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Original Research: Cardiovascular Disease |

Risk of Serious Atrial Fibrillation and Stroke With Use of BisphosphonatesAtrial Fibrillation, Stroke, and Bisphosphonate: Evidence From a Meta-analysis FREE TO VIEW

Abhishek Sharma, MD; Saurav Chatterjee, MD; Armin Arbab-Zadeh, MD, PhD; Sandeep Goyal, MD; Edgar Lichstein, MD; Joydeep Ghosh, MD; Shamik Aikat, MD
Author and Funding Information

From the Department of Medicine (Drs Sharma and Lichstein), Maimonides Medical Center, Brooklyn, NY; the Division of Cardiology (Dr Ghosh), New York-Presbyterian/Columbia University Medical Center, New York, NY; the Division of Cardiology (Dr Chatterjee), Providence VA Medical Center, and Brown University (Dr Chatterjee), Providence, RI; the Division of Cardiology (Dr Arbab-Zadeh), Johns Hopkins University School of Medicine, Baltimore, MD; the Division of Cardiology (Dr Goyal), Vanderbilt University Medical Center, Nashville, TN; and the Division of Cardiology (Dr Aikat), Lexington VA Hospital, Lexington, KY.

Correspondence to: Abhishek Sharma, MD, 1016 50th St, Apt 2C, Brooklyn, NY 11219; e-mail: abhisheksharma4mamc@gmail.com


Funding/Support: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;144(4):1311-1322. doi:10.1378/chest.13-0675
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Background:  Clinical studies have suggested an association between bisphosphonate use and the onset of atrial fibrillation (AF). However, data on the risk of developing AF, stroke, and cardiovascular mortality with the use of bisphosphonate are conflicting. The objective of this study was to evaluate the risk of serious AF (events that required hospital admission), stroke, and cardiovascular mortality with the use of bisphosphonates through a systematic review of the literature.

Methods:  We searched the PubMed, CENTRAL, and EMBASE databases for observational studies and randomized controlled trials (RCTs) on the use of bisphosphonates from 1966 to April 2012 that reported the number of patients who developed serious AF, stroke, and cardiovascular mortality at follow-up. The random-effects Mantel-Haenszel test was used to evaluate relative risk-adverse cardiovascular outcomes with the use of bisphosphonates.

Results:  Six observational studies (n = 149,856) and six RCTs (n = 41,375) were included for analysis. On pooling observational studies, there was an increased risk of AF (OR, 1.27; 95% CI, 1.16-1.39) among bisphosphonate users. Further, analysis of RCTs revealed a statistically significant increase in the risk of serious AF (OR, 1.40; 95% CI, 1.02-1.93) and no increase in the risk of stroke (OR, 1.07; 95% CI, 0.85-1.34) or cardiovascular mortality (OR, 0.92; 95% CI, 0.68-1.26) with the use of bisphosphonates.

Conclusions:  Evidence from RCTs and observational studies suggests a significantly increased risk of AF requiring hospitalization, but no increase in risk of stroke or cardiovascular mortality, with the use of bisphosphonate.

Figures in this Article

Osteoporosis and osteopenia affect > 40 million Americans and are the most common causes of fractures in the United States, especially in the elderly population.1,2 Bisphosphonates increase bone mineral density and prevent recurrent fractures in patients receiving long-term glucocorticoid therapy, patients with cancer, postmenopausal women, and elderly men,38 and bisphosphonate therapy has been recommended for osteoporosis by the American College of Physicians, the National Osteoporosis Foundation, the American College of Obstetricians and Gynecologists, and the American Association of Clinical Endocrinologists.912

However, concerns have been raised over the safety of bisphosphonates after the multicenter randomized control trial (RCT) Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) showed an increased rate of arrhythmias (6.9% vs 5.3%) among postmenopausal women who received once yearly zolendronic acid for osteoporosis.3 Various observational studies have reported mixed findings, with some suggesting an increased frequency of arrhythmias and adverse cardiovascular events, including myocardial infarction and death, among patients taking bisphosphonates.1321 An increase in the concentration of inflammatory cytokines, metabolic intermediates such as isopentenyl pyrophosphate, plaque inflammation, and rupture secondary to bisphosphonate use have been implicated as a potential basis for the observed increased frequency of arrhythmias and other adverse cardiovascular outcomes among bisphosphonate users.2232

