Hyaluronic acid as a treatment for ankle osteoarthritis

Abstract

Viscosupplementation refers to the concept of synovial fluid replacement with intra-articular injections of hyaluronic acid (HA) for the relief of pain associated with osteoarthritis (OA). Intra-articular viscosupplementation was approved by the Food and Drug Administration (FDA) in 1997. It is currently indicated only for the treatment of pain associated with knee OA. However, OA can occur in several of the weight-bearing joints of the foot and ankle. Ankle OA produces chronic disability that directly impacts the quality of life. There is only limited published literature relating to the use of HA in the ankle. This paper will review the authors' experience, indications, clinical outcomes, and complications of viscosupplementation therapy in patients with ankle OA.

Full text

Hyaluronic acid as a treatment for ankle osteoarthritis
Shu-Fen Sun ÆYi-Jiun Chou ÆChien-Wei Hsu Æ
Wen-Ling Chen
Published online: 13 March 2009
ÓThe Author(s) 2009. This article is published with open access at Springerlink.com
Abstract Viscosupplementation refers to the concept of
synovial fluid replacement with intra-articular injections of
hyaluronic acid (HA) for the relief of pain associated with
osteoarthritis (OA). Intra-articular viscosupplementation
was approved by the Food and Drug Administration (FDA)
in 1997. It is currently indicated only for the treatment of
pain associated with knee OA. However, OA can occur in
several of the weight-bearing joints of the foot and ankle.
Ankle OA produces chronic disability that directly impacts
the quality of life. There is only limited published literature
relating to the use of HA in the ankle. This paper will
review the authors’ experience, indications, clinical out-
comes, and complications of viscosupplementation therapy
in patients with ankle OA.
Keywords Osteoarthritis Hyaluronic acid Ankle joint 
Viscosupplementation
Introduction
Osteoarthritis (OA) is a common progressive degenerative
joint disease with multiple etiologies, but similar biological,
morphological, and clinical outcomes [1,2]. Individuals
with OA might suffer from pain, muscle weakness, loss of
joint range of motion, and increasing disability. The disease
process of OA is characterized by the progressive erosion of
articular cartilage, leading to joint space narrowing,
subchondral sclerosis, subchondral cysts, synovial inflam-
mation, and marginal osteophyte formation [3]. Traditional
treatments for OA include simple analgesics, nonsteroidal
anti-inflammatory drugs (NSAIDs), intra-articular cortico-
steroid injections, physiotherapy, activity modification,
weight reduction, orthotics, and surgery [4]. Prior to surgical
management of OA, which is expensive, painful, and not
risk-free, all other treatment options should be fully exploi-
ted. Taking into consideration that chronic use of some oral
pain medications may be contraindicated, a locally delivered
therapy with no known drug interactions and an excellent
safety profile is a valuable treatment option for patients.
There has been increasing interest and scientific inves-
tigation of intra-articular injection of hyaluronic acid (HA)
for the treatment of OA over the past 2 decades. Creamer
and Hochberg presented the treatment protocol of OA and
they stated that intra-articular HA played an important role
[1]. HA is a high molecular weight polysaccharide and is
an important component of synovial fluid and extracellular
matrix of articular cartilage. It contributes to the elasticity
and viscosity of synovial fluid. HA acts as a fluid shock
absorber and it helps to maintain the structural and func-
tional characteristics of the cartilage matrix. It also inhibits
the formation and release of prostaglandins, induces pro-
teoglycan aggregation and synthesis, and modulates the
inflammatory response [5,6]. Any degradation of HA is
S.-F. Sun (&)W.-L. Chen
Department of Physical Medicine and Rehabilitation, Veterans
General Hospital, Kaohsiung, No 386, Ta-Chung 1st Road,
Kaohsiung 813, Taiwan
e-mail: sfsun.tw@yahoo.com.tw
S.-F. Sun
National Yang-Ming University School of Medicine, Taipei,
Taiwan
Y.-J. Chou
Department of Orthopedic Surgery, Veterans General Hospital,
Kaohsiung, Kaohsiung, Taiwan
C.-W. Hsu
Department of Internal Medicine, Veterans General Hospital,
Kaohsiung, Taiwan
Curr Rev Musculoskelet Med (2009) 2:78–82
DOI 10.1007/s12178-009-9048-5

associated with increased vulnerability to articular cartilage
damage. OA leads to a reduction in average molecular size
and concentration of HA in the synovial fluid [6–8].
