Non-metastatic breast cancer patients discontinuing aromatase inhibitor on denosumab: what next?

Aromatase inhibitors (AIs) are one of the adjuvant endocrine therapies of choice, for estrogen receptor-positive breast cancer in postmenopausal women and premenopausal women with ovarian suppression. However, treatment with AIs leads to accelerated bone loss, and an increased fracture risk. Denosumab or bisphosphonates are recommended to prevent bone loss and reduce fracture risk during AIs treatment. However, specific attention must be paid to the "rebound phenomenon" after denosumab discontinuation. This review focuses on the therapeutic benefits of denosumab for its antiresorptive and antifracture effect in women with early breast cancer treated with AIs, risks related to denosumab discontinuation after treatment with AIs, prevention, and potential interventions for its associated fracture risk. A narrative review of available literature was carried out by International Osteoporosis Foundation Committee of Scientific Advisors Working Group on Cancer-Induced Bone Disease. Papers were retrieved by means of a PubMed enquiry (from 2006 to August 2025). A total of 126 papers closely related to our topic were included. After denosumab withdrawal in women with breast cancer treated with AIs, bone turnover increases, and there is a risk of spontaneous rebound-associated vertebral fractures, even in the absence of other risk factors for bone fragility. Therefore, expert consensus suggests initiating bisphosphonate treatment after denosumab discontinuation, even though there is no an optimal bisphosphonate regimen. There are numerous open research questions which future prospective studies will have to answer in order to personalize the most appropriate antiresorptive therapy for each patient.