Objectives: To investigate renal function during denosumab therapy using the estimated glomerular filtration rate based on cystatin C (eGFRcys) which is more accurate than creatinine (eGFRcr) for renal function. Methods: Bone mineral densities (BMDs) of lumbar spine and hip regions, eGFRcys, eGFRcr, creatinine clearance (Ccr), and serum total homocysteine (S-Hcy) were measured during 2-year denosumab therapy in 53 women with osteoporosis naïve to anti-osteoporosis drugs (new group) and 64 women who were switched from long-term bisphosphonate treatment to denosumab therapy (switch group). Results: There were no significant differences in age, eGFRcr, Ccr, eGFRcys, and S-Hcy levels at baseline between the groups. BMDs in the lumbar spine, femoral neck, and total hip increased significantly after 2-year denosumab therapy in both groups. eGFRcr decreased in the switch group, and Ccr decreased in both groups; however, eGFRcys and S-Hcy levels did not change significantly in either group. To investigate the causal factors associated with the decrease in eGFRcr and Ccr, multiple regression analysis was performed in all patients. Denosumab initiation within 3 months after fracture and eGFRcr or Ccr at baseline were independent factors for the decrease in eGFRcr or Ccr during the 2-year denosumab therapy. Decline in creatinine-based renal function could be reflected by increased muscle mass during the ongoing recovery from fracture. Conclusions Renal function was preserved in all patients, including those in the switch group during denosumab therapy. Creatinine-based renal function should be cautiously interpreted during denosumab therapy in patients with recent fractures.