Meta-analysis of RCTs revealed only a trend of higher AF risk in bisphosphonate users compared with patients on placebo. The reasons for this non-significant result are many. First, these RCTs might lack sufficient power to detect such a rare occurrence of AF. Second, the previously reported association between bisphosphonate use and AF might simply be due to chance, as so far only one RCT could demonstrate a significant risk of serious AF associated with bisphosphonate use [16
] while other studies either showed a non-significant trend [17
] or even contradictory result [11
]. Thirdly, although meta-analysis is a powerful statistical method to combine study data and generate an effect size with a greater power, it might not be the best way to draw conclusion especially when meta-analysis is based on just a few studies.
The discrepancy in the effect size between overall and serious AF warrants further discussion. At a closer look at individual RCT, the odds ratios varied widely between studies with evidence of opposing directions of the risk [11
]. The reason of such inconsistency is unclear although discrepancies in the definition, detection and reporting of serious AF may play a role. A much higher heterogeneity (I2
= 62.7) when effect size of serious AF was pooled compared with that of overall AF (I2
= 0) might partially explain the possibility we stated.
Similarly, pooling the 3 population-based studies demonstrated that bisphosphonate users had a non-significantly higher risk than non-bisphosphonate users for developing of AF. Results obtained by pooling observational studies need to be interpreted with caution in that observation studies are limited by potential confounders which could not be eliminated when the data were combined in meta-analysis. Notably, the risk of AF amongst bisphosphonate users was higher in those with diabetes mellitus and statin use [19
] and likewise, bisphosphonate users were noted to have a higher rate of antithrombotic and antihypertensive use in another study [21
]. As these factors share a common risk for atrial fibrillation and osteoporosis which warrants bisphosphonate use, this further signifies the presence of potential residual confounding which may bias the results, even though extensive matching between cases and controls were performed in these observational studies.
Although statistical significance is important in addressing whether an OR is statistically different from unity, it would be more clinically relevant if clinicians are informed of the probability of certain risks of development of AF in bisphosphonate users. Bayesian meta-analysis was therefore the method of choice in this study because (i) it provides an appropriate statistical model to combine studies of RCTs and observational studies [24
] and (ii) it offers the posterior probability which is practically relevant for clinicians. The major limitation of the Bayesian meta-analysis is that the results may be sensitive to the priors used. We thus attempted to test the sensitivity of the results by using different priors and our results showed that the pooled effect size is not sensitive to the priors used. The point estimate is not very sensitive to the priors used while the CI and the posterior probabilities of the practical significance are slightly sensitive to the priors used. This is expected as the number of studies in this analysis is not large.
While bisphosphonates have been expected to cause gastrointestinal side effects and electrolyte disturbance such as hypocalcaemia, AF is a recently acknowledged and unanticipated potential adverse event of bisphosphonates. Despite being increasingly reported in the literature, the biological mechanism for AF related to bisphosphonate use is largely enigmatic. Two putative mechanisms have been proposed. First, hypocalcaemia secondary to bisphosphonates intake or infusions might be a trigger of AF [37
]. Since the majority of AF occurred more than 1 month after bisphosphonate administration by which time the serum calcium level was normal and the bisphosphonate level was largely undetectable [16
], AF secondary to hypocalcaemia appears unlikely. Even though a transient drop of serum calcium level after administration of bisphosphonates may happen, whether such a drop of serum calcium can trigger AF is again, elusive.
Alternatively, bisphosphonates, especially when administrated intravenously, can induce release of pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α), interleukins-1 and 6 from inflammatory cells. These inflammatory cytokines may cause remodelling of the atrium, tissue organisation, fibrosis and subsequent development of AF [38
]. Because the majority of AF occurred at a considerable period of time after administration of bisphosphonates, the latter mechanism seems more probable. Without doubt, laboratory studies and human studies involving more patients are required to establish the possible pathological relationship between bisphosphonates and AF.
Although meta-analysis is a strong tool and we have taken the necessary precautions to detect publication bias and eliminate the effect of heterogeneity by using the random effects model for all the analyses, there are still limitations of the current study and some of them are intrinsic to meta-analysis. First, the occurrence of AF in patients who received bisphosphonates is low (incidence around 2%) and the duration of RCTs is short. Compounded with the insufficiency of patients participating in the trials, meta-analysis of RCTs might not be the best method to detect the possible association between bisphosphonate use and such a rare event as AF. Second, the current meta-analysis was based on a few studies only and it is subjected to random error. Third, while publication bias was not significant statistically in these studies, such a bias can never be completely eliminated even though we have included publications in the forms of abstract and letters to the editor. Fourth, current evidence seems to advocate the possible role of bisphosphonate potency on the occurrence of AF [16
]. In the present meta-analysis; however, we were not able to separately analyse the risk of AF for individual bisphosphonate because the dearth of data disallows meaningful analysis. For the same reason, the number of studies is insufficient to perform meaningful meta-regression analyses, a statistical procedure to detect covariate(s) which may explain the heterogeneity between studies. Fifth, AF was not determined prior to taking bisphosphonates in the majority of the patients, therefore whether the occurrence of AF was truly the result of bisphosphonate intake is unknown. Finally, in order to maintain homogeneity of the studies for the meta-analyses and minimize the confounding effect of the underlying conditions on the development of AF, we only included studies which evaluated the use of bisphosphonates in patients with bone loss and fractures. As a result, the cardiovascular adverse effects of bisphosphonate use in other conditions, such as malignancy, hypercalcaemia and metabolic bone diseases, were not assessed because these conditions may also be culprits of arrhythmias. Nevertheless, the precautions we implemented should render the current meta-analysis the latest available evidence to date which serves to alert clinicians to seriously consider the risk of AF and be informed the probability of certain risks of developing AF in their patients who are taking bisphosphonates.
While not being a primary objective of this study, the results underscore the potential limitation of meta-analysis of RCTs in detecting the association between treatment and rare treatment-related events. At this juncture; concurring with the FDA safety review report [40
], physicians should not refrain from prescribing bisphosphonates to patients who are truly indicated for the medication. As AF can be potentially serious, physicians must be alerted should their patients who are taking bisphosphonate develop new cardiovascular or respiratory symptoms which may be secondary to AF.