in the placebo outcomes were not good and often contradictory (23,24).
group) were so lame during the visits that no usable data Twenty years later, possibly after having stabilized the were obtained from the force plate. Two of these dogs product by freeze-drying and lyophilizing, the results of (one in the GLM group, one in the placebo group) were clinical trials for GLM have been significantly promising Green-lipped mussel for canine osteoarthritis GLM: Omega-3 PUFAs-Eicosatetraenoic acids (ETA) Figure 2. Main active constituents of the green lipped mussel and their effect on the inflammation pathways of osteoarthritis. The main activeconstituents, according to how we understand their working mechanisms now: The Omega-3 PUFAs (especially the ETAs) have anti-inflammatoryactivity; they possess significant cyclo-oxygenase (COX 1 and 2) and lipoxygenase (LOX-5) inhibitory activity. Due to their glycosaminoglycancontent (especially chondroitin sulphate with its high glucosamine content), the GLM may have chondroprotective properties. The vitamins andminerals are needed in cartilage anabolism. GLM, green-lipped mussel; Th, T helper cell; IL, interleukin; TNF, tumor necrosis factor.
(9–12). The lyophilizing process might have been the This dual inhibition of both LOX- and COX metabolic more important as in fact, the difference in lipid, sterol or pathways may offer an explanation for the reported fatty acid composition of frozen and freeze-dried GLM clinical efficacy and favorable gastrointestinal tolerability has been shown to be non-existent; the only major of GLM. Platelet aggregation remains unaltered and the difference was between total lipid composition on a dry lipid fraction be non-gastrotoxic in fasted disease-stressed weight basis because of the removal of water in the deep- arthritic rats at a dose of 300 mg/kg (treatment dose 20 mg/kg) (8,13). This shows that the GLM does not have activity of GLM powder was confirmed in vivo using the negative side-effects of the NSAIDs. Recently, new the established rat paw oedema model; rats fed mussel GLM extracts were tested (26) and a Tween-20 extract lipids perorally developed neither adjuvant-induced poly- (that draws out membrane-bound proteins by a cationic arthritis nor collagen-induced auto-allergic arthritis (8).
detergent) effectively inhibits both COX-1 and COX-2 However, these lipids showed only marginal inhibition of activity. It also induced a significant reduction in TNF-a, carrageenan-induced paw edema in rats (acute irritation IL-1, IL-2 and IL-6 and decreased IgG levels, indicating assay, which is the standard test for NSAIDs), indicating that GLM may regulate the immune system and promote that they do not mimic rapid-acting NSAIDs (8,13).
Macrides and others (7) found that the ETAs of GLM The active components possess a molecular weight had considerable anti-inflammatory activity. In vitro, the above 100 kDa and when a proteolytic enzyme was added extracted lipids have been shown to possess significant to the extract, it eliminated the component effective cyclo-oxygenase (COX) and lipoxygenase (LOX-5) inhi- against inflammatory cytokines, suggesting that at least bitory activity; hence, the GLM seems to be working on part of the active substance resides in the protein the same mechanisms as newer NSAIDs (8).
moiety associated with the glycogen, probably as a glycoprotein (26), as already had been suggested earlier significantly decreasing pain scale throughout the study (27). However, the component effective against COX (12) but obtained only close to significant differences compared to the placebo group (that in our opinion was indicating that there are different types of active quite unsuitable as a placebo, including both brewers’ components (26). It was suggested that GLM mediates yeast and dried fin-fish, which probably both would work T-(lymphocytes) helper cells Th1/Th2 regulation as it relates to inflammation and therefore plays an immuno- As far as side-effects from these products, they were modulatory role (26). The chondroitin sulfate and the neither severe nor related to any group. Carprofen and other GAGs of the GLM further work as building blocks other NSAIDs can potentially have severe side-effects in cartilage anabolism; glucosamine is one of their main such as hepatic disease (especially in Labradors), renal constituents. They help the joint capsule to hold water toxicosis and irritation of the gastrointestinal tract (1,2), and to adapt to changes in pressure, thereby absorbing whereas GLM is reported to have none (9,10,34). In fact, shock induced by abnormal join stress (28). The role of research suggests that GLM may have chondroprotective minerals and vitamins has not been studied, but it is properties due to its GAG, especially chondroitin sulfate, possible that they also contribute to the positive effects of content (35–37). In addition, GLM has a slower onset the GLM. As seen earlier, the GLM probably acts (34,38–41) but a longer effect (23). The preliminary through several different working mechanisms.