According to Balazs and coworkers [9,10], the injection of
HA into osteoarthritic joints could restore the viscoelas-
ticity of the synovial fluid, augment the flow of joint fluid,
normalize endogenous hyaluronate synthesis, inhibit hyal-
uronate degradation, reduce joint pain, and improve joint
function.
Viscosupplementation with intra-articular HA was
approved by the Food and Drug Administration (FDA) in
1997. The American College of Rheumatology guidelines
for the treatment of knee OA include the use of visco-
supplementation [11]. The Orthopedic Consensus
Conference made similar recommendations on the use of
HA for the treatment of knee OA [12]. There are five
injectable forms of HA approved by the United States FDA
including Hyalgan, Supartz, Orthovisc, Synvisc, and Eu-
flexxa. Each of these HA products differ in their origin,
method of production, molecular weight, dosing instruc-
tions, biologic characteristics, and possibly clinical
outcomes (Table 1). There is no consistent evidence from
well-controlled clinical studies that documents the superior
efficacy of one product over another.
Theoretically viscosupplementation is an approach that
should apply to all synovial joints. Off-label use in
degenerative arthritis of the hip, ankle, shoulder, and car-
pometacarpal joint of the thumb seems to be increasing and
a number of recent studies have attempted to evaluate its
efficacy in joints other than the knee [13–23]. The purpose
of this article was to review the authors’ experience,
indications, clinical outcomes, and complications of
viscosupplementation therapy in patients with ankle OA.
Indications
Treatment with HA is indicated for patients who are
functionally limited due to osteoarthritic pain and who
have failed to respond adequately to standard pharmaco-
logic and nonpharmacologic treatment options, those who
have gastrointestinal or renal intolerance to NSAIDs, and
those who wish to postpone surgical intervention or are
poor candidates for surgery.
Intra-articular injections of HA are contraindicated in
patients with known hypersensitivity to HA preparations,
avian proteins, feather and egg products, and those with
active skin disease or infections in the area of the injection
site. Patients with substantial venous or lymphatic stasis in
the legs, bleeding disorder or treatment with anticoagulants
are relatively contraindicated. HA is not recommended to
pregnant women, lactating women, and children under 18,
because the safety and effectiveness have not been
established.
The ideal candidate for intra-articular HA has yet to be
clearly defined. We reported the results of a controlled
study that patients with Kellgren-Lawrence grade I and II
ankle OA had good response to viscosupplementation
(grade 1, doubtful narrowing of joint space and possible
osteophytic lipping; grade 2, definite osteophytes and
possible narrowing of joint space) [16,24]. This suggested
that viscosupplementation was effective in mild to mod-
erate ankle OA. Whether severe cases would likely respond
to viscosupplementation remained unknown. Theoretically,
patients with severe OA might have a poor and shorter
response. Because the numbers of patients studied were
relatively small, the results were not analyzed on the basis
of disease severity, cause of OA, or preinjection functional
levels. These factors might have a role in determining the
candidates who would benefit most from this treatment and
might help determine the best overall treatment plan.
Currently, we are recruiting patients with higher X-ray
severity grades in a clinical trial to see whether intra-
articular HA injections can improve ankle pain and func-
tion in severely obliterated ankle joints. As the treatment
group increases, hopefully we could better elucidate
favorable patient response factors and identify patients who
would benefit most from ankle viscosupplementation.
