NSAIDS and Risk of Non-union

Written by Graham Van Schaik

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There was no short-term impact of NSAIDs/COX-2 inhibitors on long-bone fracture healing BUT using NSAIDs >3 weeks was associated with higher rates of non-union or delayed union.

Why does this matter?
There has been a strong push to move away from prescribing opiate analgesics if another acceptable alternative exits. NSAIDs/COX-2 inhibitors could be used to help shift away from post-surgical reliance on opiates. To date, data have been mixed, with studies pointing in both directions regarding healing in fracture: 1) Do NSAID, COX-2, or Opioid Rxs Increase Non-Union Risk? 2) Point: NSAIDs for Fractures – More Good than Harm? 3) Counterpoint: NSAIDs for Fractures – More Harm Than Good?.

Give me a break here…

  • Design: This was a retrospective registry-based case series study of 8,693 adult patients with upper or lower extremity fractures who were treated with any surgical intervention at the fracture site between 01/1998 and 12/2018. Pathologic fractures and those with initial diagnosis of non-union were excluded. Data regarding patient demographics were utilized for propensity matching. The authors divided the dataset into 2 groups, NSAID/COX-2 inhibitor users and nonusers, and the primary outcome was set as a diagnosis of “non-union” or “delayed union” at 6 to 48 months. Secondary outcome was defined as reoperation for nonunion/ delayed union.

  • Results: 208 patients had non or delayed union (178 the former, 30 the latter). Of those, 64 patients (30.8%) had reoperation. NSAID users had a significantly lower hazard of non-union compared with matched nonusers (HR 0.69 [0.48 to 0.98], 95% confidence interval), but there was no significant difference in any other matched comparison. Kaplan-Meier analysis revealed significantly higher non-union/delayed union when NSAID durations were > 3 weeks, p=.001. COX-2 inhibitors showed no significant difference among the groups with respect to medication duration.

  • Implications: This seems a bit suspect; NSAIDs for 21 days lowers risk of non-union but 22 days increases it? And what about COX-2 inhibitors? They are left hovering in the background, neither good nor bad compared to non-users. To me, this suggests that patients who felt more pain (and thus may have used medications longer than 3 weeks) may have been more susceptible to non-union or delayed union. It does indicate that perhaps duration of medication prescribing could be a red flag to providers that care for these patients rather than type of medication. Regardless, I plan on not prescribing these patients pain medications for long periods of time and would rather seek to obtain follow up with their surgeons.

  • Limitations: The authors had no way of knowing if patients took the NSAID/COX-2 inhibitor medications they were prescribed, which specific medications they took, or whether they took over-the-counter NSAIDs. Additionally, the common data model (CDM) used for this work was still in early stages, and the multicenter database was not set. Lastly, the work was limited in that many factors known to be associated with non-union (smoking, patient occupation, etc.) were not examined.

Overall, while this work supports the safety of NSAIDs and COX-2 Inhibitors for fracture healing, caution is still necessary when prescribing.

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 Aug 4;103(15):1402-1410. doi: 10.2106/JBJS.20.01663.

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