Since the 1980s, proton pump inhibitors (PPIs) have been the mainstay therapy for gastroesophageal reflux disease (GERD) and peptic/gastric ulcers. Up to 47% of primary care patients, many of whom are over 65 years old, are using these medications on a continuous or long-term basis. PPIs work by suppressing acid secretion in gastric parietal cells through inhibition of the (H+/K+)-ATPase enzyme system, thus blocking the final step in gastric acid production. By reducing the intragastric secretion and production of hydrochloric acid, PPIs may hinder calcium absorption in the small intestine. Recently, animal and human studies have shown that this potential calcium malabsorption leads to decreased bone density and an increase risk of fractures.

A nested case-control study was conducted using the General Practice Research Database (1987-2003). The study cohort consisted of 1.8 million patients over 50 years old who were users and non-users of PPI therapy or acid suppression drugs. Cases consisted of all patients with an incident of hip fracture. The main outcome measure was the risk of hip fracture associated with PPI use.

There were 13,556 hip fracture cases (10,834 among acid suppression non-users and 2,722 among PPI users) and 135,386 controls. The adjusted odds ratio (AOR) for hip fracture associated with more than 1 year of PPI therapy was 1.44 (95% confidence interval (CI) , 1.30-1.59). The risk of hip fracture was significantly increased among patients prescribed high-dose PPIs for more than one year (AOR, 2.65; 95% CI, 1.8-3.9). These patients received at least 75% of their PPI prescriptions for twice daily doses. The strength of the association was statistically significant and increased with increasing duration of PPI therapy with the AOR rising from 1.22 at 1 year to 1.59 at 4 years of therapy. These results show that long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture.

Osteoporotic fractures are common among the elderly and lead to increased morbidity and mortality. Among the various forms of low-trauma fractures, hip fractures lead to the most devastating consequences. They usually require an emergency department visit, hospitalization, surgery, and rehabilitation. During the first year after a hip fracture, the mortality rate is as high as 20%. Among those who survive this period, 1 in 5 will need nursing home care.

PPI therapy, which is widespread, may have an exaggerated effect on bone health among those at risk for osteoporosis. Many patients continue to be on PPIs long past the time for indicated use. For example, stress ulcer prophylaxis during hospitalization and treatment of H. pylori and ulcer disease should be considered time-limited indications. The new information regarding risk for osteoporotic fractures is another good reason to review a patient’s medication list periodically so as to identify and discontinue any unnecessary medications, including PPIs.

At this time, the FDA requires information about the possible risk of fractures (hip, wrist, and spine) be provided on all prescription and over-the-counter proton pump inhibitors. The FDA recommends that healthcare providers consider whether a lower dose or shorter duration of therapy would adequately treat the patient’s condition. All healthcare providers should recommend to patients who continue to receive PPIs and who are at risk for osteoporosis to receive vitamin D and calcium supplementation.

References:

1. Tauseef A, Roberts D, et al. Long-term Safety Concerns with Proton Pump Inhibitors. The American Journal of Medicine. 2009; 122:896-903.
2. Yang YX, Lewis JD, et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006; 296:2947-53
3. Cumming RG, Nevitt MC, Cummings SR. Epidemiology of hip fractures. Epidemiol Rev. 1997;19:244-257.
4. Leibson CL, Tosteson AN, Gabriel SE, Ransom JE, Melton LJ. Mortality, disability, and nursing home use for persons with and without hip fracture: a population based study. J Am Geriatr Soc. 2002;50:1644-1650.