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Advance Access Publication 29 October 2007 eCAM 2009;6(3)365–373
doi:10.1093/ecam/nem136
Original Article
Evaluating Complementary Therapies for Canine Osteoarthritis
Part I: Green-lipped Mussel (Perna canaliculus)
Anna Hielm-Bjo
¨rkman
1
, Riitta-Mari Tulamo
1
, Hanna Salonen
2
and Marja Raekallio
1
1
Faculty of Veterinary Medicine, Department of Equine and Small Animal Medicine, University of Helsinki,
PO Box 57, Fi-00014, Finland and
2
Huhtakoukku 16, 02340, Espoo, Finland
A green-lipped mussel (GLM) preparation was evaluated in a randomized, double-controlled
and 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 osteoarthritis
that were randomly allocated into one of three groups completed the study. All dogs were fed
the test products or placebo for 8 weeks. The dogs were evaluated four times, at 4-week
intervals. Six different variables were assessed: veterinary-assessed mobility index, two
force plate variables, owner-evaluated chronic pain index and pain as well as locomotion
visual 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 changed
to dichotomous variables, there were more dogs in the GLM than in the placebo group
that improved, according to veterinary-assessed mobility, owner-evaluated chronic pain index
and pain VAS (P= 0.031, P= 0.025, P= 0.011, respectively). For the same three, the
odds ratio and their confidence interval were over one. The extent of improvement was
significantly 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 orthopedic
pain 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 cannot
be used.
Keywords: Controlled – dog – LyproflexÕ– nutraceutical – OA – placebo
Introduction
Over the last few years, there has been a growing interest
in new treatment options for osteoarthritis (OA), both
for humans and pets, especially dogs. The so-called
nutraceuticals have become available, since some patients
cannot tolerate or do not want to take the risk of non-
steroidal anti-inflammatory drugs (NSAIDs) because of
their side-effects (1,2). Nutraceuticals have been described
as naturally occurring, biologically effective nutritional
supplements that can confer some degree of health
benefit and there is a whole new science referred to as
‘bioprospecting’(3) that explores and introduces these
new herbs—or animal molecules or products. Currently,
several nutraceuticals on the market are claiming to
relieve arthritic symptoms. These products generally
fall mainly into two distinct product groups, including
glucosamine and chondroitin sulfate combinations
or polyunsaturated fatty acids (PUFAs), particularly
Omega-3 series PUFAs, such as those derived
from marine sources. One of the nutraceuticals
that may benefit OA is a product based on Perna
canaliculus, or the green-lipped mussel (GLM) that
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,
Finland. Tel: +358-400885255; Fax: +358-9-19157298;
E-mail: anna.hielm-bjorkman@helsinki.fi
ß2007 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/
licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original workis
properly cited.
has been thoroughly examined by Halpern (4) [see
also (5)].
The early GLM-based products were often produced
from rejected mussel meat from human food processing,
which typically included steam processing as part of
the manufacturing process and the early trials using
these unstable GLMs, showed poor results. In the 1980s,
a method of temperature-controlled cold processing
and stabilization of GLM by adding organic acids
to prevent oxidation and freeze-drying was patented
(6). After 1986, this new stabilized GLM has been in
use and is documented to be efficacious in treating
experimental arthritis in rats (7,8), clinical arthritis
in humans (9,10) and more recently also in dogs (11,12).
The GLM product used in this study, which originates
from mussel farms in the Pacific Ocean, has been
harvested when the mussels are 12 to 18-months old,
and is stabilized, freeze-dried at 40C and packed
immediately thereafter. The GLM product is a rich
source of nutrients, including glycosaminoglycans
(GAGs), such as chondroitin sulfates, vitamins, minerals
and Omega-3 series PUFAs. It is not totally clear how
the products function (13) [this is not totally clear for
NSAIDs either (14,15)], despite substantial research.
Although there has been only a few studies published
on the use of stabilized GLM on dogs, it is already
available for dogs with OA, as a powder, as capsules or
incorporated into pebbles.
The aim of this study was to evaluate a GLM
product as an OA nutraceutical for dogs in a random-
ized, double-controlled and double-blinded trial.
We expected the positive control carprofen to signifi-
cantly reduce pain and locomotion difficulties, and
the negative control (placebo) to have no such effect.
