The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 94, Issue 1

Scientific Articles | January 04, 2012

Intra-Articular Injection of Hyaluronic Acid Is Not Superior to Saline Solution Injection for Ankle Arthritis: A Randomized, Double-Blind, Placebo-Controlled Study

Henry DeGroot, III, MD¹; Sofia Uzunishvili, MD¹; Robert Weir, MD¹; Ali Al-omari, MD²; Bruna Gomes, BS¹

¹ 2000 Washington Street, Suite 544, Newton, MA 02459. E-mail address for H. DeGroot: degrootoffice@gmail.com. E-mail address for S. Uzunishvili: Sofia.uz@gmail.com. E-mail address for R. Weir: weir02481@gmail.com. E-mail address for B. Gomes: brunnettsa@yahoo.com
² The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104-4399. E-mail address: dralio@hotmail.com

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Disclosure statement for author(s): PDF

Investigation performed at Newton-Wellesley Hospital, Newton, MassachusettsA commentary by Timothy R. Daniels, MD, FRCS(C), and Ellie Pinsker, BA&Sc, is linked to the online version of this article at jbjs.org.

Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. None of the authors, or their institution(s), have had any financial relationship, in the thirty-six months prior to submission of this work, with any entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Also, no author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

J Bone Joint Surg Am, 2012 Jan 04;94(1):2-8. doi: 10.2106/JBJS.J.01763

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Abstract

Background:

Intra-articular injections of hyaluronic acid are potentially useful to treat ankle osteoarthritis, yet their effectiveness has not been proven. Both single and multiple-dose treatments for ankle arthritis with use of various hyaluronic acid products have been recommended, but few high-quality studies have been published. The aim of this study was to compare the effectiveness of a single intra-articular injection of hyaluronic acid with a single intra-articular injection of normal saline solution (placebo) for osteoarthritis of the ankle.

Methods:

Sixty-four patients with ankle osteoarthritis who met all study criteria were randomly assigned to a single intra-articular injection of 2.5 mL of low-molecular-weight, non-cross-linked hyaluronic acid or a single intra-articular injection of 2.5 mL of normal saline solution. The primary outcome measure was the change from baseline in the American Orthopaedic Foot & Ankle Society (AOFAS) clinical rating score at the six-week and twelve-week follow-up examination. Secondary outcome measures included the Ankle Osteoarthritis Scale score and patient-reported pain with use of a visual analog pain scale.

Results:

Of the sixty-four patients randomized and treated, eight patients withdrew, leaving fifty-six patients who completed the entire study. There was one mild adverse event (1.6%) among the sixty-four patients. At six weeks and twelve weeks, the mean AOFAS scores in the hyaluronic acid group had improved from baseline by 4.9 and 4.9 points, respectively, whereas the mean AOFAS scores in the placebo group initially worsened by 0.4 point at six weeks and then improved by 5.4 points at twelve weeks. While the change at twelve weeks from baseline was substantial for both groups, the between-group differences were not significant.

Conclusions:

We found that a single intra-articular injection of low-molecular-weight, non-cross-linked hyaluronic acid is not demonstrably superior to a single intra-articular injection of saline solution for the treatment of osteoarthritis of the ankle.

Level of Evidence:

Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Figures in this Article

Introduction

Introduction | Materials and Methods | Results | Discussion

Joint injections with hyaluronic acid were approved by the United States Food and Drug Administration (FDA) for the treatment of osteoarthritis of the knee in 1997. Although hyaluronic acid has not been approved by the FDA for use in the ankle, studies have shown that it is well tolerated^1,2. Traditionally, hyaluronic acid therapy has been administered as a series of three or five injections given at one-week intervals. However, single-injection treatments with use of high-molecular-weight cross-linked hyaluronic acid products have been shown to provide significant pain relief in the knee³ as well as in the ankle⁴. Single-dose treatments for ankle arthritis with use of low-molecular-weight, non-crossed-linked hyaluronic acid products have been recently reported⁵. Single-dose hyaluronic acid treatment regimens have a lower rate of device-associated adverse events⁶. At present, the best combination of hyaluronic acid dose frequency and hyaluronic acid product type for ankle arthritis has not been determined.

