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Lumbar epidural steroid injections (LESIs) are frequently prescribed for the treatment of radiculopathy or neurogenic claudication arising from compression of spinal nerves. However, there is evidence suggesting that corticosteroids adversely affect bone strength by diminishing new bone formation and increasing bone resorption. Our study sought to assess whether LESIs increase the risk of subsequent vertebral body fracture.A retrospective cohort study was conducted to compare patients receiving LESIs with a control group. A total of 50,345 patients with ICD-9 (International Classification of Diseases, Ninth Revision) diagnosis codes involving the spine were identified by searching a corporate database, and 3415 of these were found to have received at least one LESI. We randomly selected a study population of 3000 patients from the injected population, and we selected a matched cohort of 3000 patients from the non-injected group with use of propensity matching. The incidence of vertebral body fractures in each group was assessed with use of survival analysis.There was no significant difference between the injected and non-injected groups with respect to age, predicted propensity score, sex, race, hyperthyroidism, or steroid use. In the survival analysis, an increasing number of injections was associated with an increasing likelihood of fractures. Each successive injection increased the risk of fracture by a factor of 1.21 (95% confidence interval, 1.08 to 1.30) after adjustment for covariates (p = 0.003).The findings suggest that LESIs, like other forms of exogenous steroid administration, may lead to increased bone fragility. The added exposure to glucocorticoids resulting from LESI use may carry a greater risk than previously thought, suggesting that use of LESIs should be approached cautiously in patients at risk for osteoporotic fractures.Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.