br Previous studies have also shown an
Previous studies have also shown an immunomodulatory effect of amino-bisphosphonates (N-BP) on circulating gamma-delta (gd) T cells. Increase in circulating gd T Z-Guggulsterone is linked to the acute-phase response (APR) and the release of proinflammatory cytokines such as interferon gamma (IFN-g) and tumor necrosis factor alpha (TNF-a) . The lower incidence of APR in patients previously exposed to N-BPs could be potentially explained by N-BP association with a decrease in circulating gd T cells [36,37], and this decrease in inflammation may contribute to lower CVD risk.
Several strengths and limitations of this study should be noted. As this was an observational study and patients were not randomly assigned to bisphosphonates, there may be unmeasured con-founding for which matching was not able to control. Use of bisphosphonates may reflect more comprehensive health care or increased health awareness, factors that may also be associated with lower risk of CVD. To address this limitation, we adjusted our analyses for potential confounders such as sociodemographics, comorbidities, anti-cancer treatment and other concurrent medi-cations to create a comparison group that would have had similar likelihoods of receiving bisphosphonates. There are some differ-ences in bisphosphonate dosing (even among the same bisphosphonates) when they are used for cancer indications compared with osteoporosis indications, and we were not able accurately adjust for bisphosphonates dose. Furthermore, some supplements such as vitamin D and calcium could have had a po-tential influence on the association of bisphosphonate use with incident CVD events but we were unable to adjust for them since they are mostly sold over-the-counter and thus, not identifiable by pharmacy claims. Medication use was also ascertained by phar-macy claims, and therefore we have no information on adherence to therapy. Despite this, pharmacy claims data have been shown to have high concordance with medication adherence . Further-more, lack of adherence would have biased our results towards the null. Our study was also limited to patients >65 years of age and consequently we were unable to assess the effect of bisphospho-nates in younger breast cancer survivors, although most users of bisphosphonates are older women. Strengths of our study are the
large sample size and use of the SEER-Medicare dataset which is representative of the breast cancer population in the United States.
In summary, our study provides evidence that bisphosphonate use is associated with lower incident CVD in older, early-stage breast cancer survivors. Given that CVD is the primary cause of death among older early-stage breast cancer survivors, under-standing factors that are associated with a reduction in incident CVD may have a substantial impact on decreasing overall morbidity and mortality in this group of patients. Further prospective studies evaluating the use of bisphosphonates can help determine if bisphosphonates can reduce CVD incidence and overall mortality in older breast cancer survivors and may better elucidate CVD-specific mechanisms of action for bisphosphonates.
 Haque R, Prout M, Geiger AM, et al. Comorbidities and cardiovascular disease risk in older breast cancer survivors. Am J Manag Care 2014;20(1):86.  Black DM, Bauer DC, Schwartz AV, Cummings SR, Rosen CJ. Continuing bisphosphonate treatment for osteoporosisdfor whom and for how long? N Engl J Med 2012;366(22):2051e3.  Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role
in clinical practice. In: Paper presented at: mayo clinic proceedings; 2008.
 Vestergaard P. Acute myocardial infarction and atherosclerosis of the coronary arteries in patients treated with drugs against osteoporosis: calcium in the vessels and not the bones? Calcified tissue international. Janus 2012;90(1): 22e9.
 Wolfe F, Bolster MB, O’Connor CM, Michaud K, Lyles KW, Colon-Emeric CS. Bisphosphonate use is associated with reduced risk of myocardial infarction in patients with rheumatoid arthritis. J Bone Miner Res 2013;28(5):984e91.  Steinbuch M, D’Agostino RB, Mandel JS, et al. Assessment of mortality in pa-tients enrolled in a risedronate clinical trial program: a retrospective cohort study. Regul Toxicol Pharmacol 2002;35(3):320e6.  Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM. Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med 2008;168(8): 826e31.
 Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treat-ment of postmenopausal osteoporosis. N Engl J Med 2007;356(18):1809e22.