Table 2.

Open issues for bisphosphonate adjuvant treatment in early breast cancer trials

Patient-related issues	Biological issues
Histological type (ductal, lobular, etc.)	Preclinical models: how closely do animal models of a low-estrogen environment mimic the postmenopausal status in women with breast cancer?
Molecular subtype (luminal, triple negative breast cancers, etc.)	Type of bisphosphonate (amino vs non-amino): superiority of one bisphosphonate in selective setting?
Clinical and pathological stage of disease	Interaction with hormone therapy and chemotherapy: synergy or not?
Estrogen and progesterone levels	Duration of bisphosphonate therapy: how long?
Menopausal status (different menopausal definition in trials)
Comorbidities
Personal factors