The effect of the nutraceutical was hypothesized to lie
somewhere between those of the positive and negative.
Objective, semi-objective and subjective variables were
used for assessment. Since the GLM is also used in
humans, the treatment outcome is of interest for many
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
complementary therapies for their disease (16).
Methods
Dogs
Inclusion criteria were that dogs had clinical signs and a
radiographic diagnosis of OA, in either a hip joint or an
elbow joint. The owner had to have described at least two
of the following signs as being frequent: difficulty in lying
down and/or in getting up from a lying position,
difficulty in jumping or refusing to jump, difficulty in
walking up or down stairs, or definite lameness. Dogs
were excluded from the study if they had had prior
surgery of the evaluated joint, inadequate clinical
symptoms, systemic or infectious disease, neurological
deficits, lameness from articular infection, or recent
trauma.
Sixty-eight dogs were chosen based on 124 telephone
interviews with owners. Of these, 51 dogs will be
presented here and the remaining 17 constituted a
treatment group for another study (17). Six dogs
(two in each group) were excluded from the study at
some point for the following reasons: having had a
previous operation of the affected hip joint, having
a transverse vertebra (n= 2), sustaining a cruciate
ligament injury (n= 2) and diagnosed with degenerative
myelopathy. There were 15 dogs in each group that
finished the study: 12 dogs with canine hip dysplasia
(CHD) and three dogs with elbow OA in each group, all
confirmed by radiographs. Twenty-five dogs were male
and 20 were female. The median age was 6 years
(range 1–11) and the median body weight (BW) was
34 kg (range 18–56). There were both uni- and bi-laterally
affected dogs. All dogs had either moderate or severe
radiological changes in the worst-affected hip or elbow
joint (18).
Owners were asked not to give the dogs NSAIDs or
corticosteroids for at least 30 days and no Na-pentosan
polysulfate (CarthrophenÕ, Biopharm Pty. Ltd.,
Australia) for at least 90 days prior to the study.
However, this proved not to be always the case, as
some owners felt that their dogs were in such pain that
they therefore gave them NSAIDs. The use of the
additional analgesic pre-trial was, however, recorded in
the questionnaire.
Test Products
The product tested in this study was the GLM
(LyproflexÕ500 mg; ICENI, OMNI nutraceuticals,
Cambridgeshire/Biofarm Oy, Finland). The capsules
contain 46–52% protein, 5.9–9.3% fat, 8.0–21.5%
carbohydrates, 3.9–5.8% moisture, 14–25% ash,
>12 mg eicosatetraenoic acid (ETA)/100 g, > 500 mg
eicosapentaenoic acid (EPA)/100 g and >400 mg docosa-
hexaenoic acid (DHA)/100 g. The initial dose was
4 (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 of
the study. This meant an initial dose of 20–49 mg/kg/day
depending on the BW of the dog.
Two control groups were included: the established
positive control carprofen (RimadylÕ50 mg; Pfizer,
Helsinki, Finland) at a dose of 2 mg/kg twice a day and
a negative control that received all products as placebos.
Carprofen was a white pill without the usual stamp
and its placebo an identical lactose tablet, GLM was
366 Green-lipped mussel for canine osteoarthritis
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
placebo for another study (17). The products were coded
and organized by a research assistant who was not
involved in the study thereafter.
For ethical reasons, all owners were also given a
package of 50 mg carprofen in normal packaging and
with the normal stamp on the tablet, at the start of the
trial. This could be used as additional pain relief (dose of
one tablet for a dog of 20–30 kg BW, two tablets for a
dog of 31–40 kg and three tablets for a dog of 41–60 kg)
if they felt the dog was in considerable pain. The number
of additional carprofen doses used was recorded in the
questionnaire.
Study Protocol
The study was designed as a randomized double-
controlled, double-blinded clinical trial using the
CONSORT guidelines (19). A secretary made the first
appointments, and at this first visit (W
0
), the dogs were
assigned into groups, in order of arrival using a
computer-generated random list. Only the location of
the diseased (hip or elbow OA) was stratified for in the
randomization. Initial clinical, orthopedic and neurologi-
cal examinations were performed and diagnostic criteria
included decreased range of motion and pain on
stretching the hip or flexing the elbow. Radiographs
were taken of the dogs’ hips and/or elbows and other
joints if needed. The W
0
evaluation and W
0
questionnaire
was set as baseline, except for pre-trial analgesic
medication, where the assessment was made at W
4
,as
the owners were told not to use them anymore between
W
4
and W
0
. Follow-up visits with questionnaires for
reassessment were at 4, 8 and 12 weeks (W
4
,W
8
and
W
12
). The dogs were given the products orally for
8 weeks, from W
0
to W
8
.AtW
12
, the dogs had been
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)
and all technical assistants were blinded. Owners of
the dogs were required to sign informed consent forms.
