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BMC Musculoskelet Disord. 2017 May 26;18(1):223. doi: 10.1186/s12891-017-1591-4.

Efficacy and safety of single injection of cross-linked sodium hyaluronate vs. three injections of high molecular weight sodium hyaluronate for osteoarthritis of the knee: a double-blind, randomized, multi-center, non-inferiority study.

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Department of Orthopedic Surgery, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul, South Korea.
Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102, Heukseok-ro, Dongjak-gu, Seoul, South Korea.
Department of Orthopedic Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 211, Eonju-ro, Gangnam-gu, Seoul, South Korea.
Department of Orthopedic Surgery, School of Medicine, Kyungpook National University, 130, Dongdeok-ro, Jung-gu, Daegu, South Korea.
Department of Orthopedic Surgery, Chonbuk National University Hospital, Research Institute of Clinical Medicine, Chonbuk National University Medical School, 20, Geonji-ro, Deokjin-gu, Jeonju-si, Jeollabuk-do, South Korea.
Department of Orthopedic Surgery, Ewha Womans University Mockdong Hospital, 1071, Anyangcheon-ro, Yangcheon-gu, Seoul, South Korea.
Department of Orthopedic Surgery, National Health Insurance Corporation Ilsan Hospital, 100, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, South Korea.
Department of Orthopedic Surgery, Hanyang University College of Medicine, 222-1, Wangsimni-ro, Seongdong-gu, Seoul, South Korea.
Department of Orthopedic Surgery, Busan Paik Hospital, College of Medicine, Inje University, 75, Bokji-ro, Busanjin-gu, Busan, South Korea.
Department of Orthopedic Surgery Bundang CHA Hospital, College of Medicine, CHA University, 59, Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea.
Department of Orthopedic Surgery, KonKuk University Medical Center, KonKuk University School of Medicine, 120-1, Neungdong-ro, Gwangjin-gu, Seoul, South Korea.
Department of Orthopedic Surgery, University of Ulsan, College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, South Korea.
Department of Orthopaedic Surgery, Seoul National University College of Medicine, 101 Daehak-ro, Jongnogu, Seoul, 110-744, Republic of Korea.



This randomized, double-blind, multi-center, non-inferiority trial was conducted to assess the efficacy and safety of a cross-linked hyaluronate (XLHA, single injection form) compared with a linear high molecular hyaluronate (HMWHA, thrice injection form) in patients with symptomatic knee osteoarthritis.


Two hundred eighty seven patients with osteoarthritis (Kellgren-Lawrence grade I to III) were randomized to each group. Three weekly injections were given in both groups but two times of saline injections preceded XLHA injection to maintain double-blindness. Primary endpoint was the change of weight-bearing pain (WBP) at 12 weeks after the last injection. Secondary endpoints included Western Ontario and McMaster Universities Osteoarthritis index; patient's and investigator's global assessment; pain at rest, at night, or in motion; OMERACT-OARSI responder rate; proportion of patients achieving at least 20 mm or 40% decrease in WBP; and rate of rescue medicine use and its total consumption.


Mean changes of WBP at 12 weeks after the last injection were -33.3 mm with XLHA and -29.2 mm with HMWHA, proving non-inferiority of XLHA to HMWHA as the lower bound of 95% CI (-1.9 mm, 10.1 mm) was well above the predefined margin (-10 mm). There were no significant between-group differences in all secondary endpoints. Injection site pain was the most common adverse event and no remarkable safety issue was identified.


This study demonstrated that a single injection of XLHA was non-inferior to three weekly injections of HMWHA in terms of WBP reduction, and supports XLHA as an effective and safe treatment for knee osteoarthritis.

TRIAL REGISTRATION: ( NCT01510535 ). This trial was registered on January 6, 2012.


Hyaluronic acid; Inflammation; Knee osteoarthritis; Treatment

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