Table 2

Main efficacy results of IAT for knee osteoarthritis

StudyFollow-upOutcomesEffect estimateComments
Hyaluronic acid vs placebo
Rutjes et al73 moPainOverall (ES, 0.37 (0.28 to 0.46)), favouring HA
Large-blinded RCTs (ES, 0.11 (0.04 to 0.18)), favouring HA
Effect size defined as between-group differences in means divided by the pooled SD at end of follow-up.
Minimal clinically important difference =
(−0.37 ES)
FunctionOverall (ES, 0.33 (0.04 to 0.22)), favouring HA
Large-blinded RCTs (ES, 0.09 (0.00 to 0.17)), favouring HA
Newberry et al221–12 moFunctionSMD=0.23 (0.01 to 0.45), favouring HA (WOMAC)Consistent effect in sensitivity analysis for too short (<4 weeks) or too long (>52 weeks) RCTs
QoL3 RCTs—no between-group difference (SF-36, EuroQol-5D)
Gallagher et al3112–24 moPain2 RCTs—no between-group difference (VAS)
∆ JSW2 RCTs—no between-group difference
∆ Cartilage volume1 RCT—favoured HA with 2.60% (1.20–4.10) less cartilage volume lost in the medial compartment and 2.80% (0.90–4.70) less in the lateral compartment
Bannuru et al53 moPainSMD, 0.34 (Cr I, 0.26 to 0.42), favouring HAMA result of a Bayesian hierarchical random-effects model for mixed multiple treatment comparisons
FunctionSMD, 0.3 (Cr I, 0.20 to 0.40), favouring HA
StiffnessSMD, 0.23 (Cr I, 0.13 to 0.34), favouring HA
Trojian et al302–6 moPainSMD, 0.19 (0.06 to 0.32), favouring HA (WOMAC)NMA. SMD refers to Hedges’ g
Results obtained for the time of best response
No publication bias
FunctionSMD, 0.19 (0.05 to 0.32), favouring HA (WOMAC)
StiffnessSMD, 0.12 (0.03 to 0.27), favouring HA (WOMAC)
O-O RespRR, 1.11 (1.01 to 1.20), favouring HA
Trigkilidas and Anand351–6 moPain5 RCTs—no between-group difference (VAS)No pooled analysis
7 RCTs—favoured HA (VAS) (small effect)
Function5 RCTs—no between-group difference (WOMAC, Lequesne)
7 RCTs—favoured HA (WOMAC) (small effect, Lequesne)
Lo et al332–12 moPainOverall, SMD=0.32 (0.17 to 0.47)Evidence of publication bias
Excluding high MW, SMD=0.19 (0.10 to 0.27)
Hyaluronic acid vs glucocorticoids
Bannuru et al 61–2 wkPainES, 0.39 (0.12 to 0.65), favouring IAGCES: refers to Hedges’ g corrected for small samples
Effects remained consistent after multivariable and sensitivity analysis
3–6 wkES, −0.01 (−0.23 to 0.21), no between-group difference
7–10 wkES, 0.22 (0.05 to 0.49), favouring HA
11–16 wkES, 0.35 (0.03 to 0.66), favouring HA
17–29 wkES, 0.39 (0.18 to 0.59), favouring HA
Bannuru et al 53 moPainSMD, 0.02 (Cr I, −0.12 to 0.17), no between-group differenceNMA
FunctionSMD, 0.24 (Cr I, 0.06 to 0.43), favouring HA
StiffnessSMD, 0.20 (Cr I, 0.0 to 0.41), no between-group difference
Trojian et al304–40 moPainES, −0.06 (−0.28 to 0.16), no between-group differenceNMA
SMD refers to Hedges’ g
Results retrieved at the time of best response
No publication bias
FunctionES, −0.29 (−0.53 to −0.05), favouring HA
StiffnessES, −0.17 (−0.50 to 0.16), no between-group difference
O-O RespRR, 1.15 (1.02 to 1.30), favouring HA
Trigkilidas and Anand351–6 moPain1 RCT—favoured HA at 6 months (VAS)No pooled analysis
Function1 RCT—no between-group difference
Hyaluronic acid compounds comparison
