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Research · Medication

Hyaluronic acid injections

Injected into an arthritic knee, hyaluronic acid lowered pain only slightly more than saline in large trials, below what patients notice, while serious adverse events rose about 40 to 50%. It eased pain later than steroid shots, matched daily NSAID pills, and gave less benefit than PRP. In the hip it did no better than saline.

Add to Bio HackChecked 2026-11-14
Status
In the US, hyaluronic acid products injected into the knee are regulated as medical devices through FDA premarket approval, not as drugs. Synvisc, Euflexxa, Orthovisc and Durolane are approved for knee osteoarthritis pain in people not helped enough by non-drug care and simple painkillers such as acetaminophen [1][2][3][4]. They are not approved for the hip or other joints.
Also called
viscosupplementation, gel shots, knee gel injection, hyaluronan injection, sodium hyaluronate injection, hylan G-F 20, Synvisc, Synvisc-One, Euflexxa, Orthovisc, Monovisc, Durolane, Gel-One, GenVisc, Hyalgan, Supartz, TriVisc, Visco-3, Gelsyn-3, intra-articular hyaluronic acid
Taken for
knee osteoarthritis, knee pain, joint lubrication, cushioning the knee, delaying knee replacement, hip arthritis, shoulder pain

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help1

Reported risks2

What people take it for, and what was found

Shown to help1

Limited

Delaying knee replacement

Linked to a longer time before knee replacement, 51 to 217 days on average, in an insurance claims study, without randomization.

Compared with people with knee osteoarthritis who did not receive hyaluronic acid injections, mostly treated with corticosteroids [14]

The numbers and sources
Effect
Restricted mean survival without knee replacement was longer in the hyaluronic acid group at every time point, by 51 days at 1 year and 217 days at 7.5 years (P < 0.001). Of 14,782 patients, 11.2% had a knee replacement [14].
Population
14,782 patients treated for knee osteoarthritis in a French claims database, 2006 to 2013, mean age 68 [14].
Sources
[14]
Caveats
Observational. People offered injections may differ from others in ways the model could not adjust for [14].

Mixed results2

Strong

Knee osteoarthritis pain, compared with placebo injections

Mixed results: pooled trials found a small pain reduction against placebo injections, but large blinded trials found it below the smallest difference patients notice.

Compared with saline or sham injections, or no intervention [5][6]; placebo injections, saline or arthrocentesis [7]

The numbers and sources
Effect
Across 71 trials, hyaluronic acid injected into the knee reduced pain (effect size -0.37, 95% CI -0.46 to -0.28), but 18 large trials with blinded assessment showed -0.11 (95% CI -0.18 to -0.04) and 5 unpublished trials -0.03, which the authors called clinically irrelevant [5]. In 24 large placebo-controlled trials, pain fell slightly more than placebo (SMD -0.08, 95% CI -0.15 to -0.02), about 2.0 mm on a 100 mm scale, and trial sequential analysis showed clinical equivalence with placebo since 2009. Function results were similar [6]. An older Cochrane review found pain improvements of 28% to 54% from baseline at 5 to 13 weeks and concluded it benefited pain, function and global assessment, while noting differences between products [7].
Population
12,667 adults in 89 trials [5]; 21,163 participants in 169 trials, 8,997 in the 24 large trials [6]; 76 trials [7].
Sources
[5], [6], [7]
Caveats
Both newer reviews found small-study effects and publication bias, with smaller effects in larger and better-blinded trials [5][6]. The Cochrane review is from 2006 and reported changes from baseline [7].
Strong

Knee osteoarthritis, compared with corticosteroid injections

Shown to ease knee pain less than steroid injections at 2 weeks, equally at 4 weeks, and more at 12 and 26 weeks.

Compared with corticosteroid injections into the knee [8][7]

The numbers and sources
Effect
Pooling 7 trials, corticosteroids were ahead at week 2 (effect size -0.39, 95% CI -0.65 to -0.12), the two were equal at week 4 (-0.01), and hyaluronic acid was ahead at week 12 (0.35, 95% CI 0.03 to 0.66) and week 26 (0.39, 95% CI 0.18 to 0.59) [8]. The Cochrane review also noted longer-term benefits against corticosteroid injections [7].
Population
606 participants in 7 trials [8]; 10 trials against corticosteroids [7].
Sources
[8], [7]
Caveats
Small trials. Neither product was compared with placebo in these trials [8].