The goal of this study was to compare the therapeutic effect of a single intra-articular injection of low-molecular-weight, non-crossed-linked hyaluronic acid (Supartz; Seikagaku, Tokyo, Japan) with a single intra-articular injection of normal saline solution (placebo) for osteoarthritis of the ankle.

Materials and Methods

Introduction | Materials and Methods | Results | Discussion

We conducted a randomized, prospective, double-blind (blinded patient and observer), saline solution-controlled, parallel experimental design study. The trial is registered with the U.S. National Institutes of Health on ClinicalTrials.gov (number NCT01243814). Inclusion and exclusion criteria are shown in Table I. Demographic and pretreatment score data are summarized in Table II. Subjects were recruited from the practice of the principal author (H.D.), by announcements in local newspapers, on the radio, on a study web page, and by flyers distributed in the medical center where the study was conducted. During the study period, all patients who were treated with hyaluronic acid for ankle arthritis were enrolled and treated according to the study protocol.

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TABLE I Inclusion and Exclusion Criteria

Inclusion criteria

Age of ≥18 yr

Ankle pain

Ankle arthritis classified on radiographs as Kellgren and Lawrence grade 2 or higher

American Orthopaedic Foot & Ankle Society score of ≤90 points

Willingness to discontinue all pain medications and nonsteroidal anti-inflammatory drugs other than the rescue pain medications provided in the study

Exclusion criteria

Pregnancy

Systemic inflammatory condition

Infection of the ankle or nearby soft tissues

Injection of steroid or surgery on the involved joint within 6 mo

Local cellulitis, rash, or skin condition

Diabetic or neuropathic Charcot arthropathy

Substantial vascular insufficiency

Current treatment with anticoagulants

Lower-extremity pain syndromes

Recent history of sciatica, ankle sprains, or plantar fasciitis

Severe ankle instability or malalignment

Known allergy to any of the components of either injection

Disabling degenerative joint disease of the ipsilateral hip, knee, or foot

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TABLE I Inclusion and Exclusion Criteria

Inclusion criteria

Age of ≥18 yr

Ankle pain

Ankle arthritis classified on radiographs as Kellgren and Lawrence grade 2 or higher

American Orthopaedic Foot & Ankle Society score of ≤90 points

Willingness to discontinue all pain medications and nonsteroidal anti-inflammatory drugs other than the rescue pain medications provided in the study

Exclusion criteria

Pregnancy

Systemic inflammatory condition

Infection of the ankle or nearby soft tissues

Injection of steroid or surgery on the involved joint within 6 mo

Local cellulitis, rash, or skin condition

Diabetic or neuropathic Charcot arthropathy

Substantial vascular insufficiency

Current treatment with anticoagulants

Lower-extremity pain syndromes

Recent history of sciatica, ankle sprains, or plantar fasciitis

Severe ankle instability or malalignment

Known allergy to any of the components of either injection

Disabling degenerative joint disease of the ipsilateral hip, knee, or foot

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TABLE II Baseline Characteristics for All Randomly Assigned Patients

	Active Group (N = 39)	Placebo Group (N = 25)
Age*(yr)	54.1 (14.5, 2.3)	61.9 (14.1, 2.8)
No. (%) of men	24 (61.5)	12 (48)
Body-mass index*(kg/m2)	29.3 (5.2, 0.8)	29.0 (4.5, 0.9)
Kellgren and Lawrence grade*	2.46 (0.79, 0.13)	2.72 (0.84, 0.17)
AOFAS score*	69.4 (13.9, 2.2)	63.5 (17.0, 3.4)
VAS score*	33.4 (22.4, 3.7)	35.0 (23.1, 4.7)
AOS pain score*	41.4 (18.8, 3.0)	46.4 (22.3, 4.8)

*The values are given as the mean, with the standard deviation and standard error of the mean given in parentheses. AOFAS = American Orthopaedic Foot & Ankle Society score, VAS = visual analog pain scale, and AOS = ankle osteoarthritis scale.