Table 1 Characteristics of five hyaluronans
Product Origin (method of production) Molecular
weight (kd)
Amount per
injection (ml)
Active ingredients per
injection
Number of injections
per cycle
Hylagan Rooster combs (naturally derived) 500–730 2 20 mg sodium hyaluronate 3 or 5 weekly
Supartz Rooster combs (naturally derived) 620–1170 2.5 25 mg sodium hyaluronate 5 weekly
Orthovisc Rooster combs (naturally derived) 1000–2900 2 30 mg sodium hyaluronate 3 or 4 weekly
Synvisc Rooster combs (chemically
modified
or cross-linked)
80%: 6000; 20%:
[6000
2 16 mg sodium hyaluronate
derivative
3 weekly
Euflexxa Bacterial fermentation (naturally
derived)
2600–3400 2 20 mg sodium hyaluronate 3 weekly
Curr Rev Musculoskelet Med (2009) 2:78–82 79

Clinical outcomes
To date there is only limited published literature on vi-
scosupplementation therapy for ankle OA. Two recent
studies seem to show efficacy on ankle pain and function
(Table 2)[15,16]. Salk et al. performed a randomized,
double-blind, saline solution-controlled trial of intra-artic-
ular injection of sodium hyaluronate for the treatment of
ankle OA. Both groups had significant improvement in the
ankle osteoarthritis score at 6 months. However, more of
the patients in the hyaluronate group had [30 points of
improvement on the ankle osteoarthritis score as compared
with the baseline value [15]. This is the first controlled
study to show a benefit with HA in the treatment of ankle
OA and is consistent with previous published studies using
HA in the knee.
Our group performed a prospective, controlled study in
patients with unilateral ankle OA and we concluded simi-
larly that a regimen of 5 weekly intra-articular injection of
sodium hyaluronate was safe and efficacious in the areas of
pain and ankle function [16]. The patients’ satisfaction rate
was high with only relatively few local adverse events.
These effects were rapid at 1 week post the fifth injection
and could last for 6 months or more. One limitation in this
trial includes the absence of a control group, thus the
placebo effects associated with joint injections per se were
not analyzed.
Complications
The safety of viscosupplementation has been well docu-
mented in clinical trials and practice. Because there are no
known hyaluronate–medication interactions, it is a good
option for patients on multiple medications, particularly the
elderly. Mild injection-site pain and swelling are the most
common adverse events in the injected joints. These
reactions are usually transient, lasting 1 or 2 days and
generally respond well to local modalities and NSAIDs.
Other adverse events included rash, muscle cramps, diz-
ziness, nausea, headache, local ecchymosis, and pruritus.
The overall incidence of adverse reactions has been
reported to be approximately 1–4% per injection [25–30].
Rare cases of calcium pyrophosphate dehydrate arthritis or
pseudogout flares after both sodium hyaluronate and Syn-
visc have been reported [31]. There is growing evidence
that Synvisc may be associated with an adverse event
termed pseudosepsis or a severe acute inflammatory reac-
tion [32–34]. Pseudosepsis presents as a severe
inflammatory process of the joint, with a large effusion,
and significant pain occurring within 1 to 3 days of the
injection. It requires symptomatic treatment, including use
of modalities, activity modification, analgesics, and NSA-
IDs. Once infection has been excluded, intra-articular
steroids may be of value [32,34].
No systemic adverse events were reported in the litera-
ture relating to ankle viscosupplementation. In the study by
Salk et al., injection site pain was noted in 5 (29%) of the 17
patients including 3 in HA group and 2 in the saline solution
group, with no significant difference between the groups.
This injection site pain typically lasted no more than 3 days.
In our ankle OA trial, we reported that local pain and
erythema at the injection site occurred in 5 of 75 patients. It
was mild and resolved within 48 h without sequela in all
cases. The adverse reaction rate was 5.3% per injection and
6.7% per patient. The occurrence of adverse events was
Table 2 Clinical trials of
viscosupplementation in ankle
OA
Author
date
Viscosupplement Study patients
in two different
locations
Outcome measures Outcomes
Salk et al.