Not shown to help4

Strong

Knee osteoarthritis, compared with NSAID pills

Not shown to differ from daily NSAID pills for knee osteoarthritis pain, function or stiffness at 4 to 12 weeks.

Compared with continuous oral NSAIDs [9][7]

The numbers and sources
Effect
Across 5 trials, both groups improved, and pain at trial end favored neither (effect size -0.07, 95% CI -0.24 to 0.10). Function (-0.08) and stiffness (0.03) did not differ. Injection site pain was the most common adverse event with hyaluronic acid and gut adverse events with NSAIDs [9]. The Cochrane review noted comparable efficacy against NSAIDs [7].
Population
712 participants in 5 trials [9]; 6 trials against NSAIDs [7].
Sources
[9], [7]
Caveats
Follow-up was short [9].
Strong

Knee osteoarthritis, compared with PRP injections

Shown to give less improvement in knee osteoarthritis pain and function than platelet-rich plasma injections at 3 to 12 months, with similar adverse events.

Compared with platelet-rich plasma injections [10][11]

The numbers and sources
Effect
Across 18 level 1 trials, WOMAC scores improved 12.6% after hyaluronic acid and 44.7% after PRP (P < .01) over a mean 11.1 months [10]. Across 26 RCTs, WOMAC total, function and pain scores were worse after hyaluronic acid than PRP at 3, 6 and 12 months, and adverse events did not differ (RR 1.21, 95% CI 0.95 to 1.54) [11].
Population
797 patients given hyaluronic acid and 811 given PRP [10]; 2,430 patients in 26 RCTs [11].
Sources
[10], [11]
Caveats
Neither comparison includes placebo, so neither shows the size of each injection's own effect. Many trials were not blinded. The PRP page covers PRP in full.
Moderate

Differences between products

Not shown to give more pain relief with cross-linked hylan G-F 20 (Synvisc) than other hyaluronic acids, with results near zero in the most rigorous trials.

Compared with standard hyaluronic acid preparations [12]

The numbers and sources
Effect
Across 13 trials, hylan was slightly ahead on pain (effect size -0.27, 95% CI -0.55 to 0.01), but heterogeneity was high (I² 88%), and trials with blinded patients, concealed allocation and intention-to-treat analysis had effects near zero [12].
Population
2,085 patients in 13 trials [12].
Sources
[12]
Caveats
Hylan raised local adverse events, covered under Risks [12].
Moderate

Hip osteoarthritis

Not shown to ease hip osteoarthritis pain or function more than saline injections at 2 to 6 months, nor did steroids or PRP.

Compared with saline injections, corticosteroid and PRP injections [13]

The numbers and sources
Effect
In a network meta-analysis, no injection outperformed saline for pain or function at 2 to 4 or 6 months. Every arm, saline included, improved pain past the smallest clinically important difference from baseline, except hyaluronic acid combined with PRP [13].
Population
1,353 patients with hip osteoarthritis in 11 RCTs [13].
Sources
[13]
Caveats
Not an FDA-approved use [1][2][3][4].

Doses studied

In the large placebo-controlled trials, the median course was 3 injections into the knee (interquartile range 1 to 5), and the review describes courses as a single injection or 2 to 6 injections [6], read from the open-access full text. Products differ in molecular weight and cross-linking [6][12].

Risks

Reported risks2

StrongHow often is not known

Serious adverse events

Shown to raise serious adverse events against placebo injections, by about 41% in one review and 49% in large trials in another.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Across 14 trials, serious adverse events were more common than with control (RR 1.41, 95% CI 1.02 to 1.97) [5]. In 15 large placebo-controlled trials, the relative risk was 1.49 (95% CI 1.12 to 1.98) [6].
Population
3,667 patients in 14 trials [5]; 6,462 participants in 15 large trials [6].
Sources
[5], [6]
Caveats
Safety data were often not reported, and the abstracts do not list which events these were or give rates [5][6].
ModerateHow often is not known

Flares and local reactions in the knee

Shown to raise local reactions and flares about 2-fold with hylan G-F 20 against other hyaluronic acids. Against placebo, the rise in flares was not significant.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Against standard hyaluronic acids, hylan raised any local adverse event (RR 1.91, 95% CI 1.04 to 3.49) and flares (RR 2.04, 95% CI 1.18 to 3.53) [12]. Against sham or no injection, flares rose without reaching significance (RR 1.51, 95% CI 0.84 to 2.72) [5]. Injection site pain was the most common adverse event in trials against NSAIDs [9].
Population
2,085 patients in 13 trials [12]; 811 patients in 6 trials [5]; 712 participants in 5 trials [9].
Sources
[12], [5], [9]
Caveats
Few trials reported flares [5].

