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A multicenter study of the effect of dietary supplementation with fish oil omega-3 fatty acids on carprofen dosage in dogs with osteoarthritis

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Abstract

To determine the effects of feeding a diet supplemented with fish oil omega-3 fatty acids on carprofen dosage in dogs with osteoarthritis. Randomized, controlled, multisite clinical trial. 131 client-owned dogs with stable chronic osteoarthritis examined at 33 privately owned veterinary hospitals in the United States. In all dogs, the dosage of carprofen was standardized over a 3-week period to approximately 4.4 mg/kg/d (2 mg/lb/d), PO. Dogs were then randomly assigned to receive a food supplemented with fish oil omega-3 fatty acids or a control food with low omega-3 fatty acid content, and 3, 6, 9, and 12 weeks later, investigators made decisions regarding increasing or decreasing the carprofen dosage on the basis of investigator assessments of 5 clinical signs and owner assessments of 15 signs. Linear regression analysis indicated that over the 12-week study period, carprofen dosage decreased significantly faster among dogs fed the supplemented diet than among dogs fed the control diet. The distribution of changes in carprofen dosage for dogs in the control group was significantly different from the distribution of changes in carprofen dosage for dogs in the test group. Results suggested that in dogs with chronic osteoarthritis receiving carprofen because of signs of pain, feeding a diet supplemented with fish oil omega-3 fatty acids may allow for a reduction in carprofen dosage.
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Human clinical studies1–6 and a recent meta-analysis7
have found that dietary supplementation with
fish oil and fish oil–derived fatty acids (in particular
omega-3 fatty acids) provides benefits for patients
with rheumatoid arthritis. Although the pathophysi-
ology of rheumatoid arthritis in humans differs from
the pathophysiology of OA in dogs, both conditions
have an inflammatory aspect that could be sensitive
to omega-3 fatty acids.8 In 2 recent studies,9,10 the ef-
fects of dietary supplementation with fish oil omega-3
fatty acids in dogs with OA found that feeding a diet
containing 3.4% to 3.5% omega-3 fatty acids improved
some clinical outcomes and weight bearing. In clini-
cal practice, many dogs with OA are treated long term
with NSAIDs such as carprofen,11 and neither of the
aforementioned studies9,10 examined whether dietary
supplementation with omega-3 fatty acids would allow
a decrease in NSAID dosage. The purpose of the study
reported here, therefore, was to determine the effects
of feeding a diet supplemented with fish oil omega-3
fatty acids on carprofen dosage in dogs with OA.
A multicenter study of the effect of dietary
supplementation with fish oil omega-3 fatty acids
on carprofen dosage in dogs with osteoarthritis
Dale A. Fritsch, ms; Timothy A. Allen, dvm, dacvim; Chadwick E. Dodd, dvm; Dennis E. Jewell, phd;
Kristin A. Sixby, dvm; Phillip S. Leventhal, phd; John Brejda, phd; Kevin A. Hahn, dvm, phd, dacvim
Objective—To determine the effects of feeding a diet supplemented with fish oil omega-3
fatty acids on carprofen dosage in dogs with osteoarthritis.
Design—Randomized, controlled, multisite clinical trial.
Animals—131 client-owned dogs with stable chronic osteoarthritis examined at 33 pri-
vately owned veterinary hospitals in the United States.
Procedures—In all dogs, the dosage of carprofen was standardized over a 3-week period to
approximately 4.4 mg/kg/d (2 mg/lb/d), PO. Dogs were then randomly assigned to receive
a food supplemented with fish oil omega-3 fatty acids or a control food with low omega-3
fatty acid content, and 3, 6, 9, and 12 weeks later, investigators made decisions regarding
increasing or decreasing the carprofen dosage on the basis of investigator assessments of
5 clinical signs and owner assessments of 15 signs.
Results—Linear regression analysis indicated that over the 12-week study period, carprofen
dosage decreased significantly faster among dogs fed the supplemented diet than among
dogs fed the control diet. The distribution of changes in carprofen dosage for dogs in the
control group was significantly different from the distribution of changes in carprofen dos-
age for dogs in the test group.
Conclusions and Clinical Relevance—Results suggested that in dogs with chronic
osteoarthritis receiving carprofen because of signs of pain, feeding a diet supplemented
with fish oil omega-3 fatty acids may allow for a reduction in carprofen dosage. (J Am Vet
Med Assoc 2010;236:535–539)
Materials and Methods
Study design and patient selection—The study
was designed as a randomized, controlled, multisite
clinical trial involving 33 privately owned veterinary
hospitals in the United States and was conducted be-
tween August 30, 2003, and May 21, 2004. All aspects of
the study were conducted in accordance with the Hill’s
Pet Nutrition Global Animal Welfare Policy, and the
study protocol was approved by the Hill’s Institutional
Animal Care and Use Committee and Animal Welfare
Committee. All participating owners provided written
consent prior to their dogs’ inclusion in the study.
Adult dogs with clinical signs and radiographic
changes consistent with OA involving the hip or stifle
joint that were currently receiving carprofen were con-
sidered candidates for the study. For dogs considered
for inclusion in the study, investigators were required
to obtain orthogonal radiographic views (eg, ventro-
dorsal and lateral radiographic views) and to verify the
diagnosis of OA on the basis of standard criteria.12 Dogs
were enrolled if they consumed primarily a dry canine
diet, were 1 year old, had a body condition score > 1
on a scale from 1 to 5 (1 = very thin, 2 = underweight,
3 = ideal, 4 = overweight, and 5 = obese), had radio-
From the Pet Nutrition Center, Hill’s Pet Nutrition Inc, PO Box 1658,
Topeka, KS 66601 (Fritsch, Allen, Dodd, Jewell, Sixby, Brejda,
Hahn); and 4Clinics, 8 rue de la Terrasse, 75017 Paris, France (Lev-
enthal). Dr. Allen’s present address is Dechra Pharmaceuticals, 7015
College Blvd, Ste 525, Overland Park, KS 66211.
