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Date of release: 30 March, 2015

Bisphosphonates and cancer risk in healthy women

Bisphosphonates are heavily prescribed for the prevention and treatment of postmenopausal osteoporosis, for prevention of various cancer-related or treatment-related bone loss, and for prevention of, and reduction of bone metastases in certain types of malignancies [1]. Are there any preventive effects in the population of healthy women in regard to gynecological cancers? Data from the Women's Health Initiative (WHI) observational study demonstrated such an effect on the incidence of endometrial cancer [2]. A detailed health interview was conducted at baseline, and bisphosphonate use was ascertained from an inventory of regularly used medications at baseline and over follow-up. All women had an intact uterus at the time of study entry. During a median follow-up of 12.5 years, 1123 women were diagnosed with incident invasive endometrial cancer. Ever-use of bisphosphonates was associated with reduced endometrial cancer risk (adjusted hazard ratio (HR) = 0.80; 95% CI 0.64–1.00; p = 0.05), with no interactions observed with age, body mass index, or indication for use.

Comment

With the long-term experience and vast exposure to bisphosphonate therapy to treat and prevent postmenopausal osteoporosis, it has become apparent that this family of drugs may carry additional benefits in reducing cancer risk. Another WHI study cohort included 2816 oral bisphosphonate users at entry (90% alendronate, 10% etidronate) [3]. After 7.8 mean years of follow-up, invasive breast cancer incidence was lower in bisphosphonate users (HR = 0.68; 95% CI 0.52–0.88; p < 0.01). Interestingly, an additional study was published in the same journal issue, bringing results on 4039 postmenopausal patients and controls, which were based on pharmacy records [4]. The use of bisphosphonates for longer than 1 year before diagnosis, but not for shorter than 1 year, was associated with a significantly reduced relative risk of breast cancer (odds ratio, OR = 0.61, 95% CI 0.50–0.76). This association remained significant after adjustment for age, fruit and vegetable consumption, sports activity, family history of breast cancer, ethnic group, body mass index, use of calcium supplements, hormone replacement therapy use, number of pregnancies, months of breast feeding, and age at first pregnancy. Rennert's group was also able to provide data concerning other gynecological malignancies [5]. The use of bisphosphonates prior to, and following, diagnosis was assessed in 424 cases of ovarian and endometrial cancers and 341 controls, all postmenopausal at recruitment. The use of bisphosphonates for more than 1 year prior to diagnosis was associated with a significantly reduced risk of ovarian cancer (OR = 0.49, 95% CI 0.26–0.93) and endometrial cancer (OR = 0.39, 95% CI 0.24–0.63). The association with endometrial cancer (OR = 0.48, 95% CI 0.27–0.84) remained statistically significant after adjustment for a variety of putative effect modifiers (relative risk, RR = 0.48, 95% CI 0.26–0.89). The association with ovarian cancer remained significant when adjusted to statin use (RR = 0.46, 95% CI 0.23–0.90) but not for other modifiers (RR = 0.58, 95% CI 0.29–1.18). 
 
This association between a seemingly bone drug and the prevention of various non-osseous cancers is certainly intriguing. In addition to the above discussed gynecological malignancies, bisphosphonates were found to be associated with less colorectal and other cancers [6]. What could be the underlying mechanisms? Bisphosphonates are structural analogs of pyrophosphate that embed into bone, binding to hydroxyapatite and inhibiting osteoclast activity and survival. Thus, the obvious bisphosphonate mode of action is inhibition of tumor-mediated osteolysis driven by osteoclast activation. However, bisphosphonates have also been shown to have effects independent of their antiresorptive properties. The role of bisphosphonates in the mevalonate pathway was well explored [7]: they act downstream of HMG-CoA reductase to inhibit farnesyl pyrophosphate (FPP) synthase, which in turn is involved in post-translational modification at the C-terminus of a variety of important cellular proteins. This process is referred to as protein prenylation. Many proteins that participate in signaling pathways to which tumors are frequently addicted (such as the members of the RAS superfamily) are prenylated. 
 
Protein prenylation inhibitors, like bisphosphonates, may serve as potential anticancer drugs. Beside the above immunomodulatory activities, new research has pointed at the human epidermal growth factor receptors (human EGFR or HER) as a potential new molecular entity for bisphosphonate action [8]. The results suggested that bisphosphonates can potentially be used for the prevention and therapy of HER family-driven cancers. A variety of human cancers, including non-small cell lung, breast, and colon cancers, are driven by the HER family of receptor tyrosine kinases.
 
While bisphosphonates are indicated for the treatment of bone-related effects of chemotherapy or hormone deprivation therapy, and for metastatic bone disease of specific malignancies (breast, prostate, lung, multiple myeloma), it is expected that, with accumulation of relevant data, the indication might be expanded to include prevention of non-osseous cancers.

Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    References

  1. Coleman RE, McCloskey EV. Bisphosphonates in oncology. Bone 2011;49:716.
    http://www.ncbi.nlm.nih.gov/pubmed/21320652

  2. Newcomb PA, Passarelli MN, Phipps AI, et al. Oral bisphosphonate use and risk of postmenopausal endometrial cancer. J Clin Oncol 2015 Feb 23
    http://www.ncbi.nlm.nih.gov/pubmed/25713431

  3. Chlebowski RT, Chen Z, Cauley JA, et al. Oral bisphosphonate use and breast cancer incidence in postmenopausal women. J Clin Oncol 2010;28:358290
    http://www.ncbi.nlm.nih.gov/pubmed/20567009

  4. Rennert G, Pinchev M, Rennert HS. Use of bisphosphonates and risk of postmenopausal breast cancer. J Clin Oncol 2010;28:3577-81
    http://www.ncbi.nlm.nih.gov/pubmed/20567021

  5. Rennert G, Rennert HS, Pinchev M, Lavie O. The effect of bisphosphonates on the risk of endometrial and ovarian malignancies. Gynecol Oncol 2014;133:309-13
    http://www.ncbi.nlm.nih.gov/pubmed/24556062

  6. Pazianas M, Abrahamsen B, Eiken PA, Eastell R, Russell RG. Reduced colon cancer incidence and mortality in postmenopausal women treated with an oral bisphosphonate Danish National Register Based Cohort Study. Osteoporos Int 2012;23:2693-701
    http://www.ncbi.nlm.nih.gov/pubmed/22392160

  7. Thurnher M, Nussbaumer O, Gruenbacher G. Novel aspects of mevalonate pathway inhibitors as antitumor agents. Clin Cancer Res 2012;18:3524-31
    http://www.ncbi.nlm.nih.gov/pubmed/22529099

  8. Yuen T, Stachnik A, Iqbal J, et al. Bisphosphonates inactivate human EGFRs to exert antitumor actions. Proc Natl Acad Sci USA 2014;111:17989-94
    http://www.ncbi.nlm.nih.gov/pubmed/25453081