The study protocol was approved by the Ethics
Committee of the University of Helsinki.
Veterinary Evaluation
Two veterinarians subjectively assessed three parameters
at W
0
,W
4
,W
8
and W
12
: locomotion, jumping and
walking stairs using 0–4 descriptive scales. The three
scores assigned by the two veterinarians were summed to
form a veterinary-assessed mobility index, with a possible
minimum score of 0 and a maximum of 24 (2 30–4).
Owner Assessment
Four weeks before the first visit (W
4
) and during each
following evaluation, owners answered a three-part
questionnaire. The first part used a descriptive scale of
0–4 and contained questions about attitude, behavior and
locomotion. Of these, 11 questions were combined to
form a combined owner-assessed chronic pain index, as
described previously (20). The second part contained two
10 cm visual analogue scales (VASs): one for pain and
the other for locomotion. The end of the lines to the
left represented no pain or no difficulties in locomotion,
and to the right, the worst possible pain or the most
severe difficulties in locomotion. The third part consisted
of questions about possible adverse reactions to treat-
ment, including change in appetite, vomiting, diarrhea
and atopic skin reactions. The question about additional
analgesics was not a continuous variable but used
the following scale: ‘during the last four weeks additional
carprofen was given 1 = not at all, 2 = 1–2 times,
3 = about once a week, 4 = about 3–5 times a week,
5 = daily/almost daily’.
Objective Evaluation of Gait
Gait was analyzed by force plate gait analysis
(Kistler forceplate, Type 9286, Kistler Instrumente AG
Winterhur, CH-8408, Switzerland), which assesses weight
bearing of limbs. The force plate was submerged into the
concrete floor so that the plate and floor surfaces were on
the same level. The floor was then covered with a 2 mm
thick rubber mat that extended from 7 m before to 7 m
after the plate, forming a 14 m walkway. A hole was cut
in the mat over the force plate and a 3–4 mm gap was
left between the force plate mat and the rest of the mat.
The signal from the plate was processed and stored using
a computer-based software program, and velocities
and acceleration were determined by three photoelectric
cells placed exactly 1 m apart and a start-interrupt
timer system (Aquire 6.0, Sharon Software Inc.,
DeWitt, MI, USA).
Dogs guided by their owners trotted over the walkway
from left to right. The speed was one comfortable
for each dog in trot and had to be in the same range
(0.5 m/s) for the dog each time the test was
performed (at W
0
,W
4
,W
8
and W
12
). The acceleration
was < 0.5 m/s/s and contact had to be made with the
plate first by the forelimb and shortly after with the hind
limb of the same side for the evaluation to be valid. The
test was repeated until sufficient valid results were
obtained for both left and right limbs.
Three valid measurements for each side and for each
visit were then chosen by a blinded assistant (one
not otherwise participating in the study) according to
speed, acceleration and with no interferences, such as
gait abnormalities or extra body movements. The mean
eCAM 2009;6(3) 367
of these three measurements was used for analysis.
The ground reaction forces were normalized for each
dog’s BW and mean peak vertical force (PVF) and mean
vertical impulse were used as variables. Only measure-
ments from the most severely affected leg at time
W
0
were used in the analysis.
Blood Samples
Blood samples were collected from the dogs at each visit.
Blood urea nitrogen (BUN), creatinine, serum alanine
aminotransferase (ALAT), alkaline phosphatase (AFOS),
total protein and albumin were analyzed.
Statistical Analysis
The number of dogs needed in each group was
calculated for a two-tailed test (Fisher). The sample size
(n= 15/group) was sufficiently large to detect a 47%
difference (11) in treatment outcome (effective versus not
effective) with a statistical power of 0.8 and allowing for
a5%a-error.
To counteract the effect of the extra NSAID on dogs
that at W
8
had used extra carprofen more than three
times per week, their W
8
values were changed into the
most negative value measured for any dog at that time.
