PPIs and Fracture Risk

The February 18, 2013 issue of The Medical Letter will include a short article on the possibility of an increased risk of fractures with long-term use of a proton pump inhibitor (PPI). The impetus for our article came from a new FDA requirement that the labels of all prescription PPIs include a warning about this possibility.

Concern about an increased risk of fractures in PPI users arose from observational studies. No one has randomly assigned a large cohort of patients to a PPI or placebo and followed them for 10 years, which is the only way we would really know whether this concern is justified. However, one of the two observational studies we cite in our short article was a 10-year study of a large cohort of patients from The Canadian Multicenter Osteoporosis Study, some of whom were PPI users, and some not. The PPI users had a significantly shorter time to a first nontraumatic fracture.

This study had a lot of good things in it. It was large (almost 10,000 patients). It could control for other risk factors associated with fractures, including bone mineral density, bisphosphonate use, regular physical activity, gender, etc. In addition, the investigators knew when PPIs were started and when the fractures occurred, so they could look at the difference in fracture risk between PPI users and non-PPI users over time, and they showed that the difference in risk was apparent after about 18 months and increased somewhat as time went on.

So why do we need a controlled trial to be sure that PPIs increase the risk of fractures? The authors of the Canadian study say it very well: “…as with any observational study, residual confounding by unmeasured variables is possible in our study.” People who take PPIs are different from people who do not, and they may be different in ways that we are not aware of or cannot measure.

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