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Intra-Articular Injection of Hyaluronic Acid Is Not Superior to Saline Solution Injection for Ankle ArthritisA 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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Investigation performed at Newton-Wellesley Hospital, Newton, Massachusetts

A 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.

Copyright © 2012 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2012 Jan 04;94(1):2-8. doi: 10.2106/JBJS.J.01763
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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.


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.


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.


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.

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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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