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Do PPIs Increase Risk for Hip Fracture?

It’s too soon to say.

Osteoporosis affects millions of adults, and hip fracture is the main manifestation of senile osteoporosis. Among many risk factors proposed to increase risk for hip fractures are conditions that cause low calcium absorption. Because gastric acid facilitates absorption of insoluble ingested calcium, drugs that inhibit gastric acidity might result in decreased absorption.

In this nested case-control observational study, researchers used a large U.K. database to compare 13,556 patients with incident hip fractures to135,386 age- and sex-matched controls. The investigators compared health conditions and use of medications, including proton-pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs). Risk for hip fracture was significantly higher in patients who took long-term (>1 year) PPIs (odds ratio, 1.40; 95% CI, 1.26–1.54) and was even higher in patients who took high-dose, long-term PPIs (OR, 2.65; 95% CI, 1.80–3.90). The corresponding values for use of H2RAs were OR, 1.23; 95% CI, 1.09–1.40 and OR, 1.30; 95% CI, 1.16–1.46, respectively.

Comment: These results support the finding of an association between PPI use and hip fracture in another recent report (Calcif Tissue Int 2006; 79:76). In that study, the OR for hip fracture was higher with PPI use than with no use (OR, 1.45; 95% CI, 1.28–1.65) but was lower with H2RA use than with no use (OR, 0.69; 95% CI, 0.57–0.84). Although the suggested mechanism of action posits that lower acid secretion decreases calcium absorption and leads to osteoporosis, no evidence has linked osteoporosis and hip fracture with other conditions that invoke more profound acid suppression (e.g., pernicious anemia, vagotomy). The acid suppression produced by PPIs and H2RAs does not even remotely approach the levels of achlorhydria seen in these conditions. Although the authors attempted to account for the effects of confounding variables, the hip-fracture patients were more likely than were controls to have used anti-seizure medicines (OR, 3.42; 95% CI, 3.0–3.9), anxiolytics (OR, 1.76; 95% CI, 1.67–1.85), antidepressants (OR, 2.17; 95% CI, 2.03–2.32), or antipsychotics (OR, 3.34; 95% CI, 3.03–3.67). Both benzodiazepines and phenytoin have been associated with risk for osteoporosis and hip fracture (N Engl J Med 1995; 332:767). This between-group difference might have confounded the results. Osteoclasts contain endogenous proton pumps that are used during the excretion of H⁺ ions for the resorption of bone. Osteoclast-selective PPIs could therefore have anti-resorptive potential to prevent fractures. No researchers have evaluated this hypothesis.

Patients should be made aware that these findings are not yet confirmed, and recipients of acid-suppressive therapies should consult with their physicians before discontinuing these drugs.

— David A. Johnson, MD

Published in Journal Watch Gastroenterology January 5, 2007

Citation(s):

Yang YX et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006 Dec 27; 296:2947-53.

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