Risk of Nonunion with Nonselective NSAIDs, COX-2 Inhibitors, and Opioids

J Bone Joint Surg Am. 2020 Jul 15;102(14):1230-1238. doi: 10.2106/JBJS.19.01415.


Background: Cyclooxygenase-2 (COX-2) has been found to be important for fracture-healing in animal models, raising concerns about use of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors after fractures. We evaluated associations of NSAIDs, COX-2 inhibitors, and opioids with nonunion after long-bone fracture.

Methods: Using private health insurance claims data from Optum's de-identified Clinformatics Data Mart database from January 1, 2000, to September 30, 2015, we identified adults with a single long-bone fracture or commonly paired long-bone fractures who had 1 year of available follow-up data. Using multivariable logistic regression models, we examined associations between NSAID, COX-2-inhibitor, or opioid prescription fills after the fracture and the risk of nonunion within 1 year, defined as a nonunion diagnosis with a procedure to treat the nonunion.

Results: A nonunion diagnosis with a procedure to treat the nonunion was identified after 2,996 (0.9%) of the 339,864 fracture episodes, with rates varying by fracture site. The risk of that outcome was greater in patients who had filled COX-2-inhibitor prescriptions (adjusted odds ratio = 1.84 [95% confidence interval = 1.38 to 2.46]) or opioid prescriptions (1.69 [1.53 to 1.86]), but not in patients who had filled nonselective-NSAID prescriptions (1.07 [0.93 to 1.23]) after the fracture. Results were similar when the outcome definition was changed to just a nonunion diagnosis.

Conclusions: COX-2 inhibitors, but not nonselective NSAIDs, were associated with a greater risk of nonunion after fracture. Opioids were also associated with nonunion risk, although patients filling prescriptions for opioids may have had more severe fractures.

Level of evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / adverse effects
  • Analgesics, Opioid / therapeutic use
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Cyclooxygenase 2 Inhibitors / administration & dosage
  • Cyclooxygenase 2 Inhibitors / adverse effects*
  • Cyclooxygenase 2 Inhibitors / therapeutic use
  • Databases, Factual
  • Female
  • Fracture Healing / drug effects*
  • Fractures, Bone / physiopathology*
  • Fractures, Ununited / chemically induced*
  • Humans
  • Male
  • Middle Aged
  • Risk Factors


  • Analgesics, Opioid
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase 2 Inhibitors