Adjuvant treatment for post-menopausal women with early breast cancer (BC) includes aromatase inhibitors (AI), known to decrease bone mineral density (BMD). In this study, we investigate whether denosumab is a valid second option for patients unable to receive standard adjuvant i.v. zoledronic acid (ZA). In total, 212 patients have been evaluated after they did not receive ZA. Of those 194 were included. After evaluation by an endocrinologist, all patients were offered ZA as their first choice and 15% accepted (N = 29). The remaining 85% were offered denosumab (N = 165). All patients were followed prospectively with blood tests up to 24 months. DXA scans were performed at baseline and 24 months. No difference was observed between the two treatment groups at baseline, with regard to anthropometry and standard biochemistry. Markers of bone turnover (p-PINP, p-CTX, p-bone-specific alkaline phosphatase and p-osteocalcin) all showed significant suppression compared to baseline and remained suppressed throughout the 2 years. BMD showed small and significant increases at the spine (0.024 g/cm²) and total hip (0.019 g/cm²) in the denosumab group but no change at the femoral neck(–0.011g/cm²). In the ZA group, we observed no significant change at the spine (0.015 g/cm²) and total hip (–0.001g/cm²) and a small significant decrease at the femoral neck (–0.037 g/cm²). However, when we compared BMD change between the treatment groups, we found no significant difference. Conclusions: Our data indicate that for BC patients in AI treatment who refused or were not able to receive ZA treatment, denosumab might be recommended as a second choice. Regarding markers of bone turnover and BMD denosumab is equal to ZA. Summary: Women with early breast cancer receiving anti-estrogen treatment are at risk of developing osteoporosis. We followed 194 women receiving zoledronic acid (ZA) or denosumab for up to 2 years. We find that with regard to bone protection, denosumab is a viable alternative to ZA and might be recommended as a second choice.