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The efficacy of multiple versus single hyaluronic acid injections: a systematic review and meta-analysis

  • Concoff, Andrew1
  • Sancheti, Parag2
  • Niazi, Faizan3
  • Shaw, Peter3
  • Rosen, Jeffrey4
  • 1 St. Jude Medical Center, Departments of Orthopedics and Rheumatology, Fullerton, California, USA , California (United States)
  • 2 Sancheti Institute for Orthopaedics and Rehabilitation, Maharashtra, India , Maharashtra (India)
  • 3 Ferring Pharmaceuticals Inc., Parsippany, NJ, USA , Parsippany (United States)
  • 4 Weill Medical College of Cornell University, Department of Orthopaedics & Rehabilitation, New York Presbyterian Queens; Department of Clinical Orthopaedic Surgery, New York, NY, USA , New York (United States)
Published Article
BMC Musculoskeletal Disorders
Springer (Biomed Central Ltd.)
Publication Date
Dec 21, 2017
DOI: 10.1186/s12891-017-1897-2
Springer Nature


BackgroundIntra-articular hyaluronic acid (IA-HA) is a common therapy used to treat knee pain and suppress knee inflammation in knee osteoarthritis (OA), typically prescribed in regimens ranging from a single injection to 5 weekly injections given once weekly. We conducted a systematic review to determine the efficacy of IA-HA, with subgroup analyses to explore the differences in knee pain and adverse events (AEs) across different dosing regimens.MethodsWe conducted a systematic search of the literature to identify studies evaluating IA-HA for the management of knee OA compared to IA-saline. Primary outcome measure was the mean knee pain score at 13 Weeks (3 months) or 26 weeks (6 months). Secondary outcome was the number of treatment-related AEs and treatment-related serious adverse events (SAEs). We evaluated differences in levels of pain and AEs/SAEs between dosing regimens compared to IA-Saline.ResultsThirty articles were included. Overall, IA-HA injections were associated with less knee pain compared to IA-Saline injections for all dosing regimens. 2–4 injections of IA-HA vs. IA-Saline produced the largest effect size at both 3-months and 6-months (Standard mean difference [SMD] = −0.76; −0.98 to −0.53, 95% CI, P < 0.00001, and SMD = −0.36; −0.63 to −0.09 95% CI, P = 0.008, respectively). Additionally, single injection studies yielded a non-significant treatment effect at 3 and 6 months, while ≥5 5 injections demonstrated a significant improvement in pain only at 6 months. Five or more injections of IA-HA were associated with a higher risk of treatment-related AEs compared to IA-Saline (Risk ratio [RR] = 1.67; 1.09 to 2.56 95% CI, p = 0.02), which was a result not seen within the 1 and 2–4 injection subgroups.ConclusionOverall, 2–4 and ≥5 injection regimens provided pain relief over IA-Saline, while single injection did not. Intra-articular injections of HA used in a 2–4 injection treatment regimen provided the greatest benefit when compared to IA-Saline with respect to pain improvement in patients with knee OA, and was generally deemed safe with few to no treatment-related AEs reported across studies. Future research is needed to directly compare these treatment regimens.

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