J. vet. Pharmacol. Therap. 39, 1--15. doi: 10.1111/jvp.12251.

REVIEW ARTICLE

Review of dietary supplements for the management of osteoarthritis in

dogs in studies from 2004 to 2014
F. COMBLAIN*
S. SERISIER

N. BARTHELEMY
M. BALLIGAND &
Y. HENROTIN*

*Bone and Cartilage Research Unit, Institute

of Pathology, Arthrop^ole Liege, University of
Liege, Liege, Belgium; Royal Canin
Research Center, Aimargues, France;

Department of Clinical Sciences, Faculty of

Veterinary Medicine, University of Liege,
Liege, Belgium; Department of Physical
Therapy and Rehabilitation, Princess Paola
Hospital, Vivalia, MarcheenFamenne,
Belgium

Comblain, F., Serisier, S., Barthelemy, N., Balligand, M., Henrotin, Y. Review of
dietary supplements for the management of osteoarthritis in dogs in studies
from 2004 to 2014. J. vet. Pharmacol. Therap. 39, 115.
Osteoarthritis (OA) is a chronic, painful, degenerative and inflammatory
disease that affects the synovial joints and leads finally to the loss of mobility.
It is highly prevalent in dogs. Nowadays, no cure exists, and the
pharmacological treatment is limited to clinical signs alleviation. Some
positive beneficial effects have been highlighted with dietary supplements in
the course of dog OA. The goals of this narrative review are to summarize
the scientific data available in the literature on dietary supplements assessed
in dog OA and to discuss some trails about how to improve several aspects of
research and issues with dietary supplements, such as bioavailability and
dosage regimen. Chondroitin sulphate, glucosamine, undenaturated type II
collagen, avocadosoya bean unsaponifiables, curcumin and polyunsaturated
fatty acids were studied in dog OA and therefore discussed in the present
review. Most of them showed anticatabolic and anti-inflammatory effects.
Unfortunately, few data exist concerning their pharmacokinetics. Their
bioavailability is low, but new formulations are developed to enhance their
gastrointestinal absorption. The clinical relevance of these new formulations
compared to native forms should be demonstrated in good clinical trials.
Even if further investigations are needed, dietary supplements should be
considered in OA management.
(Paper received 25 March 2014; revised 16 April 2015; accepted for
publication 21 June 2015)
Fanny Comblain, Bone and Cartilage Research Unit, Pathology Institute, B23, +5,
Avenue de lH^opital, 3 CHU Sart Tilman, 4000 Liege, Belgium. E-mail: fcomblain
@ulg.ac.be

INTRODUCTION
Osteoarthritis (OA) is a chronic, painful, degenerative and
inflammatory disease that affects the synovial joints. It is
highly prevalent in dogs (Paster et al., 2005; Smith et al.,
2006) with 20 % of the canine population over 1 year old presenting various degrees of OA (Aragon et al., 2007; Moreau
et al., 2011). This musculoskeletal disease is related to chronic
pain, lameness, functional disability and reduced quality of life,
leading finally to the loss of joint function and mobility (Henrotin et al., 2005). The management of OA in dogs is a lifetime
commitment, involving a multimodal approach. The main recommendation is to control clinical signs by reducing pain,
improving mobility and hence quality of life, while protecting
joints from OA (Aragon et al., 2007).
To decrease pain and inflammation associated with OA, nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly
prescribed (Henrotin et al., 2005). They act by inhibiting
2015 John Wiley & Sons Ltd

cyclo-oxygenase (COX) and thus reducing the concentration of

pro-inflammatory prostaglandins (PGE). Unfortunately, the use
of NSAIDs may be associated with detrimental effects, especially gastrointestinal adverse effects. Steroid injection in dogs
is usually reserved for severe end-stage OA and for cases that
have become refractory to other treatments (Henrotin et al.,
2005). Besides pain relief, preventing cartilage degradation is
an important objective for treatment. This requires the longterm use of safe modalities, while the absence of any cure reinforces the importance of prevention (Innes et al., 2003). Such
prevention and alternative solutions could come from nutrition
and more particularly from dietary supplements.
Even if it is sometimes used in the literature, the term
nutraceutical (which comes from the combination of the words
nutrition and pharmaceutical) is not recognized by the US
Food and Drug Administration, which uses instead the term
dietary supplement (Halsted, 2003). That is why we used the
term dietary supplement in this review. It was originally
1

