These data show a significant negative association between use of bisphosphonates and colorectal cancer risk, possibly suggesting a protective effect against colorectal cancer development. This study follows previous reports of similar negative association between bisphosphonate use and breast cancer risk.4–6
However, although the negative association with breast cancer could not be fully separated from the known negative association between low bone density (which could have led to the use of bisphosphonates) and lower risk of breast cancer, in the case of colorectal cancer, low bone density has never been proven to be a risk factor for colorectal cancer, with some studies suggesting that osteoporosis increases the risk of colorectal cancer18,19
and another suggesting a possible negative association in postmenopausal women.20
Recent data have raised the possibility that bisphosphonate use is associated with increased risk of esophageal cancer, but the findings were conflicting, limited to long-term use, and different for various types of bisphosphonates used.21,22
Our findings in users of oral bisphosphonate preparations are consistent with preclinical data suggesting biologic plausibility through a variety of anticancer effects of this drug group, none of which, however, were described in colon tissue.8–12
In addition, the intravenous use of a member of this drug class for bone metastasis control in patients with breast cancer was associated in randomized controlled trials with reduction in risk of contralateral breast cancers5
and reduction in risk of bone metastases.3,23,24
Bisphosphonates, as inhibitors of isoprenoid biosynthesis, have been shown to exert direct antitumor effects in vitro (inhibit tumor cell adhesion and invasion of the extracellular matrix) and in cell lines (reduce proliferation and induce apoptosis) and have antiangiogenic properties as evidenced by reduced vascular endothelial growth factor levels.14,25,26
In addition, bisphosphonates have been shown to reduce skeletal tumor burden in a variety of animal models,27–29
either by direct antitumor activity or indirect effects via osteoclast inhibition and alteration of the bone microenvironment. Recently, it was shown that ibandronate, a member of the nitro-bisphosphonate class, reduced the incidence of colorectal dysplasia and reduced expression of thymidine kinase mRNA in the colorectum of mice with induced ulcerative colitis.30
Bisphosphonates inhibit the same mevalonate pathway as do statins, and the combined effect of these two drug groups has been demonstrated, both by increased bone density in hypercholesterolemic osteoporotic women who added statins to their bisphosphonate treatment31,32
and by reduced lipid levels with the addition of bisphosphonates.33–35
In our data, the protective association of bisphosphonates was demonstrated separately from the significant protective association of statins, but no additive protection was demonstrated in users of both drugs concomitantly. Similarly, the protective effect of use of aspirin against colorectal cancer, which has also been shown to reduce estrogen levels and possibly affect the risk of osteoporosis and breast cancer,36
was demonstrated independently of the effect of bisphosphonates.
Bisphosphonates are widely used to treat osteoporosis1
and bone metastases.37
Their adverse effects profile, although not fully clear,38,39
includes the rare adverse effect of osteonecrosis of the jaw40
and a possibility of higher risk of fractures after prolonged treatment periods.41
The adverse effects profile is of major importance if bisphosphonates are to be recommended for cancer prevention in healthy people. Similar to the case with breast cancer, the protective effect of bisphosphonates in our study was demonstrated after only 1 year of use and did not change meaningfully with extended periods of use. Because this class of medications is known to be stable in the bone for many years after its administration,42
further research should focus on the optimal length of intervention needed to achieve cancer risk reduction.
This study has several limitations. Participation in the study was partial, mainly because of candidate refusal to participate. This phenomenon was more minor in patients than in controls, which could lead to participation bias. However, the participation rate among the identified patients was within commonly described rates in case-control studies, whereas the controls were randomly selected from a population register and replaced if they refused by another randomly selected control, aiming at minimized selection bias. To evaluate possible selection bias, we also analyzed the data by first chosen controls and, to a limited extent, for nonparticipants for whom we had access to pharmacy records. These analyses yielded similar point estimates and CIs as those shown in the tables. Data on possible risk factors were collected retrospectively and, therefore, could be prone to recall bias. However, all risk factors for colorectal cancer reported in this study behaved according to expectation based on other studies reported in the literature, with the exception of obesity. However, obesity has been shown not to be associated with risk of colorectal cancer in postmenopausal hormone replacement therapy users.43
Being able to assess a large variety of potential confounders helped us demonstrate the strength of the association between bisphosphonates and colorectal cancer risk in a multivariate model. Because the main effect of bisphosphonate use was ascertained through pharmacy records, no recall bias was involved. We could not evaluate the degree of compliance of the study participants with the doses recommended in the filled prescriptions. One way of doing so could be by observing changes in bone density, but such data were not available in this study. However, these results should serve as hypothesis generating only, because it cannot be excluded that unknown confounding factors, associated with healthy behavior, both trigger bisphosphonate use and lower colorectal cancer risk.
Overall, these data provide evidence that oral bisphosphonates may be effective for prevention of colorectal cancer in postmenopausal women. The study demonstrated a 59% reduction in risk after adjustment for many known risk factors for colorectal cancer. This significant negative association, as seen with breast cancer, calls for consideration of bisphosphonates for future chemoprevention studies.