The impact of menopause on bone, zoledronic acid, and implications for breast cancer growth and metastasis

Abstract

Recent data from the AZURE, ABCSG-12, and ZO-FAST clinical trials have challenged our understanding of the potential anticancer activity of zoledronic acid (ZOL). Although the results of these studies may appear to be conflicting on the surface, a deeper look into commonalities among the patient populations suggest that some host factors (i.e. patient age and endocrine status) may contribute to the anticancer activity of ZOL. Indeed, data from these large clinical trials suggest that the potential anticancer activity of ZOL may be most robust in a low-estrogen environment. However, this may be only part of the story and many questions remain to be answered to fully explain the phenomenon. Does estrogen override the anticancer activity of ZOL seen in postmenopausal women? Are hormones other than estrogen involved that contribute to this effect? Does the role of bone turnover in breast cancer (BC) growth and progression differ in the presence of various estrogen levels? Here, we present a review of the multitude of factors affected by different endocrine environments in women with BC that may influence the potential anticancer activity of ZOL.

Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

“…12,13 This led to the hypothesis [11][12][13] that treatment is of benefit only in patients with low concentrations of reproductive hormones (ie, those who are postmenopausal or undergoing ovarian suppression therapy). [14][15][16] To help clarify whether adjuvant bisphosphonates reduce the risk of bone and other metastases, and whether menopausal status affects efficacy, we undertook collab orative meta-analyses of all unconfounded randomised trials that compared breast cancer outcomes in those allocated adjuvant bisphosphonate versus those who were not.…”

The role of the bone microenvironment in skeletal metastasis

“…Furthermore, oral clodronate, when given as adjuvant therapy over 5 years, was shown to significantly reduce the rate of bone metastasis in women with breast cancer receiving standard treatment [115] , [119] . Although one clinical trial reported that clodronate had no effect on metastases and even a negative effect on survival [118] , [120] , bisphosphonates have been widely adopted in clinical practice [121] , [122] based on further positive outcomes from studies with zoledronic acid [123] , [124] , [125] , [126] , [127] , [128] , [129] , [130] , [131] , [132] , [133] , [134] and ibandronate [135] , [136] suggesting that bisphosphonates limit the progression of breast or prostate cancer in bone and other tissues [104] , [114] .…”

Neoadjuvant Chemotherapy with or without Zoledronic Acid in Early Breast Cancer—A Randomized Biomarker Pilot Study

“…However, in women who are postmenopausal, either naturally (8,10,11) or induced by goserelin (9), a consistent improvement in both DFS and OS with administration of adjuvant bisphosphonates has emerged. The biologic rationale for these observations is an area of intense study (12,13). The interaction between menopause and effects of bisphosphonates is suggested to be linked to the TGFb family (13).…”