Newberry et al 221–12 moFunction1 RCT—LMW vs MMW. SMD, −0.326 (−0.52 to −0.13), favouring MMWAll comparisons using the WOMAC function subscale
No pooled analysis
*Results of the same study54 at 2 time-points
1 RCT—LMW vs HMW. SMD, 0.053 (−0.66 to 0.77), no difference
1 RCT—LMW vs HMW. SMD, −0.882 (−1.09 to −0.68), favouring HMW
1 RCT—MMW vs HMW. SMD, −0.01 (−0.21 to 0.19), no difference
3 moQoL1 RCT*—LMW vs HMW, favouring LMW (EuroQol-5D)
12 mo1 RCT*—LMW vs HMW, favouring HMW (EuroQol-5D)
1 RCT—LMW vs HMW. No between-group difference (SF-36)
Glucocorticoids vs placebo
Jüni et al232 wkPainSMD −0.48 (−0.70 to −0.27), favouring IAGCFor pain and function, effects were reduced in large trials (>50 patients/arm)
2 moSMD −0.41 (−0.61 to −0.21), favouring IAGC
3 moSMD −0.22 (−0.44 to 0.00), no between-group difference
6 moSMD −0.07 (−0.25 to 0.11), no between-group difference
2 wkFunctionSMD −0.43 (−0.72 to −0.14), favouring IAGC
2 moSMD −0.36 (−0.63 to −0.09), favouring IAGC
3 moSMD −0.13 (−0.37 to 0.10), no between-group difference
6 moSMD 0.06 (−0.16 to 0.28), no between-group difference
6 moQoLSMD −0.01 (−0.30 to 0.28), no between-group difference
JSWSMD −0.02 (−0.49 to 0.46), no between-group difference
Arroll and Goodyear-Smith282 wkPainWMD −16.47 (−22.92 to −10.03), favouring IAGC†Pooling studies with the highest dose
2 wkImprovement of symptomsRR 1.66 (1.37 to 2.01), favouring IAGC
3–4 moRR 2.09 (1.20 to 3.65), favouring IAGC†
Bannuru et al 53 moPainSMD, 0.32 (Cr I, 0.16 to 0.47), favouring IAGCNMA
FunctionSMD, 0.06 (Cr I, −0.13 to 0.26), no between-group difference
StiffnessSMD, 0.03 (Cr I, −0.19 to 0.25), no between-group difference
Glucocorticoid compounds comparison
Silvinato and Bernardo341–6 moPain1-RCT—MPA vs TH. No between-group difference (VAS)*Results of the same study at 2 time-points
¥Results of the same study at 2 time-points
No pooled analysis
6 wk1-RCT*—MPA vs TA vs prednisolone, favouring MPA (VAS)
3 mo1-RCT*—MPA vs TA vs prednisolone, no between-group difference
1 month1-RCT¥—MPA vs TH, favouring MPA (VAS)
2 mo1-RCT¥—MPA vs TH. No between-group difference (VAS)
1–6 moFunction1-RCT—MPA vs TH. No between-group difference (WOMAC)
1–3 mo1-RCT—MPA vs TA vs prednisolone. No difference (Lequesne)
2 mo1-RCT—MPA vs TH. No between-group difference (Lequesne)
2 moO-O Response1-RCT—MPA vs TH. No between-group difference
Platelet-rich plasma vs placebo
Xu et al496 moComposite scores#Overall, SMD −2.13 (−3.29 to −0.98), favouring PRP#Effects of pooled results from WOMAC and IKDC scores
Dai et al276–12 moPain1 RCT—favoured PRP (WOMAC)
Function1 RCT—favoured PRP (WOMAC)
Kanchanatawan et al256–12 moPainNo between-group difference (WOMAC)
FunctionNo between-group difference (WOMAC)
StiffnessNo between-group difference (WOMAC)
Platelet-rich plasma vs hyaluronic acid
Xu et al266 moComposite scores¶Overall, SMD = −0.85 (−1.43 to −0.28) favouring PRP¶ Refers to observed effects when pooling results from WOMAC and IKDC scores
High-quality RCTs, SMD = −0.09 (−0.30 to 0.11). No difference
PainSMD=0.35 (−0.36 to 1.06) (VAS). No difference
FunctionMD=−0.20 (−1.00 to 0.60) (Lequesne). No difference
3 moWOMAC totalMD=−7.10 (−17.02 to 2.82). No between-group difference
