Table 1 Subgroup analysis and GRADE evidence
Results | No. of Participants | No. of Studies | Inhaled Therapy Containing ICSs | Inhaled Therapy Without ICSs | Risk Ratio (M-H, Fixed,95% CI) | P value | I 2 (%) | GRADE evidence | ||
|---|---|---|---|---|---|---|---|---|---|---|
Events | Patients | Events | Patients | |||||||
Risk of fracture for ICSs vs. controls | 87,594 | 44 | 532 | 52,630 | 351 | 34,964 | 1.19 (1.04,1.37) | 0.010 | 0 | Moderate |
Risk of fracture for ICSs vs. Controls according to different duration of treatment | ||||||||||
  < 12 months | 19,840 | 21 | 48 | 11,486 | 29 | 8354 | 1.20 (0.79,1.81) | 0.39 | 13 | Low |
  ≥ 12 months | 67,387 | 23 | 489 | 40,970 | 326 | 26,417 | 1.19 (1.04,1.38) | 0.01 | 0 | High |
Risk of fracture for ICSs vs. Controls according to different type of treatment | ||||||||||
 Triamcinolone | 412 | 1 | 14 | 201 | 21 | 211 | 0.70 (0.37,1.34) | 0.28 | NA | Very low |
 Mometasone furoate | 3162 | 3 | 16 | 1967 | 10 | 1195 | 0.95 (0.43,2.10) | 0.9 | 0 | Low |
 Beclometasone dipropionate | 4222 | 2 | 8 | 2378 | 5 | 1844 | 1.26 (0.40,3.99) | 0.69 | 0 | Moderate |
 Budesonide | 20,874 | 12 | 93 | 14,017 | 26 | 6857 | 1.64 (1.07,2.51) | 0.02 | 0 | High |
 160 ug bid | 8256 | 6 | 20 | 4024 | 17 | 4232 | 1.17 (0.62,2.18) | 0.63 | 0 | Low |
 320 ug bid | 14,342 | 9 | 60 | 8747 | 22 | 5595 | 166 (1.03,2.70) | 0.04 | 0 | High |
 Fluticasone furoate | 38,021 | 13 | 170 | 23,319 | 95 | 14,702 | 1.37 (1.05,1.78) | 0.02 | 20 | Moderate |
 50 ug qd | 2578 | 3 | 4 | 1186 | 8 | 1392 | 0.66 (0.21,2.05) | 0.47 | 32 | Moderate |
 100 ug qd | 34,522 | 11 | 160 | 20,287 | 82 | 14,235 | 1.37 (1.04,1.80) | 0.02 | 0 | Moderate |
 200 ug qd | 2767 | 3 | 6 | 1379 | 5 | 1388 | 1.18 (0.40,3.50) | 0.77 | 37 | Moderate |
 Fluticasone propionate | 20,903 | 13 | 231 | 10,748 | 206 | 10,155 | 1.10 (0.92,1.32) | 0.62 | 0 | Moderate |
 250 ug bid | 4044 | 5 | 11 | 1902 | 7 | 2142 | 1.72 (0.68,4.34) | 0.25 | 0 | Low |
 500 ug bid | 18,898 | 11 | 225 | 9346 | 204 | 9552 | 1.10 (0.92,1.32) | 0.31 | 0 | Low |
Risk of fracture for ICSs vs. Controls according to different mean age | ||||||||||
  < 65 | 45,519 | 30 | 183 | 28,000 | 115 | 17,519 | 1.08 (0.85,1.37) | 0.53 | 3 | Low |
  ≥ 65 | 42,075 | 14 | 349 | 24,630 | 236 | 17,445 | 1.26 (1.07,1.48) | 0.007 | 0 | Moderate |
Risk of fracture for ICSs vs. Controls according to different GOLD grade | ||||||||||
 GOLD 2 | 28,500 | 12 | 125 | 15,025 | 96 | 13,475 | 1.26 (0.97,1.63) | 0.08 | 22 | Low |
 GOLD 3 | 56,585 | 28 | 394 | 36,121 | 247 | 20,464 | 1.18 (1.00,1.38) | 0.04 | 0 | High |
Risk of fracture for different ICSs vs. controls | ||||||||||
 Triple therapy vs controls | 24,887 | 13 | 98 | 14,834 | 39 | 10,053 | 1.49 (1.03,2.17) | 0.04 | 0 | High |
