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Vol:7 Issue:1 Number:24 ISSN#:2564-2537
ACE Report #10023

Multi-injection HA appears to be more effective than single-injection HA versus saline for knee OA

How to Cite

OrthoEvidence. Multi-injection HA appears to be more effective than single-injection HA versus saline for knee OA. ACE Report. 2018;7(1):24. Available from:

Study Type:Meta-analysis/Systematic Review
OE Level Evidence:N/A
Journal Level of Evidence:N/A

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

BMC Musculoskelet Disord. 2017 Dec 21;18(1):542

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30 blinded randomized controlled trials evaluating the use of hyaluronic acid injections in comparison to a placebo injection in patients with knee osteoarthritis were included in this systematic review and meta-analysis. The objective of this systematic review and meta-analysis was to compare the efficacy and safety of hyaluronic acid injections across different dosing regimens. At 3 months, data were available for 2-4 injection and 5+ injection groups. The 2-4 injection groups demonstrated significantly lower pain scores compared placebo (SMD -0.76 p<0.00001), while the 5+ injection groups did not demonstrate significantly lower pain compared to placebo (SMD -0.20; p=0.09). At 6 months, both the 2-4 injection group (SMD -0.36; p=0.008) and 5+ injection group demonstrated significantly lower pain compared to placebo (SMD -0.18; p=0.04). The single injection groups did not significantly reduce pain compared to placebo at 6 months (SMD -0.04; p=0.67). When looking at the incidence of adverse events, only the 5+ injection group demonstrated a significantly greater incidence compared to placebo (RR 1.67; p=0.02).

Publication Funding Details +
Industry funded
Ferring Pharmaceuticals
Company Employee

Risk of Bias


Reporting Criteria


Fragility Index


Were the search methods used to find evidence (original research) on the primary question or questions stated?

Was the search for evidence reasonably comprehensive?

Were the criteria used for deciding which studies to include in the overview reported?

Was the bias in the selection of studies avoided?

Were the criteria used for assessing the validity of the included studies reported?

Was the validity of all of the studies referred to in the text assessed with use of appropriate criteria (either in selecting the studies for inclusion or in analyzing the studies that were cited)?

Were the methods used to combine the findings of the relevant studies (to reach a conclusion) reported?

Were the findings of the relevant studies combined appropriately relative to the primary question that the overview addresses?

Were the conclusions made by the author or authors supported by the data and or analysis reported in the overview?

How would you rate the scientific quality of this evidence?

Yes = 1

Uncertain = 0.5

Not Relevant = 0

No = 0

The Reporting Criteria Assessment evaluates the transparency with which authors report the methodological and trial characteristics of the trial within the publication. The assessment is divided into five categories which are presented below.




Accessing Data


Analysing Data





Detsky AS, Naylor CD, O'Rourke K, McGeer AJ, L'Abbé KA. J Clin Epidemiol. 1992;45:255-65

The Fragility Index is a tool that aids in the interpretation of significant findings, providing a measure of strength for a result. The Fragility Index represents the number of consecutive events that need to be added to a dichotomous outcome to make the finding no longer significant. A small number represents a weaker finding and a large number represents a stronger finding.

Why was this study needed now?

Injection therapies are a prominent topic in research of knee osteoarthritis treatment. Viscosupplementation with intra-articular injection of hyaluronic acid remains one of the most researched and controversial methods of treatment. There is a debate as to whether the number of HA injections administered significantly influences efficacy.

What was the principal research question?

In the treatment of knee osteoarthritis, is there a significant difference in effect on pain between single injection, 2-4 injection, and 5+ injection protocols when compared to placebo saline?

Study Characteristics -
Data Source:
MEDLINE, EMBASE, and PubMed were searched for relevant articles published up to February 26, 2016.
Index Terms:
Full search strategies for each database can be found in the online appendix of the full publication.
Study Selection:
Eligibility criteria included: a randomized controlled trial design; allocation of patients to the administration of either intra-articular hyaluronic acid or intra-articular saline; blinded administration and assessment; reported outcome related to pain; and published in English. Search and selection were performed in duplicate.
Data Extraction:
Data extraction was performed by one reviewer, and cross-checked for accuracy by a second reviewer.
Data Synthesis:
Statistical analyses were performed using Review Manager software (RevMan 5.3). Standardized mean differences were calculated for continuous outcomes (ie. pain), with 95% confidence intervals. Risk ratios were calculated for dichotomous outcomes, with 95% confidence intervals. Analyses were categorized by the number of injections administered, either as 1 injection, 2-4 injections, or 5+ injections.

What were the important findings?

  • Only data on 2-4 injection and 5+ injection groups were available at 3 months. The 2-4 injection groups demonstrated significantly lower pain scores compared placebo (6 studies; SMD -0.76 [95%CI -0.98, -0.53]; p<0.00001), but 5+ injection groups did not demonstrate significantly lower pain compared to placebo (3 studies; SMD -0.20 [95%CI -0.43, 0.03]; p=0.09).
  • At 6 months, 2-4 injection groups (10 studies; SMD -0.36 [95%CI -0.63, -0.09]; p=0.008) and 5+ injection groups demonstrated significantly lower pain compared to placebo (6 studies; SMD -0.18 [95%CI -0.35, -0.01]; p=0.04); single injection groups did not significantly differ in pain scores to placebo (2 studies; SMD -0.04 [95%CI -0.20, 0.13]; p=0.67).
  • The incidence of adverse events did not significantly differ between 1 injection groups and placebo (4 studies; RR 1.22 [95%CI 0.85, 1.75]; p=0.28), and 2-4 injection groups and placebo (4 studies; RR 0.97 [95%CI 0.86, 1.08]; p=0.57); 5+ injection groups demonstrated a significantly higher incidence of adverse events compared to placebo (5 studies; RR 1.67 [95%CI 1.09, 2.56]; p=0.02).

What should I remember most?

In knee osteoarthritis treatment, two to four IA HA injections demonstrated effective pain reduction compared to placebo at 3 and 6 months, without a significant increase in the rate of adverse events. Single IA HA injection did not reduce pain compared to placebo after 6 months, and while five or more IA HA injections demonstrated significant pain reduction compared to placebo at 6 months, they were also associated with a significantly greater incidence of adverse events.

How will this affect the care of my patients?

The results of this study suggest that, currently, the most optimal IA HA injection protocol for knee osteoarthritis is 2-4 injections, given the balance between both efficacy and safety measures. Nonetheless, direct comparisons are required between different numbers of injections, as well as on subgroups of particular IA HA product characteristics, such as molecular weight and crosslinking.

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luc racine 2018-02-04 9:57 PM

Orthopaedic Surgeon - Canada

choix de traitement

john arthur 2018-02-12 6:41 PM

Orthopaedic Surgeon - Canada

what about steroid injections?

Anonymous 2018-02-18 9:13 PM

Orthopaedic Surgeon - United States

at what time intervals best ?


Orthopaedic Surgeon - India

Weekly injections for 5 wks gives better relief for my patients. Single injected patients c/o pain after a few months.