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TABLE II Baseline Characteristics for All Randomly Assigned Patients

	Active Group (N = 39)	Placebo Group (N = 25)
Age*(yr)	54.1 (14.5, 2.3)	61.9 (14.1, 2.8)
No. (%) of men	24 (61.5)	12 (48)
Body-mass index*(kg/m2)	29.3 (5.2, 0.8)	29.0 (4.5, 0.9)
Kellgren and Lawrence grade*	2.46 (0.79, 0.13)	2.72 (0.84, 0.17)
AOFAS score*	69.4 (13.9, 2.2)	63.5 (17.0, 3.4)
VAS score*	33.4 (22.4, 3.7)	35.0 (23.1, 4.7)
AOS pain score*	41.4 (18.8, 3.0)	46.4 (22.3, 4.8)

The study device was Supartz (Seikagaku), a brand of sodium hyaluronate. Supartz and other hyaluronic acid products are classified by the FDA as “devices” used to treat pain associated with osteoarthritis. Supartz is a sterile, viscoelastic purified solution of non-cross-linked sodium hyaluronate derived from rooster combs with a molecular weight of 620,000 to 1,170,000 Da. Each 2.5 mL of Supartz contains 25 mg of sodium hyaluronate dissolved in saline solution.

The primary outcome measure was the change from baseline in the American Orthopaedic Foot & Ankle Society (AOFAS) clinical rating score at six weeks and twelve weeks. Secondary outcome measures were the change from baseline in the Ankle Osteoarthritis Scale (AOS) score and the change from baseline on a patient-reported visual analog pain scale (VAS).

The AOFAS score combines subjective patient data on pain and mobility with objective data from the physical examination of the ankle and hindfoot. It is a widely used outcomes instrument in the foot and ankle literature, but it has not been validated^7,8. The AOS is a reliable, visual analog-based, disease-specific self-administered instrument, which has been validated in patients with osteoarthritis, and is designed specifically to measure the disability and pain from ankle osteoarthritis⁹. The VAS is a simple, validated, and commonly used patient-administered method for the measurement of pain intensity¹⁰. The VAS pain assessment tool consisted of a 100-mm horizontal line with anchors indicating no pain at the left end point and the worst possible pain at the right end point.

Simple non-block randomization was carried out by means of the selection of one of a multitude of opaque envelopes containing a group assignment number. Subjects randomized to the active group received one injection of 2.5 mL of low-molecular-weight, non-cross-linked sodium hyaluronate solution. Subjects randomized to the placebo group received one injection of 2.5 mL of normal saline solution. The ankle injections were given by means of an anteromedial or anterolateral approach with use of fluoroscopic guidance. Prior to skin preparation, the covered needle was placed on the skin and used to visualize the joint line. Topical ethyl chloride anesthetic spray was administered, and a standard sterile skin preparation technique was used. The contents of the syringes were concealed so that the patients were blinded to the treatment. Because of the differences in the viscosity of the injected materials, the physician who performed the injections could not be blinded. A second physician, who was blinded to the treatment, performed the follow-up examinations and collected the data for the study instruments. Study data were maintained in a secure computerized spreadsheet.

Analysis-of-variance studies were conducted on the AOFAS and AOS mean score differences between the active and placebo groups at six weeks and at twelve weeks. Additionally, to test for the possibility of significance that was masked by confounding factors despite the random assignment to groups, multiple regression models were constructed, with use of the AOFAS and AOS score difference at six and twelve weeks as the primary independent variables, and controlling for the following: Kellgren and Lawrence score; baseline AOS and VAS pain scores, as well as AOFAS and AOS scores themselves; and body-mass index, sex, right or left side, and age.