Claims tested and not found

  1. That hyaluronic acid injections relieve knee pain meaningfully more than placebo. In 24 large placebo-controlled trials, the difference was about 2 mm on a 100 mm scale, which the authors judged clinically equivalent to placebo [6].
  2. That cross-linked hylan gives more relief than other hyaluronic acids. Well-designed trials found effects near zero [12].
  3. That they help hip arthritis. No injection beat saline at 2 to 6 months [13].

Related

PRP injectionsJoint corticosteroid injectionsHyaluronic acid (oral)

Sources

  1. U.S. Food and Drug Administration. Premarket Approval P940015: Synvisc (hylan G-F 20). PMA database. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P940015
  2. U.S. Food and Drug Administration. Premarket Approval P010029: Euflexxa (1% sodium hyaluronate). PMA database. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P010029
  3. U.S. Food and Drug Administration. Premarket Approval P030019: Orthovisc high molecular weight hyaluronan. PMA database. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P030019
  4. U.S. Food and Drug Administration. Premarket Approval P170007: Durolane. PMA database. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P170007
  5. Rutjes AW, Jüni P, da Costa BR, et al. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Annals of Internal Medicine. 2012. https://doi.org/10.7326/0003-4819-157-3-201208070-00473
  6. Pereira TV, Jüni P, Saadat P, et al. Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis. BMJ. 2022. https://doi.org/10.1136/bmj-2022-069722
  7. Bellamy N, Campbell J, Welch V, et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database of Systematic Reviews. 2006. https://doi.org/10.1002/14651858.cd005321.pub2
  8. Bannuru RR, Natov NS, Obadan IE, et al. Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis. Arthritis Care & Research. 2009. https://doi.org/10.1002/art.24925
  9. Bannuru RR, Vaysbrot EE, Sullivan MC, McAlindon TE. Relative efficacy of hyaluronic acid in comparison with NSAIDs for knee osteoarthritis: a systematic review and meta-analysis. Seminars in Arthritis and Rheumatism. 2014. https://doi.org/10.1016/j.semarthrit.2013.10.002
  10. Belk JW, Kraeutler MJ, Houck DA, et al. Platelet-Rich Plasma Versus Hyaluronic Acid for Knee Osteoarthritis: A Systematic Review and Meta-analysis of Randomized Controlled Trials. The American Journal of Sports Medicine. 2021. https://doi.org/10.1177/0363546520909397
  11. Tan J, Chen H, Zhao L, Huang W. Platelet-Rich Plasma Versus Hyaluronic Acid in the Treatment of Knee Osteoarthritis: A Meta-analysis of 26 Randomized Controlled Trials. Arthroscopy. 2021. https://doi.org/10.1016/j.arthro.2020.07.011
  12. Reichenbach S, Blank S, Rutjes AW, et al. Hylan versus hyaluronic acid for osteoarthritis of the knee: a systematic review and meta-analysis. Arthritis Care & Research. 2007. https://doi.org/10.1002/art.23103
  13. Gazendam A, Ekhtiari S, Bozzo A, et al. Intra-articular saline injection is as effective as corticosteroids, platelet-rich plasma and hyaluronic acid for hip osteoarthritis pain: a systematic review and network meta-analysis of randomised controlled trials. British Journal of Sports Medicine. 2021. https://doi.org/10.1136/bjsports-2020-102179
  14. Delbarre A, Amor B, Bardoulat I, et al. Do intra-articular hyaluronic acid injections delay total knee replacement in patients with osteoarthritis: A Cox model analysis. PLOS ONE. 2017. https://doi.org/10.1371/journal.pone.0187227

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