A subsequent multicenter randomized placebo-controlled trial, The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT), reported no increase in risk of adverse cardiovascular events, including atrial fibrillation (AF), with the use of IV bisphosphonates.4 Reanalysis of another randomized trial, the Fracture Intervention Trial (FIT), showed an increased risk of AF with the use of oral bisphosphonates.3335 However, on following 15,000 patients from phase 3 clinical trials of risedronate for 3 years, there was no increase in incident of any cardiovascular events, including AF.36 Further pooled analysis of pivotal trials evaluating various ibandronate regimens showed no increased risk of AF among bisphosphonate users.37

Because of the contradictory findings reported in various studies, it is not clear whether the use of bisphosphonate is associated with an increased risk of AF and other adverse cardiovascular events. This issue raises considerable concern because osteoporosis predominantly affects elderly populations, who are also at higher risk of AF and other cardiovascular diseases. Hence, any causal relation between bisphosphonate use and adverse cardiovascular outcomes could have major implications on public health. Accordingly, we systematically evaluated the risk of AF and cardiovascular end points associated with the use of bisphosphonates through a systematic review of the published literature.

PubMed, EMBASE, CINAHL, Scopus, the Web of Science, and the Cochrane Register of Controlled Clinical Trials (CENTRAL) were searched for studies evaluating the safety and efficacy of bisphosphonates that reported on AF as an outcome. The search terms used were bisphosphonate, amino bisphosphonate, AF, arrhythmia, myocardial infarction, stroke, cardiovascular mortality (last updated on April 30, 2012). Pertinent trials were also searched in clinicaltrials.gov and major international cardiology meetings (American College of Cardiology, American Heart Association, European Society of Cardiology, Transcatheter Cardiovascular Therapeutics). References of original and review articles were cross checked. Study selection was performed by two independent reviewers (A. S. and S. C.), with divergences resolved by consensus. Citations were first scanned at the title/abstract level. Shortlisted studies were then retrieved in full text. Studies were included if they met all the following criteria: (1) human studies with participants ≥ 18 years of age requiring bisphosphonate therapy for any indication; (2) RCTs or observational studies with contemporaneous control groups; and (3) outcomes including at least one of the following: serious AF (events that required hospital admission), stroke, or cardiovascular mortality.

Abstraction and Appraisal

Data abstraction and study appraisal were performed by two independent reviewers (A. S. and S. C.), with divergences resolved by consensus. Key study and patient characteristics, as well as relevant outcomes, were extracted by two authors independently (A. S. and S. C.).

Review Manager 5.1 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration) was used for analysis.38 Outcomes were assessed using a random-effects models, to exclude the presence of significant heterogeneity (evaluated and quantified with the I2 statistic), and then pooled random-effect risk ratios (RRs) were calculated with 95% CIs. Publication bias was ascertained with visual inspection of funnel plots and the regression test of Egger.

Our MEDLINE search returned 98 studies. After elimination of duplicate results, the EMBASE and Cochrane and the other registries did not return any additional studies, leaving 98 studies for evaluation. Through a review of titles and abstracts, 67 studies were excluded, and the remaining 31 articles were reviewed and assessed for satisfaction of the inclusion or exclusion criteria. Twelve studies (six RCTs and reports analyzing data from RCTs, and six observational studies) that met all criteria were included in this analysis (Fig 1, Tables 1-3).

Figure Jump LinkFigure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for RCTs. RCT = randomized control trial.Grahic Jump Location
Table Graphic Jump Location
Table 1 —Baseline Characteristics of Various Randomized Controlled Trials

BONE = Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe; DIVA = Dosing Intravenous Administration; IVF = Intravenous Fracture Study; MOBILE = Monthly Oral Ibandronate in Ladies.