2 F. Comblain et al.

defined as a food or food product, devoid of adverse effects, that

provides health benefits, including prevention of a disease onset
or progression (Kalra, 2003; Henrotin et al., 2011). Regulatory
differences between drugs and dietary supplements are large.
No official evidence of efficacy is necessary to market dietary
supplements and manufacturers do not have to conduct a
thorough regulatory process and expensive studies that are
mandatory to obtain official approval for selling drugs. Therefore, the market access is easier for dietary supplement than
for drug. Moreover, veterinary dietary supplements are not
subject to regulation.
Osteoarthritis has important clinical consequences on dogs.
Some positive beneficial effects have been highlighted with dietary supplements in the course of OA, such as anticatabolic and
anti-inflammatory properties (Henrotin et al., 2005, 2011;
Ameye & Chee, 2006). Nowadays, few reviews on the effects of
dietary supplements in dog OA have been published (Rychel,
2010; Perea, 2012; Vandeweerd et al., 2012). However, it is
important to better know the efficacy of dietary supplements
used in veterinary medicine. The goal of this present review
was also to discuss some trails about how to improve several
aspects of research and issues with dietary supplements, such
as bioavailability and dosage regimen.
The search was performed in PubMed/MEDLINE, The
Cochrane Library and CAB Abstracts databases between January 2004 and August 2014. The review focused in vivo studies evaluating the effects of dietary supplements on OA in dogs.
Only articles published in English have been taken into
account. In order to identify all studies and to confirm the
effectiveness of our search, published review focusing on controlled studies evaluating the efficacy of dietary supplements in
OA dogs (Vandeweerd et al., 2012) was consulted. In the current review, we also included uncontrolled studies and those
investigating induced OA. In addition, all types of outcome
measures (histological, biochemical, clinical) were eligible. Ten
papers, not eligible in the previous reviews, were identified
((Colitti et al., 2012; Gupta et al., 2012; Hielm-Bjorkman et al.,
2012; Rialland et al., 2013) (published after 2010) (Altinel
et al., 2007; Hansen et al., 2008; LeBlanc et al., 2008; Boileau
et al., 2009) (assessed histological or biochemical parameters)
(Reichling et al., 2004; Servet et al., 2006) (observational,
noncontrolled studies). Two other controlled studies, not
included in previous reviews, were found (Altilio et al., 2007;
Hielm-Bjorkman et al., 2009).

management. A study evaluating the oral absorption of glucosamine hydrochloride (G-HCl) and CS in beagle dogs gave
data concerning glucosamine absorption (Cmax = 8.95 lg/mL
and Tmax 1.5 h after 1500 mg dose). The extent of absorption
of CS, as indicated by the mean Cmax (21.5 lg/mL) and mean
AUC (187 lg/mL
h) of total disaccharides after 1600 mg dose,
provides evidence that CS is absorbed orally. The mean
bioavailability of G-HCl was approximately 12% and that of CS
ranged from 4.8 to 5%, after single dosing (Adebowale et al.,
2002). However, we dont know how fast it is absorbed. Interestingly, the Cmax of total disaccharides is superior to the CS
concentration showing a biological activity in vitro. The Cmax
of G-HCl is inferior to the concentration showing a biological
activity in vitro (Henrotin & Lambert, 2013). An effective
approach to improve glucosamine intestinal absorption and
hence its bioavailability was described. Effects of chitosan on
oral bioavailability of glucosamine were evaluated in beagle
dogs. It was shown that chitosan could enhance the absorptive
transport and the bioavailability of glucosamine, in comparison
with its commercial products (Qian et al., 2013).
In dogs, CS, GS and G-HCl have been studied for their antiOA properties. Dogs administered per os with G-HCl and CS
significantly showed improvements in pain scores, compared to
dogs treated with carprofen (McCarthy et al., 2007). However,
G-HCl/CS pain relief was delayed compared to carprofen. In
this study, pain scores were subjectively assessed by veterinarians (McCarthy et al., 2007). In a study comparing the effects
of G-HCl/CS mixture and G-HCl/CS mixture supplemented with
glycosylated undenaturated type II collagen (UC-II), both treatment significantly alleviated pain compared to placebo (Altilio
et al., 2007). Further, overall dog activity was better in dogs
receiving G-HCl/CS mixture plus UC-II than in those receiving
G-HCl/CS mixture alone. Overall activity was assessed using a
questionnaire, and pain was assessed by detailed observation
and by ground force plate. Following withdrawal of these supplements, all dogs experienced a relapse of pain (Altilio et al.,
2007; Gupta et al., 2012). These results contrasted with those
of Moreau et al. published in 2003 (Moreau et al., 2003),
showing no significant effect of G-HCl/CS mixture on the
ground reaction forces and on assessments by orthopaedic surgeons and by owners. No adverse effect had been detected
(Moreau et al., 2003; Altilio et al., 2007; Gupta et al., 2012).

UNDENATURATED TYPE II COLLAGEN

CHONDROITIN SULPHATE AND GLUCOSAMINE
Chondroitin sulphate (CS) and glucosamine sulphate (GS) are
aminosaccharides that act as a preferred substrate for the
biosynthesis of glycosaminoglycans (GAG) chains, and subsequently for the production of aggrecan. They also exert anti-inflammatory and anticatabolic effects through the inhibition of
nuclear factor jB (NF-jB) binding activity (Henrotin & Lambert, 2013). However, the oral bioavailability and pharmacokinetics of GS and CS play an important role in optimizing OA

Collagen hydrolysate is determined by the enzymatic hydrolysis

of collagenous tissues, like bone, for example, from animals,
and is generally recognized as a safe food ingredient by regulatory agencies (European Food Safety Authority, 2005; Schadow et al., 2013). The main characteristic of UC-II is its amino
acid composition, providing high levels of glycine and proline,
two amino acids essential for the stability and regeneration of
cartilage (Walrand et al., 2008).
It was shown that UC-II as dietary supplement reduced pain
(overall and upon limb manipulation), lameness and stiffness
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Use of dietary supplements in dog osteoarthritis 3

in dogs suffering from OA. UC-II also helped in improving

activity (Deparle et al., 2005; Peal et al., 2007; Beynen et al.,
2010). In all studies, UC-II effect was compared to a placebo.
One trial was double-blinded, which excluded any observer
bias (Beynen et al., 2010). In another trial, only dog owners
were blinded (Deparle et al., 2005). Reproducibility needs to be
demonstrated, but UC-II was reported to be safe and well tolerated in arthritic dogs.

