BACKGROUND: Dialysis patients have high rates of fracture morbidity, but evidence on optimal management strategies for osteoporosis is scarce. OBJECTIVE: To determine the risk for cardiovascular events and fracture prevention effects with denosumab compared with oral bisphosphonates in dialysis-dependent patients. DESIGN: An observational study that attempts to emulate a target trial. SETTING: A Japanese administrative claims database (April 2014 to October 2022). PATIENTS: Adults aged 50 years or older who have initiated denosumab or oral bisphosphonates for osteoporosis in dialysis-dependent patients. MEASUREMENTS: The safety outcome was major adverse cardiac events (MACE). The effectiveness outcome was a composite of all fractures. Follow-up was 3 years. RESULTS: A total of 1032 patients were identified (658 denosumab users and 374 oral bisphosphonate users). Overall average age was 74.5 years, and 62.9% were women. The weighted 3-year risk difference for MACE was 8.2% (95% CI, -0.2% to 16.7%), with a weighted 3-year risk ratio of 1.36 (CI, 0.99 to 1.87). The weighted 3-year risk difference for composite fractures was -5.3% (CI, -11.3% to -0.6%), and the weighted 3-year risk ratio was 0.55 (CI, 0.28 to 0.93). LIMITATIONS: Lack of clinical data on kidney or osteoporosis disease severity and cardiovascular or other metabolic risk with residual confounding. Safety outcomes did not include kidney end points. CONCLUSION: It was estimated that, compared with oral bisphosphonates, denosumab lowered the risk for fractures by 45% and increased the risk for MACE by 36%. The estimates, however, are imprecise and need to be confirmed in future studies. PRIMARY FUNDING SOURCE: None.