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Oral bisphosphonates and risk of ischemic stroke: a case–control study

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Abstract

Summary

Bisphosphonates have been associated with an increased risk of atrial fibrillation and may thus be associated with an increased risk of ischemic stroke. This would have substantial clinical and public health implications. We found no evidence of an association between bisphosphonate use and risk of ischemic stroke.

Introduction

Bisphosphonates have been associated with an increased risk of atrial fibrillation in some studies and may be associated with an increased risk of ischemic stroke. However, data regarding these possibilities are limited.

Methods

We conducted a population-based case–control study of 6,257 female cases of ischemic stroke and 31,285 age- and gender-matched population controls. Data on bisphosphonate use, other medication use, comorbidity, and ischemic stroke were obtained from medical databases. Current bisphosphonate use was defined as at least one redeemed prescription within 90 days before diagnosis/index date. We estimated the odds ratio (OR) of ischemic stroke among users and nonusers of bisphosphonates using conditional logistic regression, controlling for potential confounding factors.

Results

One hundred eighty-two (2.9%) cases and 901 (2.9%) controls were current users of bisphosphonates. Etidronate and alendronate were prescribed with similar frequency among cases and controls. The adjusted OR of ischemic stroke for bisphosphonate users compared with nonusers was 0.97 (95% confidence interval [CI], 0.82–1.15). New and continuing bisphosphonate users had adjusted ORs for ischemic stroke of 1.16 (95% CI, 0.69–1.96) and 0.97 (95% CI, 0.81–1.16), respectively. Excluding patients with known atrial fibrillation/flutter yielded an OR of 1.00 (95% CI, 0.85–1.19). The OR for ischemic stroke was 0.59 (95% CI, 0.32–1.09) among patients with a history of previous hospitalization for cardiovascular disease and 1.07 (95% CI, 0.88–1.18) among those without (P < 0.001). The OR for former users was 1.23 (95% CI, 1.01–1.49).

Conclusion

We found no evidence of an association of oral bisphosphonate use with the risk of ischemic stroke.

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Acknowledgments

This study was funded by the Danish Medical Research Council (grant 271-05-0511) and the Clinical Epidemiological Research Foundation, Denmark.

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Alle 43-45, 8240, Aarhus N, Denmark

    S. Christensen, F. Mehnert & H. T. Sørensen

  2. INSERM Research Unit 831, Department of Orthopedics and Rheumatology, Hôpital E Herriot, Université de Lyon, Lyon, France

    R. D. Chapurlat

  3. Department of Medicine, Dartmouth Medical School, Hanover, MD, USA

    J. A. Baron

  4. Department of Community and Family Medicine, Dartmouth Medical School, Hanover, MD, USA

    J. A. Baron

Authors
  1. S. Christensen
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  2. F. Mehnert
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  3. R. D. Chapurlat
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  4. J. A. Baron
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  5. H. T. Sørensen
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Corresponding author

Correspondence to S. Christensen.

Appendix

Appendix

ICD and ATC codes

Hospital Diagnoses (ICD-8 and ICD-10 codes)

Cardiovascular diseases

  • ICD-8: 393–398 (Chronic rheumatic heart disease, valve disorders), 410–414 (Ischemic heart disease), 427.09, 427.10, 427.19 (Heart failure)

  • ICD-10: I05–I09 (Chronic rheumatic heart disease, valve disorders), I20–I25 (Ischemic heart diseases), I50 (Heart failure)

Atrial fibrillation/flutter

  • ICD-8: 427.93, 427.94

  • ICD-10: I48.9

Renal failure

  • ICD-8: 581–584

  • ICD-10: N17–N19

Diabetes

  • ICD-8: 249.01–249.09, 250.00

  • ICD-10: E10, E11

Pulmonary diseases

  • ICD-8: 073, 471, 490–492, 480–486

  • ICD-10: A481, A709, J12–J18, J40–J44

Cancer

  • ICD-8: 140–149, 150, 151, 152, 153, 154, 155–159, 160, 161, 163, 162, 170–173, 174, 180–184, 185–187, 188–189, 190–194, 195–199, 200–207, 275.59

  • ICD-10: C00–C26, C30–C34, C37–C39, C40–C41, C43–C58, C60–C85, C88, C90–C96

Osteoporosis

  • ICD-8: 723.09

  • ICD-10: M80–M82

Hip or wrist fractures

  • ICD-8: 813.21, 820–821

  • ICD-10: S52.5, S52.6, S72.0, S72.1, S72.2

Liver disease

  • ICD-8: 577.10, 571.11, 571.19, 571.90, 571.92, 571.93, 571.99

  • ICD-10: A48.1, A70.9, B18, I85, J12–J18, K70.0, K70.3, K71.7, K73, K74, K74.3, K74.4, K74.5, K74.6, K76.0

Obesity

  • ICD-8: 277

  • ICD-10: E65–E68

Alcoholism

  • ICD-8: 291, 303, 571.09, 571.10, 577.10

  • ICD-10: F10 (except F10.0), G31.2, G62.1, G72.1, I42.6, K29.2, K86.0, Z72.1

  • AND/OR

  • Previous prescriptions of disulfiram (ATC: N07BB01)

Drug Use (ATC codes)

Cardiovascular drugs

  • ACE-inhibitors C09

  • Beta-blockers C07

  • Low-dose aspirin N02BA01

  • Statins B04AB01, C10AA

  • Calcium antagonists C08D

  • Diuretics C03

  • Nitrates C01D, C01DA

  • Antihypertensives C02

Postmenopausal hormone replacement therapy

  • G03C, G03F

Respiratory drugs

  • R03

Oral glucocorticoids

  • H02AB04, H02AB06

Antidiabetics

  • A10A, A10B

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Christensen, S., Mehnert, F., Chapurlat, R.D. et al. Oral bisphosphonates and risk of ischemic stroke: a case–control study. Osteoporos Int 22, 1773–1779 (2011). https://doi.org/10.1007/s00198-010-1395-y

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  • DOI: https://doi.org/10.1007/s00198-010-1395-y

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