This enabled us to use the whole data in the statistical
analyses.
For calculating the percentage of dogs/group
that improved between baseline and W
8
and the odds
ratio, the results of each variable were converted into
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
placebo was calculated using a chi-squared test. The odds
ratio was calculated using the common Mantel–Haenszel
odds ratio estimate and the confidence interval (CI) was
set to 95%. An odds ratio more than 1.0 indicated a
beneficial effect of the test treatments.
The changes from baseline to W
8
were also calculated
for each variable. The difference between the GLM and
placebo group was analyzed using the Mann–Whitney
test. The changes from W
0
to W
8
in the force plate
variables were proportional in the front and hind legs,
although the values were different. Therefore, force plate
data of all four legs were analyzed together. The dogs, for
which no force plate results could be registered, were
considered ‘not improved’ in the dichotomous evalua-
tions and excluded in the median analyses. A correlation
test was used to evaluate the association between
the assessments of the two veterinarians. Statistical
significance was set at P< 0.05. Statistical tests
were preformed using SPSS 12.0 for Windows (SPSS
Inc., Chicago, IL, USA).
Results
Baseline Values
Baseline variable median (range) values were: for the
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 no
statistical bias between the groups at baseline. The
evaluations of the two veterinarians correlated well
(R= 0.853, P< 0.01).
Dichotomous Responses
There were four dogs (all from the placebo group) that
had used extra carprofen more than three times per week
at W
8
. For three of the variables [veterinary-assessed
mobility index (P= 0.031), chronic pain index
(P= 0.028) and pain VAS (P= 0.011)] there were
significantly more improved dogs in the GLM group
compared to the placebo group (Table 1). The odds
ratio for the veterinary-assessed mobility index was 5.5
(95% CI 1.14–26.41) indicating that a dog that had
received the GLM product was 5.5 times more likely to
have a positive response compared to a dog that had
received the placebo. The odds ratio for the force plate
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
locomotion VAS 4.12 (95% CI 0.88–19.27).
Medians of the Change from W
0
to W
8
All variables showed a similar trend of improvement,
with carprofen being the most efficient, placebo the
least and GLM being between these two (Table 1). There
was a significant difference between the GLM and the
placebo in two variables [veterinary-assessed mobility
index (P= 0.012) and pain VAS (P= 0.004)] and a
third variable was close to significant [locomotion VAS
(P= 0.057)].
Extra Carprofen
At W
4
, before the owners were requested to stop all
medication, 14% of the carprofen group, 13% of the
GLM group and 8% of the placebo group were given
NSAIDs once a week or more. At W
8
, (Fig. 1) 0, 7 and
27% of the respective groups were given additional
carprofen once a week or more. At follow-up (W
12
),
the respective numbers were 33, 14 and 29%. The
differences between both GLM and carprofen compared
to the placebo group at time W
8
were significant
(P= 0.021 and P= 0.008, respectively).
368 Green-lipped mussel for canine osteoarthritis
Complications and Side-effects
Three dogs (one in the GLM group, two in the placebo
group) were so lame during the visits that no usable data
were obtained from the force plate. Two of these dogs
(one in the GLM group, one in the placebo group) were
euthanized between W
8
and W
12
due to severe pain.
In populations, neither our findings of clinical side-
effects nor clinical chemistry in any of the blood
parameters were severe or related to any particular
group. Palatability was never a concern.
Discussion
In our study, dogs showed a beneficial clinical response
to treating OA-induced pain and locomotion difficulties
with GLM. More dogs improved in the GLM group
compared to the placebo group and the extent of
treatment effects was between that of our two control
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 same
studies showed improvement in only 23–38% of the
cases (21, 22). As these numbers are close to the results
we obtained in our study for the two control groups
(Table 1), they indicate that our cohort reflects reality
well and that we can trust the results of our treatment
group. The fact that extra carprofen was used signifi-
cantly more often in the placebo group at W
8
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
outcomes were not good and often contradictory (23,24).