Supported by Hill’s Pet Nutrition Inc.
Address correspondence to Dr. Hahn (Kevin_Hahn@hillspet.com).
Abbreviation
OA Osteoarthritis
536 Scientific Reports JAVMA, Vol 236, No. 5, March 1, 2010
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graphic evidence of OA involving a hip or stifle joint
with associated clinical signs of lameness (eg, altered
gait), were currently being treated with carprofen be-
cause of the OA, and were otherwise healthy, as deter-
mined on the basis of results of a physical examination,
CBC, serum biochemical panel, and urinalysis. Dogs
were excluded from the study if they were participating
in another clinical study or had participated in a clini-
cal study at Hill’s Pet Nutrition during the 6 months
prior to the start of the present study; had any acute
traumatic injuries or any conditions for which surgery
was indicated (eg, fractures or chronic malunion); were
receiving any medications for OA other than carpro-
fen; were receiving corticosteroids; had undergone ar-
throcentesis during the 30 days prior to the start of the
study; had received an intra-articular injection of any
material into any joint during the 90 days prior to the
start of the study or had undergone surgery on any joint
during the 180 days prior to the start of the study; had
any concurrent diseases involving the liver, kidneys, or
gastrointestinal tract or any systemic diseases, such as
lupus, borreliosis, hypothyroidism, or hyperadrenocor-
ticism, that may have complicated evaluation of ther-
apeutic responses; had a condition for which surgery
was anticipated or planned during the feeding period;
were pregnant or likely to become pregnant during the
study period; or had a history of fractious behavior.
Dogs were dismissed during the course of the study if
they developed any adverse reactions, incurred any in-
juries, or developed any illnesses warranting medical
or surgical treatment that prevented compliance with
the study protocol or required unmasking of the experi-
mental treatment; the investigator became unmasked;
the investigator determined that the dog was unable
to continue in the study because of signs of excessive
pain, other complications of OA, or concurrent medical
conditions; the dog owner did not comply with study
restrictions or withdrew the dog from the study; or the
dog was lost to follow-up, died, or was euthanatized.
Finally, dogs were removed from the analysis if it was
determined ex post facto that they did not meet eligibil-
ity criteria.
Study diets—Diets used in the study were the
same as those used in a previous study.10 The control
diet consisted of typical adult commercial drya and wetb
formulations. The test diets consisted of dry and wet
formulations of a therapeutic diet.c Total omega-3 fatty
acid contents of the control and test diets were approxi-
mately 0.1% and 3.5%, respectively.10 Control and test
diets met or exceeded Association of American Feed
Control Officials’ guidelines for complete and balanced
nutrition for maintenance of adult dogs.13
Study protocol—For dogs enrolled in the study,
the dosage of carprofend was standardized over a 3-
week period (week 3 to week 0) to approximately 4.4
mg/kg (2 mg/lb), PO, every 24 hours or 2.2 mg/kg (1
mg/lb), PO, every 12 hours. Dosing regimen was chosen
according to size of the dog, the investigator’s and own-
er’s preference, and the manufacturer’s dosage chart. At
week 0, dogs were randomly assigned to receive either
the test or control diet. Owners were given the option
of feeding their dogs the wet formulation only, the dry
formulation only, or a combination of the wet and dry
formulations. Owners and investigators were blinded to
diet group assignment. Owners were instructed to tran-
sition dogs to the new diet over 3 to 7 days by mixing
increasing amounts of the study diet with decreasing
amounts of the diet the dogs had been fed prior to en-
rollment in the study. Feeding guidelines were provided
to owners with the intent that dogs be fed according to
their usual feeding regimen (free choice or meal fed)
and to maintain body weight and condition. The feed-
ing period for each dog continued for 12 weeks from
the time of diet assignment (ie, from week 0 to week
12). Dogs were maintained in their owners’ households
during and following completion of the study.
For each dog, at weeks 3, 0, 3, 6, 9, and 12, the
investigator performed a clinical evaluation of the dog,
which included obtaining a complete medical history
(including drug history) and performing complete
physical and orthopedic examinations. A score rang-
ing from 1 to 6 (1 = none, 2 = mild, 3 = moderate, 4
= marked, 5 = severe, and 6 = unable to assess) was
assigned by the investigator to each of the following 5
items: overall arthritic condition, lameness, reluctance
to bear weight, reduction in range of motion, and signs
of pain on palpation of the affected joint. At the same
times, a urinalysis, CBC, and serum biochemical panel,
including measurement of serum fatty acids concentra-
tion, were performed. In addition, at weeks 3, 6, 9, and
12, the owner completed a questionnaire assessing the
change in severity of the following 15 signs, as related
to the dog’s arthritic condition: difficulty in rising from
rest, limping, stiffness, soreness when touched, lagging
behind during walks, vocalizing in pain, aggression,
difficulty in running, difficulty in walking, difficulty in
stair climbing, difficulty in jumping, difficulty in play-
ing, impaired mobility, lameness, and impaired overall
activity level. Potential scores ranged from 1 to 7 (1 =
dramatically improved, 2 = moderately improved, 3 =
slightly improved, 4 = no difference, 5 = slightly wors-
ened, 6 = moderately worsened, and 7 = dramatically
worsened). Investigator and owner questionnaires were
similar to those used in previous studies.9,10
Following the week 3, 6, 9, and 12 examinations,
the investigator made a decision about adjusting the
carprofen dosage, with the goal of maintaining the dog’s
condition. This decision was made on the basis of the
investigator’s and owner’s evaluations, although the in-
vestigator was free to adjust the dosage according to his
or her overall perception of the dog’s condition.
During the course of the study, all adverse events
were reported to the investigator, who recorded wheth-
er it was a new event, the severity of the event, whether
the event was related to the study diet or concomitant
medication, the nature of the event, and other relevant
details. For each dog, the same veterinarian performed
all clinical assessments.
