Main efficacy results of IAT for knee osteoarthritis
| Study | Follow-up | Outcomes | Effect estimate | Comments |
| Hyaluronic acid vs placebo | ||||
| Rutjes et al7 | 3 mo | Pain | Overall (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) |
| Function | Overall (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 al22 | 1–12 mo | Function | SMD=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 |
| QoL | 3 RCTs—no between-group difference (SF-36, EuroQol-5D) | |||
| Gallagher et al31 | 12–24 mo | Pain | 2 RCTs—no between-group difference (VAS) | |
| ∆ JSW | 2 RCTs—no between-group difference | |||
| ∆ Cartilage volume | 1 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 al5 | 3 mo | Pain | SMD, 0.34 (Cr I, 0.26 to 0.42), favouring HA | MA result of a Bayesian hierarchical random-effects model for mixed multiple treatment comparisons |
| Function | SMD, 0.3 (Cr I, 0.20 to 0.40), favouring HA | |||
| Stiffness | SMD, 0.23 (Cr I, 0.13 to 0.34), favouring HA | |||
| Trojian et al30 | 2–6 mo | Pain | SMD, 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 |
| Function | SMD, 0.19 (0.05 to 0.32), favouring HA (WOMAC) | |||
| Stiffness | SMD, 0.12 (0.03 to 0.27), favouring HA (WOMAC) | |||
| O-O Resp | RR, 1.11 (1.01 to 1.20), favouring HA | |||
| Trigkilidas and Anand35 | 1–6 mo | Pain | 5 RCTs—no between-group difference (VAS) | No pooled analysis |
| 7 RCTs—favoured HA (VAS) (small effect) | ||||
| Function | 5 RCTs—no between-group difference (WOMAC, Lequesne) | |||
| 7 RCTs—favoured HA (WOMAC) (small effect, Lequesne) | ||||
| Lo et al33 | 2–12 mo | Pain | Overall, 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 6 | 1–2 wk | Pain | ES, 0.39 (0.12 to 0.65), favouring IAGC | ES: refers to Hedges’ g corrected for small samples Effects remained consistent after multivariable and sensitivity analysis |
| 3–6 wk | ES, −0.01 (−0.23 to 0.21), no between-group difference | |||
| 7–10 wk | ES, 0.22 (0.05 to 0.49), favouring HA | |||
| 11–16 wk | ES, 0.35 (0.03 to 0.66), favouring HA | |||
| 17–29 wk | ES, 0.39 (0.18 to 0.59), favouring HA | |||
| Bannuru et al 5 | 3 mo | Pain | SMD, 0.02 (Cr I, −0.12 to 0.17), no between-group difference | NMA |
| Function | SMD, 0.24 (Cr I, 0.06 to 0.43), favouring HA | |||
| Stiffness | SMD, 0.20 (Cr I, 0.0 to 0.41), no between-group difference | |||
| Trojian et al30 | 4–40 mo | Pain | ES, −0.06 (−0.28 to 0.16), no between-group difference | NMA SMD refers to Hedges’ g Results retrieved at the time of best response No publication bias |
| Function | ES, −0.29 (−0.53 to −0.05), favouring HA | |||
| Stiffness | ES, −0.17 (−0.50 to 0.16), no between-group difference | |||
| O-O Resp | RR, 1.15 (1.02 to 1.30), favouring HA | |||
| Trigkilidas and Anand35 | 1–6 mo | Pain | 1 RCT—favoured HA at 6 months (VAS) | No pooled analysis |
| Function | 1 RCT—no between-group difference | |||
| Hyaluronic acid compounds comparison | ||||
| Newberry et al 22 | 1–12 mo | Function | 1 RCT—LMW vs MMW. SMD, −0.326 (−0.52 to −0.13), favouring MMW | All 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 mo | QoL | 1 RCT*—LMW vs HMW, favouring LMW (EuroQol-5D) | ||
| 12 mo | 1 RCT*—LMW vs HMW, favouring HMW (EuroQol-5D) | |||
| 1 RCT—LMW vs HMW. No between-group difference (SF-36) | ||||
| Glucocorticoids vs placebo | ||||
| Jüni et al23 | 2 wk | Pain | SMD −0.48 (−0.70 to −0.27), favouring IAGC | For pain and function, effects were reduced in large trials (>50 patients/arm) |
| 2 mo | SMD −0.41 (−0.61 to −0.21), favouring IAGC | |||
| 3 mo | SMD −0.22 (−0.44 to 0.00), no between-group difference | |||
| 6 mo | SMD −0.07 (−0.25 to 0.11), no between-group difference | |||
| 2 wk | Function | SMD −0.43 (−0.72 to −0.14), favouring IAGC | ||
| 2 mo | SMD −0.36 (−0.63 to −0.09), favouring IAGC | |||
| 3 mo | SMD −0.13 (−0.37 to 0.10), no between-group difference | |||
| 6 mo | SMD 0.06 (−0.16 to 0.28), no between-group difference | |||
| 6 mo | QoL | SMD −0.01 (−0.30 to 0.28), no between-group difference | ||
| JSW | SMD −0.02 (−0.49 to 0.46), no between-group difference | |||
