Regular Non-steroidal Anti-inflammatory Drug Use Increases Stress Fracture Risk in the General Population: A Retrospective Case-Control Study
Authors: Ciuciu Alexandra , Mulholland Christopher , Bozzi Michael A. , Frymoyer Chris C. , Cavinatto Leonardo , Yaron David , Harwood Marc I. , Close Jeremy D. , Mehallo Christopher J. , Tomlinson Ryan E. 
Published: October 2023

ABSTRACTPrevious studies have shown that the use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with increased stress fracture risk, potentially due to diminished skeletal adaptation. This phenomenon has been studied predominantly in high-activity individuals like dancers, athletes, and soldiers, so current data regarding the general population is limited despite the substantial economic and resource burden of stress fracture injuries within the general US population. Furthermore, our preclinical studies demonstrate that regular use of NSAIDs also diminishes the intrinsic ability of bone to resist fracture. To determine the association of regular NSAID use with stress fractures in the general population, we surveyed subjects presenting with either stress fracture or uncomplicated ankle sprain to assess their use of NSAIDs over the three months before their injury. We hypothesized that subjects with stress fractures would have increased regular NSAID usage as compared to controls. Subjects diagnosed with a stress fracture (n=56) and subjects with uncomplicated ankle sprains (n=51; control) were surveyed about their NSAID use at the time of their diagnosis and in the previous three months using a questionnaire based on the National Health and Nutrition Examination Survey (NHANES). Subjects were surveyed in person on the day of their injury diagnosis or by phone within 30 days of their injury diagnosis. Fisher’s exact test was used to determine significant differences in NSAID usage between stress fracture and control subjects. Subjects diagnosed with stress fractures had a statistically significant increase in both current use (p=0.03) and regular use (p=0.04) of ibuprofen/naproxen/celecoxib as compared to control subjects. There were no significant differences in the use of aspirin, acetaminophen, or prescription medications containing acetaminophen between groups. Consistent with previous clinical reports, we observed a strong correlation between regular ibuprofen/naproxen/celecoxib use and stress fracture incidence in the general population. These results indicate that any patients at high risk for stress fracture should avoid regular use of ibuprofen, naproxen, or celecoxib.KEY POINTSThis retrospective case-control study found that use of ibuprofen, naproxen, and/or celecoxib by subjects within the general population three or more times per week for three months (regular use) was highly associated with stress fracture diagnosis.No significant correlation between stress fracture diagnosis and the use of acetaminophen, aspirin, or prescription drugs containing acetaminophen was found.Pooled analysis of all surveyed drugs indicated a strong association between stress fracture diagnosis and NSAID or acetaminophen usage in the general population, consistent with previous work done in US Army soldiers and athletes.Due to the differences in mechanisms of action of the drugs surveyed in this study, future work is needed to conclude which NSAID, if any, is safest for regular use by those at higher risk of stress fracture formation.The findings of this study highlight the need for future studies to include subjects from the general population in addition to high-activity subjects as they indicate that these individuals are also at higher risk of stress fracture formation with regular NSAID use.