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Table 1 Meta-analysis based on several subgroups showing the effect of NSAID administration on three-points mechanical bending measurements (maximum force, stiffness, and work to failure) of healing bones after fracture

From: Non-steroidal anti-inflammatory drugs and bone healing in animal models—a systematic review and meta-analysis

Subgroup N SZ
NSAID
SZ
C.
SMD 95% CI P effect(adj. P value) Q statistic P within heterog. I2% P between heterog.
Maximum Force
NSAID vs Control
Overall 94 995 594 − 0.58 [− 0.74, − 0.42] 0.000 206.89 < 0.001 55.04
Species     
Rats 56 655 370 − 0.64 [− 0.85, − 0.43] 0.000(< 0.001) 117.18 < 0.001 53.06 0.336
Mice a 17 181 95 − 0.28 [− 0.68, 0.10] 0.154(0.205) 54.53 < 0.001 70.66
Rabbits 20 153 124 − 0.66 [− 1.02, − 0.31] 0.000(< 0.001) 32.9 0.025 42.26
Dogs 1 NA NA NA NA
Sex
Female 22 261 148 − 0.61 [− 0.95, − 0.28] 0.000(< 0.001) 62.93 < 0.001 66.63 0.45
Male 63 667 377 − 0.52 [− 0.72, − 0.32] 0.000(< 0.001) 129.09 < 0.001 51.97
Not mentioned 9 67 70 − 0.87 [− 1.38, − 0.35] 0.000(< 0.001) 12.34 0.136 35.2
Age/weeks
< 8 3 24 21 0.26 [− 0.56, 1.09] 0.536(0.536) 0.249 0.883 0 0.023a
8–16 39 471 270 − 0.40 [− 0.64, − 0.16] 0.001(0.002) 93.64 < 0.001 59.41
> 16 14 120 63 − 0.66 [− 1.10, − 0.21] 0.003(0.004) 14.514 0.339 10.43
Not mentioned 38 380 241 − 0.81 [− 1.05, − 0.56] 0.000(< 0.001) 80.64 < 0.001 54.12
Type of NSAID
NS-COX 53 528 349 − 0.55 [− 0.76, − 0.34] 0.000(< 0.001) 122.32 < 0.001 57.48 0.695
S-COX2 41 467 245 − 0.61 [− 0.86, − 0.37] 0.000(< 0.001) 83.79 < 0.001 52.26
Time point
< 21 days 20 214 123 − 0.62 [− 0.97, − 0.27] 0.001(0.002) 51.81 < 0.001 63.33 0.957
21–48 days 58 628 343 − 0.54 [− 0.75, − 0.33] 0.000(< 0.001) 124.99 < 0.001 54.39
> 48 days 15 129 104 − 0.65 [− 1.07, − 0.24] 0.002(0.003) 29.25 0.01 52.15
NM 1 NA NA NA NA  
Type of fractured bone
Femur 57 662 409 − 0.68 [− 0.88, − 0.48] 0.000(< 0.001) 120.03 < 0.001 53.34 0.01a
Tibiaa 28 264 133 − 0.19 [− 0.49, 0.10] 0.2(0.2) 62.49 < 0.001 56.79
Fibula 4 27 11 − 0.69 [− 1.55, 0.16] 0.115(0.153) 5.67 0.128 47.15
Ulna 5 42 42 − 1.20 [− 1.86, − 0.55] 0.000(< 0.001) 1.03 0.906 0
Stiffness
NSAID vs control
Overall 76 809 441 − 0.56 [− 0.76, − 0.37] 0.000 189.46 < 0.001 60.41
Species     
Rats 50 582 318 − 0.57 [− 0.80, − 0.33] 0.000(< 0.001) 109.04 < 0.001 55.06 0.046a
Mice a 14 145 59 − 0.07 [− 0.55, 0.40] 0.758(0.785) 55.63 < 0.001 76.63
Rabbits 11 76 58 − 1.06 [− 1.58, − 0.53] 0.000(< 0.001) 11.14 0.34 10.3
Dogs 1 NA NA NA NA
Sex
Female 18 223 124 − 0.82 [− 1.21, − 0.44] 0.000(< 0.001) 40.88 0.001 58.41 0.022a
Male 55 568 299 − 0.42 [− 0.64, − 0.19] 0.000(< 0.001) 133.42 < 0.001 59.52
Not mentioned 3 18 18 − 1.63 [− 2.64, − 0.62] 0.002(0.003) 0.78 0.675 0