AVOCADO SOYBEAN UNSAPONIFIABLES

Avocadosoybean unsaponifiables (ASU) are plant extracts
derived from unsaponifiable residues of avocado and soya bean
oils, commonly mixed at a ratio of one-third to two-thirds,
respectively (Gabay et al., 2008; Henrotin, 2008; Boileau et al.,
2009; Henrotin et al., 2011). ASU contain many compounds
including fat-soluble vitamins, sterols, triterpene alcohols and
possibly furan fatty acids. The major components of ASU are
the phytosterols b-sitosterol, campesterol and stigmasterol
(Lippiello et al., 2008). In vitro, ASU showed anticatabolic (inhibition of MMP-3 and MMP-13 expressions) and anti-inflammatory [inhibition of TNF-a, IL-1beta, COX-2, induced-nitric
oxide synthase (iNOS) and PGE2 synthesis] effects (Henrotin
et al., 1998, 2003; Au et al., 2007). ASU also increased aggrecan synthesis (Henrotin et al., 1998, 2003; Au et al., 2007;
Lippiello et al., 2008). These effects were mediated through the
inhibition of NF-jB translocation. The degradation of inhibitor
of jB (I-jB) was also abolished in the presence of ASU (Gabay
et al., 2008).
Few studies have evaluated the in vivo efficacy of ASU in
dogs. The first showed that sheepdogs who received ASU
(4 mg/kg) every 3 days or every day had an increase in TGFb1 and TGF-b2 levels in synovial fluid compared to dogs eating
a normal diet (Altinel et al., 2007). However, the beneficial
effects of this increase on articular cartilage were not known
(Altinel et al., 2007). A second study investigated the effects of
ASU treatment in an induced OA model (Boileau et al., 2009).
OA was induced in dogs by the anterior cruciate ligament
transection. The size and the severity of the macroscopic cartilage lesions, as well as the scores of histological parameters,
were decreased in dogs treated with 10 mg/kg per day of ASU.
MMP-13 (playing a predominant role in the degradation of collagen type II in OA cartilage) and iNOS productions were also
reduced in these dogs, compared to placebo. Finally, loss of
subchondral bone volume was reduced when dogs were treated
with ASU. This study presented some limitations like the short
duration of the study (8 weeks) and the prophylactic administration of ASU (Boileau et al., 2009). Moreover, it was an
experimentally induced model that may not duplicate the
natural course of OA. Even if both anti-inflammatory and
chondroprotective properties were described in dogs suffering
from mechanically induced OA, additional studies are needed
to support the effectiveness of ASU in canine OA. Besides,
unfortunately, there is a lack of data concerning concentrations of ASU components achieved in blood.
2015 John Wiley & Sons Ltd

CURCUMIN
Curcumin is the major component of turmeric, a yellow spice
derived from the roots of the plant Curcuma longa. Curcumin is
a polyphenol and it has long been used in traditional Chinese
and Ayurvedic medicine (Henrotin et al., 2010). In vitro, anticatabolic, anti-apoptotic and anti-inflammatory effects of curcumin have been largely described, on different cell culture
models. It was shown that curcumin decreased NO, PGE2, IL6, IL-8, COX-2, iNOS, MMP-3 and MMP-9 synthesis through
the inhibition of NF-jB translocation and TNF-a signalling
pathways in chondrocytes (Schulze-Tanzil et al., 2004; Mathy
et al., 2007; Shakibaei et al., 2007; Mathy-Hartert et al.,
2009). Curcumin also had capacity to increase type II collagen
synthesis (Shakibaei et al., 2007), but no effect on aggrecan
synthesis has been reported. A major concern met with natural
curcumin is the absence of information concerning its bioavailability in dog. In fact, natural curcumin is known for its very
low bioavailability. This point is crucial to envisage its administration by oral route. The challenge is to develop a curcumin
with an increased bioavailability. In this purpose, curcumin
has been dissolved in oil and then absorbed into chylomicrons,
with no modification of its structure (Henrotin et al., 2013).
Curcumin was also co-administered with piperine, an inhibitor
of hepatic and intestinal glucuronidation (Shoba et al., 1998).
Recently, a new curcumin formulation for human has been
proposed in which curcumin is entrapped in micro-emulsions
formed by turmeric essential oil and polysorbate 80, a high
hydrophiliclipophilic balance emulsifier (Henrotin et al.,
2013). However, polysorbate 80 can cause severe hypersensitive reactions in dogs, which are typical non-immune anaphylactic severe reactions (pseudoallergy) characterized by the
release of histamine and univaried IgE antibodies. These findings raise concerns with regard to its use in dogs (Qiu et al.,
2013). In order to better know the pharmacodynamics of curcumin, plasma concentrations of curcumin and its metabolite,
tetrahydrocurcumin (THC), were measured in Beagle dogs, following the intravenous infusion of liposomal curcumin (total
dose of 10 mg/kg infused over a period of either 2 or 8 h). Stabilizing curcumin with phosphoric acid was needed to allow
accurate quantitative determinations of curcuminoids in the
plasma. THC concentrations (2 h: AUC = 3796 ng/mL
h and
Cmax = 983 ng/mL; 8 h: AUC = 1171 ng/mL
h and Cmax =
293 ng/mL) were 6.3- to 9.6-fold higher than curcumin (2 h:
AUC = 394 ng/mL
h and Cmax = 319 ng/mL; 8 h: AUC =
187 ng/mL
h and Cmax = 66 ng/mL) during both infusion
rates. The plasma half-lives of both compounds following the
2-h infusion ranged from 0.4 to 0.7 h (Helson et al., 2012). Of
course, the use of intravenous curcumin for long-term treatment of OA by a pet owner is not practical and is not the subject of this review but this study helped to understand the
pharmacodynamics of curcumin. The concentration of curcumin measured in blood after intravenous infusion of liposomal curcumin in dog is below the concentration given
biological activities in in vitro study. Therefore, the interpreta-