Twenty years later, possibly after having stabilized the
product by freeze-drying and lyophilizing, the results of
clinical trials for GLM have been significantly promising
Table 1. Percentage of improved dogs and median (range) of improvement for evaluated variables, per group from W
0
to W
8
Carprofen (n= 15) GLM (n= 15) Placebo (n= 15)
Improved
P=
Improvement
Median (range), P=
Improved
P=
Improvement
Median (range), P=
Improved Improvement
Median (range)
Veterinary mobility index 66.7% 3 (0–8) 66.7% 1 (3 to 7) 26.7% 3(14 to 3)
0.031 0.001 0.031 0.012
Force plate PVF 66.7% 3.2 (8.2 to 11.8) 46.7% 0.17 (5.6 to 12) 26.7% 0.9 (33.6 to 10)
0.031 0.079 0.264 0.201 n=14 n=13
Force plate Impulse 80.0% 0.4 (0.5 to 1.3) 53.3% 0.20 (1 to 1.54) 33.3% 0.0 (3.3 to 0.8)
0.011 0.009 0.277 0.123 n=14 n=13
Chronic pain index 80.0% 9 (9 to 19) 80.0% 2 (2 to 6) 40.0% 3(25 to 8)
0.028 <0.001 0.028 0.102
Pain VAS 85.7% 1.4 (6 to 8.4) 66.7% 0.6 (3.3 to 3.3) 20.0% 1.7 (7 to 3.2)
0.001 <0.001 0.011 0.004
Locomotion VAS 85.7% 3.1(1.9 to 6.2) 60.0% 0.2 (3.8 to 3.5) 26.7% 1(6.6 to 5)
0.002 0.001 0.070 0.057
For each treatment group: First column: Percentage of dogs in the group that improved. Below: P= Difference in percentage of improved between
treatment groups and placebo. Second column: Median (with range) of change from W
0
to W
8
[(+), improvement; (), deterioration] in evaluated
variables for the carprofen-, GLM- and placebo-groups. P= Difference in improvement between treatment groups and placebo (the force plate
values do not include three dogs for whom no results were obtained). n, number of patients per group; GLM, green-lipped mussel; PVF, peak
vertical force; VAS, visual analogue scale.
carprofen GLM placebo
0
3
6
9
12
15
n of dogs per group
Additional
carprofen given
at week 8
.
Not at all
1-2 x / 4 weeks
about 1 x / week
3-5 x / week
daily / almost daily
Figure 1. At the end of the treatment period (W
8
), there was 4/15 dogs
in the placebo group given extra carprofen 3–7 days/week (n= number
of dogs).
eCAM 2009;6(3) 369
(9–12). The lyophilizing process might have been the
more important as in fact, the difference in lipid, sterol or
fatty acid composition of frozen and freeze-dried GLM
has been shown to be non-existent; the only major
difference was between total lipid composition on a dry
weight basis because of the removal of water in the deep-
frozen product (25). The potent anti-inflammatory
activity of GLM powder was confirmed in vivo using
the established rat paw oedema model; rats fed mussel
lipids perorally developed neither adjuvant-induced poly-
arthritis nor collagen-induced auto-allergic arthritis (8).
However, these lipids showed only marginal inhibition of
carrageenan-induced paw edema in rats (acute irritation
assay, which is the standard test for NSAIDs), indicating
that they do not mimic rapid-acting NSAIDs (8,13).
Macrides and others (7) found that the ETAs of GLM
had considerable anti-inflammatory activity. In vitro, the
extracted lipids have been shown to possess significant
cyclo-oxygenase (COX) and lipoxygenase (LOX-5) inhi-
bitory activity; hence, the GLM seems to be working on
the same mechanisms as newer NSAIDs (8).
This dual inhibition of both LOX- and COX metabolic
pathways may offer an explanation for the reported
clinical efficacy and favorable gastrointestinal tolerability
of GLM. Platelet aggregation remains unaltered and the
lipid fraction be non-gastrotoxic in fasted disease-stressed
arthritic rats at a dose of 300 mg/kg (treatment dose
20 mg/kg) (8,13). This shows that the GLM does not have
the negative side-effects of the NSAIDs. Recently, new
GLM extracts were tested (26) and a Tween-20 extract
(that draws out membrane-bound proteins by a cationic
detergent) effectively inhibits both COX-1 and COX-2
activity. It also induced a significant reduction in TNF-a,
IL-1, IL-2 and IL-6 and decreased IgG levels, indicating
that GLM may regulate the immune system and promote
humoral and cellular activity (26).
