Introduction
Osteoporosis is a major public health threat for an estimated 44 million Americans or 55% of the population 50 years of age and older [
1]. There were approximately two million new fractures in the US in 2005 with a direct medical cost of US$17 billion [
2]. Bisphosphonates are the main therapy for postmenopausal and glucocorticoid-induced osteoporosis. Currently, four oral or intravenous forms of bisphosphonates (alendronate, risedronate, ibandronate, and zoledronic acid) are approved for the treatment of osteoporosis in the US. Known side effects of bisphosphonates include gastrointestinal mucosal irritation, such as esophageal ulcer, bone pain, muscle cramps or pain, hyperphosphatemia, hypocalcemia, and rarely osteonecrosis of the jaw [
3,
4].
An increased risk of atrial fibrillation (AF) has been noted with use of bisphosphonates, especially with intravenous zoledronic acid [
5‐
7]. AF is the most common arrhythmia among older adults. Common risk factors include older age, male gender, dilated cardiomyopathy, diabetes, hypertension, coronary artery disease, obstructive sleep apnea, cardiac surgery, high-dose corticosteroid therapy, alcohol excess, and alcohol withdrawal [
8‐
10]. AF contributes to approximately 35% of strokes in an octogenarian population, increases the overall risk of stroke by five-fold, and is associated with particularly severe strokes [
11]. With the aging population, AF and its consequences will become an increasingly common medical and economic problem.
In October 2007, the US Food and Drug Administration (FDA) first announced that the agency was assessing the potential risk of AF associated with bisphosphonate use [
12]. After reviewing data from spontaneous post-marketing reports and clinical trials of bisphosphonates, the FDA stated that healthcare providers and patients should not change either their prescribing practices or their use of bisphosphonates [
12]. A year later, the FDA released updated information based on further information from four placebo-controlled clinical trials and concluded that there was no clear association between bisphosphonate exposure and the rate of serious or non-serious AF events [
13]. At that time, the FDA stated that that they would explore the feasibility of conducting additional epidemiologic studies to further examine the issue. Subsequently, a number of large population-based studies examining the risk of AF with bisphosphonates have been published [
7,
14‐
19]. The results from two meta-analytic studies [
20,
21] are also available but information one could draw from these studies are somewhat limited owing to a small study size and significant heterogeneity among the included studies. Population-based epidemiologic studies offer several advantageous over clinical trial data, particularly to study unexpected and rare adverse reactions such as AF in bisphosphonate users (incidence rate of AF is less than 2 per 100 person-year [
14,
17]). Clinical trials are often underpowered to detect rare adverse events and lack of generalizability owing to specific inclusion and exclusion criteria [
22]. Given such potential limitations of clinical trials and meta-analyses of clinical trials, we therefore conducted a systematic review and meta-analysis of non-experimental studies to determine the association between the use of bisphosphonates and the risk of AF or flutter.
Discussion
Although a few plausible mechanisms exist for the association between the use of bisphosphonates and AF -- electrolyte imbalance such as hypocalcemia or bisphosphonate-induced inflammation affecting atrial remodeling and fibrosis [
31‐
34] - our meta-analysis of non-experimental studies found no significant association between bisphosphonate exposure and AF.
