Introduction <p>Eldecalcitol is an active vitamin D₃ derivative approved for the treatment of osteoporosis in Japan and postmenopausal osteoporosis in China. However, the impact of concomitant calcium supplementation on its safety profile is unclear.</p> Materials and methods <p>This was a prospective, observational, non-interventional post-marketing drug intensive monitoring study in Chinese postmenopausal women with osteoporosis (NCT05433207). Data were collected using an electronic case report form at baseline, before initial eldecalcitol dosing, and during routine clinical visits over a 1-year follow-up period.</p> Results <p>One thousand patients were enrolled from 29 Chinese clinical sites; 958 received eldecalcitol (853 without/105 with calcium supplementation). The mean age (standard deviation [SD]) of patients was 65.6 (9.0) years and mean (SD) time since osteoporosis diagnosis was 2.7 (3.8) years. Adverse drug reactions (ADRs) affected 39.2% and 42.9% of patients in the without and with calcium supplementation groups, respectively. 22 (2.3%) patients developed hypercalcemia including 17 (1.99%) and 5 (4.76%) in the without and with calcium supplementation groups, respectively. Multivariable logistic regression analyses indicated that those receiving calcium were more likely to experience hypercalcemia (adjusted odds ratio [OR] 3.07, 95% confidence interval [CI] 1.16, 8.10, <i>P</i> = 0.02) than those not receiving calcium. ADRs of urolithiasis were experienced by three patients (0.35%) in the without calcium supplementation group.</p> Conclusion <p>This study confirmed the real-world safety profile of eldecalcitol in a large population of Chinese women with postmenopausal osteoporosis. Hypercalcemia incidence was higher in patients with compared to without calcium supplementation, indicating that concomitant eldecalcitol and calcium should be carefully considered.</p>