Adjuvant bisphosphonates

Abstract

Current clinical evidence is insufficient to support using oral bisphosphonates as a standard adjuvant therapy in breast cancer; however, additional studies are warranted. In contrast, zoledronic acid may be considered a new standard of care in adjuvant breast cancer, at least for some postmenopausal women and premenopausal women undergoing ovarian suppression.

Geranylgeranyl diphosphate synthase inhibition induces apoptosis that is dependent upon GGPP depletion, ERK phosphorylation and caspase activation

“…As a result of its activity in the bone microenvironment, the third generation bisphosphonate zoledronate also has become useful for treatment of metastatic bone disease associated with solid tumors, 9, 10, 11, 12 as well as multiple myeloma. 13, 14, 15, 16, 17 It is thought that zoledronate functions to reduce the cellular intermediates of isoprenoid biosynthesis including farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP), which are required for cell proliferation (Figure 1).…”

Molecular mechanisms linking geranylgeranyl diphosphate synthase to cell survival and proliferation

“…Although they can be associated with mechanism-based side effects such as osteonecrosis in a small percentage of patients, these drugs greatly reduce the risk of fractures resulting from osteoporosis (Russell et al, 2008). Additionally, they are now frequently used for treatment of cancer-related skeletal complications (Ibrahim et al, 2003) that arise from both solid tumor metastases (Gnant, 2012) and hematological diseases such as myeloma (Terpos et al, 2014) where they prevent growth of the malignant cells in the bone environment. The nitrogen-containing bisphosphonates appear to function primarily by blocking isoprenoid biosynthesis (Amin et al, 1992, Shipman et al, 1998) leading to protein prenylation (van Beek et al, 1999b, Bergstrom et al, 2000).…”