4 F. Comblain et al.

tion of in vitro data to in vivo situation has to be performed

with caution.
In vivo, it was shown that, in white blood cells from 12 OA
dogs, gene expression involved in inflammatory response and
in connective tissue development and function decreased
more in dogs fed with curcumin than in dogs receiving
NSAIDs. Curcumin also inhibited macrophages proliferation
(Colitti et al., 2012). In this study, curcumin was administered
in phytosome, a complex of curcumin and phospholipids, to
enhance its bioavailability. These results contrasted with those
of Innes et al. published in 2003 (Innes et al., 2003) describing
no significant difference between dogs receiving placebo and
dogs receiving an extract of curcuma, in terms of the peak
vertical force of the affected limb.

POLYUNSATURATED FATTY ACIDS

Polyunsaturated fatty acids (PUFAs) are classified as omega-3,
omega-6 or omega-9 depending on the position of the last double bond along the fatty acid chain. In omega-3, the latter is
located between the third and fourth carbon atom from the
methyl end of the fatty acid chain. The main dietary PUFAs are
omega-3 [such as linolenic acid (ALA), docosahexaenoic acid
(DHA) and eicosapentaenoic acid (EPA)] and omega-6 (such as
linoleic acid and arachidonic acid). Omega-3 is mainly present
in fish oils, flaxseeds and walnuts, whereas omega-6 is found in
safflower, corn, soya bean and sunflower oils as well as in meat
fat. Omega-3 and omega-6 can then be metabolized by COXs
and lipoxygenases (LOXs) into distinct eicosanoids. The omega6-derived eicosanoids tend to be proinflammatory, whereas the
omega-3-derived eicosanoids tend to be anti-inflammatory (Darlington & Stone, 2001). Omega-3 PUFAs reduced aggrecanases,
MMPs and inflammatory cytokines expressions by bovine
chondrocytes stimulated by IL-1alpha (Zainal et al., 2009).
Moreover, in the presence of IL-1beta, omega-3 PUFAs inhibited
sGAG loss from bovine cartilage explants (Wann et al., 2010).
Several recent studies have evaluated the in vivo efficacy of
omega-3 in dogs. The use of carprofen was reduced in clientowned dogs with stable chronic OA when their food was
enriched during 12 weeks with fish oil omega-3 fatty acids.
However, it existed a bias in this clinical study because each
veterinarian used different criteria to assess the severity of OA
and therefore to determine whether the dosage of carprofen
could be modified (Fritsch et al., 2010b). In other researches,
the degree of lameness, the mean peak vertical force, the ability to rise from a resting position, the ability to walk and overall arthritic condition were significantly improved in OA dogs
that had received a diet with higher concentrations of omega-3
fatty acids compared to dogs that had received a more conventional diet (Fritsch et al., 2010a,b; Roush et al., 2010a,b). The
progression of arthritis, based on clinical signs and an owners
interview, was also limited in dogs that have received a diet
with omega-3 fatty acids, compared to placebo (Fritsch et al.,
2010a,b). However, in these studies, they used subjective
scores and no validated objective scoring systems. They also

noted relative insensitivity of the scales used. In another study,

OA dogs administered with fish oil (containing omega-3
PUFAs) during 16 weeks had a reduced consumption of
NSAIDs, a greater peak vertical force and a better quality of life
at the end of the study, compared with the baseline values.
However, there was no significant benefit on pain relief, compared to placebo (Hielm-Bjorkman et al., 2012). Other
researchers observed a reduction in inflammatory markers
plasma concentrations (arachidonic acid, IL-1, IL-6 and PGE2)
in dogs receiving diet with fish oil (containing omega-3 PUFAs)
compared to dogs receiving diet with low omega-3 PUFAs content (Hansen et al., 2008; LeBlanc et al., 2008). This could
explain the improvement in the quality of OA dogs life, which
is the main goal for OA treatments.
Perna Canaliculus is a lipid extract from New Zealand GLM
rich in omega-3 PUFAs, vitamins, amino acids and minerals
(Halpern, 2000; Bui & Bierer, 2003).
GLM has been extensively studied in trials including dogs
suffering from OA. In these dogs fed with GLM, mobility, movement and musculoskeletal scores were improved while pain
and swelling were reduced, in comparison with dogs receiving
a placebo diet (Pollard et al., 2006; Hielm-Bjorkman et al.,
2009). A part of the improvement in the placebo group may
be attributable to warmer weather conditions, at the end of the
study (Hielm-Bjorkman et al., 2009). Further, increased focus
by owners on their dogs, and sometimes, unblinding of the
owners and veterinarians, could have influenced the data (Pollard et al., 2006). Therefore, the conclusions of these studies
should be considered with caution. In an observational, noncontrolled study, the total arthritic score was better for dogs
fed with GLM, compared to baseline (Servet et al., 2006). A
double-blinded, longitudinally controlled study showed that a
GLM-enriched balanced diet improved significantly peak vertical force, pain evaluated by the owners and motor activity
(Rialland et al., 2013). No sign of toxicity was detected (Pollard
et al., 2006). A systematic review on GLM in the management
of human OA has also demonstrated that adverse effects were
minor and transient (Brien et al., 2008). GLM could act, as
omega-3 PUFAs, by inhibiting membrane arachidonic acid
metabolism by blocking the LOX and COX pathways, thus
decreasing PGE2 and leukotriene synthesis and down-regulating the inflammatory sequence (Brien et al., 2008). The inconvenience of this product is that GLM has a strong taste.
However, the above-mentioned studies demonstrated that dogs
accepted eating capsules or kibbles with GLM incorporated in
and that they had positive effects on OA dogs.

