JCR: Journal of Clinical Rheumatology:
Letters to the Editor
Konsta, Maria MD; Bournia, Vasiliki-Kalliopi MD; Dania, Vasiliki MD; Iliopoulos, Alexios MD
Department of Rheumatology Veterans Administration Hospital (NIMTS) Athens, Greece firstname.lastname@example.org
To the Editor
Since the publication of the HORIZON-Pivotal Fracture Trial in 2007,1 there has been a great concern regarding the possible association of intravenous (IV) zolendronic acid treatment of postmenopausal osteoporosis with atrial fibrillation (AF). The frequency of serious AF was found to be increased 2.5-fold in patients treated with zolendronic acid compared with placebo. A retrospective review of the safety data from the Fracture Intervention Trial,2 a randomized study of alendronate involving 6459 postmenopausal women revealed a trend toward a significant increase of serious AF events in alendronate-treated patients (hazard ratio, 1.51; 95% confidence interval, 0.97–2.40; P = 0.07). This finding raised further concern for a possible class effect of bisphosphonates. However, a later meta-analysis did not associate the use of alendronate with an increased risk of AF.3 In addition, other randomized controlled trials of zolendronic acid in patients with hip fracture (HORIZON-Recurrent Fracture Trial4), in osteoporotic men,5 or in the 6-year extension of the HORIZON-Pivotal Fracture Trial,6 did not confirm the initial results. Nevertheless, the latter study did report a significant increase of strokes in the zolendronic acid group.6 A report issued in 2008 by the US Food and Drug Administration found no association between overall bisphosphonate exposure and the rate of serious or nonserious AF.7 However, in cancer patients, where much higher doses of bisphosphonates are used for hypercalcemia and bone metastasis, an increased frequency of AF was found in case-control8 and cohort studies.9,10 Likewise, a recent meta-analysis pooling data from both osteoporotic and cancer patients derived from 6 randomized controlled trials and 6 observational studies suggested an association between bisphosphonate use and the onset of AF.11 It should be mentioned that data from large registries regarding the use of IV bisphosphonates in osteoporosis are lacking. In addition, there is no published information on AF in osteoporotic patients treated with IV zolendronic acid from single centers, reflecting everyday clinical practice where comorbidities and concomitant medications have to be taken into consideration.
Several potential mechanisms have been proposed by which bisphosphonates could predispose to the development of AF. One possibility is that these drugs exert their arrhythmogenic effect by reducing serum levels of calcium and phosphate. Another possibility could be the release of proinflammatory cytokines following parenteral administration of bisphosphonates. Finally, a third hypothesis is that bisphosphonates could affect atrial remodeling and increase susceptibility to AF in the long term, by inducing zinc-dependent matrix metalloproteinases.12,13
Given the uncertainty of the causative effect of bisphosphonates in AF, we reviewed the medical records of 182 osteoporotic patients treated with yearly IV infusions of zolendronic acid in our department, between 2008 and 2011. The female-to-male ratio in our group was 13:1, and the mean age at treatment initiation was 70.7 (SD, 9.7) years. Seventy-six patients had received a single infusion, whereas 59, 39, and 8 patients had received 2, 3, or 4 infusions, respectively. Nine had a previous history of AF. Four women among our patients developed AF, between 1 week and 10 months after the infusion of zolendronic acid. All 4 patients had severe comorbidities, with one being followed in our department for systemic lupus erythematosus, another for ankylosing spondylitis, and a third one for dermatomyositis. In addition, 2 of these patients had hypertension, and 3 among them also had a previous history of neoplasia, for which they had received or were currently receiving treatment (Table). Calcium and phosphate levels had not been measured.
TABLE Characteristic...Image Tools
It should be here mentioned that in all cases zolendronic acid was administered on a once-yearly basis, solely for the treatment of osteoporosis and not as part of cancer treatment regiment. Of note, some of the described comorbidities could have contributed to the development of arrhythmia in this group. Another 2 cases of AF were reported within 2 and 8 weeks of zolendronate infusion, respectively, in 2 of the 9 patients with a previous history of AF (Table). Because neither had experienced an episode of AF for at least 2 years before zolendronic acid administration, we included these 2 patients in our report, as this event could have been related to treatment. In fact, a major concern in clinical practice is whether IV bisphosphonates can be safely administered to the subset of patients with a prior history of arrhythmia. Three of the 6 cases described here were considered to be of mild severity and were treated as outpatients, whereas the remaining 3 needed hospitalization. One of the latter presented a transient ischemic attack. None of the patients developed permanent AF, although 2 remain on anticoagulant treatment.
In conclusion, we found symptomatic AF in 3.26% (any event) of osteoporotic patients treated with IV zolendronic acid, the ratio being 1.63% when only serious events are considered. This figure is higher than that reported in the HORIZON study. Our findings should be taken cautiously, as our report is based on retrospective data and lacks a control group. Atrial fibrillation is the most common arrhythmia, with an incidence increasing with age.13 In the setting of a rheumatology department, the underlying systemic autoimmune diseases, the concomitant medications, and comorbidities could predispose to AF. Nevertheless, we believe that there should be increased vigilance regarding cardiac arrhythmias in older patients who receive IV zoledronate for the treatment of osteoporosis.
Maria Konsta, MD
Vasiliki-Kalliopi Bournia, MD
Vasiliki Dania, MD
Alexios Iliopoulos, MD
Department of Rheumatology
Veterans Administration Hospital (NIMTS)
The authors declare no conflict of interest.
1. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med
. 2007; 356: 1809–1822.
2. Cummings SR, Schwartz AV, Black DM. Alendronate and atrial fibrillation. N Engl J Med
. 2007; 356: 1895–1896.
3. Barrett-Connor E, Swern AS, Hustad CM, et al. Alendronate and atrial fibrillation: a meta-analysis of randomized placebo-controlled clinical trials. Osteoporos Int
. 2012; 23: 233–245.
4. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med
. 2007; 357: 1799–1809.
5. Boonen S, Reginster JY, Kaufman JM, et al. Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med
. 2012; 367: 1714–1723.
6. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res
. 2012; 27: 243–254.
8. Wilkinson GS, Baillargeon J, Kuo YF, et al. Atrial fibrillation and stroke associated with intravenous bisphosphonate therapy in older patients with cancer. J Clin Oncol
. 2010; 28: 4898–4905.
9. Erichsen R, Christiansen CF, Froslev T, et al. Intravenous bisphosphonate therapy and atrial fibrillation/flutter risk in cancer patients: a nationwide cohort study. Br J Cancer
. 2011; 105: 881–883.
10. Yazici O, Aksoy S, Ucar O, et al. Arrhythmias during and after zoledronic acid infusion patients with bone metastasis. Med Oncol
. 2013; 30: 609.
11. Sharma A, Chatterjee S, Arbab-Zadeh A, et al. Risk of serious atrial fibrillation and stroke with use of bisphosphonates: evidence from a meta-analysis. Chest
. 2013; 144: 1311–1322.
12. Howard PA, Barnes BJ, Vacek JL, et al. Impact of bisphosphonates on the risk of atrial fibrillation. Am J Cardiovasc Drugs
. 2010; 10: 359–367.
13. Charlemagne A, Blacher J, Cohen A, et al. Epidemiology of atrial fibrillation in France: extrapolation of international epidemiological data to France and analysis of French hospitalization data. Arch Cardiovasc Dis
. 2011; 104: 115–124.
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