The active components possess a molecular weight
above 100 kDa and when a proteolytic enzyme was added
to the extract, it eliminated the component effective
against inflammatory cytokines, suggesting that at least
part of the active substance resides in the protein
moiety associated with the glycogen, probably as a
Cell damage
Release of pro-inflammatory
cytokines (IL-1,-2,-6, TNF-α…)
Arachnidonic acid
Cyclooxygenase
(COX-1, COX-2…)
Lipoxygenase
(LOX-5)
Prostaglandines Leukotrienes
GLM: Omega-3 PUFAs
-Eicosatetraenoic acids (ETA)
-Docosahexaenoic acid (DHA)
inhibit…
Glycosaminoglycans (GAG)
-Chondroitin sulphate
-Heparan sulphate
-Keratan sulphate
Vi tam ins : B
6
, C, E
Minerals: Cu, Zn, Mn, S
GLM induces
reduction in…
T-cell
B-cell
GLM: Chondroprotective GLM: Anti-inflammatory
help…
Induce
secretion of…
GLM: Decrease IgG levels
Mediate Th1/Th2 regulation
Release of phospholipids
from cell membranes
Figure 2. Main active constituents of the green lipped mussel and their effect on the inflammation pathways of osteoarthritis. The main active
constituents, according to how we understand their working mechanisms now: The Omega-3 PUFAs (especially the ETAs) have anti-inflammatory
activity; they possess significant cyclo-oxygenase (COX 1 and 2) and lipoxygenase (LOX-5) inhibitory activity. Due to their glycosaminoglycan
content (especially chondroitin sulphate with its high glucosamine content), the GLM may have chondroprotective properties. The vitamins and
minerals are needed in cartilage anabolism. GLM, green-lipped mussel; Th, T helper cell; IL, interleukin; TNF, tumor necrosis factor.
370 Green-lipped mussel for canine osteoarthritis
glycoprotein (26), as already had been suggested earlier
(27). However, the component effective against COX
enzymes was resistant to this induced proteolysis,
indicating that there are different types of active
components (26). It was suggested that GLM mediates
T-(lymphocytes) helper cells Th1/Th2 regulation as it
relates to inflammation and therefore plays an immuno-
modulatory role (26). The chondroitin sulfate and the
other GAGs of the GLM further work as building blocks
in cartilage anabolism; glucosamine is one of their main
constituents. They help the joint capsule to hold water
and to adapt to changes in pressure, thereby absorbing
shock induced by abnormal join stress (28). The role of
minerals and vitamins has not been studied, but it is
possible that they also contribute to the positive effects of
the GLM. As seen earlier, the GLM probably acts
through several different working mechanisms.
Three studies exist on stabilized GLM as a treatment
for canine OA and our findings are consistent with two
of them. Bierer and Bui (11) conducted three 6-week,
randomized, double-blinded trials, in which they com-
pared three different GLM dog feeds with control feeds.
They used a total arthritic score by summing eight
variables. As in our study, all individual variables showed
no significant improvement, although a significant change
was observed in the total arthritis score in favor of all
three GLM test groups. In our study, a different set of
variables was used. The veterinarians evaluated only
mobility and not range of motion, crepitus, etc., as we
had noted that owner compliance was much higher if
provocations that hurt the dogs were not used.
Two force plate measurements were chosen as objective
variables. Force plate has been used in similar studies
to evaluate treatments of hip (22,29–31) and elbow
(22,31,32) joints. The best variables for these conditions
were considered to be PVF and vertical impulse, both
of which were included here. The change from baseline
to end of treatment in vertical impulse and PVF in our
study was in the same range as in previous studies (30)
but the range was larger. Furthermore, we used three
owner-assessed variables: two VAS scores, one of them
widely used in studies assessing human pain and a
chronic pain index that has been shown to correlate well
with chronic pain due to hip OA in dogs (20). In our
study two of these three owner-assessed variables showed
significance between the GLM group and the placebo.
Thus, while our variables were different from the eight
variables of Bierer and Bui (11), also only three of our
six variables showed a significant improvement between
W
0
and W
8
in the GLM group, compared to the placebo
group.
In the second dog trial, Dobenecker (33) used a
smaller dose of GLM [25% of what was used by Bierer
and Bui (11) and of our initial dose] and found no
statistical improvement in the GLM dogs, compared to
the placebo group. The third canine trial showed a
significantly decreasing pain scale throughout the study
(12) but obtained only close to significant differences
compared to the placebo group (that in our opinion was
quite unsuitable as a placebo, including both brewers’
yeast and dried fin-fish, which probably both would work
positively in OA).
