What Is the Association Between Gastric Acid Inhibition and Risk for Hip Fracture?

David A. Johnson, MD, FACG, FACP


January 25, 2007

Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture

Yang YX, Lewis JD, Epstein S, Metz DC
JAMA. 2006;296:2947-2953

Osteoporosis is a common disease affecting millions of adults. Hip fracture is the main manifestation of senile osteoporosis. Hip fracture clearly is not only a prevalent problem, but it also has significant associated morbidity and mortality. The reported mortality is 20% within the first year following fracture,[1] and 1 in 5 patients require nursing home care.[2] Many risk factors for hip fractures have been suggested and conditions that result in low calcium absorption have been implicated in the causality of this disorder. Because gastric acid facilitates the absorption of insoluble ingested calcium, it has been suggested that drugs that inhibit gastric acidity may result in decreased absorption.

This nested case-control observational study was performed using a large database from the United Kingdom. The study cohort consisted of 13,556 patients with an incident first occurrence of a hip fracture; subjects were compared with 135,386 age- and sex-matched controls. Patient use of medications and health conditions was also compared between the 2 groups, including the use of proton-pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs). The risk for hip fracture was significantly increased among patients who were taking long-term (> 1 year) PPI therapy (odds ratio [OR] 1.44, 95% confidence interval [CI]: 1.30-1.59), and even higher in patients taking high-dose PPIs for more than 1 year (OR 2.65, 95% CI: 1.80-3.90). The corresponding values for H2RAs were also reported (OR 1.23, 95% CI: 1.09-1.40; and OR 1.30, 95% CI: 1.16-1.46, respectively). When these analyses were restricted to only patients with known gastroesophageal reflux disease, there were no significant changes based on the disease for which the PPI or H2RA was used.

These findings extend a concern reported in another recent study suggesting a slight increased association between PPI use and hip fracture.[3] In this article, the odds ratio for hip fracture was increased (1.45, 95% CI: 1.28-1.65) for PPIs, but actually decreased for exposures to H2RAs (0.69, 95% CI: 0.57-0.84). Although the mechanism of action suggested for osteoporosis is decreased calcium absorption due to reduced acid secretion, there has not been evidence that other conditions of more profound acid suppression, such as pernicious anemia or vagotomy, are associated with osteoporosis and hip fracture. Recognizably, the acid-suppression activity of PPIs and H2RAs does not even remotely approach the level of achlorydria seen in these conditions/settings.

In the present study, although the authors did attempt to balance for confounding variables, it must be noted that in the hip fracture patients, there was a higher likelihood of the use of antiseizure medications (OR 3.42, 95% CI: 3.0-3.9), anxiolytics (1.76, 95% CI: 1.67-1.85), antidepressants (2.17, 95% CI: 2.03-2.32), and antipsychotics (3.34, 95% CI: 3.03-3.67). This is notable because the use of benzodiazepines and phenytoin is an associated risk factor for osteoporosis and hip fracture.[4] Accordingly, this imbalance may have had an unknown confounding influence.

Osteoclasts also possess proton pumps that are used during the excretion of H+ ions for the resorption of bone. Osteoclast-selective PPIs may therefore have antiresorptive potential to actually prevent fractures. No such study to evaluate this hypothesis exists.

Osteopenia is a recognizable precursor to osteoporotic-related fracture. This entity is also a treatable condition if appropriate use of calcium, vitamin D, and other pharmacologic therapies is initiated. Patients at risk should be screened by bone densitometry. It appears somewhat premature, however, to include patients taking acid-suppressive agents on this list of clearly defined associated risks.

Further studies are warranted before observations from this present study can be corroborated. Patients should be made aware that these findings are not yet confirmed, and patients taking acid-suppressive therapies should discuss any concerns that they may have with their physician before stopping the use of these medications on their own.



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