MISCELLANEOUS
In addition to these compounds described in previous paragraphs, other compounds have also been tested in vivo in dog.
Even if they are less discussed in the literature, we thought
important to quote these dietary supplements.
Dietary beta-1,3/1,6-glucans, derived from bakers yeast
(Saccharomyces cerevisiae), showed beneficial effects on the
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 2015 John Wiley & Sons Ltd

Altilio et al. (2007)

Glucosamine/chondroitin sulphate
Gupta et al. (2012)

Reference

G-HCl/CS/UC-II

Glucosamine hydrochloride
(G-HCl)/chondroitin
sulphate (CS)/glycosylated
undenaturated type
II collagen (UC-II)

Product

4 groups: placebo, 10 mg UC-II,

2000 mg G-HCl + 1600 mg
CS, 10 mg UC-II + 2000 mg
G-HCl + 1600 mg CS daily
120 days

4 groups: placebo, 10 mg UC-II,

2000 mg G-HCl + 1600 mg
CS, 10 mg UC-II + 2000 mg
G-HCl + 1600 mg CS daily
150 days

Dose and duration

Table 1. Summary of in vivo dog effects of nutritional compounds on osteoarthritis

Client-owned
dogs with OA
N = 20

Client-owned
dogs with OA
N = 4 groups
from 7 to 10

Model

Clinical effects
Placebo: no change
UC-II: significant
reduction in
pain by day 30, maximum
reduction in pain on day 120,
compared to baseline
G-HCl + CS: alleviated some pain
UC-II + G-HCl + CS: overall
activity significantly better than
the G-HCl + CS group, significant
reductions in overall pain,
pain upon
limb manipulation and
exercise-associated lameness

(continued)

Clinical effects
Placebo: no change
UC-II: significant
reduction in pain by
day 60, maximum
reduction in pain on day 150;
significant increase in peak
vertical force and impulse area
on day 90, compared with baseline
G-HCl + CS:
significant reduction in pain by day 120,
maximum reduction
in pain on day 150, compared
with baseline
UC-II + G-HCl + CS: significant
reduction in pain
by day 120, maximum
reduction in pain on day 150, compared
with baseline

Results

Use of dietary supplements in dog osteoarthritis 5

Peal et al. (2007)

Collagen
Beynen et al. (2010)

McCarthy et al. (2007)

Reference

Table 1. (continued)

UC-II and/or (-)-hydroxycitric

acid (HCA-SX) and/or
ChromeMate (CM)

Gelatin hydrolysate

G-HCl/CS

Product

5 groups: placebo, 10 mg
UC-II, 1800 mg HCA-SX,
1800 mg HCA-SX + 100 lg CM,
1800 mg HCA-SX + 100 lg
CM + 10 mg UC-II daily
120 days

2 groups: placebo
or 10 g daily
8 weeks

2 groups:
G-HCl/CS
1 g twice daily (dogs 519.9 kg)
1.5 g twice daily (dogs 2040 kg)
2 g twice daily (dogs > 40 kg)
for 42 days and then the daily
dose was reduced by
one-third for the subsequent
28 days
or carprofen
(positive control)
70 days

Dose and duration

Client-owned
dogs with OA
N = 25

Client-owned
dogs with OA
N = 30

Client-owned
dogs with OA
of hips or elbow
N = 35

Model

(continued)

Clinical effects
Placebo: no change
UC-II: reduction in overall pain by
day 30, reduction in pain upon
limb manipulation by
day 60, reduction in
pain after physical exertion by day 60,
compared to baseline
HCA-SX: no change
HCA-SX + CM: reduction
in overall pain by day 90, reduction in
pain after physical exertion by
day 90, compared to baseline
HCA-SX + CM + UC-II: reduction
in overall pain by day 60, reduction
in pain upon limb
manipulation by day 90, reduction
in pain after physical exertion
by day 90, compared to
baseline

Clinical effects
Gelatin hydrolysate: improved
activity (vitality), reduced stiffness,
reduced lameness compared to
placebo; no reduction in
swelling, paralysis, pain and
body condition
compared to placebo

Clinical effects
G-HCl/CS: improvements in
scores for pain, weight-bearing and
severity of the condition by day 70,
compared to baseline
Lameness and joint
mobility scores were not
significantly
better than baseline
Carprofen: improvements
in scores
for pain, weight-bearing,
severity of the condition, lameness
and joint mobility, compared
to baseline

Results

6 F. Comblain et al.

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 2015 John Wiley & Sons Ltd

Avocado/soya bean unsaponifiables

Boileau et al. (2009)

Deparle et al. (2005)

Reference

Table 1. (continued)

Avocado/soya bean
unsaponifiables (ASU)

UC-II

Product

2 groups: placebo or
10 mg/kg daily
8 weeks

3 groups: placebo, 1 mg
daily, 10 mg daily
90 days

Dose and duration

Experimental knee
dog model
(anterior cruciate
ligament
transection)
N = 16

Client-owned obese
dogs with OA
N = 15

Model

(continued)

Disease-modifying effects
ASU: decrease in the size of the
macroscopic lesions (tibial plateaus),
decrease in the severity of cartilage
lesions (tibial plateaus and
femoral condyles), decrease in
the scores of all histological
parameters (structural changes,
cellularity, Safranin-O
staining and pannus
invasion on the femoral
condyles), reduction of
iNOS and MMP-13 production
in cartilage, reduction in the total
histological changes and cellular
infiltration in synovium, reduction
in loss of subchondral bone volume
and calcified cartilage thickness,
compared to placebo
No difference on the tibial plateaus
for Safranin-O and pannus invasion