Table Graphic Jump Location
Table 2 —Summary of Randomized Controlled Trials

DBP = diastolic BP; FIT = Fracture Intervention Trial; HORIZON-PFT = Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial; n/a = not available; SBP = systolic BP; ZOL = zolendronic acid. See Table 1 legend for expansion of other abbreviations.

a 

Vertebral Efficacy with Risedronate Therapy Trial, the Bone Mineral Density Trial, the Risedronate 5 mg Daily Prevention Trial, the Glucocorticosteroid-induced Osteoporosis Prevention and Treatment Trials, and the Hip Intervention Program Trial.

b 

BONE, DIVA, MOBILE, and IVF.

Table Graphic Jump Location
Table 3 —Baseline Characteristics of Various Observational Studies

SEER = Surveillance, Epidemiology, and End Results. See Table 2 for expansion of other abbreviation.

a 

Registry of patients who underwent coronary angiography.

b 

Bisphosphonate therapy in the overall health plan database.

In RCTs, adverse events were monitored by investigator inquiry and physical examination. In the HORIZON-Pivotal Fracture Trial and HORIZON-RFT, a “blinded” committee adjudicated adverse cardiovascular events,3,4,39 whereas in the report analyzing the risk of AF with bisphosphonate use among patients enrolled in the FIT, an independent “blinded” physician confirmed the potential atrial-fibrillation adverse events.33 However, adverse events were nonadjudicated in the report by Karam et al,36 and stratification for baseline AF risk was not done by Lewiecki et al37 while evaluating the risk of AF with ibandronate use.

We also included six observational studies that reported on the outcomes of interest as ascertained by the International Classification of Diseases (ICD) codes (Tables 3, 4). In a register-based cohort study of patients with fracture with no history of AF, 14,302 patients who received oral bisphosphonate therapy were found to have an increased risk of serious AF (ICD-10 code I48.9) as compared with nonexposed patients of the same age and sex and with the same fracture type.11 Similarly, patients with cancer from the Danish and Surveillance, Epidemiology and End Results (SEER) Medicare databases with no known AF who received IV bisphosphonate therapy were reported to have an increased incidence of AF when matched against nonexposed patients with cancer of same age and sex and with the same cancer type and stage at the time of diagnosis.16,21 However, no increased risk of AF (ICD-9) with bisphosphonate exposure was reported on evaluation of patients from a population-based retrospective cohort study (comparing the risk of AF and cardiovascular outcomes among osteoporotic women taking alendronate or raloxifene) and two prospective databases (Intermountain Heart Collaborative Study [an ongoing registry of consecutive patients who underwent coronary angiography] and the Intermountain Healthcare health plans database).13,15

Table Graphic Jump Location
Table 4 —Newcastle-Ottawa Scale of Bias Risk for Observational Studies

Studies demonstrate that the outcome of interest was not present at the start of the study. Asterisks are the star rating as per the Newcastle-Ottawa Scale; ** and *** indicate highest ratings for these categories.

a 

Registry of patients who underwent coronary angiography.

b 

Bisphosphonate therapy in the overall health plan database.

Study Characteristics

Trials were fairly homogenous with respect to inclusion and exclusion criteria, with a few key differences (Tables 1-4). We used the published standard criteria for reporting randomized clinical trials studies and the observational studies checklist to select the studies for this review (Fig 1).40 Among the 12 studies included, all were intermediate- to low-bias risk as assessed by the Downs and Black quality assessment scale.41

Primary Outcome

Six observational studies (n = 149,856) and six RCTs (n = 41,375) were included. On pooling observational studies, there was an increased risk of AF (RR, 1.27; 95% CI, 1.16-1.39) among bisphosphonate users (Fig 2). Further, an analysis of RCTs revealed a statistically significant increase in the risk of serious AF (RR, 1.40; 95% CI, 1.02-1.93) (Fig 3). There was no appreciable publication bias on inspection of the funnel plot, or with the regression test of Egger (two-tailed P = .32) (Fig 4).

Figure Jump LinkFigure 2. Forest plot of risk of atrial fibrillation in observational studies. df = degrees of freedom; M-H = Mantel-Haenszel.Grahic Jump Location
Figure Jump LinkFigure 3. Forest plot of risk of serious atrial fibrillation in randomized control trials. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4. Funnel plot of randomized control trials.Grahic Jump Location
Secondary Outcomes

Bisphosphonate use was not significantly associated with a higher risk of stroke (OR, 1.07; 95% CI, 0.85-1.34) or cardiovascular mortality (OR, 0.92; 95% CI, 0.68-1.26) with the use of bisphosphonates (Figs 5, 6).