| Arroll and Goodyear-Smith28 | 2 wk | Pain | WMD −16.47 (−22.92 to −10.03), favouring IAGC | †Pooling studies with the highest dose |
| 2 wk | Improvement of symptoms | RR 1.66 (1.37 to 2.01), favouring IAGC | ||
| 3–4 mo | RR 2.09 (1.20 to 3.65), favouring IAGC† | |||
| Bannuru et al 5 | 3 mo | Pain | SMD, 0.32 (Cr I, 0.16 to 0.47), favouring IAGC | NMA |
| Function | SMD, 0.06 (Cr I, −0.13 to 0.26), no between-group difference | |||
| Stiffness | SMD, 0.03 (Cr I, −0.19 to 0.25), no between-group difference | |||
| Glucocorticoid compounds comparison | ||||
| Silvinato and Bernardo34 | 1–6 mo | Pain | 1-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 wk | 1-RCT*—MPA vs TA vs prednisolone, favouring MPA (VAS) | |||
| 3 mo | 1-RCT*—MPA vs TA vs prednisolone, no between-group difference | |||
| 1 month | 1-RCT¥—MPA vs TH, favouring MPA (VAS) | |||
| 2 mo | 1-RCT¥—MPA vs TH. No between-group difference (VAS) | |||
| 1–6 mo | Function | 1-RCT—MPA vs TH. No between-group difference (WOMAC) | ||
| 1–3 mo | 1-RCT—MPA vs TA vs prednisolone. No difference (Lequesne) | |||
| 2 mo | 1-RCT—MPA vs TH. No between-group difference (Lequesne) | |||
| 2 mo | O-O Response | 1-RCT—MPA vs TH. No between-group difference | ||
| Platelet-rich plasma vs placebo | ||||
| Xu et al49 | 6 mo | Composite scores# | Overall, SMD −2.13 (−3.29 to −0.98), favouring PRP | #Effects of pooled results from WOMAC and IKDC scores |
| Dai et al27 | 6–12 mo | Pain | 1 RCT—favoured PRP (WOMAC) | |
| Function | 1 RCT—favoured PRP (WOMAC) | |||
| Kanchanatawan et al25 | 6–12 mo | Pain | No between-group difference (WOMAC) | |
| Function | No between-group difference (WOMAC) | |||
| Stiffness | No between-group difference (WOMAC) | |||
| Platelet-rich plasma vs hyaluronic acid | ||||
| Xu et al26 | 6 mo | Composite 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 | ||||
| Pain | SMD=0.35 (−0.36 to 1.06) (VAS). No difference | |||
| Function | MD=−0.20 (−1.00 to 0.60) (Lequesne). No difference | |||
| 3 mo | WOMAC total | MD=−7.10 (−17.02 to 2.82). No between-group difference | ||
| 12 mo | MD=−8.93 (−27.56 to 9.71). No between group difference | |||
| Shen et al29 | 3–12 mo | Pain | MD=−3.77 (−5.07 to −2.47), favouring PRP (WOMAC) | Results obtained from pooling outcomes at 3, 6, and 12 months |
| Function | MD=−13.91 (−18.53 to −9.28), favouring PRP (WOMAC) | |||
| WOMAC total | MD=−17.39 (−22.32 to −12.46), favouring PRP | |||
| Dai et al27 | 6 mo | Pain | MD=−1.54 (−4.27 to 1.20). No between-group difference | §Results from pooling WOMAC total, IKDC,EQ and Lequesne Index |
| 12 mo | MD=−2.83 (−4.26 to −1.39), favouring PRP | |||
| 6 mo | Function | MD=−4.39 (−10.51 to 1.74). No between-group difference | ||
| 12 mo | MD=−12.53 (−14.58 to −10.47), favouring PRP | |||
| 6 mo | Composite scores§ | SMD=0.68 (−0.04 to 1.41). No between-group difference | ||
| 12 mo | SMD=1.05 (0.21 to 1.89), favouring PRP | |||
| Kanchanatawan et al25 | 6–12 mo | Composite 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) | ||||
| Pain | No between-group difference (WOMAC) | |||
| Function | No between-group difference (WOMAC) | |||
| Stiffness | No between-group difference (WOMAC) | |||
| QoL | MD=7.37 (4.33 to 10.05), favouring PRP (EQ-VAS) | |||
| Di et al32 | 1–12 mo | Pain | 5 RCTs—favoured PRP (VAS, WOMAC) | No pooled analysis |
| 1 RCT—no between-group difference (VAS) | ||||
| Function | 3 RCTs—favoured PRP (WOMAC, Lequesne, KOOS) | |||
| 3 RCTs—no between-group difference (WOMAC, Lequesne, etc) | ||||
| Stiffness | 2 RCTs—favoured PRP (WOMAC) | |||
| 2 RCTs—no between-group difference (WOMAC) | ||||
| O-O Response | 1 RCT—favoured PRP | |||
| QoL | 3 RCTs—no between-group difference (EQ-VAS, SF-36) | |||
| Mesenchymal stem cells vs controls | ||||
| Ding et al24 | 6 mo | Composite scores | SMD=−0.36 (−0.90 to 0.18). No difference (WOMAC total) vs controls | NMA. Controls include HA, PBO, and GC. High-dosage adipose-derived MSC showed a longer effect |
| 12 mo | SMD=0.68 (0.07 to 1.30), favouring MSC (KOOS) vs controls | |||
| 12 mo | Pain | SMD= −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.