Bisphosphonates: Beyond Prevention of Bone Metastases

Abstract

Bisphosphonates have traditionally been indicated for treatment and control of osteoporosis because they inhibit osteoclastmediated bone resorption and reduce the release of calcium into the blood stream (1). They are currently being used by millions of people (mostly women) worldwide (2). Accumulating evidence over the past 10 years has demonstrated that the use of third-generation nitrogen-containing bisphosphonates can effectively treat bone metastases in women with breast cancer (3). It has been hypothesized that bisphosphonates can also prevent bone metastases altogether and could therefore be implemented in an adjuvant setup in women with breast cancer (4,5). A recent randomized controlled study failed to demonstrate such an effect using third-generation bisphosphonate (6). If bisphosphonate use is associated with a generalized reduced risk of malignancy, one would expect to see reduced risk of developing breast cancer or other cancers in regular users of secondgeneration bisphosphonates, such as osteoporotic women. One would also expect to see reduced risks of developing contralateral breast cancer in women with breast cancer who were further treated with bisphosphonates. Three descriptive studies have thus far shown a strong and similar negative association between the use of common second-generation oral bisphosphonates and the risk of breast cancer (7–9). These findings raised the possibility of con founding by indication. Bisphosphonates are used by osteoporotic women, and osteoporosis is the result of reduced circulating estrogen levels. Estrogen is strongly associated with risk of breast cancer, and women with low estrogen levels are expected to have lower breast cancer rates. Thus, the negative association with bisphosphonate use could actually reflect a negative association with low estrogen levels in the body. However, evidence that the degree of breast cancer risk reduction among bisphosphonate users was not correlated with the degree of bone density loss (7), that risk reduction was seen only after a year of treatment (8), and that postmenopausal bisphosphonates users also demonstrated a reduced risk of colorectal cancer (10,11), all suggest that the association between bisphosphonate use and reduced risk of cancer is real. Mechanistically, nitrogen-containing bisphosphonates inhibit protein prenylation by blocking the mevalonate pathway. Selective inhibition of farensyl pyrophosphate synthase by bisphosphonates can lead to diminished posttranslational prenylation of small GTPase proteins (including signaling molecules such as proteins of the Ras and Rho families) that promote tumorigenesis and metastases (12). In a mouse model, use of bisphosphonates was associated with the suppression of Rho and Ras pathways (13). Further support for a possible role of bisphosphonates in primary prevention of cancer comes from numerous previous reports on the negative association between the use of statins and the risk of cancer in various organs [eg, (14–20)]. Statins, which use the same mevalonate pathway as do bisphosphonates (acting upstream of the farensylation–geranylation step), have been shown to be associated with cancer risk reduction and with possibly improved survival of patients with cancers in multiple sites (21).