(2006)
[15]
Hyalgan
(five injections)
1 ml per injection
17
9HA
8 placebo
AOS
WOMAC pain domain
Ankle ROM
QOL (EQ-5D, SF-12)
Rescue medication table
count
Safe and efficacious at
6 months
Saline solution group
also demonstrated a
significant clinical
benefit, albeit to a
lesser degree
Sun et al.
(2006)
[16]
Supartz (five
injections)
2.5 ml per
injection
75
75 HA
No placebo
AOS
AOFAS ankle/hindfoot score
Ankle ROM
Patients’ global satisfaction
Rescue medication table
count
Safe and efficacious,
effects rapid at
1 week post the fifth
injection, lasting for
6 months or more
High patients’
satisfaction rate.
Significant reduction in
medication
consumption
80 Curr Rev Musculoskelet Med (2009) 2:78–82

difficult to predict. They sometimes occurred after several
injections without any reaction previously, and sometimes
they did not occur in subsequent injections. Interestingly, we
found that local adverse reactions did not predict treatment
failure. All ofthese patient received subsequent injections and
they still improved clinically and reported high satisfaction.
Injection technique
Intra-articular injection of the ankle joint is easy to perform
and requires no radiologic guidance.
We position the patient in the supine position, with the
knee flexed and the foot flat on the plinth. The ankle is
placed in a degree of plantarflexion, which opens the
anterior aspect of the joint. We identify the space between
the anterior border of the medial malleolus and the medial
border of the tibialis anterior tendon and palpate this space
for the articulation of the talus and tibia to locate a suitable
entry point into the ankle joint. An alternative point of
entry may also be made at the upper, inner aspect of either
malleolus. The injections are performed in aseptic condi-
tions. We insert an 18–22 G needle into the identified space
and direct posterolaterally to run parallel to the upper
surface of the talus, which is slightly convex (Figs. 1and
2). Joint effusion, if present, should be aspirated before
injection to prevent dilution of the viscosupplement.
Excessive weight bearing and strenuous activity are dis-
couraged for 48 h after each injection.
Further studies needed
Despite the fact that HA has been proposed as a useful
treatment of symptomatic knee OA, its role in the treatment
of ankle OA is still not clear, due fundamentally to the
dearth of studies and to the methodological limitations of
those that have been published. The exact mechanisms of
viscosupplementation action on osteoarthritic joints are
uncertain. Although recent attention has focused on the
disease-modifying potential of HA, especially the chon-
droprotective mechanism, definitive evidence is still
lacking. We believe that HA can be used as an adjunct
therapy, after failure of one or more courses of oral pain
medications, or perhaps as a first choice in the treatment of
ankle OA before prescription of pain medications. It is
important to understand the distinct mechanisms of HA to
help appropriately place viscosupplementation into the
physicians’ treatment algorithms.
Future studies regarding optimal dosing regimen; opti-
mal number of injections in a course of treatment;
favorable prognostic factors; effectiveness and safety of
repeated courses of therapy; different concentration and
molecular weight options for ankle viscosupplementation;
as well as the biochemical, morphologic, and histopatho-
logic effects on cartilage are warranted. Cost-effectiveness
needs to be addressed. The robust placebo effect deserves
special attention when critically interpreting outcome data.
Comparison studies or combination therapies with other
treatment options, such as intra-articular steroid injections,
NSAIDs, and therapeutic exercise, are also needed.
We hoped that this review will stimulate interest in
research to assess the potential role of viscosupplementa-
tion in treating ankle OA and more research is needed to
demonstrate its true benefit before this treatment option
will be fully accepted.
