Background: The objective of this study was to analyze the direct medical expenses of a vertebral fracture cohort (VC) and a matched cohort (MC) over 5 years preceding and following the fracture, analyze the duration of the rise in medical expenses due to the fracture, and examine whether the expenses vary with age group, utilizing a national claims database. Methods: Subjects with vertebral fractures and matched subjects were chosen from the National Health Insurance Service Sample cohort (NHIS-Sample) of South Korea. Patients with vertebral fractures were either primarily admitted to acute care hospitals (index admissions) or those who received kyphoplasty or vertebroplasty during the follow-up period (2002–2015). A risk-set matching was performed using 1 : 5 random sampling to simulate a real-world situation. Individual-level direct medical expenses per quarter were calculated for 5 years prior and subsequent to the vertebral fracture. In this analysis using a comparative interrupted time series design, we examined the direct medical expenses of a VC and an MC. Results: A total of 3,923 incident vertebral fracture patients and 19,615 matched subjects were included in this study. The mean age was 75.5 ± 7.4 years, and 69.5% were women. The mean difference in medical expenses between the two groups increased steadily before the fracture. The medical expenses of the VC peaked in the first quarter following the fracture. The cost changes were 1.82 times higher for the VC than for the MC (95% confidence interval, 1.62–2.04; p < 0.001) in the first year. Subsequently, there were no differential changes in medical expenses between the two groups (p > 0.05). In the < 70-year subgroup, there were no differential changes in medical expenses between the two groups (p > 0.05). However, in the ≥ 80-year subgroup, the cost changes for the VC were higher than those for the MC up to 5 years after time zero. Conclusions Based on our study results, we suggest that health and medical policies for vertebral fractures should be designed to last up to approximately 1 year after the fracture. Health policies should be differentiated according to age group.