Does Zoledronic Acid Have Additive Effect on Suppression of Plasma Estrogen Levels ?

Obesity has been associated with abnormally highexpression of the enzyme aromatase in the breast,increased local estrogen production and predispositionto the cancer and recurrence. In postmenopausal women,fat tissue is the major source of estrogens, thus higheraromatase enzyme levels in obese patients can increase theestrogen levels. On these grounds, expression of aromataseenzyme increased with high body mass index (BMI), mayinfluence the effects of aromatase inhibitors. Folkerd etal. (2012) recently published an article about the effect ofaromatase inhibitors on suppression of plasma estrogenlevels according to the BMI in patients with breast cancer.The authors suggest that the plasma estrogen levels wereassociated with BMI and letrozole compared to anastrazolereduced estrogen levels by an additional 43%. We havesome comments about the additive effect of zoledronicacid on aromatase activity.Intravenous bisphosphonate zoledronic acid has beenevaluated in adjuvant breast cancer clinical trials. In theZometa–Femara Ajuvant Synergy Trial (ZFAST) andZOFAST (Zoledronic acid in the prevention of cancertreatment-induced bone loss in postmenopausal womenreceiving letrozole as adjuvant therapy for early breastcancer), there were 35% fewer breast cancer recurrences(Brufsky et al., 2007; Eidtmann et al., 2010). In anotherstudy, patients with early-stage breast cancer in theAustrian Breast Cancer Study Group trial 12 (ABCSG-12),the addition of zoledronic acid to adjuvant endocrinetherapy significantly improves disease-free survivaland fewer locoregional recurrences and contralateralbreast cancers in premenopausal patients (Gnant etal., 2009). Zoledronic acid therapy prevents bone lossassociated with aromatase inhibitors in premenopausaland postmenopausal breast cancer patients (Brufsky etal., 2007; Gnant et al., 2007; 2008). Thus, zoledronic acidhave been widely used in osteoporotic patients, for theprotective effect of bone loss of aromatase inhibitors andin the adjuvant treatment of early breast cancer patientsin recent years.The significant benefit of zoledronic acid is byinhibition of tumor-cell adhesion, invasion, proliferationand inducing apoptosis in cell lines (Gnant et al., 2009).Also zoledronic acid can stimulate antitumor immunereactions and exert and antiangiogenic effects (Kunzmannet al., 2000; Santini et al., 2007). In a recent trial, Schechet al. ( 2012) found that the combination of zoledronicacid and letrozole lead to increased inhibition of aromataseenzyme compared to letrozole alone. Zoledronic acidcan inhibit aromatase activity by inhibition of serinephosphorylation. This study showed that zoledronicacid potentiates the aromatase inhibition of letrozole. InABSCG-12 trial, zoledronic acid compared to placeboimproved disease-free survival in normal weight andoverweight patients (Pfeiler et al., 2011).In the light of the recent publications, zoledronic acidmay have additive effect on the inhibition of aromataseenzyme. On these grounds, it is intriguing to wonder aboutthe distribution of zoledronic acid usage in the study ofFolkerd et al. (2012).