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Original Article: Long-term PPI Therapy and the Risk of Hip Fracture (AFP Journal Club)

Issue Date: February 1, 2008

to the editor: The “AFP Journal Club” concerning hip fracture risk in patients on long-term proton pump inhibitor (PPI) therapy highlighted an important association which, if causal, could have important public health implications given the common use of PPIs.

Unfortunately, the authors explanation of the methodologic limitations of the study confused cohort and case-control studies. The study by Yang and colleagues was a cohort study rather than a case-control study.1 The authors may have been confused because the study researchers1 used a nested case-control analysis, which is a common approach when the cohort contains a large number of participants.2 Although both study methods are prone to uncontrolled confounding (as the authors point out), cohort studies are generally less prone to bias than case-control studies and can be used to calculate incidence,2 as was done in the study by Yang and associates.1

A meta-analysis of randomized controlled trials of PPI therapy would be the most valid proof that this association is causal, but will probably not be practical because trials of PPIs have not had follow-up long enough to detect differences in hip fracture incidence.

to the editor: The “AFP Journal Club” on long-term proton pump inhibitor (PPI) therapy and the risk of hip fracture was informative and entertaining. The authors suggest that patients on long-term PPI therapy who need a calcium supplement should consider taking calcium citrate rather than calcium carbonate, and to take it with meals. The evidence base to support this advice is questionable.

Studies have shown that the absorption of calcium carbonate is markedly reduced in fasting patients with achlorhydria1 or who are receiving a PPI.2 However, the absorption of calcium carbonate taken with a meal is normal in patients with achlorhydria.1 To our knowledge, the bioavailabilities of calcium carbonate and calcium citrate have not been compared when taken with a meal in patients receiving PPI therapy. Recommendations for these patients can only be inferred from studies in patients with achlorhydria. Therefore, the best available evidence regarding the choice of a calcium supplement for a patient receiving long-term PPI therapy suggests using calcium carbonate during meals, or calcium citrate at any time. However, calcium citrate costs 50 to 80 percent more than calcium carbonate for the same amount of elemental calcium.3

In reply: We thank Drs. Millard and Steichen for their comments on the Journal Club Live department in American Family Physician.

With regard to Dr. Millard’s comment, we believe the study1 to be a case-control study. It is confusing because the authors of the study use the term “cohort” to refer to the population they studied. The critical point here is that the participants were selected based on their outcome status, not their exposure status. The investigators identified cases, matched them to controls, and then measured their exposure status. In a cohort study, the two groups are chosen before a specified outcome and both groups are followed to some endpoint.

For example, it would be unethical to conduct a randomized trial of smoking, but we can do a cohort study: watch patients who smoke or do not smoke and see if there are any differences in lung cancer over time. We could also conduct a case-control study: identify patients with lung cancer (an outcome) versus no lung cancer and retrospectively determine their smoking history. The design of the proton pump inhibitor (PPI) and fracture study is the latter type. The authors identified people who had a hip fracture at least one year after being entered into the database. The researchers then looked back to see if these people were more likely to be using PPIs than the control group who had no fractures.1

With regard to Dr. Steichen’s comments, it is true that there are no studies that directly compare the bioavailability of calcium carbonate and calcium citrate preparations in patients receiving PPIs. However, a nicely done meta-analysis by Sakhaee and colleagues indicates that when taken on an empty stomach or with meals, calcium citrate has up to 25 percent greater bioavailability than calcium carbonate.2 Additionally, a brief review of products at a pharmacy web site showed that the cost of calcium citrate preparations was slightly less than or equal to that of calcium carbonate preparations. Given this information, we still recommend that patients at increased risk of poor absorption use calcium citrate as their main form of supplementation.

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