Clinical effects
Placebo: no change
1 mg UC-II: reduction in overall
pain, reduction in pain during
limb manipulation, reduction
in lameness after physical exertion on day 90,
compared to baseline
Increased physical activity level
on day 90, compared to baseline
10 mg UC-II: reduction in
overall pain, reduction in pain
during limb manipulation,
reduction in lameness after
physical exertion on day 90,
compared to baseline
Increased physical activity level
on day 90, compared to baseline

Results

Use of dietary supplements in dog osteoarthritis 7

Curcumin

ASU

Product

Fritsch et al. (2010a)

Fish oil

Fish oil [docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)]

Hielm-Bjorkman
Fish oil
et al. (2012)

Curcumin
Colitti et al. (2012)

Altinel et al. (2007)

Reference

Table 1. (continued)

3 groups: commercially therapeutic

diet (placebo), experimental
diet with 2-fold higher EPA + DHA
concentrations, experimental
diet with 3-fold higher
EPA + DHA concentrations
90 days

2 groups:
Corn oil (placebo): 1.7
mg  0.09 (SD)
omega-3 fatty acids
(predominantly a-linolenic acid),
Fish oil: 110.25 mg  5.75 (SD)
omega-3 fatty acids (predominantly
EPA and DHA) or
16 weeks

3 groups: dogs with OA receiving

4 mg/kg twice a day, dogs with
OA receiving NSAIDs,
healthy dogs
20 days

3 groups: placebo or 300 mg

(approximately 4 mg/kg)
every day (high dose)
or every 3 days (low dose)
3 months

Dose and duration

Client-owned dogs with

stable chronic OA of the
hip or stifle
N = 177

Client-owned dogs
with OA
N = 71

12 dogs with OA
(6 received
curcumin = tested
group
and 6 received
NSAID = positive
control) and 6
healthy dogs
(negative control)
from a kennel
N = 18

Male outbred
sheepdogs
N = 24

Model

(continued)

Clinical effects
Placebo: no change
2-fold higher EPA + DHA: no change
3-fold higher EPA + DHA: improvement
for lameness, weight
bearing, overall arthritic
condition and progression of
arthritis, compared
to baseline

Clinical effects
Placebo: between the baseline and
the end of trial, improvement of Helsinki
Chronic Pain Index and deterioration
according to veterinary assessment
Fish oil: between the baseline and
the end of trial, improvement
of peak vertical force, Helsinki Chronic
Pain Index, the use of NSAIDs and
quality of life

Disease-modifying effects
Genes expression involved in
inflammatory response and in
connective tissue
development and function
decreased more in
curcumin group than in NSAID group
Curcumin targets I-jB upregulation
and IL-18 downregulation
Curcumin inhibits macrophages
proliferation

Disease-modifying effects
Placebo: no change
300 mg every 3 days: increase
in both TGF-b1
and TGF-b2 levels in knee joint fluid,
compared to placebo
300 mg every day: increase in both TGF-b1
and TGF-b2 levels in knee
joint fluid,
compared to placebo

Results

8 F. Comblain et al.

2015 John Wiley & Sons Ltd

Fish oil

Fish oil with high

concentrations of
n-3 fatty acids

Fish oil with high

concentrations of
n-3 fatty acids
Low n-6/n-3

Fish oil

Fish oil
Ratio n-6/n-3 = 3.4

Roush et al. (2010a)

Roush et al. (2010b)

Hansen et al. (2008)

LeBlanc et al. (2008)

Product

Fritsch et al. (2010b)

Reference

Table 1. (continued)

2015 John Wiley & Sons Ltd

3 groups: diet with sunflower oil
(control), diet with fish oil
(5 dogs), diet with fish
oil + a-tocopherol
acetate (five dogs)
75 g EPA/kg diet
2.2 g DHA/kg diet
12 weeks

2 groups: 90 mg EPA+DHA/kg daily

or 4,5 mg EPA+DHA/kg daily
63 days (1 week prior to
surgery and 56 days postsurgery)

2 groups: commercially
typical diet (placebo)
or diet with 31-fold increase
in the total omega-3 fatty acids
24 weeks

2 groups: commercially typical diet

(placebo) or diet containing
3.5% fish oil omega-3 fatty acids
90 days

2 groups: control diet with low

omega-3 fatty acids content
or diet supplement with
fish oil omega-3 fatty acids
12 weeks

Dose and duration

Young healthy dogs

N = 15

Spontaneously knee
dog model
(acute cranial cruciate
ligament injury)
N = 24

Client-owned dogs
with OA
N = 127

Client-owned dogs
with OA
N = 38

Client-owned
dogs with
stable chronic OA
N = 131

Model

(continued)

Disease-modifying effects
Fish oil: reduction in the rising
of the serum concentrations of
IL-1, IL-6 and
PGE2, compared to dogs
receiving sunflower oil
Serum concentration of TNF-a and
platelet-activating factor increased
significantly after lipopolysaccharides
injection in all groups and did
not differ significantly
among groups

Disease-modifying effects
90 mg EPA+DHA/kg: reduction in the plasma
total arachidonic acid concentration
No differences in MMP
expression or activity in the
surgical joint
synovial fluid at any time throughout
the study