An a priori power analysis was performed to determine an adequate sample size for this study¹¹. Given a one-tailed matched-pairs t test with an effect size of the primary outcome measure of 0.4, a probability of alpha error (significance) of 0.95, and a required power (1 – beta) of 0.90, the total required sample size (both groups combined) was calculated to be fifty-five. From our original pool of sixty-four individuals, fifty-six subjects completed our study.

Source of Funding

No external funding was received from any source for this study.

Results

Introduction | Materials and Methods | Results | Discussion

The study was approved by the institutional review board at Newton-Wellesley Hospital. Potential subjects were initially screened by a study coordinator and then interviewed by the principal investigator. If available, radiographs of the ankle made within the previous six months were used to verify eligibility. Because of guidelines for the protection of human subjects, new radiographs of the ankle could not be made prior to enrollment and obtaining informed consent. As a result, the final eligibility status of some patients could be determined only after enrollment. Approximately 300 potential subjects were screened between November 2009 and February 2010 (Fig. 1). A total of seventy-nine patients (forty-five men and thirty-four women) were enrolled. On the basis of ankle radiographs and examination after enrollment, fifteen of the seventy-nine subjects enrolled were found to be ineligible. These fifteen patients had changes on ankle radiographs that were less than grade 2, according to the Kellgren and Lawrence grading system¹², or they were determined to be having pain from other causes, such as subtalar joint arthritis, osteochondral defects of the talus, or posterior tibial tendon pathology. Thus, sixty-four of the seventy-nine enrolled patients met all inclusion and exclusion criteria. All sixty-four were then randomized and treated according to the study protocol.

Fig. 1

Study flow chart. ITT = intention to treat, and AE = adverse event.

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Of the sixty-four patients treated, four patients did not return for the six-week examination. Three of them were from the placebo group, and one was from the active treatment group. Four other patients who returned at six weeks failed to return for the second visit at twelve weeks. One of these was from the placebo group, and three were in the active treatment group. We were able to contact all eight patients by telephone or by electronic mail at the time of the missed follow-up visits, and none reported an adverse event. The patients cited loss of interest in the study or lack of perceived benefit as their reasons for withdrawal. At baseline, the two study groups were similar in terms of sex, side, body-mass index, Kellgren and Lawrence grade, and baseline scores on the AOFAS, VAS, and AOS scales (Table II). The mean age (and standard deviation) of the patients was 54.1 ± 14.5 years in the active treatment group and 61.9 ± 14.1 years in the placebo group.

Changes from baseline in the AOFAS, AOS, and VAS scores at six and twelve weeks are shown in Table III. The patients in both the active treatment group and in the placebo group had improvements in the primary outcome measure at twelve weeks. At six weeks and twelve weeks, the mean AOFAS scores had improved from baseline by 4.9 and 4.9 points, respectively, in the active treatment group, whereas the mean AOFAS scores initially worsened by 0.4 point at six weeks and then improved by 5.4 points at twelve weeks in the placebo group. The improvement in AOFAS scores at six and twelve weeks from baseline was significant for the active group (p < 0.01) but not for the placebo group (Fig. 2). However, the between-group differences were not significant at either follow-up time (p = 0.20 and p = 0.90 at six and twelve weeks, respectively). Additionally, to test for the possibility of significance that was masked by confounding factors despite the random assignment to groups, multiple regression models were constructed, with use of the AOFAS score differences at six and twelve weeks as the primary independent variables, and controlling for the following: Kellgren and Lawrence score; baseline scores for AOS, VAS, and the AOFAS; as well as for body-mass index, sex, side, and age. No significant predictive power was found by adding the group variable to the model compared with the predictive power of the control variables alone.