It is possible that our result was negative because mild or asymptomatic AF cases were missed in large non-experimental studies, because the majority of the included studies defined outcomes mainly with diagnosis codes. Also, as there is only a small fraction of patients exposed to intravenous forms of bisphosphonates such as ibandronate or zoledronic acid in our meta-analysis, it still remains uncertain whether the risk of AF increases with intravenous bisphosphonates. Our study is consistent with the FDA's safety review and supported by two previously published meta-analyses [
20,
21]. In the previous meta-analysis of four randomized clinical trials based on total 519 (230 serious, 289 non-serious) AF events among 26,352 patients [
20], a significant association was observed between the risk of serious AF events and use of bisphosphonates (OR = 1.47; 95% CI = 1.01 to 2.14), but no significant association was noted for any AF events (OR = 1.14, 95% CI = 0.96 to 1.36). The elevated risk of serious AF might have been overestimated as two of the four clinical trials [
5,
6,
35,
36] were performed to study the effect of monthly zoledronic acid infusion on osteoporosis [
5,
36]. Another meta-analysis by Mak and colleagues [
21] showed no evidence of an increased risk of AF related to bisphosphonate use in their meta-analysis of four randomized clinical trials [
5,
6,
36,
37] and three non-experimental studies (one cohort and two case-control studies) [
7,
14,
19]. The pooled estimate of crude ORs based on three non-experimental studies [
7,
14,
19] was 1.25 (95% CI = 0.98 to 1.73). Our study included four additional studies [
15‐
18] that were not analyzed in any of previous meta-analyses and yielded similar results.
Several other limitations of our study should be noted. Due to a relatively small number of studies included in our analysis, we were unable to examine the risk of AF relative to the type or dose of bisphosphonates. Non-experimental studies are subject to measured and unmeasured confounding and other biases. Thus, our meta-analysis may suffer these limitations as well. Not every study included in our meta-analysis was adjusted for all the potential risk factors of AF, as observed in Tables
1 and
2. As raw data of individual studies were not available to us, we pooled the multivariate, or adjusted, ORs from the final model of each study. In addition, significant heterogeneity between studies was noted, as often expected in meta-analyses of observational studies [
38,
39]. In order to account for both within- and between-study variance, we used a random effects model for our analysis. Potential sources of heterogeneity between the studies include variations in the study size, patient characteristics (age, gender, geographic location, underlying comorbidities and use of other drugs), type of bisphosphonates, exposure and outcome ascertainment methods, and the study quality. Due to the limited number of the included studies in our analysis, we could not further identify causes of heterogeneity using the meta-regression technique. Although all meta-analyses are inherently vulnerable to publication bias, we attempted to minimize this bias by searching two major electronic databases with no geographic restriction. Three different statistical tests examined the issue of publication bias and revealed no statistical evidence for significant publication bias.
Our study also has several important strengths. This meta-analysis is up to date and comprehensive including seven large epidemiologic studies conducted in various countries [
7,
14‐
19]. We assessed the quality of individual studies using the Newcastle-Ottawa Scale [
23]. The majority of the included studies had adequate sample sizes, follow-up lengths (applicable for cohort studies only), and adjustments for known AF risk factors. Our pooled estimates are based on multivariate ORs of individual studies adjusting for a number of known AF risk factors. We furthermore provided a subgroup analysis of the studies by study design and yielded a similar result.
Conclusions
Our meta-analysis of published non-experimental studies suggests that there is no increased risk of AF associated with the use of bisphosphonates for osteoporosis. Physicians should be vigilant for all potential drug-associated toxicities, although the use of oral bisphosphonates probably does not increase a risk of AF, independent of known risk factors for AF. Future research studying a risk associated with intravenous bisphosphonates or a dose-response relation might provide further information.
Acknowledgements
SYK received support from the National Institutes of Health (T32 AR 055885). SMC received the New Investigator Award in the Area of Aging and Osteoporosis from the Canadian Institutes of Health Research. DHS was supported by several National Institutes of Health programs (K24 AR055989, P60 AR047782, R21 DE018750, and R01 AR056215). DHS also received research grants from Abbott Immunology, Amgen and Novartis, as well as support from BMS for an educational course on clinical research in Rheumatology. The funders of this study had no role in any aspect of the study design, implementation or evaluation and did not contribute to the decision to submit the manuscript for publication.
Competing interests
SYK, MJK, and SMC declare that they have no competing interests. DHS received research grants from Merck & Co., Inc. Novartis, and Amgen, Inc.
Authors' contributions
All authors participated in the study conception. SYK, SMC, and DHS participated in the study design and data interpretation. SYK and MJK participated in data acquisition and analysis. All authors participated in manuscript preparation and revision. All authors read and approved the final manuscript.