Statistical analysis—A random sequence of test
and control diets was generated for 20 potential pa-
tients each at 40 potential clinics by means of standard
software.e The only restriction placed on the random-
ization scheme was that there had to be an equal num-
ber of test and control diets on the list for each clinic.
As a dog was enrolled in the study, it was assigned to
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the first available diet in the randomization sequence
for the designated clinic.
Sample size was calculated with standard softwaref
on the basis of an anticipated reduction in carprofen
dosage of 1.1 mg/kg (0.5 mg/lb) by the end of the study
for dogs receiving the test diet, SD of 1.0, α value of
0.05, and minimum power of 0.70. This calculation in-
dicated that a minimum of 50 dogs would be required
per treatment in the study. When a dismissal rate of
20% was factored in, it was decided to recruit 120 dogs
for the study.
Data for carprofen dosage from all time points were
analyzed by means of repeated-measures ANOVA.g The
33 clinics involved were considered a random effect,
and the model included random effect terms for clinic
and the clinic-by-treatment interaction. However, the
variance component associated with the clinic-by-treat-
ment interaction was 0; therefore, this factor was omit-
ted from subsequent analyses.14 To account for correla-
tion between repeated measures, 5 common covariance
models, including compound symmetry, first-order au-
toregressive, first-order antedependence, Toeplitz, and
an unstructured model, were considered. Comparison
of the Akaike information criteria for the 5 models indi-
cated that an unstructured covariance model provided
the best fit.15 The unstructured covariance model was
used to estimate separate variances for each time point
and separate covariances for each pair of time points.
The Kenward-Rogers procedure was used to adjust SEs
and test statistics for random effects and correlated er-
rors in the model.15 The time main effect and the diet-
by-time interaction effect were partitioned into linear,
quadratic, and higher-order trends by means of orthog-
onal polynomial contrasts.16 Separate linear regression
models were fit to the carprofen dosage data over time
for the test and control diets with standard software.h
Slopes for the 2 regression lines were then compared by
means of a t test.
Sensitivity analysis was performed with a multiple
imputation procedure to examine the effects of dis-
missed dogs.17 Missing data were assumed to follow
a monotone missing pattern, and the Markov-chain
Monte Carlo method18 was used to impute missing val-
ues. Each missing value was replaced 10 times to gener-
ate 10 complete data sets. Each complete data set was
analyzed with the same model used to analyze the in-
complete data set, and results obtained were combined
to provide the inferential test statistic.
The change in dosage for each dog was calculated
by subtracting the dog’s dosage at the end of the study
(week 12) from the dog’s dosage at the start of the study
(week 0). Changes in carprofen dosages were assigned
to 6 interval classes centered at –4.4, –3.3, –2.2, –1.1, 0,
and 1.1 mg/kg (–2.0, –1.5, –1.0, –0.5, 0, and 0.5 mg/lb,
respectively). Distributions of dogs among these inter-
val classes for the test and control diets were compared
by means of the Cochran-Mantel-Haenzel χ2 test. For all
analyses, a value of P < 0.05 was considered significant.
Results
Dogs—A total of 142 dogs were considered for in-
clusion in the study. Of these, 11 were excluded because
they did not meet the inclusion criteria or met 1 or
more exclusion criteria. Reasons for exclusion included
a concurrent medical condition (n = 6), noncompliance
(4), and a nontargeted form of arthritis (1).
The remaining 131 dogs were randomly assigned
to receive the control (n = 66) or test (65) diet. Thirty-
three clinics participated in the study, with 1 to 8 dogs
enrolled/clinic. Of the 131 enrolled dogs, 22 were dis-
missed during the course of the study, including 9 in
the control group and 13 in the test group. One dog in
the control group was dismissed because of a concur-
rent condition (dismissed on day 38), 2 were dismissed
because of lack of owner compliance (days 30 and 39),
Characteristic Control diet Test diet P value
Age at study enrollment (y) 8.9 0.4 (2 to 15) 8.8 0.5 (2 to 15) 0.85
Weight (kg)
Week 0 30.2 1.5 (3.6 to 50.3) 32.1 1.9 (3.6 to 65.8) 0.41
Week 12 30.6 1.5 (3.6 to 50.3) 32.4 1.9 (3.6 to 63.0) 0.45
Change 0.39 0.21 (3.6 to 5.0) 0.24 0.23 (3.2 to 5.0) 0.62
Body condition score
Week 0 3.54 0.09 (2 to 5) 3.56 0.10 (2 to 5) 0.91
Week 12 3.58 0.09 (2 to 5) 3.46 0.10 (2 to 5) 0.38
Change 0.04 0.08 (1 to 1) –0.10 0.06 (1 to 1) 0.19
Sex 0.40
Female 32 (56) 25 (48)
Male 25 (44) 27 (52)
Reproductive status 0.89
Sexually intact 4 (7) 4 (8)
Neutered 53 (93) 48 (92)
Primary affected joint at study enrollment 0.56
Stifle (single joint) 5 (9) 7 (13)
Stifle (multiple joints) 11 (19) 7 (13)
Hip (single joint) 15 (26) 18 (35)
Hip (multiple joints) 26 (46) 20 (38)
Data are given as mean SD (range) or as number of dogs (percentage).
Table 1—Characteristics of dogs with OA fed a diet supplemented with fish oil omega-3 fatty acids (n
= 52) or a control diet with standard omega-3 fatty acids content (57) in a study designed to assess the
effect of dietary supplementation with omega-3 fatty acids on carprofen dosage in dogs with OA.
538 Scientific Reports JAVMA, Vol 236, No. 5, March 1, 2010
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1 was euthanatized (day 79), 3 were dismissed because
of an adverse event (days 5, 31, and 37), 1 was dis-
missed because of poor food palatability (day 22), and
1 was dismissed because of deterioration in the arthritic
condition (day 66). Four dogs in the test group were
dismissed because of a concurrent condition (days 5,
13, 25, and 26), 4 were dismissed because of lack of
owner compliance (days 40, 45, 50, and 106), 2 were
euthanatized (days 19 and 97), 2 were dismissed be-
cause of poor food palatability (days 22 and 40), and 1
was dismissed because of deterioration in the arthritic
condition (day 40).
