07-039 EBCQuest - McCluskey 11/04/07 10:50 am Page 2
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Evidence-based Clinical Question
Does the addition of hyaluronan to intra-articular
glucocorticoids provide any additional clinical benefit?
M. MCCLUSKEY
AllCare Equine Centre, PO Box 145, Newcomb, Geelong, Victoria 3219, Australia.
Introduction
The 2 main goals of the medical treatment of osteoarthritis
(OA) in the horse are the reduction of pain and lameness, and
the minimisation of the progression of joint deterioration
(McIlwraith 2005; Frisbie 2006).
Intra-articular glucocorticoids (GC) play an important role
in the treatment of equine OA. Controlled studies confirm the
clinical benefit of some of the commonly used medications
(Foland et al. 1994; Gaustad and Larsen 1995). Hyaluronan
(HA) is a glycosaminoglycan that is commonly combined with
intra-articular GC for the treatment of OA in the horse. This
practice of combination GC/HA therapy, however, has been
suggested to be based on tradition rather than scientific proof
(Foland et al. 1994; McIlwraith 2005).
Search method
A literature search, using Pubmed, Google Scholar and
Dogpile, of studies relating to the use of intra-articular GC and
HA for the treatment of OA was conducted. Proceedings of
conferences of the American Association of Equine
Practitioners as well as Australian Equine Veterinarian were
also searched.
Discussion
Many reports on the intra-articular use of HA in the horse
are subjective and lacking definitions of criteria for success
of treatment (Frisbie 2006). One randomised, double-blind
and placebo controlled clinical study carried out on
Standardbred trotters concluded that 2 intra-articular HA
injections, when compared with 2 ml saline injection,
significantly reduced lameness score during the treatment
period (P = 0.03) and the total study period (P<0.01), time
until soundness (P = 0.04), as well as the prevalence of
sound horses at the last examination (P<0.01), although this
effect did not become significant until after 2 weeks, and
saline injection did cause significant lameness reduction
(Gaustad and Larsen 1995).
Meta-analyses of the use of intra-articular HA in OA in
EQUINE VETERINARY EDUCATION
Equine vet. Educ. (2007) 19 (4) 210-211
doi: 10.2746/095777307X197125
man have produced conflicting results. A recent Cochrane
review claimed that viscosupplementation with HA for the
treatment of OA of the knee was an effective treatment
with beneficial effects on pain, function and patient global
assessment (Bellamy et al. 2006). A review by Wang et al.
(2004) also found that HA was of therapeutic benefit for
intra-articular treatment of OA of the knee. Others have
suggested intra-articular HA had only a small effect when
compared with an intra-articular placebo. The presence of
publication bias was suggested as possibly overestimating
this effect (Lo et al. 2003). Other trials, however, have
concluded that there is little evidence to support the use of
HA in human hip OA. A recent review claimed that to date
the efficacy of intra-articular injections of HA or its
derivatives in the symptomatic treatment of hip OA cannot
be determined conclusively based on the currently available
evidence (Conrozier and Vignon 2005). Clinical trials of HA
in man are reported to reflect significant publication bias
and most clinical trials involve industry sponsorship
(Anon 2004).
Evidence-based trials proving the superiority of combined
GC/HA over GC alone in the treatment of equine OA are
lacking. Combined injection of GC and high molecular
weight HA has been shown to reduce proteoglycan
breakdown in equine joints when compared to GC alone,
suggesting a protective effect of hyaluronate on the articular
cartilage. However, treated joints were normal; therefore, this
study provided no evidence to support the use of
combination GC/HA over GC alone in joints affected with OA
(Roneus et al. 1993).
One uncontrolled and unblinded series of case-studies,
unaccompanied by statistical analysis, with poorly defined
entry criteria and end-points, concluded that a laboratory-
produced HA of varying molecular weight combined with
100 mg methylprednisolone acetate (MPA) provided a better
and longer lasting effect for the treatment of OA in 20
racing Thoroughbred and Standardbred horses than did
MPA injection alone (Butler et al. 1970). This study’s
conclusions are tempered by design factors and the results
cannot be extrapolated to other GCs under any
circumstance.
07-039 EBCQuest - McCluskey 11/04/07 10:50 am Page 3
M. McCluskey
A combination of HA/GC was recommended based on the
results of an uncontrolled, nonblinded, retrospective study of
the management of joint disease in 50 horses. Forty-three
joints were treated with HA and various GCs including
dexamethasone, MPA, triamcinolone acetonide and
dexamethasone isonicotinate. Combination HA/GC was
suggested to be very effective in relieving lameness associated
with joint disease (Kannegieter 2003). However, GCs alone
have been shown to be effective in improving the
inflammation associated with OA. (Foland et al. 1994; Frisbie
et al. 1997) The lack of GC-treated controls and an
independent blinded assessment of post treatment responses
means this study produced weak evidence to demonstrate
that HA provided any additional clinical benefit when added to
intra-articular GC therapy.
In an experimental model of OA in the rabbit’s knee, an
additive effect for HA has been demonstrated when used in
conjunction with intra-articular GC as compared to
treatment with either HA or GC alone. However, HA and GC
were not given as a combined injection but were spaced
apart by at least 7–14 days (Karakurum et al. 2003).