As far as side-effects from these products, they were
neither severe nor related to any group. Carprofen and
other NSAIDs can potentially have severe side-effects
such as hepatic disease (especially in Labradors), renal
toxicosis and irritation of the gastrointestinal tract (1,2),
whereas GLM is reported to have none (9,10,34). In fact,
research suggests that GLM may have chondroprotective
properties due to its GAG, especially chondroitin sulfate,
content (35–37). In addition, GLM has a slower onset
(34,38–41) but a longer effect (23). The preliminary
human study by Gibson et al. (23) indicated that
the beneficial effects of GLM treatment, could last for
2–3 weeks after cessation of therapy, if given at least for
2 months. Our follow-up evaluation was at W
12
, 4 weeks
after discontinuation of the trial, and the beneficial
effects were still evident as could be seen e.g. by a smaller
intake of extra carprofen in the GLM group compared to
the two other groups.
Carprofen, by contrast, rapidly triggers the clinical
response, but this vanishes quickly upon discontinuing
the drug, which also was documented in our study where
a third of owners in the carprofen group were using extra
carprofen at follow up, compared to none at the end of
the treatment period. The placebo group seemed to react
in accordance with the seasonal disease pattern of our
geographical region, although the means changed only
slightly and the CI were large, making an exact inter-
pretation difficult: they started showing more signs of
pain when the weather changed (42,43) to a humid,
raw cold (our placebo group became worse between W
0
to W
8
) (Fig. 1) and later in the spring when the weather
turned warm and dry (W
8
to W
12
) the dogs were better
again.
In future studies, to obtain an optimal effect from
the GLM product, should reconsider some aspects of the
treatment regime. As OA often is a clinically variable
disease, not having homogeneous groups is a major
drawback, and this likely influenced the results. However,
although the cohort of dogs was non-homogeneous,
observed as a wide range even at the start of the trial, the
documented trend of improvement was clear and similar
for all variables and may even have been more evident,
if we had more dogs. The positive effects of the GLM
could eventually have been underestimated, rather than
overestimated: if a non-articular concurrent pain such as
spondylosis or secondary muscle pain, etc. was present,
there would have been a positive analgesic effect for these
also in the NSAID carprofen group, while the GLM
might have helped primarily in arthritic disorders (9–12).
eCAM 2009;6(3) 371
The choice of patients and the treatment time might also
have an impact on the results.
Radiographically, all dogs in our study had moderate
or severe OA. Although the radiological data does not
correlate well with the true clinical picture, at least not
in dog hip joint (20), these dogs might have been too
seriously affected to benefit optimally from the product.
In one of the older human studies, severity of the disease
was shown to have an impact on treatment outcome;
mild and moderate knee OA responded very well to
GLM treatment, whereas patients with severe knee OA
did not benefit from treatment (34). Also, our 2-month
study period might have been too short, as some earlier
human studies have been unable to show a significant
improvement compared to controls until patients had
ingested fatty acid products for 3–6 months (34,38–41).
In conclusion, our results suggest that the modern
stabilized and freeze-dried GLM is more effective than
the placebo in treating chronic pain due to moderate
to severe OA and that it has no side-effects. For dogs
that can not use NSAIDs or corticosteroids and for
patients who need analgesic support over extended
periods of time, oral GLM may be an acceptable
alternative for treating chronic arthritis pain, although
it does not alleviate pain as well as carprofen. As dogs
are used as models for human OA, we hope these
promising results will stimulate new human research in
this area.
Acknowledgements
Funding was provided by Finnish Foundation of
Veterinary Research, Helvi Knuuttila Foundation.
The authors are grateful for grants received from the
Finnish Kennel Club, Pfizer Finland, Boeringer
Ingelheim Germany, Vetcare Finland and Heel
Germany, which financed the acquisition of a force
plate that made objective analyses possible. Further,
we would like to thank Pfizer Finland and ICENI
England for contributing the products and their
placebos used in the different treatment groups in this
study, without cost. We also wish to thank our two
anonymous reviewers, Ms Patty Willis and the Editor for
their valuable comments.
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Received March 20, 2007; accepted July 12, 2007
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