Figure Jump LinkFigure 5. Forest plot of risk of cardiovascular mortality in randomized control trials. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 6. Forest plot of risk of stroke in randomized control trials. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location

On pooling the observational studies and RCTs, there was an increased risk of serious AF (OR, 1.27; 95% CI, 1.16-1.39 and OR, 1.40; 95% CI, 1.02-1.93, respectively) among bisphosphonate users (Figs 2,3). Parenteral administration of aminobisphosphonates induces a release of tumor necrosis factor-α, IL 6, and inhibition farnesyl pyrophosphate synthase in the mevalonate pathway, leading to the accumulation of isopentenyl pyrophosphate.2227 An increase in the concentration of these inflammatory cytokines and metabolic intermediates, which, in turn, activate an inflammatory cascade and alter the expression of proteins that handle the intracellular calcium (proteins SERCA2a, CSQ, and CRT), may lead to an increased risk of arrhythmias, especially AF.2832,42 It is important to note that bisphosphonate could be present in a meaningful concentration near the conducting system because there is good evidence from autopsies about the prevalence of calcification in the conducting system and atria.43 In addition, it has been shown that long-term treatment with alendronate, even in very low concentrations, alters the calcium dynamics in atrial cells by inducing self-sustained Ca2+ oscillations, thus, causing irregular depolarization of atrial cells (ie, AF).42

HORIZON was the first multicenter RCT reporting an increased risk of AF with the use of bisphosphonates. However, these events were unanticipated and were not adjudicated for other multiple related conditions prospectively.3 The subsequent RCT, HORIZON-RFT, further studied the association between bisphosphonate use and cardiovascular outcomes.4 Patients included in HORIZON-RFT were older and were at a higher risk of developing AF than were those in its preceding trial.4 However, HORIZON-RFT reported no statistically significant difference in the rate of any cardiac arrhythmias (including AF) among bisphosphonate users. It is noteworthy that osteoporotic patients are at an increased risk of cardiovascular disease, which is independent of traditional risk factors and is directly proportional to the severity of osteoporosis.44 Also, there is an epidemiologic association between osteoporosis and cardiovascular disease.1,2,45 Hence, patients who are prescribed bisphosphonate therapy are already at higher risk at baseline.44 Moreover, there were differences in the prevalence of cardiovascular risk factors such as age, diabetes, hypertension, and dyslipidemia, and history of coronary artery disease between the study and control arms in the observational studies that reported higher rates of adverse cardiovascular events with the use of bisphosphonate.1321 A retrospective study from the Danish database initially reported an association between the use of bisphosphonates and cardiac arrhythmia, but when adjusted for presence of confounders such as COPD, there was no net increased risk.14 Another interesting finding noted on subanalyses of the Danish database was the inverse relationship between the rate of arrhythmias and the degree of bisphosphonate exposure, hence questioning the potential causal relation between the two. Thus, differences in baseline characteristics have the potential for confounding, and results should be interpreted with extreme caution.

We further evaluated the impact of bisphosphonate use on stroke and cardiovascular mortality and found no statistically significant increase in the risk of stroke (OR, 1.07; 95% CI, 0.85-1.34) or cardiovascular mortality (OR, 0.92; 95% CI, 0.68-1.26) with the use of bisphosphonates (Figs 5, 6). Further, considering the documented benefits of bisphosphonates in improving bone density and reducing the risk of fracture and morbidity, we recommend that the decision to use bisphosphonate therapy for the long term should be individualized, and that associated cardiovascular risk factors should be taken into consideration when considering long-term bisphosphonate therapy.