Whether this additive effect also occurs with concurrent
administration of HA and GC is unknown. A preliminary
open, randomised study of the use of very small doses of
dexamethasone, with or without hyaluronic acid, in
40 human patients with OA suggested that, while both
treatments provided clinical improvement, in the combined
treatment group pain intensity decreased more rapidly and
to lower levels in all but weightbearing pain, and joint
mobility was improved (Grecomoro et al. 1992). Lack of
blinding, small sample size, species differences and the use
of a GC not commonly used in equine OA mean the results
of this study provide little evidence to support combination
intra-articular HA/GC therapy in the horse.
Studies to assess the cost-benefit of the intra-articular use
of combination GC/HA compared to GC alone are needed.
The cost to the client of treating joints intra-articularly with
combination GC/HA is likely to be significantly higher than
the cost of treatment with intra-articular GC alone. The need
for an examination of the cost effectiveness of the clinical use
of HA in human OA has also been suggested (Walker-Bone et
al. 2000; Modawal et al. 2005)
In conclusion, there is weak evidence, obtained mostly
from uncontrolled case studies, to provide support for the
current practice of combining HA with GC for the intra-
articular treatment of OA in the horse. Prospective,
randomised, blinded and controlled studies are required to
resolve the clinical issue of whether or not combination
GC/HA is superior to GC alone for intra-articular therapy of
OA in the horse.
References
Anon (2004) Clinical trials of hyaluronic acid reflect significant
publication bias. Johns Hopkins Arthritis Centre Online News
Accessed February 2007 http://www.hopkins-arthritis.com/news-
archive/2004/hyaluronic_acid.html
211
Bellamy, N., Campbell, J., Robinson, V., Gee, T., Bourne, R. and Wells,
G. (2006) Viscosupplementation for the treatment of osteoarthritis
of the knee. Cochrane Database Syst. Rev. Issue 2. Art. No.:
CD005321.
Butler, J., Rydell, N.W. and Balazs, E.A. (1970) Hyaluronic acid in
synovial fluid. VI. Effect of intra-articular injection of hyaluronic
acid on the clinical symptoms of arthritis in track horses. Acta. vet.
Scand. 11, 139-155.
Conrozier, T. and Vignon, E. (2005) Is there evidence to support the
inclusion of viscosupplementation in the treatment paradigm for
patients with hip osteoarthritis? Clin. expt. Rheumatol. 23, 711-716.
Foland, J.W., McIlwraith, C.W., Trotter, G.W., Powers, B.E. and Lamar,
C.H. (1994) Effect of betamethasone and exercise on equine
carpal joints with osteochondral fragments. Vet. Surg. 5, 369-376.
Frisbie, D.D. (2006) Principles of treatment of joint disease. In: Equine
Surgery, 3rd edn., Eds: J. Auer and J. Stick, Saunders, Missouri.
pp 1055-1079.
Frisbie, D.D., Kawcak, C.E., Trotter, G.W., Powers, B.E., Walton, R.M.,
McIlwraith, C.W. (1997) Effects of triamcinolone acetonide on an
in vivo equine osteochondral fragment exercise model. Equine vet.
J. 29, 349-359.
Gaustad, G. and Larsen, S. (1995) Comparison of polysulphated
glycosaminoglycan and sodium hyaluronate with placebo in
treatment of traumatic arthritis in horses. Equine vet. J. 27, 356-362.
Grecomoro, G., Piccione, F. and Letizia, G. (1992) Therapeutic
synergism between hyaluronic acid and dexamethasone in the
intra-articular treatment of osteoarthritis of the knee: a preliminary
open study. Curr. med. Res. Opinion 13, 49-55.
Kannegieter, N. (2003) The clinical use of a new sodium hyaluronate
(Enhance) in the management of joint disease in the horse. Aust.
equine Vet. 22, 28-34.
Karakurum, G., Karakok, M., Tarakcioglu, M., Kocer, N.E., Kocabas, R.
and Bagci, C. (2003) Comparative effect of intra-articular
administration of hyaluronan and/or cortisone with evaluation of
malondialdehyde on degenerative osteoarthritis of the rabbit’s
knee. Tohoku J. expt. Med. 199, 127-134.
Lo, G.H., LaValley, M., McAlindon, T. and Felson, D.T. (2003) Intra-
articular hyaluronic acid in treatment of knee osteoarthritis: a
meta-analysis. J. Am. med. Ass. 290, 3115-3121.
McIlwraith, C.W. (2005) From arthroscopy to gene therapy - 30 years
of looking in joints. Proc. Am. Ass. equine Practnrs. 51, 65-113.
Modawal, A., Ferrer, M., Choi, H. and Castle, J. (2005) Hyaluronic acid
injections relieve knee pain. J. Fam. Prac. 54, 758-767.
Roneus, B., Lindblad, A., Lindholm, A. and Jones, B. (1993) Effects of
intraarticular corticosteroid and sodium hyaluronate injections on
synovial fluid production and synovial fluid content of sodium
hyaluronate and proteoglycans in normal equine joints. Zentralbl
Veterinarmed A. 40, 10-16.
Walker-Bone, K., Javaid, K. and Arden, N. (2000) Medical
management of osteoarthritis. Br. med. J. 321, 936-940.
Wang, C.T., Lin, J., Chang, C.J., Lin, Y.T. and Hou, S.M. (2004)
Therapeutic effects of hyaluronic acid on osteoarthritis of the
knee. A meta-analysis of randomized controlled trials. J. Bone Joint
Surg. Am. 86, 538-545.
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