A total of 109 dogs completed the study, includ-
ing 57 in the control group and 52 in the test group.
There were no significant differences between groups in
regard to baseline (week 0) age, body weight, or body
condition score or in regard to distribution of involved
joint, sex distribution, or distribution of reproductive
status (Table 1). There was also no significant differ-
ence in veterinarian-assessed overall arthritic condition
between the groups at baseline.
Adjustments in carprofen dosage—For dogs that
completed the study, carprofen dosage at the time of
assignment to diet groups (ie, week 0) ranged from
2.19 to 6.42 mg/kg/d (0.99 to 2.91 mg/lb/d) for dogs in
the control group and from 3.15 to 6.80 mg/kg/d (1.43
to 3.09 mg/lb/d) for dogs in the test group (Table 2).
When carprofen dosage at week 12 was compared with
dosage at week 0, 35 of the 57 (61%) dogs in the control
group had no change in dosage, 3 (5%) had an increase
in dosage, and 19 (33%) had a decrease in dosage. By
contrast, 27 of the 52 (52%) dogs in the test group had
no change in dosage, 1 (2%) had an increase in dosage,
and 24 (46%) had a decrease in dosage.
Analysis of data for carprofen dosage revealed a sig-
nificant (P = 0.044) day-by-diet interaction, indicating
that the 2 diets had significantly different effects over the
course of the study that were attributable to a significant-
ly (P = 0.025) more rapid decrease in carprofen dosage
for dogs in the test group, compared with the decrease in
dosage for dogs in the control group (Figure 1). We did
not detect significant effects of prestudy dosage adjust-
ments, administration frequency (once vs twice daily),
time of carprofen administration, or body weight of the
dog at the beginning of the study on the difference be-
tween the control and test groups. Sensitivity analysis
involving data for the 22 dogs dismissed from the study
revealed a significant (P = 0.027) linear diet-by-time in-
teraction, indicating that inclusion of dogs dismissed
from the study would not have altered the finding of a
significant difference between the 2 groups.
The distribution of changes in carprofen dosage for
dogs in the control group was significantly (P = 0.049)
different from the distribution of changes in carprofen
dosage for dogs in the test group (Figure 2). Evalua-
tion of the distributions suggested that results were not
skewed by extreme values.
Discussion
Results of the present study suggested that in dogs
with chronic OA receiving carprofen because of signs of
pain, feeding a diet supplemented with fish oil omega-3
fatty acids may allow for a more rapid reduction in carpro-
Week Diet Mean SE Median Range
0 Control 4.17 0.09 4.16 2.19–6.42
Test 4.39 0.10 4.40 3.15–6.80
3 Control 4.16 0.12 4.22 2.01–6.13
Test 4.21 0.12 4.35 1.72–6.80
6 Control 3.74 0.14 3.85 1.87–6.13
Test 3.86 0.15 4.04 1.07–6.80
9 Control 3.63 0.16 3.89 0.94–6.13
Test 3.42 0.16 3.63 0.84–6.80
12 Control 3.58 0.16 3.85 0.94–6.16
Test 3.26 0.17 3.52 0.54–5.22
Dogs were examined every 3 weeks, and carprofen dosage was
adjusted by the attending veterinarian on the basis of veterinarian
and owner assessments of OA severity. During the 3 weeks prior to
week 0, carprofen dosage was adjusted in all dogs to approximately
4.4 mg/kg/d. To convert dosages in mg/kg/d to dosages in mg/lb/d,
divide by 2.2.
Table 2—Daily carprofen dosage (mg/kg/d) in dogs with OA fed a
diet supplemented with fish oil omega-3 fatty acids (n = 52) or a
control diet with standard omega-3 fatty acids content (57).
Figure 1—Mean daily carprofen dosage in dogs with OA fed a diet
supplemented with fish oil omega-3 fatty acids (n = 52) or a control diet
with standard omega-3 fatty acids content (57). Dogs were examined
every 3 weeks, and carprofen dosage was adjusted by the attending
veterinarian on the basis of veterinarian and owner assessments of OA
severity. Solid lines represent results of least squares linear regression
analysis. Slopes of the lines were significantly (P = 0.025) different.
Figure 2—Distribution of changes in carprofen dosage (ie, week 12
dosage minus week 0 dosage) for the dogs in Figure 1. Distribution
of changes in carprofen dosage was significantly (P = 0.049) differ-
ent between groups.
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SMALL ANIMALS/
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fen dosage, compared with feeding a control diet. Specifi-
cally, dogs in the test group had a significantly more rapid
decrease in carprofen dosage over the 12-week study pe-
riod, compared with the decrease in carprofen dosage for
dogs in the control group. In addition, the distribution of
changes in carprofen dosage between week 12 and week 0
differed significantly between the 2 groups.
The present study included a 3-week period prior to
assignment to diet groups during which carprofen dosage
in enrolled dogs was adjusted to a standard dosage. We
considered it possible that an increase in dosage during
this period, compared with the dosage prescribed by the
primary care veterinarian prior to study enrollment, could
have accounted in part for the reduction in carprofen dos-
age over time in the 2 groups. Although this may have
occurred, the statistical analysis indicated that changes in
dosage during this adjustment period did not affect the
relative difference between effects of the 2 diets. Reduc-
tions in carprofen dosage in both groups may also have
been attributable, in part, to a bias toward decreasing car-
profen dosage because of knowledge that dogs were par-
ticipating in a clinical study for which this was a goal.
Each investigator in the present study used his or
her own criteria to determine the severity of clinical
signs of OA and therefore to determine whether the
dosage of carprofen could be changed. This could have
resulted in heterogeneity among participating veteri-
nary clinics related to, for example, differences in skills
and training of the participating veterinarians, severity
of OA at participating clinics, the way the assessments
were done, or the standard of care. In fact, we found
that there were significant site-to-site variations in the
absolute dosage of carprofen; however, heterogeneity
among sites did not significantly affect the relative dif-
ference between effects of the 2 diets.
