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
An increased risk of atrial fibrillation (AF) has been noted with use of bisphosphonates, especially with intravenous zoledronic acid [5
]. 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
]. 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
]. The results from two meta-analytic studies [20
] 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
]). 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.