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TABLE III Change in AOFAS, AOS, and VAS Scores from Baseline to the Six-Week and Twelve-Week Follow-Up Evaluations*

	Change from Baseline to Six Weeks			Change from Baseline to Twelve Weeks
	Change in Score†	Within-Group Difference (p value)	Between-Group Difference (p value)	Change in Score†	Within-Group Difference (p value)	Between-Group Difference (p value)
AOFAS score			0.196			0.897
Active group	4.97 ± 12.3 (0.9 to 9.0)	0.022		4.97 ± 10.3 (1.6 to 8.3)	0.006
Placebo group	–0.38 ± 18.3 (–8.2 to 7.5)	0.925		5.43 ± 16.3 (–1.6 to 12.4)	0.144
AOS score			0.577			0.138
Active group	–5.0 ± 21.6 (–12.2 to 2.2)	0.180		–5.3 ± 21.6 (–12.5 to 2.0)	0.165
Placebo group	–8.4 ± 21.7 (–17.6 to 0.9)	0.093		–14.8 ± 24.8 (–25.4 to –4.2)	0.013
VAS score			0.632			0.309
Active group	–6.4 ± 26.7 (–15.4 to 2.6)	0.173		–4.1 ± 26.5 (–13.0 to 4.8)	0.374
Placebo group	–3.0 ± 24.0 (–13.2 to 7.3)	0.580		–11.1 ± 21.6 (–20.4 to –1.9)	0.029

*AOFAS = American Orthopaedic Foot and Ankle Society score, VAS = visual analog pain scale, and AOS = Ankle Osteoarthritis Scale.
†Data are given as the mean and the standard deviation, with the 95% confidence interval in parentheses.

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TABLE III Change in AOFAS, AOS, and VAS Scores from Baseline to the Six-Week and Twelve-Week Follow-Up Evaluations*

	Change from Baseline to Six Weeks			Change from Baseline to Twelve Weeks
	Change in Score†	Within-Group Difference (p value)	Between-Group Difference (p value)	Change in Score†	Within-Group Difference (p value)	Between-Group Difference (p value)
AOFAS score			0.196			0.897
Active group	4.97 ± 12.3 (0.9 to 9.0)	0.022		4.97 ± 10.3 (1.6 to 8.3)	0.006
Placebo group	–0.38 ± 18.3 (–8.2 to 7.5)	0.925		5.43 ± 16.3 (–1.6 to 12.4)	0.144
AOS score			0.577			0.138
Active group	–5.0 ± 21.6 (–12.2 to 2.2)	0.180		–5.3 ± 21.6 (–12.5 to 2.0)	0.165
Placebo group	–8.4 ± 21.7 (–17.6 to 0.9)	0.093		–14.8 ± 24.8 (–25.4 to –4.2)	0.013
VAS score			0.632			0.309
Active group	–6.4 ± 26.7 (–15.4 to 2.6)	0.173		–4.1 ± 26.5 (–13.0 to 4.8)	0.374
Placebo group	–3.0 ± 24.0 (–13.2 to 7.3)	0.580		–11.1 ± 21.6 (–20.4 to –1.9)	0.029

Fig. 2

The mean AOFAS (American Orthopaedic Foot & Ankle Society) scores (and standard deviation) at baseline and at six and twelve weeks after saline solution or hyaluronic acid (Supartz) injections. The difference between groups was not significant at any time point.

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At six weeks and twelve weeks, the mean AOS scores in the active treatment group were improved from baseline by 5.0 and 5.3 points, respectively, while the mean AOS scores in the placebo group improved by 8.4 and 14.8 points, respectively. At six weeks, the improvement in the AOS scores from baseline was not significant for either group. At twelve weeks, the improvement from baseline was significant for the placebo group but not for the active group. The between-group differences were not significant.

At six weeks and twelve weeks, the mean VAS pain scores in the active group were improved from baseline by 6.4 and 4.1 points, respectively, while VAS scores in the placebo group improved by 3.0 and 11.1 points, respectively. At six weeks, the improvement in the VAS pain scores from baseline was not significant for either group. At twelve weeks, the improvement from baseline was significant for the placebo group but not for the active group. The between-group differences were not significant (p = 0.63 and p = 0.30 at six and twelve weeks, respectively).

There was one adverse event (1.6%), judged to be possibly related to the treatment, among the sixty-four patients. One patient in the active treatment group reported an enlarged lymph node in the ipsilateral groin, which resolved without treatment.

