Effect of non-steroidal anti-inflammatory drugs on fracture healing in children: A systematic review

Table 1 Newcastle-Ottawa scale for assessing the quality of nonrandomized studys

Ref.	Representativeness of the exposed cohort	Selection of the non-exposed cohort	Ascertainment of exposure	Demonstration that outcome of interest was not present at start of study	Comparability of cohorts on the basis of the design or analysis	Assessment of outcome	Was follow-up long enough for outcomes to occur?	Adequacy of follow up of cohorts	Total, n
Zura et al[30], 2018	1	1	1	1	1	1			6
Kay et al[31], 2010	1	1	1	1	1	1			6
Kay et al[32], 2011	1	1	1	1	1	1			6
DePeter et al[33], 2017	1	1	1	1	2	1			7

Table 2 Evidence table

Study	Ref.	Level of evidence
Risk factors for nonunion of bone fracture in pediatric patients: An inception cohort study of 237033 fractures	Zura et al[30], 2018	Level II
Perioperative ketorolac use in children undergoing lower extremity osteotomies	Kay et al[31], 2010	Level III
Complications of ketorolac use in children undergoing operative fracture care	Kay et al[32], 2011	Level III
Does the use of ibuprofen in Children with extremity fractures increase their risk for bone healing complications?	DePeter et al[33], 2017	Level I
A randomized clinical trial of ibuprofen versus acetaminophen with codeine for acute pediatric arm fracture pain	Drendel et al[34], 2009	Level I
Effect of NSAID use on bone healing in pediatric fractures: A preliminary, prospective, randomized, blinded study	Nuelle et al[35], 2020	Level I

NSAIDs: Non-steroidal anti-inflammatory drugs.

Table 3 Summary of evidence of non-steroidal anti-inflammatory drugs use and nonunions in children

Ref.	Study population	Age	Number of patients	NSAID studied	Comparison group	Delayed healing/nonunion rate (%)	NSAID specific results	Notes
Zura et al[30], 2018	18 most commonly fractures	< 18 yr	237033	All prescription NSAIDs	No analgesics	0.85	Multivariate OR for nonunion was 1.05 (95% CI: 0.81-1.35) for ‘NSAID’ vs ‘No analgesic’ group	Data from a large, private insurance database in the United States from 2011. Included both operative and nonoperatively managed fractures
Kay et al[31], 2010	Operative fracture care	Mean = 6.7 yr	221	Ketorolac	No ketorolac	0	There were no cases of delayed union or nonunion in either group	Included 169 patients who received ketorolac vs 52 who did not. Only accounted for NSAID use in the immediate post-operative period. Fractures were predominantly in the upper extremity
Kay et al[32], 2011	Lower extremity osteotomies	Mean = 8.5 yr	327 patients (682 osteotomies)	Ketorolac	No ketorolac	0.70	Delayed healing in 0.6% in the ketorolac group (4/625) vs 1.8% in the control group (1/57; P = 0.89)	Included osteotomies of the pelvis, femur, tibia and foot. Only accounted for NSAID use in the immediate post-operative period
DePeter et al[33], 2017	Fractures of the tibia, femur, humerus, scaphoid or fifth metatarsal	Median = 7 yr	808	Ibuprofen	No ibuprofen	1.4	3% (10/338) of ibuprofen group developed a bone healing complication vs 4% (17/470) of controls (OR = 0.8, 95%CI: 0.4-1.8)	Exposure to ibuprofen included either administration during hospitalization or a prescription for ibuprofen at discharge. A bone healing complication was defined as radiographic evidence of nonunion, delayed union or future re-displacement as determined by a pediatric radiologist. Total complications (27/808; 3.5%) included 1% (n = 8) with nonunion, 0.4% (n = 3) with delayed union and 2% (n = 16) with re-displacement
Drendel et al[34], 2009	Upper extremity fractures (non-op)	Mean = 7.8 yr	244 patients	Ibuprofen	Acetaminophen with codeine	0	No documented fracture nonunions	Excluded fractures that required reduction/manipulation or surgery. Four (1.6%) children had another fracture at the same site within 1 yr of the original fracture, including 3 who had received acetaminophen and 1 received ibuprofen
Nuelle et al[35], 2020	Skeletally immature patients with long-bone fractures	Mean = 7.7 yr	95 patients (97 fractures)	Ibuprofen	Acetaminophen	0	At 6 wk, there was radiographic healing in 92% of the NSAID group vs 82% of the control group (P = 0.22). This increased to 100% and 98%, respectively, at 10-12 wk post-injury (P = 0.48)	Included females < 16 and males < 14 with open physes. Fractures managed both operatively and nonoperatively. Healing was documented at a mean of 41 d in the control group and 40 d in the NSAID group (P = 0.76). No cases of nonunion were documented in either group

NSAIDs: Non-steroidal anti-inflammatory drugs; CI: Confidence interval; OR: Odds ratio.