Table 5

Main safety outcomes of all included compounds

StudyComparisonFollow-upOutcomesEffect estimateComments
Knee osteoarthritis
Bannuru et al4HA vs PBO4–52 weeksAny AEsNo between group differences (vs PBO)NMA specifically aimed at analysing safety.
Comparisons are between PBO and all RCTs of individual HA products.
No pooled analysis of HA as a group was carried on.
Local reactionsAnalyses favoured PBO for 2/17 products assessed
Withdrawal due to AEsAnalyses favoured PBO for 1/11 products assessed
Bannuru et al5HA vs PBO
2–6 monthsAny AEHA vs PBO: 16 (54.6) vs 21.7 (56.0)No pooled analysis was carried on. Results are median (IQR) of event rates, %
HA vs IAGC: 0.0 (64.6) vs 5.5 (57.2)
IAGC vs PBO: No data
SAEsHA vs PBO: 0 (0.9) vs 0 (0)
HA vs IAGC: 0.0 (2.0) vs 0.0 (4.3)
IAGC vs PBO: No data
Withdrawal due to AEsHA vs PBO: 0.9 (3.9) vs 1.0 (2.6)
HA vs IAGC: 1.9 (3.7) vs 2.7 (6.0)
IAGC vs PBO: 0.0 (3.5) vs 0.0 (1.7)
Local reactionsHA vs PBO: 8.4 (14.4) vs 4.7 (16.1)
HA vs IAGC: 2.2 (21.8) vs 3.0 (9.1)
IAGC vs PBO: 3.3 (17.9) vs 6.9 (8.0)
Septic jointHA vs PBO: 0 (0) vs 0 (0)
HA vs IAGC: 0 (0) vs 0 (0)
IAGC vs PBO: 0 (0) vs 0 (0)
Newberry et al22HA vs PBO1–12 monthsLocal reactionsOR 0.70 (0.48 to 1.03). No between-group difference
Joint painOR 0.83 (0.60 to 1.15). No between-group difference
Serious join reactionsOR 0.77 (0.25 to 2.31). No between-group difference
Other AEOR 1.26 (0.94 to 1.68). No between-group difference
Other SAEOR 0.62 (0.23 to 1.57). No between-group difference
Trojian et al30HA vs PBO2–6 monthsJoint pain1 RCT—HA vs IAGC —17% vs 3.2%, p<0.05Some RCTs did not report data on withdrawal due to AE
IAGC vs PBO10 RCT—no between-group difference
HA vs IAGCAny AE11 RCTs—no between-group difference
SAEs11 RCTs—no between-group differences
Withdrawal due to AEs4 RCTs—no between-group differences
Rutjes et al7HA vs sham or no intervention3 monthsLocal reactionsRR=1.34 (1.13 to 1.60)†RR for SAE resulted from pooling 14 RCTs. ¥RR for withdrawals resulted from pooling 23 RCTs. The effect was not maintained when pooling large unblinded RCTs.
Any AERR=1.04 (0.99 to 1.09). No between-group differences
SAEs†Overall, RR=1.41 (1.02 to 1.97)
Large blinded RCTs, RR=1.55 (1.07 to 2.24)
Withdrawal due to AEs¥RR=1.33 (1.01 to 1.74)
Jüni et al23IAGC vs sham or no intervention2 weeks to 6 monthsAny AERR=0.89 (0.64 to 1.23)
SAEsRR=0.63 (0.15 to 2.67)
Withdrawal due to AEs¥RR=0.33 (0.05 to 2.07)
Brazilian Medical Association34MPA vs TA or TH or BP4–24 weeksAny AE1 RCT—o AE reported
1 RCT—no data on AE
1 RCT—no between-group differences
Shen et al29PRP vs HA or IAGC or PBO3–12 monthsAny AERR=1.40 (0.80 to 2.45).Comparisons were mainly with HA
SAENo SAEs were identified
Kanchanatawan et al25PRP vs HA or PBO6–12 monthsAny AERR=0.85 (0.57 to 1.28) (vs HA)
RR=6.30 (0.34 to 117.48) (vs PBO)
SAEsNo data reported
Dai et al27PRP vs HA or PBO6–12 monthsAny AERR=0.63 (0.20 to 1.98) (vs HA)
RR=2.63 (0.04 to 158.93) (vs PBO)
SAEsNo data reported
Di et al32PRP vs HA1–12 monthsAny AE1 RCT—significantly more pain in PRP group
1 RCT—reported no AEs
1 RCT—o safety data reported
4 RCT—no between-group differences
SAE5 RCT—reported no SAEs
Ding et al24MSC vs PBO or HA or IAGC6–12 monthsAny AENo data reported
SAEOR=1.95 (0.89 to 4.26)
Hip osteoarthritis
Leite et al40HA vs PBO or MPA1–12 monthsAny AERR=1.07 (0.78 to 1.48) (vs PBO)
RR=2.24 (0.24 to 20.85) (vs MPA)
3 RCTs—no between-group differences. (vs PBO)
Liao et al37HA vs PBO2 weeks to 6 monthsAny AE4 RCTs—no between-group differences
SAE1 RCT—one septic arthritis episode on the HA group
Withdrawal due to AEs1 RCT—no between-group differences
McCabe et al38IAGC vs PBO1–3 monthsAny AE2 RCTs—none reported
2 RCTs—no between-group differences
Medina-Porqueres et al41PRP vs HA1–12 monthsAny AE1 RCT—more pain in PRP group (p<0.05)
1 RCT—reported one sup haematoma on PRP group
Ye et al42PRP vs HA2–12 monthsAny AERR=0.95 (0.40 to 2.24)
Shoulder capsulitis
Lee et al44HA vs PBO3–6 monthsAny AE2 RCTs—no AE reported
2 RCTs—no data on AE
Buchbinder et al43TA 40 mg vs TA 10 mg4–6 weeksAny AENo between-group differences
Sun et al45IAGC vs PBO4–26 weeksAny AE3 RCTs—no between-group differences
5 RCTs—no data on AE
Rheumatoid arthritis
Saito and Kotake47HA vs PBO1 weekAny AERR=0.98 (0.94 to 1.02)
and Bernardo34
MPA vs TH or TA1–6 monthsAny AE1 RCT—no AE reported
1 RCT—no data on AE
  • All effect sizes are presented as the point estimate (95% CI) unless otherwise stated.

  • AE, adverse events; HA, hyaluronic acid; IAGC, intra-articular glucocorticoids; MPA, methylprednisolone acetate; MSC, mesenchymal stem cells; NMA, Network Meta-analysis; PBO, placebo; PRP, platelet-rich plasma; RCT, randomised controlledl trials; RR, relative risk; SAE, serious adverse events; TA, triamcinolone acetonide; TH, triamcinolone hexacetonide.