Discussion

Introduction | Materials and Methods | Results | Discussion

Joint injections with hyaluronic acid products were approved by the U.S. Food and Drug Administration for the treatment of osteoarthritis of the knee in 1997. Since then, the safety and efficacy of hyaluronic acid for the treatment of knee arthritis has been demonstrated in well-controlled studies^6,13-15. Only a small number of reports on the use of hyaluronic acid in the ankle have been published^1-5,16-20, and only two of them used a randomized, blinded, controlled design. Salk et al.¹ studied the efficacy and safety of five weekly injections of a low-molecular-weight, non-cross-linked hyaluronic acid product (Hyalgan) in the ankle, using a saline solution control, in a total of twenty patients randomized into two groups. Both the active group and the placebo group showed improvements from baseline in AOS and VAS scores at three months and at six months, but there was no significant difference between the two groups.

Cohen et al.² performed a randomized, double-blind, saline solution-controlled study of five weekly injections of a low-molecular-weight, non-cross-linked hyaluronic acid product (Hyalgan) for ankle osteoarthritis. A total of twenty-eight patients completed the study. Both the active treatment group and the saline solution group showed improvements from baseline in AOS scores at up to six months. At two weeks and six weeks, no significant difference between the groups was observed. At three months, the AOS scores in the active group were significantly better than the scores in the saline solution group; however, at six months, no significant difference between the groups was noted. Both the study by Salk et al. and that by Cohen et al. were supported by the manufacturer of the device, creating a potential source of bias^21,22.

To our knowledge, no other randomized, blinded, and controlled study of hyaluronic acid treatments in the ankle has been reported. Karatosun et al.¹⁶ randomized forty-three patients to three weekly injections of low-molecular-weight, non-cross-linked hyaluronic acid or six weeks of physical therapy in an unblinded trial. Both groups showed improvements over baseline in the AOS and the AOFAS scores, and no significant differences in outcomes were identified between the groups. In a nonrandomized, uncontrolled study for ankle osteoarthritis, Sun et al.¹⁷ found that five weekly injections of a low-molecular-weight, non-cross-linked hyaluronic acid product (Supartz [Artz] in Japan) led to significant improvements in AOS and AOFAS scores at one week, one month, three months, and six months. A nonrandomized, nonblinded study of three weekly injections of high-molecular-weight cross-linked hyaluronic acid after arthroscopy of the ankle²⁰ showed that patients who received hyaluronic acid had better scores on a nonvalidated pain rating scale.

Recently, single-injection treatments of hyaluronic acid for ankle arthritis have been reported. Witteveen et al.⁵ performed a manufacturer-sponsored, randomized, prospective, uncontrolled study using low-molecular-weight, non-cross-linked hyaluronic acid (Orthovisc; Anika Therapeutics, Bedford, Massachusetts). The patients were randomized to receive either a single injection of 1, 2, or 3 mL of the hyaluronic acid or three weekly injections of 1 mL of the hyaluronic acid. Only seventeen (65%) of twenty-six patients completed the study. At seven and fifteen weeks, improvement in the VAS scores was noted in 30% of those who had a single 1-mL injection and in 70% of those who had three 1-mL injections, but none of those who had a single 2-mL injection had improvement in the VAS scores at either time point. At twenty-seven weeks, the group that had three 1-mL injections had improved VAS scores.

Witteveen et al. also performed a study of a single injection and of two injections of a high-molecular-weight cross-linked hyaluronic acid product (Synvisc; Genzyme, Cambridge, Massachusetts) in a manufacturer-sponsored, uncontrolled multicenter trial⁴. In that study, patients were given one 2-mL injection and later were offered a second injection after one, two, or three months if they continued to have substantial pain. A total of thirty-one (56%) of fifty-five patients received one injection. Both the group that received one injection and the group that received two injections had significant improvement in VAS scores at three months. At three months, the VAS scores of the single-dose group were better than the scores of the two-dose group, and this difference was significant. On the basis of that study, the authors concluded that one dose of high-molecular-weight cross-linked hyaluronic acid results in a significant and sustained decrease in ankle osteoarthritis pain.