Our results are in agreement with those of previous reports, which were limited in their clinical applicability because of smaller sample sizes or because they evaluated the impact of bisphosphonates on a specific patient population (eg, postmenopausal women).46,47 Because of its large sample size, our meta-analysis was better able to evaluate the relationship between bisphosphonate use and cardiovascular outcomes by capturing even rare adverse events and studying their statistical significance. However, one of the major limitations of the current study is that the included randomized trials were not designed specifically to study the cardiovascular outcomes of bisphosphonates and the outcomes reported in this study were not primary or secondary end points of the RCTs included in the analyses. Thus, there may be differential surveillance or reporting in the studies that were conducted after initial reports that bisphosphonates might cause AF. Hence, it is possible that events were underreported or misclassified. Further, not every trial reported all parameters of cardiovascular outcomes; in addition, detailed data on cardiovascular risk factors such as lipid profile, thyroid profile, history of coronary artery disease, diabetes, smoking, and alcohol use were not reported in every study included in the analyses, and, thus, could not be assessed in the current analysis. It is also important to note that the included studies defined serious AF as AF events that required hospital admission; however, AF that does not lead to hospitalization initially can still ultimately lead to stroke and other devastating sequelae. Results from RCT data (which is the most powerful comparison) just achieve statistical significance, which could be because of one outlying study, HORIZON; and this may also be the reason for conflicting results among studies. There could be several potential explanations for an increase in the risk of AF but not in the risk of stroke with bisphosphonate. A possibility may be that bisphosphonates have a protective effect, or that there is a bias (advertent or inadvertent) in the analysis, because the duration of follow-up was between 2 and 6 years in these studies and one would have expected a higher rate of stroke in older patients with AF. Further, other risk factors for stroke (as predicted by CHA2DS2-VASc [congestive heart failure, BP > 140/90 mm Hg, age ≥ 75 years, diabetes, prior stroke, vascular disease, age 65-74 years, sex] score) were not reported and adequately controlled for in the study and control arms in the included studies. Hence, prospective randomized data with various adverse cardiovascular outcomes as predefined end points are needed to further establish the possibility of an increased risk of cardiovascular events with bisphosphonate use.

Evidence from RCTs and observational studies suggests a significantly increased risk of AF requiring hospitalization, but no increase in risk of stroke or cardiovascular mortality with the use of bisphosphonate. Additional prospective studies are required to further investigate and assess this association.

Author contributions: Drs Sharma and Chatterjee had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Sharma: contributed to the study concept and design; acquisition, analysis, and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and administrative, technical, and material support.

Dr Chatterjee: contributed to the acquisition, analysis, and interpretation of data; statistical analysis; and drafting of the manuscript.

Dr Arbab-Zadeh: contributed to the study supervision; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

Dr Goyal: contributed to drafting of the manuscript and critical revision of the manuscript for important intellectual content.

Dr Lichstein: contributed to the study supervision; analysis and interpretation of data; critical revision of the manuscript for important intellectual content; and administrative, technical, and material support.

Dr Ghosh: contributed to critical revision of the manuscript for important intellectual content.

Dr Aikat: contributed to critical revision of the manuscript for important intellectual content.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

AF

atrial fibrillation

FIT

Fracture Intervention Trial

HORIZON

Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly

HORIZON-RFT

Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Recurrent Fracture Trial

ICD

International Classification of Diseases

RCT

randomized control trial

RR

risk ratio

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Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100. [CrossRef] [PubMed]
 
Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377-384. [CrossRef] [PubMed]
 
Kemeny-Suss N, Kasneci A, Rivas D, et al. Alendronate affects calcium dynamics in cardiomyocytes in vitro. Vascul Pharmacol. 2009;51(5-6):350-358. [CrossRef] [PubMed]
 
Haring G, Kralj E, Balažic J, Ermenc B. Diagnostic value of post-mortem examination of the cardiac conduction system. Forensic Science International Supplement Series. 2009;1(1):72-75. [CrossRef]
 
Tankó LB, Christiansen C, Cox DA, Geiger MJ, McNabb MA, Cummings SR. Relationship between osteoporosis and cardiovascular disease in postmenopausal women. J Bone Miner Res. 2005;20(11):1912-1920. [CrossRef] [PubMed]
 
Ylitalo R. Bisphosphonates and atherosclerosis. Gen Pharmacol. 2000;35(6):287-296. [CrossRef] [PubMed]
 
