Long-term PPI use linked to increased fracture risk
This article was originally published in Scrip
Long-term use of proton-pump inhibitors (PPIs) is associated with an increased risk of fracture, suggests a retrospective study of 15,792 individuals over age 50 who had osteoporosis-related fractures of the hip, vertebra or wrist.
Use of PPIs for seven years or longer was associated with a 92% increased risk of all osteoporosis-related fractures (adjusted odds ratio 1.92, 95% confidence interval 1.16-3.18, p=0.011), while use for five years or more was associated with a62% increased risk of hip fracture (adjusted OR 1.62, 1.02-2.58, p=0.04). The results are reported in the August 12th issue of the Canadian medical journal CMAJby Dr Laura Targownik from the University of Manitoba in Winnipeg.
The researchers say that, although these increases in relative risk are modest, osteoporotic fractures are common and associated with substantial morbidity and mortality, particularly with increasing age. "Even if only few percent of the older population are long term PPI users this would translate into a large number of fractures and costs," William Leslie, one of the study authors, told Scrip.
The calculated odds ratios are similar in magnitude to other known fracture risk factors, such as smoking, low body mass index and excessive alcohol consumption, they add.
The authors point out that PPI use is increasing, that evidence suggests that they are frequently given to patients with no obvious indication and that many long-term PPI users can be transferred to less intensive therapies without symptoms recurring. Clinicians must, therefore, be increasingly vigilant in ensuring that PPIs are used sparingly and only when absolutely indicated, they say.
PPIs inhibit production and intragastric secretion of hydrochloric acid, which is believed to be an important mediator of calcium absorption in the small intestine. A study published in the Journal of the American Medical Association in 2006 also showed that patients prescribed long-term PPI therapy, particularly at high doses, had a significantly (p<0.0001) greater="" risk="" of="" hip="" fracture="" with="" exposure="" of="" one="" year="" or="" longer="">Scrip Online, January 5th, 2007). That study did not set out to assess the effect of length of exposure, however, and so did not study the distribution of fractures among patients with different lengths of exposure.
The new study, conducted in Canada, explicitly sought to examine whether the occurrence of osteoporotic fractures was associated with duration of exposure to PPIs. 15,792 patients over 50 years old who had suffered osteoporosis-related vertebral fractures were each case-matched with three controls who had no history of hip, vertebral or wrist fractures (47,289 controls). Exposure to PPIs was established using data from the Drug Program Information Network database, a Canadian population-based database which records all prescription drugs. As well as showing an increased risk for osteoporosis-related fractures after seven years' use and for hip fractures after five years' use, the analysis also showed that the risk of hip fracture increased with longer exposure. The adjusted ORs were 2.49 after six years (1.33-4.67) and 4.55 after seven years (1.68-12.29).
Currently marketed PPI products include AstraZeneca's multi-billion dollar blockbuster Nexium (esomeprazole) and Losec (omeprazole), Nycomed's pantoprazole (marketed as Protonix, Pantoloc and Zurcale), Eisai's rabeprazole (marketed as Aciphex and Pariet) and Takeda's Prevacid (lansoprazole). These products' labels do not include information on fracture risk, but medicines regulators are assessing the association between PPI use and fracture risk.
A US FDA spokesman said that the agency was looking at the evidence for an association and would be examining the CMAJ article as part of that review. UK-based Nycomed told Scrip that the UK's medicines agency, the MHRA, wrote to manufacturers of PPIs earlier this year, asking asked them to examine their data for any association between PPI use and fracture risk. Nycomed said it had reviewed its data and did not find any trend suggesting an increased risk of hip fractures in patients treated with pantoprazole. The company has since sent its response to the MHRA and is awaiting the agency's reply. Nycomed said it would continue to look at pantoprazole's adverse event data, but had no plans to change the product's labelling.
AstraZeneca said it had been looking at this issue and that the available data do not suggest a connection between use of esomeprazole or omeprazole and fracture risk. The company said, based on post-marketing surveillance data, it had only received a few reports of hip fracture during esomeprazole or omeprazole treatment and an association with long-term use of PPIs could not be established with any of the reports.