In this large case-control study we found no evidence of an increased risk of atrial fibrillation and flutter associated with use of the bisphosphonates etidronate and alendronate.
Our data are consistent with a recent reanalysis of a clinical placebo controlled trial of about 15
000 patients followed up for up to three years. In that study the cumulative incidence of atrial fibrillation was 1.4% in the placebo group compared with 1.3% among patients treated with 2.5 mg risedronate and 1.4% among patients treated with 5 mg risedronate.3
Similarly, in a recent trial of patients with hip fracture, participants assigned to intravenous zoledronic acid had a rate of serious atrial fibrillation similar to that in participants given placebo (14 of 1065 v
12 of 1062).15
In contrast, Black et al reported a significant increase in the risk of atrial fibrillation, classified as a “serious” event among patients treated with intravenous zoledronic acid,2
and another study reported a trend towards an increased risk of atrial fibrillation among patients treated with oral alendronate.4
The events in Black et al’s zoledronic acid trial were uniformly distributed over time in the year after treatment. The majority of events occurred more than 30 days after infusion, by which time zoledronic acid is not detectable in the circulation.2
The mechanisms that might explain such an association are not clear but it has been suggested that hypocalcaemia and associated secondary hyperparathyroidism might be responsible for the arrhythmia.16
Thus an increase in risk of atrial fibrillation has been observed with potent nitrogen containing bisphosphonates, alendronate and zoledronic acid. Some side effects of bisphosphonates have been attributed to the nitrogen containing moiety—for example, a flu-like syndrome.17
Alendronate is a nitrogen containing bisphosphonate but etidronate is not. We found, however, no difference between etidronate and alendronate, despite their different structure and potency.
Strengths and limitations
The strengths of our study include the population based design within a free tax supported universal healthcare system with a complete hospital prescription history and access to appropriate population controls. This reduces the risk of referral, diagnostic, and information bias.8
In addition our analysis adjusted for the most important risk factors for atrial fibrillation.6
Although it is well known that some hospital discharge diagnoses are not accurate,8
the specificity of the diagnosis of atrial fibrillation and flutter is reported to be high, and less than 5% of the patients with atrial fibrillation have only atrial flutter.10
The accuracy of most of the other hospital discharge diagnoses we used in this study is likewise high.8 18
The universal provision of health care (including support for prescription drugs) considerably reduced the likelihood that our null finding was due to selection bias or unmeasured confounding. In particular since osteoporosis and cardiovascular disease share risk factors such as smoking and obesity and evidence is increasing that osteoporosis in itself is a risk factor for cardiovascular disease in post-menopausal women.19
Zoledronic acid was not used by outpatients and risedronate use was limited. Therefore our results do not necessary hold for those bisphosphonates.
In conclusion, in this large population based study we did not find that use of etidronate or alendronate for osteoporosis was associated with an increased risk of atrial fibrillation and flutter.
What is already known on this topic
- Bisphosphonates are widely used in the treatment of osteoporosis
- Data from clinical trials have reported that bisphosphonates may increase the risk of atrial fibrillation but data on their potential toxicity are scanty and conflicting
What this study adds
- Patients with atrial fibrillation and flutter had a similar frequency of use of etidronate and alendronate as population controls
- No evidence was found that use of bisphosphonates increases the risk of atrial fibrillation and flutter