The reductions in carprofen dosage found in the pres-
ent study may help minimize the possibility of adverse
effects associated with long-term use. It is possible that
the supplemented diet enhanced the effect of carprofen
indirectly by, for example, altering drug bioavailability.
However, because the pharmacokinetics of carprofen are
not affected by food intake,19 alteration of the bioavailabil-
ity of carprofen was probably not the principal reason for
the effects of the supplemented diet in the present study.
Finally, results of the present study agree well with find-
ings of 2 previous studies,9,10 which showed that dietary
supplementation with fish oil omega-3 fatty acids can help
reduce the severity of OA, although further studies are
needed to assess the long-term effects of fish oil omega-3
fatty acids in the treatment of this disease.
a. Purina Dog Chow, Nestlé Purina PetCare Co, St Louis, Mo.
b. Pedigree Choice Cuts, Mars Petcare US, Brentwood, Tenn.
c. Prescription Diet j/d Canine, Hill’s Pet Nutrition Inc, Topeka, Kan.
d. Rimadyl, Pfizer Animal Health, New York, NY.
e. PROC PLAN, SAS, version 9.1.3, SAS Institute Inc, Cary, NC.
f. PROC POWER, SAS, version 9.1.3, SAS Institute Inc, Cary, NC.
g. PROC MIXED, SAS, version 9.1.3, SAS Institute Inc, Cary, NC.
h. PROC REG, SAS, version 9.1.3, SAS Institute Inc, Cary, NC.
References
1. Berbert AA, Kondo CR, Almendra CL, et al. Supplementation of
fish oil and olive oil in patients with rheumatoid arthritis. Nutri-
tion 2005;21:131–136.
2. Kremer JM. Effects of modulation of inflammatory and immune
parameters in patients with rheumatic and inflammatory dis-
ease receiving dietary supplementation of n-3 and n-6 fatty ac-
ids. Lipids 1996;31(suppl):S243–S247.
3. Kremer JM, Jubiz W, Michalek A, et al. Fish-oil fatty acid sup-
plementation in active rheumatoid arthritis. A double-blinded,
controlled, crossover study. Ann Intern Med 1987;106:497–503.
4. Kremer JM, Lawrence DA, Jubiz W, et al. Dietary fish oil and olive
oil supplementation in patients with rheumatoid arthritis. Clini-
cal and immunologic effects. Arthritis Rheum 1990;33:810–820.
5. Nielsen GL, Faarvang KL, Thomsen BS, et al. The effects of di-
etary supplementation with n-3 polyunsaturated fatty acids in
patients with rheumatoid arthritis: a randomized, double blind
trial. Eur J Clin Invest 1992;22:687–691.
6. van der Tempel H, Tulleken JE, Limburg PC, et al. Effects of
fish oil supplementation in rheumatoid arthritis. Ann Rheum Dis
1990;49:76–80.
7. Goldberg RJ, Katz J. A meta-analysis of the analgesic effects of
omega-3 polyunsaturated fatty acid supplementation for inflam-
matory joint pain. Pain 2007;129:210–223.
8. Henrotin Y, Sanchez C, Balligand M. Pharmaceutical and nu-
traceutical management of canine osteoarthritis: present and
future perspectives. Vet J 2005;170:113–123.
9. Roush JK, Cross AR, Renberg WC, et al. Evaluation of the ef-
fects of dietary supplementation with fish oil omega-3 fatty ac-
ids on weight bearing in dogs with osteoarthritis. J Am Vet Med
Assoc 2010;236:67–73.
10. Roush JK, Dodd CE, Fritsch DA, et al. Multicenter veterinary
practice assessment of the effects of omega-3 fatty acids on os-
teoarthritis in dogs. J Am Vet Med Assoc 2010;236:59–66.
11. Aragon CL, Hofmeister EH, Budsberg SC. Systematic review of
clinical trials of treatments for osteoarthritis in dogs. J Am Vet
Med Assoc 2007;230:514–521.
12. Renberg WC. Pathophysiology and management of arthritis. Vet
Clin North Am Small Anim Pract 2005;35:1073–1091.
13. 2003 official publication. San Diego: Association of American
Feed Control Officials, 2003.
14. Brown H, Prescott R. Applied mixed models in medicine. 2nd ed.
Chichester, West Sussex, England: John Wiley and Sons Ltd, 2006.
15. Littell RC, Milliken GA, Stroup WW, et al. SAS for mixed models.
2nd ed. Cary, NC: SAS Institute Inc, 2006.
16. Milliken GA, Johnson DE. Analysis of messy data. 2nd ed. Boca
Raton, Fla: Chapman and Hall/CRC, 2009.
17. Rubin DB. Multiple imputation for nonresponse in surveys. New
York: John Wiley & Sons Inc, 1987.
18. Schafer JL. Analysis of incomplete multivariate data. New York:
Chapman & Hall, 1997.
19. Crevoisier C. Pharmacokinetic properties of carprofen in hu-
mans. Eur J Rheumatol Inflamm 1982;5:492–502.
... Quercetin and kaempferol also influence STAT-1. Thus, quercetin inhibits LPS-induced STAT-1 and has an inhibitory effect on iNOS Improves symptoms and prevents the degenerative process in cartilage [108,109] Linoleic acid (omega 6) ...
... The results of linear regression analysis showed that the dose of carprofen decreased significantly more rapidly over the 12-week study period in the dog fed the supplement diet than in the control group. The distribution of the change of carprofen dose in the control group was significantly different from the distribution of the change of dose for the dogs in the test group, with the conclusion that dogs with chronic OA who received carprofen showed a clinically relevant reduction in the dose of carprofen by a diet supplemented with omega-3 fatty acid fish oil[109]. ...
