Open Access Highly Accessed Open Badges Research article

Intra-articular hyaluronic acid injection versus oral non-steroidal anti-inflammatory drug for the treatment of knee osteoarthritis: a multi-center, randomized, open-label, non-inferiority trial

Muneaki Ishijima1*, Toshitaka Nakamura2, Katsuji Shimizu3, Kunihiko Hayashi4, Hiraku Kikuchi5, Satoshi Soen6, Go Omori7, Toshihiko Yamashita8, Yuji Uchio9, Junji Chiba10, Yuki Ideno4, Mitsuaki Kubota1, Hisashi Kurosawa1, Kazuo Kaneko1 and for the Research Group of Cartilage Metabolism

Author Affiliations

1 Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan

2 Department of Orthopaedic Surgery, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan

3 Department of Orthopaedic Surgery, Gifu University, School of Medicine, 1-1, Yanagido, Gifu City 501-1193, Japan

4 Department of Basic Medical Sciences, School of Health Sciences, Faculty of Medicine, Gunma University, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan

5 Department of Orthopaedic Surgery, Sakai Hospital Kinki University Faculty of Medicine, 2-7-1, Harayamadai, Minami-ku, Sakai-city 590-0132, Osaka, Japan

6 Department of Orthopaedic Surgery and Rheumatology, Nara Hospital Kinki University Faculty of Medicine, 1481-1, Otodacho, Ikoma, Nara 630-0293, Japan

7 Department of Health and Sports, Niigata University of Health and Welfare, 1398, Shimamicho, Niigata Kita-ku, Niigata 950-3198, Japan

8 Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan

9 Department of Orthopaedics, Shimane University, School of Medicine, 89-1, Enya-cho, Izumo-shi, Shimane 693-8501, Japan

10 Department of Orthopaedic Surgery, Tokyo Women’s Medical University, Medical Center East, 2-1-10, Nishiogu, Arakawa, Tokyo 116-8567, Japan

For all author emails, please log on.

Arthritis Research & Therapy 2014, 16:R18  doi:10.1186/ar4446

Published: 21 January 2014



While many of the commonly used conservative treatments for knee osteoarthritis (OA) have been recognized to be effective, there is still insufficient evidence available. Among the pharmacological treatments for knee OA, oral non-steroidal anti-inflammatory drugs (NSAIDs) act rapidly and are recommended for the management of OA. However, frequent and serious adverse effects of NSAIDs have been recognized. Intra-articular injections of hyaluronic acid (IA-HA) for the treatment of knee OA have been shown to reduce pain and improve joint function. However, there has been no qualified direct comparison study of the efficacy and safety between IA-HA and NSAIDs for patients with knee OA. The aim of this study was to clarify the efficacy and safety of early-phase IA-HA in comparison to those of NSAIDs for patients with knee OA.


This multicenter, randomized, open-label, parallel-group, non-inferiority comparison study with an oral NSAID involved a total of 200 patients with knee OA. An independent, computer-generated randomization sequence was used to randomly assign patients in a 1:1 ratio to NSAIDs three times per day for five weeks (n = 100) or IA-HA once a week for five weeks (n = 100). The primary endpoint was the percentage change in the patient-oriented outcome measure for knee OA, the Japanese Knee Osteoarthritis Measure (JKOM) score. All patients were questioned regarding any adverse events during treatment. The full analysis set (FAS) was used for analysis. The margin of non-inferiority was 10%.


The analyses of primary endpoint included 98 patients in the IA-HA group and 86 patients in the NSAID group. The difference in the percentage changes of the JKOM score between the two intervention arms (IA-HA; -34.7% (P<0.001), NSAID; -32.2% (P<0.001)) was -2.5% (95% confidence interval (CI): -14.0 to 9.1), indicating IA-HA was not inferior to NSAID. The frequency of both withdrawal and adverse events in the IA-HA group were significantly lower than those in the NSAID group (P = 0.026 and 0.004, respectively).


The early efficacy of IA-HA is suggested to be not inferior to that of NSAIDs, and that the safety of the early phase of IA-HA is superior to that of NSAIDs for patients with knee OA.

Trial registration

UMIN Clinical Trials Registry (UMIN-CTR), UMIN000001026.