Age/ weeks
< 8 3 24 21 0.00 [− 0.89, 0.91] 0.98(0.98) 0 1 0 0.047a
8–16 30 373 193 − 0.39 [− 0.7, − 0.08] 0.01().02) 100.04 < 0.001 71.01
> 16a 13 96 36 − 0.31 [− 0.82, 0.18] 0.21(0.28) 18.97 0.08 36.75
Not mentioned 30 316 188 − 0.88 [− 1.18, − 0.58] 0.000(< 0.001) 54.75 0.003 47.03
Type of NSAID
NS-COX 40 411 255 − 0.41 [− 0.67, − 0.15] 0.002(0.003) 78.83 < 0.001 50.52 0.091
S-COX2 36 398 186 0.75 [− 1.04, − 0.46] 0.000(< 0.001) 102.1 < 0.001 65.77
Time point
< 21 days 14 160 84 − 0.99 [− 1.43, − 0.54] 0.000(< 0.001) 21.48 0.06 39.49 0.085
21–48 days 51 560 292 − 0.42 [− 0.66, − 0.19] 0.000(< 0.001) 144.11 < 0.001 65.3
> 48 days 11 89 64 − 0.65 [− 1.16, − 0.13] 0.014(0.01) 12.11 0.27 17.46
Type of Fractured bone
Femur 46 531 299 − 0.59 [− 0.84, − 0.34] 0.000(<0.001) 100.78 < 0.001 55.34 0.458
Tibia 23 227 107 − 0.39 [− 0.76, − 0.02] 0.038(0.05) 78.93 < 0.001 72.12
Fibula 4 27 11 − 0.77 [− 1.71, 0.16] 0.107(0.1) 3.95 0.267 24.06
Ulna 3 24 24 − 1.16 [− 2.11, 0.20] 0.017(0.034) 0.32 0.848 0
Work to failure
NSAID vs control
Overall 16 148 121 − 0.58 [− 0.95, − 0.20] 0.002 34.32 0.003 56.29
Species     
Rats 12 117 92 − 0.52 [− 0.96, − 0.09] 0.017(0.034) 25.28 0.008 56.49 0.619
Rabbits 4 31 29 − 0.75 [− 1.51, 0.01] 0.054(0.054) 7.72 0.052 61.18
Sex
Femalea 6 65 66 − 0.09 [− 0.55, 0.36] 0.694(0.0694) 12.59 0.028 60.29 0.007a
Male 10 83 55 − 0.94 [− 1.37, − 0.52] 0.000(< 0.001) 9.63 0.381 6.59
Age/weeks
< 8 0 0.267
8–16 3 24 24 − 1.16 [− 1.99, − 0.32] 0.006(0.007) 0.32 0.848 0
> 16 3 27 15 − 0.67 [− 1.54, 0.20] 0.131(0.131) 7.42 0.024 73.07
Not mentioned 10 97 82 − 0.38 [− 0.83, 0.05] 0.089(0.118) 19.88 0.019 54.73
Type of NSAID
NS-COX 11 411 255 − 0.58 [− 1.05, − 0.11] 0.015(0.03) 26.52 0.003 62.30 0.99
S-COX2a 5 398 186 − 0.58 [− 1.26, 0.09] 0.092(0.092) 7.72 0.102 48.18
Time point
< 21 days 1 NA NA NA NA 0.03a
21–48 days 12 102 75 − 0.71 [− 1.10, − 0.32] 0.000(< 0.001) 19.54 0.052 43.73
> 48 days 3 35 35 − 0.59 [− 1.26, 0.07] 0.083().12) 2.174 0.33 8.00
Type of fractured bone
Femura 10 97 82 − 0.38 [− 0.83, 0.05] 0.089(0.12) 19.88 0.019 54.73 0.267
Tibia 3 27 15 − 0.67 [− 1.54, 0.20] 0.131(0.131) 7.42 0.024 73.07
Ulna 3 24 24 − 1.16 [− 1.99, − 0.32] 0.006(0.018) 0.32 0.848 0
  1. N number of comparisons in analysis, SZ NSAID number of animals in non-steroidal anti-inflammatory drug (NSAID) group, SZ C. number of animals in control group, SMD standardized means of differences (Hedges’ g), CI confidence interval, NS-COX non-selective cyclooxygenase inhibitor, S-COX2 selective cyclooxygenase 2 inhibitor, NA not analyzed because of insufficient data, adj.P value adjusted P value through Holm-Bonferroni correction
  2. aNeed to be explained—more details in Tables S5–S22 (supplementary information file)