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Osteoarthritis (OA) is a chronic inflammatory disorder of the joints caused by fluid and cartilage matrix component reduction. This disease results in symptoms of pain, deformity, and limitation of movement. In general, OA is treated with anti-inflammatory drugs and chondroprotection compounds, besides natural nutraceutical ingredients, which are expected to be effective and have minimal side effects. Arecaceae plants are widely spread worldwide, especially in tropical areas. The objective of this review is to collect information about the Arecaceae family as anti-OA agents, with the main study focusing on the primary and secondary metabolites of plants of the Arecaceae family, i.e., sugar palm (Arenga pinnata), nipa palm (Nypa fruticans), palmyra palm (Borassus flabellifer), date palm (Phoenix dactylifera), and betel nut (Areca catechu) have potential as anti-OA agents. The Arecaceae's metabolites that show anti-inflammatory and chondroprotective effects are galactomannan, fatty acids (linoleic and linolenic acids), flavonoids (quercetin, luteolin, isorhamnetin), phenolics (coumaric acid, ferulic acid), polyphenols (epicatechin), and steroids (stigmasterol, campesterol, spirostane). Based on the reports, the Arecaceae family plants become worthy of being explored and developed into natural anti-OA products, such as supplements or nutraceuticals.
... Fritsch et al. (2010) discovered that feeding a fish oil-rich diet to dogs with OA for 12 weeks reduced caporofen (NSAID) dosage significantly compared to a control diet. Omega-3 fatty acid supplementation was used to treat OA-prone and OA-resistant guinea pig strains using a random OA model in a significant trial [97]. When OA-prone and-resistant strains were compared, OA markers such as lysyl-pyridinoline, active MMP-2, and complete collagen cross-links were altered. ...
... When OA-prone and-resistant strains were compared, OA markers such as lysyl-pyridinoline, active MMP-2, and complete collagen cross-links were altered. When compared to a non-pathological strain fed an omega-3 diet, subchondral bone parameters such as calcium to phosphate ratios and epiphyseal bone density improved significantly [97,98]. ...
... Fritsch et al. (2010) discovered that feeding a fish oil-rich diet to dogs with OA for 12 weeks reduced caporofen (NSAID) dosage significantly compared to a control diet. Omega-3 fatty acid supplementation was used to treat OA-prone and OA-resistant guinea pig strains using a random OA model in a significant trial [97]. When OA-prone and-resistant strains were compared, OA markers such as lysyl-pyridinoline, active MMP-2, and complete collagen cross-links were altered. ...
... When OA-prone and-resistant strains were compared, OA markers such as lysyl-pyridinoline, active MMP-2, and complete collagen cross-links were altered. When compared to a non-pathological strain fed an omega-3 diet, subchondral bone parameters such as calcium to phosphate ratios and epiphyseal bone density improved significantly [97,98]. ...
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The rising prevalence of osteoarthritis (OA) in the general population has necessitated the development of novel treatment options. It is critical to recognize the joint as a separate entity participating in degenerative processes, as well as the multifaceted nature of OA. OA is incurable because there is currently no medication that can stop or reverse cartilage or bone loss. As this point of view has attracted attention, more research is being directed toward determining how the various joint components are impacted and how they contribute to OA pathogenesis. Over the next few years, several prospective therapies focusing on inflammation, cartilage metabolism, subchondral bone remodelling, cellular senescence, and the peripheral nociceptive pathway are predicted to transform the OA therapy landscape. Stem cell therapies and the use of various biomaterials to target articular cartilage (AC) and osteochondral tissues are now being investigated in considerable detail. Currently, laboratory-made cartilage tissues are on the verge of being used in clinical settings. This review focuses on the update of clinical prospects and management of osteoarthritis, as well as future possibilities for the treatment of OA.
... Category 1. Omega-3-enriched therapeutic diets Green-lipped mussels [21][22][23][24] Fish oil [25][26][27][28][29] Category 2. Omega-3-based nutraceuticals Green-lipped mussels [ The null hypothesis was that no statistically significant difference existed between the scores of the five categories for trial quality or analgesic efficacy. For statistical analyses, we used R ® software (Version 4.0.3, ...
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With osteoarthritis being the most common degenerative disease in pet animals, a very broad panel of natural health products is available on the market for its management. The aim of this systematic review and meta-analysis, registered on PROSPERO (CRD42021279368), was to test for the evidence of clinical analgesia efficacy of fortified foods and nutraceuticals administered in dogs and cats affected by osteoarthritis. In four electronic bibliographic databases, 1578 publications were retrieved plus 20 additional publications from internal sources. Fifty-seven articles were included, comprising 72 trials divided into nine different categories of natural health compound. The efficacy assessment, associated to the level of quality of each trial, presented an evident clinical analgesic efficacy for omega-3-enriched diets, omega-3 supplements and cannabidiol (to a lesser degree). Our analyses showed a weak efficacy of collagen and a very marked non-effect of chondroitin-glucosamine nutraceuticals, which leads us to recommend that the latter products should no longer be recommended for pain management in canine and feline osteoarthritis.
... In the present study, as expected Rimadyl TM in the first 6 weeks of treatment had an almost immediate effect on the perceived assessment of pain and activity, as it has been reported in previous clinical studies with carprofen, meloxicam, or etodolac in OA dogs [7,43,37]. In several clinical studies conducted in OA dogs, carprofen (Rimadyl TM ) has been used: 1) alone for the treatment of OA in dogs [26,59,40] as a positive control or in combination with nutraceuticals [37,25,18]. In addition to inhibition of COX-1 and COX-2 activities [51], carprofen has been reported to simultaneously reduce progression of morphological changes in cartilage and subchondral bone in OA dogs [45]. ...
