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  • br Bisphosphonates inhibit bone resorption and are broadly used in


    Bisphosphonates inhibit bone resorption and are broadly used in clinical practice for the treatment and prevention of skeletal conditions characterized by increasing osteoclast-mediated bone remodeling [4,5]. Adjuvant use of bisphosphonates has been shown to reduce rates of cancer recurrence and death in patients with early-stage breast cancer [6]. Recent studies also suggest that bisphosphonates may modulate CVD risk in older patients; how-ever results have been mixed [7,8]. Wolfe at al. reported a sub-stantial risk reduction in myocardial infarction (MI) among patients with rheumatoid arthritis who were treated with bisphosphonates [9]. An analysis of participants in a retrospective cohort study
    investigating the safety profile of risedronate found a tendency toward a lower cardiovascular mortality, driven mainly by a reduction in stroke mortality [10]. Conversely, concerns have been raised regarding associations between bisphosphonate use and increased rates of atrial fibrillation [11,12]. However, it is not known whether bisphosphonate use impacts CVD risk among breast can-cer survivors.
    In this study, we used population-based cancer data to evaluate the association between bisphosphonate use and incident CVD events after cancer diagnosis in older women diagnosed with pri-mary breast cancer.
    2. Methods
    We used the Surveillance, Epidemiology and End Results (SEER) registry linked to Medicare data. This database combines two large population-based data sources that provide detailed information about Medicare beneficiaries with cancer. We excluded individuals in health care maintenance organizations or those without Part B Medicare insurance due to lack of complete claims data and those without Part D coverage for whom we could not ascertain outpa-tient medication use.
    2.2. Study participants
    We identified women >65 years who were diagnosed primary early-stage (0-III) breast cancer between January 1, 2007, and December 31, 2010. We excluded women who had CVD prior to breast cancer diagnosis, including those who had undergone NSC232003 transplant surgery, cardiac valve surgery, coronary artery bypass grafting (CABG), patients with uncorrected atrial or ventricular septal defects (congenital heart disease), or anyone with a history of angina, atrial fibrillation/flutter, heart failure, myocarditis, myocardial infarction or stroke. We also excluded patients with end-stage renal disease as these patients have a significantly higher risk for CVD or those who were diagnosed with breast cancer on autopsy or at death.
    We extracted variables about sociodemographic characteristics (including age, race/ethnicity, marital status, income quartile), comorbidities, medication prescriptions, chemotherapy, radio-therapy and surgical treatment for breast cancer, and survival. We used the Deyo adaptation of Charlson’s index to assess the burden of comorbidities [13,14]. Bisphosphonates included were alendro-nate, pamidronate, ibandronate, zoledronic acid, risedronate, and etidronate. Bisphosphonate use was defined as having at least one Medicare part D claim in the period from 6 month prior to breast cancer diagnosis to the first CVD event. CVD and other comorbid-ities were identified by searching the hospital discharge summary and outpatient claims for diagnostic (International Classification of Diseases, Ninth Revision [ICD-9]) codes. Specific comorbidities that were abstracted included arterial hypertension (ICD-9 codes: 401.0e402.0), type 2 diabetes mellitus (ICD-9 codes: 250.0e250.9), hyperlipidemia (ICD-9 codes: 272.4, 272.2, 272.0), hyperthyroidism (ICD-9 codes: 242.0e242.40, 242.80e242.90), and osteoporosis (ICD-9 codes: 733.0, 733.03, 733.09) Hypertension, diabetes, hyperlipidemia and hyperthyroidism were included in the adjusted analyses as these are known risk factors for CVD. The Health Care Procedure Coding System (HCPCS) was used to identify receipt of chemotherapy, radiation therapy, and surgical treatment any time from cancer diagnosis to 36 months after diagnosis.