SLR - September 2021 - Jacqueline C. Lucke

Do Nonsteroidal Anti-Inflammatory or COX-2 Inhibitor Drugs Increase the Nonunion or Delayed Union Rates After Fracture Surgery? A Propensity-Score-Matched Study

Reference: Kim H, Kim DH, Kim DM, Kholinne E, Lee ES, Alzahrani WM, Kim JW, Jeon IH, Koh KH. Do Nonsteroidal Anti-Inflammatory or COX-2 Inhibitor Drugs Increase the Nonunion or Delayed Union Rates After Fracture Surgery? A Propensity-Score-Matched Study. J Bone Joint Surg Am. 2021 Jun 8. doi: 10.2106/JBJS.20.01663.

Level of Evidence: Therapeutic Level III

Scientific Literature Review

Reviewed By: Jacqueline C. Lucke, DPM
Residency Program: University of Florida Health Jacksonville – Jacksonville, FL

Podiatric Relevance: Postoperative pain control may be accomplished with multimodal therapy consisting of both opioid and non-opioid agents. NSAIDs have played an essential role in reducing postsurgical opioid use. However, in orthopedic surgery, bone healing must be considered in choosing pharmacologic therapy. Previous studies have implicated NSAID administration as a risk factor for nonunion of fractures. NSAIDs theoretically can impede bone healing through inhibition of COX1 and two and associated pathways, leading to increased risk of malalignment and delayed or nonunion. In this study, the authors aimed to determine the effects of NSAIDs/COX2 inhibitors on postoperative fracture healing in a large patient cohort who underwent operative fracture treatment.

Methods: This retrospective, registry-based, case series study included 8,693 patients with both upper and lower extremity fractures that were operatively treated between 1998 and 2018. Patients were divided into two groups, the NSAID/COX2 inhibitor user and nonuser group. The primary outcome measured was the occurrence of a delayed union or nonunion, determined by diagnosis coding > 6 months after surgery. The secondary outcome was reoperation for delayed or nonunion. The effect of NSAID duration of use on fracture healing was also examined using Kaplan-Meier survival analysis. Additional variables evaluated included demographics, fracture conditions (open fracture, surgery performed, SSI, etc.), comorbidities, and steroid use. Comparative analysis between the two groups was performed by 1:1 propensity score matching using these variables.

Demographic data-
•    Of 8,693 patients, there were 208 nonunion (178, 2.05 percent) and delayed unions (30, 0.35 percent).
•    64 of the 208 patients (30.77 percent) had reoperation for nonunion or delayed union.
•    All patients included were Asian.
•    Demographics and fracture/surgical variables were significantly different between the two groups.
Comparison of NSAID/COX2 inhibitor users and nonusers-
•    3,264 patients were allocated to each group after matching.
•    Hazard ratio (HR) was lower for the user group than the nonuser group but did not reach significance.
•    In subgroup analysis of NSAIDs versus COX2 inhibitors, NSAIDs were associated with significantly lower HR for nonunion.
NSAID duration-
•    Medication user group in time periods < 1 week and > 1 to < 3 had lower non-union rates compared to nonuser group.
•    Groups that used medication for > 3 weeks showed higher rates of nonunion/delayed union.

Conclusions: In this study, NSAID/COX2 inhibitor use after operatively treated fracture was not associated with increased risk of nonunion/delayed union, however, use for > 3 weeks did show an increased risk. Overall, the results of this study lend more evidence to an insignificant impact of NSAIDs on fracture healing, but cannot provide definitive conclusions due to many study limitations. In conclusion, the present study suggests caution should be taken in long term administration of NSAIDs after fracture surgery and should be considered in patients with multiple risk factors. 

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