Article
The typical canine rehabilitation patient with orthopedic disease may differ in its nutritional needs, with the assumption that most patients will be on a complete and balanced commercial dog food that is not enriched with agents for ameliorating their condition. For a significant number of rehabilitation patients, obesity is a major issue where hypocaloric diet plans are often implemented and are covered extensively elsewhere (VCNA Small Animal Practice May 2021). The focus of this article will be implementation of physical activity or structured physical exercise protocols and how they might be used in combination with a typical hypocaloric diet plan, a diet low in calories. Considering the limited information regarding physical activity or structured exercise programs in dogs, a human comparative assessment of efficacy is fundamental as a baseline of information regarding typical interventions. In addition, many of these long-term rehabilitation cases typically exhibit osteoarthritis (OA) and as part of case management, there is a need to implement nutrient or nutraceutical intervention to either diminish the progression of OA or help with pain control measures, particularly for the nonsteroidal anti-inflammatory intolerant patient. Nutraceutical intervention comes in many forms from botanicals to nutritional enhancement; botanicals will be covered elsewhere in this issue. This overview of nutraceuticals will cover nonbotanical interventions including fish oil, glucosamine/chondroitin, avocado/soybean unsaponifiables, undenatured collagen, green lipped mussel, and egg shell membrane supplementation.
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In order to evaluate the interaction of betaine and n-3 PUFA in foods consumed by the dog, six extruded dry foods were formulated. The control food had no specific source of added betaine or n-3 fatty acids, while the test foods were supplemented with betaine, flax or fish oil in a 2 × 3 factorial design (no added n-3 source, added flax, added menhaden fish oil, and all with or without added betaine). Forty eight adult dogs were used in this study. All dogs were assigned to one of the six dietary treatments and consumed that food for the length of the 60-day study. Blood was analyzed for metabolomics (plasma), fatty acids and selected health-related analytes (serum) at the beginning and the end of the study. Added dietary betaine increased single-carbon metabolites (betaine, dimethyl glycine, methionine and N-methylalanine), decreased xenobiotics (stachydrine, N-acetyl-S-allyl-L-cysteine, 4-vinylguaiacol sulfate, pyrraline, 3-indoleglyoxylic acid, N-methylpipecolate and ectoine) and enhanced the production of eicosapentaenoic acid (EPA). Dietary betaine also decreased the concentration of circulating carnitine and a number of carnitine-containing moieties. The addition of the n-3 fatty acids alpha-linolenic, EPA and docosahexaenoic acid (DHA) increased their respective circulating concentrations as well as those of many subsequent moieties containing these fatty acids. The addition of alpha-linolenic acid increased the concentration of EPA when expressed as a ratio of EPA consumed.
Article
Owners often reach for over-the-counter supplements for the management of canine osteoarthritis, believing them to be natural, side effect-free options. Some may ask for your opinion as a veterinary professional, whereas others will come to you already using certain products. It is imperative to be aware of the evidence for the relevant products and to encourage the use of good quality products as the first option. The aim should be to help prevent owners of arthritic dogs wasting their money buying multiple products with little or no evidence to back up their use, to be wary of bold unsubstantiated claims for improvements or health benefits, and to ensure that supplements are not used as a sole intervention for the management of arthritic pain, as they are unlikely to have the evidence base to support this claim.
Article
Objectives The purpose of this study was to evaluate the pain-alleviating and activity-enhancing effects of glucosamine/chondroitin sulfate (Dasuquin) in cats that had degenerative joint disease (DJD) and owner-noted mobility/activity impairment. We hypothesized that the nutritional supplement would produce pain-relieving and activity-enhancing effects in cats with painful DJD. Methods In this prospective, randomized, stratified, double-blind, placebo-controlled clinical trial, 59 cats with DJD pain were assigned to receive a placebo (n = 30) or supplement (n = 29) for 6 weeks after 2 weeks of placebo. Outcome measures (at-home accelerometry and client-specific outcome measures [feline (CSOMf); Feline Musculoskeletal Pain Index (FMPI); quality of life (QoL)]; and veterinarian examination) were collected at days 14, 28, 42 and 56. Results Twenty-seven cats in the treatment group and 30 in the placebo group completed the trial. Within the first 2 weeks (placebo administration to all cats), 78% of all cats had an improvement in CSOMf scores. Both groups showed significant improvement at most time points in CSOMf, FMPI, QoL and pain scores, with the placebo group showing greater improvement than the supplement group (significant for CSOMf [ P = 0.01]). Overall, no differences in activity were seen between the groups. Cumulative distribution function analysis indicated that for most levels of activity, the placebo-treated cats were more active; however, the least active cats were more active on the supplement ( P = 0.013). Conclusions and relevance This study showed a strong placebo effect. The glucosamine/chondroitin sulfate supplement did not show pain-relieving effects when compared with placebo.
Article
Osteoarthritis is prevalent in the UK canine population and has a clear impact on animal welfare. Treatment of osteoarthritis is advised to be multimodal, with nutraceuticals becoming a popular part of this approach. However, veterinary nutraceuticals are not subject to any regulation and systematic reviews are still uncommon in the veterinary field, which makes evaluating these products difficult. This article looks at the most commonly used veterinary supplements and how to critically evaluate the evidence of their efficacy. Evidence is promising for omega-3 fatty acids but is limited for other common ingredients. There are limited numbers of rigorous, randomised controlled trials and veterinary studies are often hampered by small sample sizes. Standardisation of reporting, as performed in human medicine, is needed to allow more robust systematic reviews of nutraceuticals to subsequently enable vets to make more informed decisions.
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To evaluate the effects of a food supplemented with fish oil omega-3 fatty acids on weight bearing in dogs with osteoarthritis. Randomized, double-blinded, controlled clinical trial. 38 client-owned dogs with osteoarthritis examined at 2 university veterinary clinics. Dogs were randomly assigned to receive a typical commercial food (n = 16) or a test food (22) containing 3.5% fish oil omega-3 fatty acids. On day 0 (before the trial began) and days 45 and 90 after the trial began, investigators conducted orthopedic evaluations and force-plate analyses of the most severely affected limb of each dog, and owners completed questionnaires to characterize their dogs' arthritis signs. The change in mean peak vertical force between days 90 and 0 was significant for the test-food group (5.6%) but not for the control-food group (0.4%). Improvement in peak vertical force values was evident in 82% of the dogs in the test-food group, compared with 38% of the dogs in the control-food group. In addition, according to investigators' subjective evaluations, dogs fed the test food had significant improvements in lameness and weight bearing on day 90, compared with measurements obtained on day 0. At least in the short term, dietary supplementation with fish oil omega-3 fatty acids resulted in an improvement in weight bearing in dogs with osteoarthritis.