human study by Gibson et al. (23) indicated that Three studies exist on stabilized GLM as a treatment the beneficial effects of GLM treatment, could last for for canine OA and our findings are consistent with two 2–3 weeks after cessation of therapy, if given at least for of them. Bierer and Bui (11) conducted three 6-week, 2 months. Our follow-up evaluation was at W12, 4 weeks randomized, double-blinded trials, in which they com- after discontinuation of the trial, and the beneficial pared three different GLM dog feeds with control feeds.
effects were still evident as could be seen e.g. by a smaller They used a total arthritic score by summing eight intake of extra carprofen in the GLM group compared to variables. As in our study, all individual variables showed no significant improvement, although a significant change Carprofen, by contrast, rapidly triggers the clinical was observed in the total arthritis score in favor of all response, but this vanishes quickly upon discontinuing three GLM test groups. In our study, a different set of the drug, which also was documented in our study where variables was used. The veterinarians evaluated only a third of owners in the carprofen group were using extra mobility and not range of motion, crepitus, etc., as we carprofen at follow up, compared to none at the end of had noted that owner compliance was much higher if the treatment period. The placebo group seemed to react provocations that hurt the dogs were not used.
in accordance with the seasonal disease pattern of our Two force plate measurements were chosen as objective geographical region, although the means changed only variables. Force plate has been used in similar studies slightly and the CI were large, making an exact inter- to evaluate treatments of hip (22,29–31) and elbow pretation difficult: they started showing more signs of (22,31,32) joints. The best variables for these conditionswere considered to be PVF and vertical impulse, both pain when the weather changed (42,43) to a humid, of which were included here. The change from baseline raw cold (our placebo group became worse between W0 to end of treatment in vertical impulse and PVF in our to W8) (Fig. 1) and later in the spring when the weather study was in the same range as in previous studies (30) turned warm and dry (W8 to W12) the dogs were better but the range was larger. Furthermore, we used three owner-assessed variables: two VAS scores, one of them In future studies, to obtain an optimal effect from widely used in studies assessing human pain and a the GLM product, should reconsider some aspects of the chronic pain index that has been shown to correlate well treatment regime. As OA often is a clinically variable with chronic pain due to hip OA in dogs (20). In our disease, not having homogeneous groups is a major study two of these three owner-assessed variables showed drawback, and this likely influenced the results. However, significance between the GLM group and the placebo.
although the cohort of dogs was non-homogeneous, Thus, while our variables were different from the eight observed as a wide range even at the start of the trial, the variables of Bierer and Bui (11), also only three of our documented trend of improvement was clear and similar six variables showed a significant improvement between for all variables and may even have been more evident, if we had more dogs. The positive effects of the GLM 0 and W8 in the GLM group, compared to the placebo could eventually have been underestimated, rather than In the second dog trial, Dobenecker (33) used a overestimated: if a non-articular concurrent pain such as smaller dose of GLM [25% of what was used by Bierer spondylosis or secondary muscle pain, etc. was present, and Bui (11) and of our initial dose] and found no there would have been a positive analgesic effect for these statistical improvement in the GLM dogs, compared to also in the NSAID carprofen group, while the GLM the placebo group. The third canine trial showed a might have helped primarily in arthritic disorders (9–12).
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Received March 20, 2007; accepted July 12, 2007

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