PPIs linked with fractures and infection
This article was originally published in Scrip
Proton pump inhibitors (PPIs) including AstraZeneca's Nexium (esomeprazole) and Takeda's Prevacid (lansoprazole) are associated with significant side effects that may outweigh their benefits, suggest a series of articles published in the Archives of Internal Medicine. Whereas one study showed that these drugs increased the risk of fracture by a modest 25%, another showed they increased the risk of Clostridium difficile infection by 75–136%.
"For most patients the adverse effects of PPIs outweigh the benefits," concluded Dr Mitchell Katz, from the San Francisco Department of Public Health, in an accompanying editorial. "We should offer treatments other than PPIs for functional dyspepsia, prescribe short courses of PPI treatment (after disclosure of possible risks and benefits), and consider a trial of discontinuing PPI therapy in patients who are asymptomatic." Other approved antiulcer and heartburn drugs include the histamine2-receptor antagonists (H2RA), like GlaxoSmithKline's Acidex (ranitidine).
The PPIs – which are approved for several indications but are most commonly used for heartburn –however are the third highest selling class of drugs in the US. In 2009, annual sales of PPIs in the US hit nearly $15 billion, according to IMS health. Yet, says Dr Katz, between 53% and 69% of PPI prescriptions are for patients who do not meet drug-use guidelines.
AstraZeneca, whose best-selling Nexium had sales of nearly $5 billion worldwide in 2009, maintains that its PPIs are safe. "The safety profile of Nexium has been consistently demonstrated through clinical data obtained in prospective, randomised controlled studies, as well as ongoing safety surveillance. We have full confidence in the overall benefit/risk and safety profile of Nexium, " it said in a statement.
Fractures
While an increased risk of fracture has previously been noted with PPIs, the data to date have been mixed. Study investigator Dr Zhao Chen, of the University of Arizona, and his colleagues therefore performed a prospective analysis of 130,487 postmenopausal women aged 50-79 years without history of hip fracture. Of these subjects, 127,756 subjects were not currently using a PPI compared with 2,731 who had been on a PPI for one to three years.
The main outcome measures were self-reported fractures (hip, clinical spine, forearm or wrist, and total fractures), and three-year change in bone mass density in a subpopulation of women.
Analysis revealed that PPI treatment was not associated with hip fracture, but was associated with a 47% increase risk for clinical spine fracture, a 26% increased risk of forearm or wrist fracture and a 25% increased risk of total fractures.
PPI use also had a significant negative effect on total hip BMD after three years, but the effect did not reach significance at other sites.
"The mechanism by which long-term PPI use may increase fractures is unknown but is postulated to be related to profound acid-suppressive effects that may reduce intestinal calcium absorption, eventually leading to bone resorption," the authors comment.
Infection
As with fractures, some previous studies have associated PPIs with increased risk of infections, whereas others have found no link.
Dr Daniel Talmor, of the Harvard Medical School, and his colleagues therefore conducted a prospective study of 101,796 patients who had been discharged from a tertiary care medical centre. Patients were classified on the basis of acid suppression therapy – no acid suppression, histamine2-receptor antagonist (H2RA), daily PPI or PPI more frequently than daily.
Patients who had not received any acid suppression therapy had a 0.3% risk of nosocomial C. difficile infection, compared with 0.6% for H2RA treatment, 0.9% for once daily PPIs and 1.4% for more frequent PPI use. After adjusting for other factors, H2RAs were associated with a 53% increased risk of infection, once daily PPIs were associated with a 74% risk and more frequent PPI use was associated with a 136% increased risk.
One possible explanation for the association is that gastric acid may act as a line of defence against the C difficile pathogen, suggests Dr Katz.