Table 3.

Meta-analyses of NSAIDs effect on fracture healing and heterotopic ossification.

Study	Condition	Study type	Length of follow up	Type of NSAIDs	number of studies and participants	Result
Dodwellet al, 2010 [67]	Fracture Healing	Mostly retrospective cohort; one prospective cohort study	5 month to 3.8 years	Diclofenac, indomethacin, ibuprofen, ketorolac, and not defined.	11 studies/2067 patients exposed to NSAIDs	Increased risk for non-union: OR = 3.0 (1.6 – 5.6); in 7 high-quality studies, no statistical significant risk, OR = 2.2 (0.8 – 6.3).
Wheatly, 2018 [68]	Fracture Healing	RCTs, cohort studies, and case-control studies	> 6 months	All type of NSAIDs	16 studies/3283 exposed bones to NSAIDs	Increased risk for delayed union or nonunion: OR = 2.07 (1.19 to 3.61). No risk for low dose (< 125mg/d diclofenac, 150mg/d of indomethacin or 120mg/d ketorolac) or shorter duration (< 1 week): OR = 1.68 (0.63 to 4.46)
Ma, 2018 [69]	Heterotopic Ossification	RCTs	1.5 to 12 months	Naproxen vs. Placebo	4 RCTs/total of 269 patients	Decreased risk for HO: RR = 0.21 (0.12 to 0.35) at 12 months.
Joice, 2018 [70]	Heterotopic Ossification	RCTs	3 – 24 months	Non-selective NSAIDs vs. Placebo	17 RCTs/ total of 4979 patients	Decreased risk for HO: Log OR = −1.35 (−1.83 to −0.86)
				Selective NSAIDs vs. Placebo	5 RCTs/ total of 628 patients	Decreased risk for HO: Log OR = −1.58 (−2.41 to −0.75)
				Non-selective vs. selective NSAIDs	7 RCTs/ total of 1096 patients	No difference in risk for HO: Log OR = 0.22 (−0.36 to 0.79)

NSAIDs: non-steroidal anti-inflammatory drugs; OR: odds ratio; RCT: randomized controlled trial; RR: relative risk.