12 moMD=−8.93 (−27.56 to 9.71). No between group difference
Shen et al293–12 moPainMD=−3.77 (−5.07 to −2.47), favouring PRP (WOMAC)Results obtained from pooling outcomes at 3, 6, and 12 months
FunctionMD=−13.91 (−18.53 to −9.28), favouring PRP (WOMAC)
WOMAC totalMD=−17.39 (−22.32 to −12.46), favouring PRP
Dai et al276 moPainMD=−1.54 (−4.27 to 1.20). No between-group difference §Results from pooling WOMAC total, IKDC,EQ and Lequesne Index
12 moMD=−2.83 (−4.26 to −1.39), favouring PRP
6 moFunctionMD=−4.39 (−10.51 to 1.74). No between-group difference
12 moMD=−12.53 (−14.58 to −10.47), favouring PRP
6 moComposite scores§SMD=0.68 (−0.04 to 1.41). No between-group difference
12 moSMD=1.05 (0.21 to 1.89), favouring PRP
Kanchanatawan et al256–12 moComposite scores§MD= −15.4 (−28.6 to −2.30), favouring PRP (WOMAC total)§Results for WOMAC total and IKDC reached the prespecified MCID
MD=8.83 (5.88 to 11.78), favouring PRP (IKDC)
PainNo between-group difference (WOMAC)
FunctionNo between-group difference (WOMAC)
StiffnessNo between-group difference (WOMAC)
QoLMD=7.37 (4.33 to 10.05), favouring PRP (EQ-VAS)
Di et al321–12 moPain5 RCTs—favoured PRP (VAS, WOMAC)No pooled analysis
1 RCT—no between-group difference (VAS)
Function3 RCTs—favoured PRP (WOMAC, Lequesne, KOOS)
3 RCTs—no between-group difference (WOMAC, Lequesne, etc)
Stiffness2 RCTs—favoured PRP (WOMAC)
2 RCTs—no between-group difference (WOMAC)
O-O Response1 RCT—favoured PRP
QoL3 RCTs—no between-group difference (EQ-VAS, SF-36)
Mesenchymal stem cells vs controls
Ding et al246 moComposite scoresSMD=−0.36 (−0.90 to 0.18). No difference (WOMAC total) vs controlsNMA.
Controls include HA, PBO, and GC.
High-dosage adipose-derived MSC showed a longer effect
12 moSMD=0.68 (0.07 to 1.30), favouring MSC (KOOS) vs controls
12 moPainSMD= −1.05 (−1.46 to −0.64), favouring MSC vs controls
  • Results are ordered by compounds and quality. The colour of the cell denotes quality: the darker the higher the quality. All effect sizes (ESs) are presented as a point estimate (95% CI) unless otherwise noted.

  • Cr I, credible intervals; EQ-VAS, Euro Quality of Life – Visual Analogue Scale; EuroQol-5D, Euro Quality of Life – 5 Dimension questionnaire; GC, glucocorticoids; HA, hyaluronic acid; HMW, high molecular weight; IAGC, intra-articular glucocorticoids; IAT, intra-articular therapies; IKDC, International Knee Documentation Committee; ∆JSW, change in joint space width; KOOS, Knee injury and Osteoarthritis Outcome Score; LMW, low molecular weight; MCID, minimal clinically important difference; MD, mean difference; MMW, medium molecular weight; mo, months; MPA, methylprednisolone acetate; MSC, mesenchymal stem cells; NMA, network meta-analysis; O-O Resp, OMERACT-OARSI Responder Index; PBO, placebo; PRP, platelet-rich plasma; QoL, quality of life; RCT, randomised controlled trials; RR, relative risk; SF-36, Short Form 36 health survey; SMD, standardised mean difference; TA, triamcinolone acetonide; TH, triamcinolone hexacetonide; VAS, Visual Analogue Scale; wk, weeks; WMD, weighted mean difference; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.