Disease-modifying effects
Fish oil: higher serum concentration
of total omega-3 fatty acids, lower serum
concentration of arachidonic acid,
compared to placebo
Clinical effects
Fish oil: significant improvement
of the ability to rise from a resting position,
ability to play, ability to walk,
compared to placebo

Clinical effects
Placebo: no change
Fish oil: improvement of
peak vertical force, improvement in lameness
and weight-bearing, compared to baseline

Clinical effects
Fish oil: reduction significantly
faster in carprofen use and dosage,
compared to control

Results

Use of dietary supplements in dog osteoarthritis 9

GLM (Perna
Canaliculus)

Servet et al. (2006)

Beta-1,3/1,6-glucans

GLM (Perna
Canaliculus)

Pollard et al. (2006)

Miscellaneous
Beynen et al. (2010)

GLM (Perna
Canaliculus)

Green-lipped Mussel
(GLM) (Perna
Canaliculus)

Product

Hielm-Bjorkman
et al. 2009

Green-lipped Mussel
Rialland et al. (2013)

Reference

Table 1. (continued)

2 groups: placebo or 800 ppm

beta-1,3/1,6-glucans daily
8 weeks

1 group: 0,3% of the finished feed

compared to baseline
45 days

2 groups: placebo diet or

125 mg GLM/tablet
375 mg daily (dogs 515 kg)
625 mg daily (dogs 1620 kg)
750 mg daily (dogs 2125 kg)
1000 mg daily (dogs 2645 kg)
1125 mg daily (dogs 4656 days

2 groups: placebo diet or

2049 mg/kg daily, depending on the
body weight of the dog, for 10 days,
and then, half of the loading dose for
the rest of the study
8 weeks

1 group: balanced control

diet (30 days)
and then commercially diet
enriched with GLM (60 days)
90 days

Dose and duration

Client-owned dogs
with OA
N = 46

Client-owned dogs
with OA
N = 85

Client-owned dogs
diagnosed
with degenerative
joint
disease
N = 81

Client-owned dogs
with chronic
pain and a radiographic
diagnosis of OA
N = 45

Client-owned dogs
with OA
N = 23

Model

(continued)

Clinical effects
Placebo: reduced stiffness
Beta-1,3/1,6-glucans: improved
activity (vitality), reduced stiffness, reduced
lameness and reduced pain,
compared with baseline
No statistically significant differences
between the 2 groups but greater
numerical improvement for the
beta-1,3/1,6-glucans group

Clinical effects
Reduction in mobility impairments,
compared to baseline
Reduction in a score including pain,
swelling, crepitus and reduction in range
of movement, compared to baseline
Reduction in the total arthritic score,
compared to baseline

Clinical effects
Placebo: improved clinical signs on day 28
GLM: improved clinical signs on day
28, a higher proportion of dogs had improved
clinical signs on day 56, compared
to placebo, better musculoskeletal
scores, compared to placebo
No signs of toxicity

Clinical effects
GLM: improved mobility, according to
veterinary assessment, compared to placebo
Reduction in pain, according to owner
assessment, compared to placebo

Disease-modifying effects
Increase in concentrations of plasma
omega-3 fatty acids on day 90,
compared to day 30
Clinical effects
Improvement of peak vertical force on
day 90, compared to day 30

Results

10 F. Comblain et al.

2015 John Wiley & Sons Ltd

Clinical effects
Reduction in severity compared to baseline
Resolution in typical
clinical signs such
as intermittent lameness,
local pain and stiff gait compared to baseline
Reduction in the effects of external factors that
aggravate lameness such as
lameness when moving, lameness
after a long rest compared to baseline
Client-owned dogs
with OA
N = 24
1 group: 4 mg/kg daily
6 weeks
Natural resin extract
of Boswellia serrata
Reichling et al. (2004)

Reference

Table 1. (continued)

Product

Dose and duration

Model

Results

Use of dietary supplements in dog osteoarthritis 11

2015 John Wiley & Sons Ltd

clinical signs of dogs suffering from OA. A double-blinded, placebo-controlled trial allowed to indicate improved activity and
reduced stiffness, lameness and pain in privately owned dogs
having received beta-1,3/1,6-glucans for 8 weeks, compared
with the baseline values. However, the differences between the
placebo and the treatment group did not reach statistical
significance (Beynen & Legerstee, 2010).
Boswellia resin is a natural resin extract of Boswellia serrata.
An open multicentre veterinary clinical trial included dogs
with manifestations of chronic joint and spinal disease. It
showed that Boswellia resin administered for a period of
6 weeks helped to reduce lameness (when moving or after a
long rest), local pain and stiff gait, compared with baseline
(Reichling et al., 2004). Nevertheless, because of the open
nature of the study and the absence of a placebo group, the
observed effect cannot be taken as evidence for a beneficial
impact of Boswellia resin.

DISCUSSION
We have gathered here all the in vivo dog studies, published
since 2004, about some dietary supplements. A summary is
available in Table 1. We have limited our research to compounds that have already been tested in dogs. Some results
seem to be really promising and encouraging. However, several
concerns remain, especially the low number of studies, the
small sample size and the robustness of statistical analysis. The
small sample size may be due to the fact that, in some studies,
researchers resort to induced OA in animal for ethical reasons.
An alternative is to operate on animals owners with OA, but,
in that case, the challenge is to convince pet owners to seriously participate in the study. A greater number of animals
could enhance the robustness of statistical analysis. There is a
need of additional serious and well-designed studies to conclude
about the safety and efficacy of such compounds. Before starting each study, a statistical analysis must be carried out to precisely know the number of animals needed, according to the
outcome measures. It is generally accepted to consider a power
of 80%, an uncertainty of 0.05% and an effect size of 10%.
Another major concern with dietary supplements is the
absence of information concerning their bioavailability. New
formulations are needed. For example, the bioavailability of
polyphenols can be modified by the addition of glycosyl groups,
by encapsulation in micro-emulsions or by decreasing their
metabolization. A good example is curcumin that shows an
increased bioavailability after bio-optimization with turmeric
essential oil and polysorbate 80 (Henrotin et al., 2013). The
clinical relevance of these new formulations compared to native
forms should be demonstrated in good clinical trials. Indeed, for
most compounds, potencies demonstrated in preclinical studies
are not concordant with their clinical efficacy. This requires
determining gold standard to evaluate clinical and structural
efficacy of treatments. The development of guidelines for the
management of clinical trials in dog OA would be helpful.
Safety and toxicity of dietary supplements should be addressed,