Conclusion
The published data suggest that viscosupplementation may
be a safe and effective method in the treatment of ankle
Fig. 1 Ankle joint injection
Fig. 2 Ankle joint injection
Curr Rev Musculoskelet Med (2009) 2:78–82 81

OA. However, the limited number of patients with ankle
OA enrolled in clinical trials precludes any definitive
conclusion about its safety and efficacy. To date, ankle
viscosupplementation should only be used under careful
supervision by the clinician. Many uncertainties on the use
of HA remain. More studies with larger patient populations
are required before viscosupplementation should be inclu-
ded into the treatment paradigm for patients with ankle
OA.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
References
1. Creamer P, Hochberg MC. Osteoarthritis. Lancet. 1997;350:503–
8.
2. Felson DT, Lawrence RC, Dieppe PA, et al. Osteoarthritis: new
insights. Part 1: the disease and its risk factors. Ann Intern Med.
2000;133:635–46.
3. Buckwalter JA, Mankin HJ. Articular cartilage: degeneration and
osteoarthritis, repair, regeneration, and transplantation. Instr
Course Lect. 1998;47:487–504.
4. Adams ME. An analysis of clinical studies of the use of cross
linked hyaluronan, hylan, in the treatment of osteoarthritis.
J Rheumatol Suppl. 1993;39:16–8.
5. Frizziero L, Govoni E, Bachin P. Intraarticular hyaluronic acid in
the treatment of osteoarthritis of the knee: clinical and morpho-
logical study. Clin Exp Rheumatol. 1998;16:441–9.
6. Adams ME, Atkinson MH, Lussier AJ, et al. The role of visco-
supplementation with hylan G-F 20 (Synvisc) in the treatment of
osteoarthritis of the knee: a Canadian multicenter trial comparing
hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-
inflammatory drugs (NSAIDs) and NSAIDs alone. Osteoarthritis
Cartilage. 1995;3(4):213–25.
7. Belcher C, Yaqub R, Fawthrop F, Bayliss M, et al. Synovial fluid
chondroitin and keratan sulphate epitopes, glycosaminoglycans,
and hyaluronan in arthritic and normal knees. Ann Rheum Dis.
1997;56:299–307.
8. Engstro
¨m-Laurent A. Hyaluronan in joint disease. J Int Med.
1997;242:57–60.
9. Balazs EA, Denlinger JL. Viscosupplementation: a new concept
in the treatment of osteoarthritis. J Rheumatol Suppl. 1993;39:
4–9.
10. Rydell N, Balazs EA. Effect of intra-articular injection of hyal-
uronic acid on the clinical symptoms of osteoarthritis and on
granulation tissue formation. Clin Orthop. 1971;80:25–32.
11. American College of Rheumatology Subcommittee on Osteoar-
thritis Guidelines. Recommendations for the medical manage-
ment of osteoarthritis of the hip and knee 2000 update. Arthritis
Rheum. 2000;43:1905–15.
12. Kelly MA, Goldberg VM, Healy WL, et al. Osteoarthritis and
beyond: a consensus on the past, present, and future of hyalu-
ronans in orthopedics. Orthopedics. 2003;26:1064–81.
13. Pleimann JH, Davis WH, Cohen BE, et al. Viscosupplementation
for the arthritic ankle. Foot Ankle Clin. 2002;7(3):489–94.
14. Wang CW, Gao LH, Jin XY, et al. Clinical study of sodium
hyaluronate in supplementary treatment of comminuted fracture
of ankle. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2002;
16(1):21–2.
15. Salk RS, Chang TJ, D’Costa WF, et al. Sodium hyaluronate in the
treatment of osteoarthritis of the ankle: a controlled, randomized,
double-blind pilot study. J Bone Jt Surg Am. 2006;88:295–302.
16. Sun SF, Chou YJ, Hsu CW, et al. Efficacy of intra-articular
hyaluronic acid in patients with osteoarthritis of the ankle: a
prospective study. Osteoarthritis Cartilage. 2006;14(9):867–74.