In our study of one dose of low-molecular-weight, non-cross-linked hyaluronic acid, both the active treatment group and the placebo group had significant improvements in the AOFAS scores at twelve weeks. However, the improvements in the groups were not significantly different. There are several possible reasons why our data show no difference between an injection of low-molecular-weight, non-cross-linked hyaluronic acid and an injection of saline solution. These include the dose regimen we used, the physical properties of the hyaluronic acid product we investigated, a potentially strong placebo effect due to saline solution, and a potentially weak treatment effect of a single dose of a low-molecular-weight, non-cross-linked hyaluronic acid product.

We administered a single injection of hyaluronic acid rather than three or five weekly injections, and this may explain our lack of positive findings. Studies of single-injections of other low-molecular-weight, non-cross-linked hyaluronic acid products have shown mixed results⁵. Single injections of high-molecular-weight, cross-linked hyaluronic acid products (Synvisc) have been shown to be effective in the ankle⁴. Single-dose treatments may be preferable to multiple-dose treatments because of lower rates of adverse events⁶. Therefore, other single-dose treatment regimens appear to be worth investigating.

One might argue that a single intra-articular injection of low-molecular-weight, non-cross-linked hyaluronic acid such as Supartz is not effective to treat arthritis of the ankle. However, our data appear to contradict this statement, since they show that patients in the active group had sustained improvements in AOFAS, AOS, and VAS pain scores over three months. Moreover, there is controversy over the relative benefits of high and low-molecular-weight hyaluronic acid products as well as cross-linked and non-cross-linked hyaluronic acid products. In high-quality, head-to-head studies comparing low and high-molecular-weight hyaluronic acid products^23,24 as well as cross-linked and non-cross-linked hyaluronic acid products for knee arthritis^25,26, no significant differences were found. On the basis of the available data, the ideal combination of dose regimen and hyaluronic acid product for the treatment of ankle arthritis has not been determined.

Other than differences in dosing and hyaluronic acid formulations, another possible explanation for our lack of positive findings is a strong placebo effect due to saline solution. A strong placebo effect from injections of saline solution in joints has been previously reported. In a recent large study of hyaluronic acid for shoulder pain with >200 randomized patients²⁷, the improvement in the saline solution placebo group was larger than that in both hyaluronic acid treatment groups. In addition, certain study design factors have been shown to be associated with a stronger placebo effect²⁸, including administration of the placebo by means of an injection and a blinded study design, both of which were features of this trial. Thus, the significant positive effect of a saline solution injection in this study is not unusual. More importantly, the treatment effect of hyaluronic acid for ankle osteoarthritis may be weak. Even in the knee, where hyaluronic acid injections are routinely used, the size of the treatment effect is low. In one large meta-analysis of knee trials, Strand et al.²⁹ concluded that the true hyaluronic acid treatment effect size was just 0.2, which is defined as small³⁰.

Other factors, such as differences in the etiology of knee and ankle osteoarthritis or differences in the tribology of the two joints, may explain why hyaluronic acid treatments might be more effective in the knee than in the ankle. While most knee arthritis is primary, most ankle arthritis is posttraumatic³¹, and this may have an effect on the response to hyaluronic acid treatment. In addition, studies^32,33 have shown that, while the knee is an unstable hinge with a contact surface area of 1120 mm², the ankle is a stable hinge with high congruency and a contact surface area of 350 mm². Furthermore, the articular cartilage of the ankle is stiffer, denser, and less permeable and has a lower content of both water and sulfated glycosaminoglycans³⁴.

The strengths of this study include the randomized, prospective, double-blind design; the large number of patients; and the absence of any financial support from the manufacturer of the device. In addition, we used careful selection to include only the patients who clearly had ankle-related pain and corresponding radiographic findings.

