David Leader DMD, MPH Associate Clinical Professor, Tufts University
There is no association between bisphosphonate usage and atrial fibrillation (AF).
Moderately heterogeneous, limited evidence reported in this review of seven studies demonstrates that bisphosphonate use does not increase risk of AF.
In adults with osteoporosis, do those who take bisphosphonates have a higher rate of atrial fibrillation compared to those who do not take bisphosphonates?
Reviewers searched two electronic databases for articles published from 1981 to September 2009 and hand searched abstracts of scientific meetings and bibliographies of selected reports and review articles. The authors defined a priori inclusion criteria. They limited inclusion to papers published in English and included population-based, non-experimental studies of adult patients, studies reporting the risk of AF associated with bisphosphonate use, and studies examining the effects of bisphosphonates for the prevention or treatment of osteoporosis or fractures. The quality of each study was assessed.
The review included seven studies: three cohort, three case-controlled and one self-controlled (which was counted as a case-controlled study for the purposes of this review). The seven studies report the experience of eight groups including 266,761 participants. One cohort study reported on two groups. The authors did separate and combined meta-analysis of the cohort and the case-controlled studies. The overall pooled estimate of multivariate Odds Ratio (OR) for AF based on eight patient groups from seven studies, adjusted for known AF risk factors, was 1.04 (95% Confidence Interval (CI), 0.92 -1.16). The authors noted moderate heterogeneity. The pooled estimate of the three cohort studies was 1.01 (95% CI, 0.80 - 1.23) with moderate-to-severe heterogeneity. The pooled estimate of the four case-control studies was 1.05 (95% CI, 0.91 - 1.19) with moderate heterogeneity. The CI of the combined cohort studies, case-controlled studies and the results of all of the studies combined include 1.0, which demonstrates that the use of bisphosphonates has no effect on the risk of AF.
This meta-analysis of published non-experimental studies suggests no significant risk of AF associated with the use of bisphosphonates for the treatment of osteoporosis.
Source of Funding:
The authors received support from the Canadian Institutes of Health Research and the National Institutes of Health. One author received support from Merck & Co., Inc. Novartis and Amgen, Inc.
Importance and Context:
Osteoporosis affects an estimated 44 million Americans.(1) Bisphosphonates are a primary treatment for osteoporosis. Physicians often refer patients for oral health care when prescribing bisphosphonates due to the increased possibility of developing osteonecrosis of the jaw (ONJ). The authors indicate few plausible mechanisms exist for the association between bisphosphonate use and AF including electrolyte imbalance (hypocalcemia) or bisphosphonate-induced inflammation affecting atrial remodeling and fibrosis.
Strengths and Weaknesses of the Systematic Review:
The authors followed accepted protocols and a priori inclusion and exclusion criteria. The authors report no conflicts of interest, although one author reports receiving research grants from Merck & Co. and Inc. Novartis, both of which manufacture bisphosphonate medications.
Strengths and Weaknesses of the Evidence:
The seven studies demonstrated low incidence of AF. The authors point out that this may be due to the use of diagnostic codes as the definition of outcome measures. Sometimes AF doesn't cause signs or symptoms. Thus, it may be found during a physical exam or electrocardiogram (EKG) done for another purpose.(2) It is likely that AF is under-reported. Knowing the actual number of cases could change the conclusions of the individual studies and the systematic review. The authors assessed the quality of six of the seven studies as moderate to high. They did not determine the quality of one study that was only available as an abstract. The evidence does not include enough separate studies to determine a dose relationship of bisphosphonates and AF, or recommendations about parenteral bisphosphonates and risk. There is no evidence of publication bias.
Readers should note additional systematic reviews that explore the relationship of bisphosphonate medications and AF. For example, a 2011 retrospective cohort study by Pazianas et. al., offers similar results to Kim et. al. This cohort study of 144,548 bisphosphonate users, women aged 50 – 89, compared to 668,891 sex and age matched controls was not able to demonstrate increased risk of AF for women treated for up to three years with oral alendronate or risedronate (overall hazard ratio for AF was 0.93 (95% CI 0.88 – 0.99). (3) This study has the same limitations of Kim et al. Foremost, results were interpreted from diagnosis and prescription codes gleaned from medical and billing records.
Another systematic review by Bhuriya et. al. demonstrated different results with higher quality evidence. Seven observational studies, four randomized controlled trials (RCTs) and three population based controlled trials demonstrated a positive relationship between AF and Bisphosphonates. Their meta-analysis of the four RCTs of 26,126 post-menopausal women demonstrated that serious AF was more likely in the bisphosphonate group (RR 1.525; 95% CI 1.166 – 1.997 p= 0.002). Two out of the three cohort studies demonstrated a statistically significant risk of serious AF in the active treatment groups. The outcome measures in these prospective studies included clinical evidence of AF. (4)
Implications for Dental Practice:
The use of bisphosphonates demonstrates that dentists and physicians share the responsibility to monitor and maintain patients' health. This systematic review demonstrates that bisphosphonates are not a risk factor for AF. The systematic review by Pazianas et. al. confirms that result with a larger number of age and sex matched subjects.(3) However, Bhuriya et. al. performed a systematic review of randomized controlled trials (RCT). The higher quality results gleaned from a smaller number of subjects demonstrate the opposite outcome – that there is a relationship between bisphosphonate use and AF in post-menopausal women.(4) Further research utilizing more consistent outcome measures would improve our understanding of the relationship between the use of bisphosphonates and AF.
1. National Osteoporosis Foundation. Fast facts. http://www.nof.org/node/40. Accessed 5/24/12.
2. National Heart, Lung and Blood Institute (National Institutes of Health). How is atrial fibrillation diagnosed? http://www.nhlbi.nih.gov/health/health-topics/topics/af/diagnosis.html. Accessed 5/24/12.
3. Pazianas M, Cooper C, Wang Y, Lange J, and Russell RGG; Atrial Fibrillation and the Use of Oral Bisphosphonates. Therapeutics and Clinical Risk Management 2011:7:131-144.
4. Bhuriya R, Singh M, Molnar J, Arora R, and Khosla Sandeep; Bisphosphonate Use in Women and the Risk of Atrial Fibrillation: A Systematic Review and Meta-Analysis. International Journal of Cardiology 2010: 142:213-7.