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To assess the effect of food containing high concentrations of fish oil omega-3 fatty acids and a low omega-6-omega-3 fatty acid ratio on clinical signs of osteoarthritis in dogs. Randomized, double-blinded, controlled clinical trial. 127 client-owned dogs with osteoarthritis in 1 or more joints from 18 privately owned veterinary clinics. Dogs were randomly assigned to be fed for 6 months with a typical commercial food or a test food containing a 31-fold increase in total omega-3 fatty acid content and a 34-fold decrease in omega-6-omega-3 ratio, compared with the control food. Dog owners completed a questionnaire about their dog's arthritic condition, and investigators performed a physical examination and collected samples for a CBC and serum biochemical analyses (including measurement of fatty acids concentration) at the onset of the study and at 6, 12, and 24 weeks afterward. Dogs fed the test food had a significantly higher serum concentration of total omega-3 fatty acids and a significantly lower serum concentration of arachidonic acid at 6, 12, and 24 weeks. According to owners, dogs fed the test food had a significantly improved ability to rise from a resting position and play at 6 weeks and improved ability to walk at 12 and 24 weeks, compared with control dogs. Ingestion of the test food raised blood concentrations of omega-3 fatty acids and appeared to improve the arthritic condition in pet dogs with osteoarthritis.
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Preface to Second Edition. Mixed Model Notations. 1 Introduction. 1.1 The Use of Mixed Models. 1.2 Introductory Example. 1.3 A Multi-Centre Hypertension Trial. 1.4 Repeated Measures Data. 1.5 More aboutMixed Models. 1.6 Some Useful Definitions. 2 NormalMixed Models. 2.1 Model Definition. 2.2 Model Fitting Methods. 2.3 The Bayesian Approach. 2.4 Practical Application and Interpretation. 2.5 Example. 3 Generalised Linear MixedModels. 3.1 Generalised Linear Models. 3.2 Generalised Linear Mixed Models. 3.3 Practical Application and Interpretation. 3.4 Example. 4 Mixed Models for Categorical Data. 4.1 Ordinal Logistic Regression (Fixed Effects Model). 4.2 Mixed Ordinal Logistic Regression. 4.3 Mixed Models for Unordered Categorical Data. 4.4 Practical Application and Interpretation. 4.5 Example. 5 Multi-Centre Trials and Meta-Analyses. 5.1 Introduction to Multi-Centre Trials. 5.2 The Implications of using Different Analysis Models. 5.3 Example: A Multi-Centre Trial. 5.4 Practical Application and Interpretation. 5.5 Sample Size Estimation. 5.6 Meta-Analysis. 5.7 Example: Meta-analysis. 6 RepeatedMeasures Data. 6.1 Introduction. 6.2 Covariance Pattern Models. 6.3 Example: Covariance Pattern Models for Normal Data. 6.4 Example: Covariance Pattern Models for Count Data. 6.5 Random Coefficients Models. 6.6 Examples of Random Coefficients Models. 6.7 Sample Size Estimation. 7 Cross-Over Trials. 7.1 Introduction. 7.2 Advantages of Mixed Models in Cross-Over Trials. 7.3 The AB/BA Cross-Over Trial. 7.4 Higher Order Complete Block Designs. 7.5 Incomplete Block Designs. 7.6 Optimal Designs. 7.7 Covariance Pattern Models. 7.8 Analysis of Binary Data. 7.9 Analysis of Categorical Data. 7.10 Use of Results from Random Effects Models in Trial Design. 7.11 General Points. 8 Other Applications of MixedModels. 8.1 Trials with Repeated Measurements within Visits. 8.2 Multi-Centre Trials with Repeated Measurements. 8.3 Multi-Centre Cross-Over Trials. 8.4 Hierarchical Multi-Centre Trials and Meta-Analysis. 8.5 Matched Case-Control Studies. 8.6 Different Variances for Treatment Groups in a Simple Between-Patient Trial. 8.7 Estimating Variance Components in an Animal Physiology Trial. 8.8 Inter- and Intra-Observer Variation in Foetal Scan Measurements. 8.9 Components of Variation and Mean Estimates in a Cardiology Experiment. 8.10 Cluster Sample Surveys. 8.11 Small AreaMortality Estimates. 8.12 Estimating Surgeon Performance. 8.13 Event History Analysis. 8.14 A Laboratory Study Using aWithin-Subject 4 x 4 Factorial Design. 8.15 Bioequivalence Studies with Replicate Cross-Over Designs. 8.16 Cluster Randomised Trials. 9 Software for Fitting MixedModels. 9.1 Packages for Fitting Mixed Models. 9.2 Basic use of PROC MIXED. 9.3 Using SAS to Fit Mixed Models to Non-Normal Data. Glossary. References. Index.
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Introduction Assumptions EM and Inference by Data Augmentation Methods for Normal Data More on the Normal Model Methods for Categorical Data Loglinear Models Methods for Mixed Data Further Topics Appendices References Index
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Introduction General Conditions for the Randomization-Validity of Infinite-m Repeated-Imputation Inferences Examples of Proper and Improper Imputation Methods in a Simple Case with Ignorable Nonresponse Further Discussion of Proper Imputation Methods The Asymptotic Distribution of (Q̄m, Ūm, Bm) for Proper Imputation Methods Evaluations of Finite-m Inferences with Scalar Estimands Evaluation of Significance Levels from the Moment-Based Statistics Dm and Δm with Multicomponent Estimands Evaluation of Significance Levels Based on Repeated Significance Levels