12 F. Comblain et al.

especially if bioavailability is increased. Pharmacokinetics of

compounds should be described and safety monitoring should
be done. Additional studies should also assess the potential of
dietary supplements in a long-term use and should be interested
in their structure-modifying effect which is the great challenge
in seeking new OA treatment. For this purpose, soluble
biomarkers investigating joint tissues metabolism could be helpful for monitoring the efficacy of an intervention. Recently, we
have demonstrated that Coll2-1, a biomarker of cartilage degradation, was positively and highly significantly correlated with
the severity of macroscopic and histological lesions of cartilage
in dog with OA induced by section of the anterior cruciate ligament. On the other hand, Coll2-1NO2 concentrations were
found to be significantly correlated with the size of the osteophytes (Henrotin et al., 2012). These results showed that these
biomarkers clearly reflect key events that happened in the knee
joint during the development of OA in animal model. These
findings suggest that they could be helpful to monitor OA progression in dog and to evaluate the effects of dietary supplements on cartilage metabolism.
Another concern is the dosage regimen. In general, the
choice of the dose is rather empiric than based on pharmacokinetic and efficacy outcomes. The doses used in vitro are most
of the time higher that the ones used in clinical trials. This
contributes to explain the contradictory existing in the literature about the clinical efficacy of dietary supplements. This
point can be illustrated by comparing the results determined in
studies investigating the effects of GLM-enriched diet. One
study reported no effect on clinical signs improvement assessed
by owners and by veterinarians (Dobenecker et al., 2002),
while the others showed significant effects of GLM on mobility,
movement, musculoskeletal scores, pain, swelling and total
arthritic score, assessed by owners and by veterinarians
(Pollard et al., 2006; Servet et al., 2006; Hielm-Bjorkman et al.,
2009; Rialland et al., 2013). The difference could be attributed
to the dose administered, which was lower in the study showing no effect. Concerning G-HCl and CS, a study showed that
their mean bioavailabilities were approximately 12% and 5%,
respectively (Adebowale et al., 2002). From a clinical point of
view, this means that if we want to reach a plasma concentration with biological activities, we have to orally administer 10
times the quantity for G-HCl and 20 times for CS. Doses needed
can also vary according to the stage of the disease. It is therefore difficult to standardize the doses. But it could be facilitated
if future studies described pharmacokinetics of compounds in
different contexts (early or later stages of OA).
Dietary supplements have no treatment claim but could be
good candidates as they combine several advantages. Firstly,
OA is a chronic disease and products with minor adverse
effects are needed for long-term administration. Dietary supplements could provide long-term rather than short-term effects
as long as they are regularly and conscientiously administered.
Their minor adverse effects allow their administration early, as
soon as the appearance of the first OA signs. Their good safety
also explains that these compounds are added in pet food, to
prevent OA in elderly dogs. Secondly, as highlighted in this

review, dietary supplements have the capacity to provide anticatabolic, anti-inflammatory and anabolic effects and then
could protect joints. This protection includes not only cartilage,
but also synovium and subchondral bone, on which some dietary supplements can also act. Thirdly, dietary supplements
could be added in dog kibbles during the production process. It
means that dog owners would not have to administer inconvenient pills to their dogs but they would simply have to feed
their dogs normally with kibbles enriched with some dietary
supplements. The ease of use is very attractive.

CONCLUSION
In conclusion, the pharmacological management of OA in dogs
remains dominated by NSAIDs but these may cause adverse
side effects, even if some dogs can accept them during all their
lifetime. Further, they have no disease-modifying effect, and
then, they cannot positively interfere with the degradation of
cartilage. Dietary supplements are increasingly studied and
open new and large horizons for the management of chronic
musculoskeletal diseases such as OA in dogs. Firstly, they offer
anti-inflammatory and chondroprotective effects. However, the
mechanism of action of some products is often speculative and
their efficacy not always supported by rigorous scientific studies (Ameye & Chee, 2006; Henrotin et al., 2011). Secondly,
dietary supplements administration is associated with only
minor adverse effects, suggesting that they could be administrated for a long term in subjects with comorbidities. However,
the majority of the existing studies suffered of limitations and
bias. Clinical studies with dogs suffering from OA are
requested. There is a need for serious and well-designed in vivo
animal studies that could bring relevant data and answer most
of the questions related to the safety and efficacy of such
compounds. So, dietary supplements could provide an alternative means of preventing and managing the natural OA
process in the dog, and, above all, they offer interesting
research potential.

ACKNOWLEDGMENTS
The authors would like to thank Christelle Boileau for her
assistance with this manuscript preparation.

CONFLICT OF INTEREST
Samuel Serisier is employed by Royal Canin. FC receives her
PhD fellow from Royal Canin SAS.

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