Background and Objectives <p>Vitamin D receptor activators (VDRAs) are widely used in patients with osteoporosis; however, the frequency of acute kidney injury (AKI) due to VDRAs is unclear. This study aimed to investigate whether the incidence of AKI after VDRA initiation differed among patients with different renal functions.</p> Methods <p>The medical records of Japanese patients who were newly prescribed with VDRAs for osteoporosis at the Fujita Health University Hospital or Kyoto University Hospital between April 2012 and March 2022 were retrospectively reviewed in this study. The RIFLE (Risk, Injury, Failure, Loss of function, End-stage kidney disease) criteria were used to assess the incidence of AKI within 7 days after initiation of VDRA therapy. Additionally, the AKI algorithm was used to assess the incidence of AKI from 8 to 365 days after initiation of VDRA therapy.</p> Results <p>The incidence of AKI, as defined by the RIFLE criteria, was significantly higher in patients with normal renal function or end-stage renal failure than in those with mild renal decline (<i>p</i> &lt; 0.05); the incidence of AKI, defined using the AKI algorithm, showed a similar trend. We found that the lack of serum calcium level monitoring before the initiation of VDRAs might be a risk factor for AKI defined by the RIFLE criteria (odds ratio = 2.004, <i>p</i> = 0.096).</p> Conclusions <p>The incidence of AKI after the initiation of VDRA therapy was high, even if renal function was normal. Thus, our results suggest that monitoring serum calcium levels before the initiation of VDRA therapy is necessary, regardless of renal function.</p> Graphical abstract <p></p>