The most important finding from this study demonstrated that the use of NSAIDs increased the rate of delayed union/nonunion in patients treated initially nonoperatively for 5th metatarsal fractures. In the group initially managed nonoperatively, the rate of delayed union/nonunion as evidenced by undergoing ORIF or non/malunion repair greater than sixty days after initial diagnosis was found to be 16/1,409 (1.14%) in the NSAID group and 46/9,217 (0.50%; P=0.003483) in the non-NSAID group. However, we did not find a difference in non/malunion rate in patients who were treated with initial operative intervention. In the group initially managed with early ORIF, 1/68 (1.5%) of subjects who received NSAID prescriptions required secondary surgeries compared to 5/297 (1.7%, P=0.900876) in the non-NSAID group.
There has been considerable research utilizing in-vitro cellular models and animal models to determine the effects of NSAIDs on the inflammatory cascade, fracture healing, and cellular modification. Given the difficulty in controlling over-the-counter use of NSAIDs, the wide range of medications falling under the NSAID classification, and the power necessary to assess a small but potentially important effect on nonunion rate, there are few level 1 randomized controlled trials assessing the true risk of nonunion or delayed union in patients receiving NSAIDs . Thus, some studies have utilized databases to retrospectively assess the effect of NSAIDS on the rate of fracture complications including nonunion, delayed union, malunion, or infection, most of these studies having no more than a few hundred patients . The current study is the first of its kind to use a large insurance database to specifically assess the effects of NSAIDs on 5th MT fracture healing.
Retrospective studies have demonstrated an increased rate of nonunion or delayed union in patients experiencing a fracture who are treated with NSAIDs. A study by Giannoudis et al.  retrospectively reviewed 377 patients with a femoral shaft facture managed with intramedullary nailing, finding a higher rate of nonunion in patients treated with ibuprofen and/or diclofenac. Specifically, 62.5% of patients with a nonunion had received NSAIDs versus 13.4% of patients who did not have nonunion . Additionally, the average time to union was 7.5 months in the NSAID treated group and 5.5 months in the non-NSAID group . Furthermore, a large retrospective insurance database study analyzing a total of 309,330 patients with fractures demonstrated a higher rate of nonunion in patients prescribed NSAIDs with an odds-ratio of 1.84 . Therefore, these large database studies are demonstrating the potentially detrimental effects of NSAIDs on fracture hea ling. The current study adds to the body of literature demonstrating the same for an isolated foot fracture initially managed nonoperatively with a significantly increased rate of clinically relevant nonunion/delayed union in patients managed with NSAIDs (1.14% in the NSAID group vs 0.50% in the non-NSAID group (P=0.003483)).
Furthermore, while this study includes pa tients of all ages (Table 2), and does not delineate outcomes based on age groups, there is literature suggesting that NSAIDs do not have the same detrimental effect on fracture union in pediatric models. Specifically, large retrospective studies of pediatric patients with fractures managed nonoperatively by the emergency department have demonstrated no effect of Ibuprofen on nonunion . Furthermore, juvenile animal models of tibial fractures exposed to Ketorolac demonstrated no significant reduction in strength and stiffness on mechanical testing . The purpose of this study was to use a private payer database to assess the effects of NSAIDs on 5th MT fracture healing.
This study is limited in the retrospective nature of its design. This study relies upon accurate provider coding and billing information, and the use of a private, single payer database. The use of a private payer database may have biased our results; however, the authors were reassured by the large sample size with demographics as represented in Table 2. The coding systems used in this analysis do not specify the zone of fracture, which may be an important consideration. Additionally, due to the nature of the design, the study was unable to determine which patients received an NSAID while inpatient or those taking NSAIDs over-the-counter. It was also unable to determine which patients received a prescription but did not take the NSAID. Finally, it lacks any subjective outcome measures, and patients may have changed insurance companies resulting in loss to follow up.