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Comment & Response
April 2020

Oral Anticoagulants, Proton Pump Inhibitors, and Fracture

Author Affiliations
  • 1Department of Medicine, Harcourt House, Sheffield, United Kingdom
  • 2Department of Gastroenterology, Stepping Hill Hospital, Stockport, United Kingdom
  • 3Department of Medicine and Nursing, University of Cordoba, Cordoba, Spain
JAMA Intern Med. 2020;180(4):617. doi:10.1001/jamainternmed.2020.0268

To the Editor The original and instructive work of Lutsey et al1 is an important contribution to the literature exploring potential osteotropic effects of anticoagulants. The authors report a lower risk of fracture related to the use of direct oral anticoagulants (DOACs) compared with warfarin, with apixaban carrying the lowest risk. However, they overlook one potentially important confounder, namely the effect of proton pump inhibitor (PPI) copharmacy. Proton pump inhibitors are often coprescribed with oral anticoagulants. The extent to which this occurs is contingent on the specific anticoagulant.2 Proton pump inhibitors increase the risk of fracture. Indeed, so incontrovertible has been the evidence on this front that the US Food and Drug Administration issued a drug safety alert in relation to this particular complication in 2010.3 Proton pump inhibitors are thought to inhibit the osteoclast proton pump, thereby rendering the bone hard but brittle, like chalk.4 Evidence suggests that PPIs are more likely to be prescribed in the context of warfarin rather than DOAC use, given that the risk of gastrointestinal bleeding requiring hospitalization following use of this coumarin is higher than that with the DOACs collectively.5 Lutsey et al1 also observed that apixaban was the least likely among the DOACs and warfarin to be associated with fracture. Tellingly, of all the DOACs, apixaban has also been found to be the least likely to be coprescribed with PPIs2 and has the lowest risk of gastrointestinal bleeding.5 The fracture risk associated with anticoagulant use may be in part due to, or entirely an artifact of, PPI coadministration.

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