17. Conrozier T, Bertin P, Mathieu P, et al. Intra-articular injections
of hylan G-F 20 in patients with symptomatic hip osteoarthritis:
an open label, multicentre, pilot study. Clin Exp Rheumatol.
2003;21:605–10.
18. Migliore A, Tormenta S, Martin LSM, et al. Open pilot study of
ultrasound-guided intra-articular injection of hylan G-F 20
(Synvisc) in the treatment of symptomatic hip osteoarthritis. Clin
Rheumatol. 2005;24:285–9.
19. Tikiz C, Unlu Z, Sener A, et al. Comparison of efficacy of lower
and higher molecular weight viscosupplementation in the treat-
ment of hip osteoarthritis. Clin Rheumatol. 2005;24:244–50.
20. Labbe M, Ridgeland E, Savoie FH, et al. The short-term efficacy
of hyaluronic acid injections for the treatment of degenerative
arthrosis of the shoulder. Arthroscopy. 2003;19:S13–8.
21. Marshall KW. Intra-articular hyaluronan therapy. Foot Ankle
Clin N Am. 2003;8:221–32.
22. Clarke S, Lock V, Duddy J, et al. Intra-articular hylan G-F 20 in
the management of patellofemoral osteoarthritis of the knee. The
Knee. 2005;12:57–62.
23. Roux C, Fontas E, Breuil V, et al. Injection of intra-articular
sodium hyaluronidate (Sinovial) into the carpometacarpal joint of
the thumb (CMC1) in osteoarthritis. A prospective evaluation of
efficacy. Jt Bone Spine. 2007;74(4):368–72.
24. Kellgren JH, Lawrence JS. Atlas of standard radiographs: the
epidemiology of chronic rheumatism, vol. 2. Oxford, UK:
Blackwell Scientific Publications; 1963.
25. Hammesfahr JF, Knopf AB, Stitik T. Safety of intra-articular
hyaluronates for pain associated with osteoarthritis of the knee.
Am J Orthop. 2003;32:277–83.
26. Watterson JR, Esdaile JM. Viscosupplementation: therapeutic
mechanisms and clinical potential in osteoarthritis of the knee. J
Am Acad Orthop Surg. 2000;8:277–84.
27. Lussier A, Cividino AA, McFarlane CA, et al. Viscosupple-
mentation with hylan for the treatment of osteoarthritis: findings
from a clinical practice in Canada. J Rheumatol. 1996;23:1579–
85.
28. Kemper F, Gebhardt U, Meng T, et al. Tolerability and short-term
effectiveness of hylan G-F 20 in 4253 patients with osteoarthritis
of the knee in clinical practice. Curr Med Res Opin.
2005;21:1261–9.
29. Waddell DD. The tolerability of viscosupplementation: low
incidence and clinical management of local adverse events. Curr
Med Res Opin. 2003;19:575–80.
30. Waddell DD, Bricker DC. Clinical experience with the effec-
tiveness and tolerability of hylan G-F 20 in 1047 patients with
osteoarthritis of the knee. J Knee Surg. 2006;19:19–27.
31. Hamburger MI, Lakhanpal S, Mooar PA, et al. Intraarticular
hyaluronans: a review of product-specific safety profiles. Semin
Arthritis Rheum. 2003;32:296–309.
32. Goldberg VM, Coutts RD. Pseudoseptic reactions to hylan vi-
scosupplementation: diagnosis and treatment. Clin Orthop.
2004;419:130–7.
33. Marino AA, Waddell DD, Kolomytkin OV, et al. Assessment of
immunologic mechanisms for flare reactions to Synvisc. Clin
Orthop. 2006;442:187–94.
34. Leopold SS, Warme WJ, Pettis PD, et al. Increased frequency of
acute local reaction to intra-articular hylan G-F 20 in patients
receiving more than one course of treatment. J Bone Jt Surg.
2002;84A:1619–23.
82 Curr Rev Musculoskelet Med (2009) 2:78–82