Bisphosphonates and atrial fibrillation: revisiting the controversy

Abstract

Bisphosphonates (BPs) are widely prescribed drugs used to treat osteoporosis, commonly arising in postmenopausal women and in chronic glucocorticoid use. Their mechanism of action is through inhibiting osteoclast‐induced bone remodeling, and they also possess calcium sequestering properties. Common side effects involve the gastrointestinal system and rare but serious side effects, including osteonecrosis of the jaw. However, a link between BPs and atrial fibrillation (AF) has been proposed, with early clinical trials, such as the Fracture Intervention Trial and the HORIZON Pivotal Fracture Trial, reporting that BPs are associated with increased risk of AF. Nevertheless, subsequent studies have reported contrasting results, ranging from no effect of BPs to antiarrhythmic effects of BPs. Preclinical and electrophysiological studies on any proarrhythmic effect of BPs are limited in scope and number, but suggest possible mechanisms that include antiangionesis‐related myocardial remodeling, calcium handling abnormalities, and inflammatory changes. Contrastingly, some studies indicate that BPs are antiarrhythmic by inhibiting fibrotic myocardial remodeling. In order to continue established clinical prescribing of BPs within absolute margins of safety, it will be necessary to systematically rule in/rule out these mechanisms. Thus, we discuss these studies and examine in detail the potential mechanistic links, with the aim of suggesting further avenues for research.

The Dibenzyl Isoquinoline Alkaloid Berbamine Ameliorates Osteoporosis by Inhibiting Bone Resorption

“…For example, bisphosphonate has been widely used to treat PMOP because it inhibits osteoclast activation and osteoclast bone resorption function ( 19 ). However, bisphosphonate has side effects that cannot be ignored, such as atrial fibrillation and jaw osteonecrosis ( 21 , 22 ). Thus, it is important to identify new drugs that can inhibit osteoclast activation and function effectively without significant side effects.…”

The Association between Treatment with Bisphosphonates and the Risk of Atrial Fibrillation: A Meta-Analysis of Observational Studies

“…5) Because of their high affinity to calcium and hydroxyapatite, BPs may accumulate in the calcified matrix outside of bones, including in atherosclerotic arteries. 8,34) Moreover, BPs may accumulate in an inhomogeneous manner in different histological vessel layers, thereby affecting arterial contraction. However, further studies are needed to clarify this mechanism.…”

“…However, further studies are needed to clarify this mechanism. 8,35) Third, electrolyte imbalance, such as hypocalcemia or hypophosphatemia, can cause AF. 13,14,36) BPs, such as calcium, phosphate, zinc, and magnesium, tend to bind to several key electrolytes involved in cardiac conduction.…”

“…3,6) Although BPs are considered firstline treatments for osteoporosis, they are associated with various side effects, including gastrointestinal disorders, renal toxicity, flu-like symptoms with fever, ocular events, and, more rarely, osteonecrosis of the jaw and atrial fibrillation (AF). 8,9) Studies evaluating the association between treatment with BPs and an increased risk of AF have yielded conflicting results, making the association between BPs with AF uncertain. [3][4][5]7,[10][11][12][13][14][15][16][17] Globally, AF is one of the most common clinical arrhythmias, especially in older persons.…”

Cardiovascular Safety and Effectiveness of Bisphosphonates: From Intervention Trials to Real-Life Data

“…Nonetheless, in the majority of population-based case-control studies in real life, no evidence of increased risk of AF and flutter has been found overall in BPS users [63]. A recent systematic review has clearly highlighted the contradictory findings ensuing from RCT and mainly retrospective, real-life studies, as highlighted in Table 1 [64]. Retrospective Fracture patients Nonarrhythmic Sorensen et al [63] Retrospective Atrial fibrillation/flutter patients Nonarrhythmic Bunch et al [65] Prospective Coronary angiography patients Nonarrhythmic Grosso et al [66] Retrospective BP patients Nonarrhythmic Wilkinson et al [67] Retrospective Cancer patients Proarrhythmic Vestergaard et al [68] Retrospective Osteoporotic patients Nonarrhythmic Huang et al [69] Retrospective Osteoporotic patients Nonarrhythmic Erichsen et al [70] Retrospective Cancer patients Proarrhythmic Lu et al [71] Retrospective Osteoporotic patients Proarrhythmic a Pazianas et al [72] Retrospective BP users Nonarrhythmic Arslan et al [73] Cross-sectional Cancer patients Nonarrhythmic Rhee et al [74] Retrospective Osteoporotic patients Antiarrhythmic Herrera et al [75] Retrospective Osteoporotic patients Proarrhythmic Wang et al [76] Retrospective Osteoporotic patients Proarrhythmic Thadani et al [77] Prospective Older male patients Proarrhythmic b a Lower dose was proarrhythmic, but higher dose was antiarrhythmic compared with raloxifene users.…”