 ICS/LABA VS controls | 56,250 | 31 | 274 | 28,144 | 292 | 28,106 | 1.30 (1.10,1.53) | 0.002 | 0 | High |
 ICSs vs. PLACEBO | 17,557 | 12 | 164 | 9037 | 149 | 8520 | 1.07 (0.86,1.33) | 0.52 | 4 | Moderate |
Risk of fracture for triple therapy vs. different controls | ||||||||||
 triple therapy vs LAMA/LABA | 19,578 | 8 | 90 | 11,914 | 35 | 7664 | 1.51 (1.01,2.25) | 0.04 | 0 | High |
 triple therapy vs LAMA | 5309 | 5 | 8 | 2920 | 4 | 2389 | 1.38 (0.49,3.88) | 0.54 | 0 | Low |
Risk of fracture for triple therapy vs. LAMA/LABA according to different duration of treatment | ||||||||||
 6 months | 2594 | 3 | 2 | 1304 | 3 | 1290 | 0.74 (0.17,3.31) | 0.7 | 0 | Low |
 12 months | 16,984 | 5 | 88 | 10,610 | 32 | 6374 | 1.59 (1.05,2.41) | 0.03 | 0 | High |
Risk of fracture for triple therapy vs. LAMA/LABA according to different mean age | ||||||||||
  < 65 | 10,763 | 4 | 45 | 6459 | 22 | 4304 | 1.29 (0.76,2.20) | 0.34 | 0 | Moderate |
  ≥ 65 | 8815 | 4 | 45 | 5455 | 13 | 3360 | 1.82 (0.99,3.36) | 0.06 | 0 | Low |
Risk of fracture for triple therapy vs. LAMA/LABA according to different GOLD grade | ||||||||||
 GOLD 2 | 2317 | 2 | 1 | 1165 | 3 | 1152 | 0.42 (0.06,2.86) | 0.38 | 0 | Moderate |
 GOLD 3 | 16,616 | 4 | 87 | 10,416 | 31 | 6200 | 1.61 (1.05,2.45) | 0.03 | 19 | High |
Risk of fracture for ICS/LABA vs. different controls | ||||||||||
 ICS/LABA VS LAMA/LABA | 17,413 | 8 | 63 | 9703 | 36 | 7710 | 1.28 (0.94,2.10) | 0.10 | 0 | Moderate |
 ICS/LABA VS LABA | 29,059 | 19 | 204 | 16,865 | 146 | 12,194 | 1.24 (1.01,1.44) | 0.04 | 0 | High |
 ICS/LABA VS LAMA | 2203 | 3 | 6 | 1095 | 1 | 1108 | 3.55 (0.74,17.03) | 0.11 | 0 | Moderate |
 ICS/LABA VS PLACEBO | 13,249 | 6 | 143 | 6878 | 105 | 6371 | 1.32 (1.04,1.69) | 0.02 | 35 | Moderate |
Risk of fracture for ICS/LABA vs. LABA according to different duration of treatment | ||||||||||
 3 months | 1620 | 1 | 0 | 806 | 3 | 814 | 0.14 (0.01, 2.79) | 0.2 | NA | Low |
 6 months | 6372 | 7 | 22 | 3987 | 9 | 2385 | 1.67 (0.83, 3.37) | 0.15 | 7 | Moderate |
 12 months | 9450 | 8 | 36 | 6258 | 19 | 3192 | 1.07 (0.62, 1.83) | 0.82 | 0 | Low |
 36 months | 11,617 | 3 | 146 | 5814 | 115 | 5803 | 1.26 (1.00, 1.47) | 0.05 | 0 | High |
Risk of fracture for ICS/LABA vs. LABA according to different mean age | ||||||||||
  < 65 | 14,736 | 13 | 52 | 9716 | 27 | 5020 | 1.12 (0.72, 1.76) | 0.61 | 0 | Moderate |
  ≥ 65 | 14,323 | 6 | 152 | 7149 | 119 | 7174 | 1.27 (1.01, 1.61) | 0.04 | 0 | Moderate |
Risk of fracture for ICS/LABA vs. LABA according to different GOLD grade | ||||||||||
 GOLD 2 | 12,627 | 5 | 59 | 6733 | 43 | 5894 | 1.29 (0.87,1.90) | 0.20 | 0 | Moderate |
 GOLD 3 | 15,799 | 13 | 141 | 9708 | 98 | 6091 | 1.27 (0.99,1.63) | 0.06 | 0 | High |