We acknowledge several weaknesses in this study, including a relatively short period of follow-up after the treatment. However, the literature has shown that a treatment effect is observed as soon as one week after injection, and the maximal effect appears to occur between five and thirteen weeks after injection³⁵. The follow-up time of six to twelve weeks in our study should have been sufficient to detect the possible benefits of the treatment regimen.

In addition, because of the simple non-block randomization procedure we used, the treatment and placebo groups were of unequal size, which could be a source of bias. The patients in the placebo group were older, on the average, than the patients in the active group. However, published data have shown that patient response to hyaluronic acid is not dependent on age³⁶. To examine any possible age effect, we reanalyzed our data after stratifying the patients into two groups according to age, but the results were no different.

Finally, although the number of patients we enrolled is more than double the number in the next largest trial, the possibility remains that this study is underpowered. Statistical power is strongly influenced by the magnitude of the true treatment effect. Our a priori power analysis¹¹ suggests that we achieved adequate statistical power to detect an effect size of 0.4, if an effect exists, and this is within the range of reported effect size for hyaluronic acid treatments^22,35.

Some health-care systems and insurance companies have concluded that hyaluronic acid therapy for the ankle remains experimental and investigational, or that it lacks sufficient evidence for routine use^37,38. Our data, together with the data from the other two Level-I studies published to date^1,2, raise some concerns about the substantial cost of hyaluronic acid for the treatment of ankle arthritis. We believe that alternative nonsurgical treatments for ankle osteoarthritis are required and should be investigated.

On the basis of our data, we can conclude that, in the ankle, a single injection of low-molecular-weight, non-cross-linked hyaluronic acid of the type we studied is not superior to a single injection of saline solution for the treatment of arthritis. Different dose regimens and different hyaluronic acid products deserve further study; however, entirely new types of nonsurgical treatments for ankle osteoarthritis are also needed.

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Topics

ankle ; hyaluronic acid ; intra-articular injections ; osteoarthritis of ankle ; saline solution

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Angelique G.H. Witteveen*, Gino M. M. J. Kerkhoffs and C. Niek van Dijk**

Posted on February 07, 2012

Is one intra-articular injection of hyaluronic acid superior to saline solution injection for ankle arthritis?

* Sint Maartenskliniek Nijmegen the Netherlands, ** Academical Medical Centre Amsterdam, the Netherlands Corresponding author Angeligue G.H. Witteveen; agh.witteveen@hotmail.com

With pleasure we read the study by Henry de Groot III, MD, et al: “Intra-articular injection of Hyaluronic Acid is not superior to Saline Solution Injection for Ankle Arthritis. A randomized, Double –Blind , Placebo-Controlled Study” and the commentary written by Timothy R. Daniels and Ellie Pinsker, published in the Commentary and Perspective section .First we congratulate Henry de Groot III and co-authors for their well conducted study. Secondly we would like to make some remarks in reaction to both the study as well as the commentary. The title of the manuscript fails to inform the reader about the fact that there is only a single injection Supartz comparison versus placebo. The current study was performed without a dose finding study to determine the optimal dose. We know from earlier studies [Witteveen et al.] that it is important to perform a dose finding study for each type of Hyaluronic Acid and for each joint type. As an example for Orthovisc®, also a sodium hyaluronate like Supartz, it was found that a single injection was not successful; a dosing schedule of 3 weekly injections was the most successful. Without knowing the optimum dosing schedule of Supartz one cannot draw definite conclusions. It is very well possible that a 2 weekly or 3 weekly injection therapy with Supartz would be successful on pain when compared to placebo. Based on the outcome of the current study it can be concluded that a single injection with Supartz is not more successful when compared to placebo.

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Henry DeGroot, III, Sofia Uzunishvili, Robert Weir, Ali Al-omari, Bruna Gomes; Intra-Articular Injection of Hyaluronic Acid Is Not Superior to Saline Solution Injection for Ankle ArthritisA Randomized, Double-Blind, Placebo-Controlled Study. The Journal of Bone & Joint Surgery. 2012 Jan;94(1):2-8.

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