Bhuriya R, Singh M, Molnar J, Arora R, Khosla S. Bisphosphonate use in women and the risk of atrial fibrillation: a systematic review and meta-analysis. Int J Cardiol. 2010;142(3):213-217. [CrossRef] [PubMed]
 
Loke YK, Jeevanantham V, Singh S. Bisphosphonates and atrial fibrillation: systematic review and meta-analysis. Drug Saf. 2009;32(3):219-228. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for RCTs. RCT = randomized control trial.Grahic Jump Location
Figure Jump LinkFigure 2. Forest plot of risk of atrial fibrillation in observational studies. df = degrees of freedom; M-H = Mantel-Haenszel.Grahic Jump Location
Figure Jump LinkFigure 3. Forest plot of risk of serious atrial fibrillation in randomized control trials. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4. Funnel plot of randomized control trials.Grahic Jump Location
Figure Jump LinkFigure 5. Forest plot of risk of cardiovascular mortality in randomized control trials. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 6. Forest plot of risk of stroke in randomized control trials. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Baseline Characteristics of Various Randomized Controlled Trials

BONE = Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe; DIVA = Dosing Intravenous Administration; IVF = Intravenous Fracture Study; MOBILE = Monthly Oral Ibandronate in Ladies.

Table Graphic Jump Location
Table 2 —Summary of Randomized Controlled Trials

DBP = diastolic BP; FIT = Fracture Intervention Trial; HORIZON-PFT = Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial; n/a = not available; SBP = systolic BP; ZOL = zolendronic acid. See Table 1 legend for expansion of other abbreviations.

a 

Vertebral Efficacy with Risedronate Therapy Trial, the Bone Mineral Density Trial, the Risedronate 5 mg Daily Prevention Trial, the Glucocorticosteroid-induced Osteoporosis Prevention and Treatment Trials, and the Hip Intervention Program Trial.

b 

BONE, DIVA, MOBILE, and IVF.

Table Graphic Jump Location
Table 3 —Baseline Characteristics of Various Observational Studies

SEER = Surveillance, Epidemiology, and End Results. See Table 2 for expansion of other abbreviation.

a 

Registry of patients who underwent coronary angiography.

b 

Bisphosphonate therapy in the overall health plan database.

Table Graphic Jump Location
Table 4 —Newcastle-Ottawa Scale of Bias Risk for Observational Studies

Studies demonstrate that the outcome of interest was not present at the start of the study. Asterisks are the star rating as per the Newcastle-Ottawa Scale; ** and *** indicate highest ratings for these categories.

a 

Registry of patients who underwent coronary angiography.

b 

Bisphosphonate therapy in the overall health plan database.

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Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377-384. [CrossRef] [PubMed]
 
Kemeny-Suss N, Kasneci A, Rivas D, et al. Alendronate affects calcium dynamics in cardiomyocytes in vitro. Vascul Pharmacol. 2009;51(5-6):350-358. [CrossRef] [PubMed]
 
Haring G, Kralj E, Balažic J, Ermenc B. Diagnostic value of post-mortem examination of the cardiac conduction system. Forensic Science International Supplement Series. 2009;1(1):72-75. [CrossRef]
 
Tankó LB, Christiansen C, Cox DA, Geiger MJ, McNabb MA, Cummings SR. Relationship between osteoporosis and cardiovascular disease in postmenopausal women. J Bone Miner Res. 2005;20(11):1912-1920. [CrossRef] [PubMed]
 
Ylitalo R. Bisphosphonates and atherosclerosis. Gen Pharmacol. 2000;35(6):287-296. [CrossRef] [PubMed]
 
Bhuriya R, Singh M, Molnar J, Arora R, Khosla S. Bisphosphonate use in women and the risk of atrial fibrillation: a systematic review and meta-analysis. Int J Cardiol. 2010;142(3):213-217. [CrossRef] [PubMed]
 
Loke YK, Jeevanantham V, Singh S. Bisphosphonates and atrial fibrillation: systematic review and meta-analysis. Drug Saf. 2009;32(3):219-228. [CrossRef] [PubMed]
 
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