Does the long-term use of proton pump inhibitors (PPIs) increase the risk of hip fracture?

Long-term use (greater than one year) of proton pump inhibitors (PPIs) is associated with an increased risk of hip fracture in adults over age 50 years. Risk is also higher among individuals taking higher doses of PPIs and increases with duration of use. Appropriate use, dose, and duration of therapy should be carefully assessed on an individual basis. (LOE = 3b)

Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006;296:2947-53.  [PMID:17190895]

Case-control

Industry + govt

Population-based

Significant hypochlorhydria as a result of proton pump inhibitor (PPI) therapy may cause calcium malabsorption, resulting in a higher risk of bone fractures. These investigators analyzed data obtained from the United Kingdom General Practice Research Database relating to prescription use and subsequent diagnoses and hospitalizations for hip fracture. Previous studies validate information obtained in this manner from the same source. Cases consisted of individuals older than 50 years of age with first occurrence of hip fracture at least 1 year after the beginning of their standard follow-up period. Up to 10 controls were selected for each case matching for multiple variables, including sex, year of birth, and duration of follow-up. The exposure of interest was the effect of cumulative duration of PPI therapy for up to 4 years. The authors performed a statistical analysis of the data to control for other potential confounders, including body mass index, smoking history, alcoholism, impaired mobility, atherosclerotic vascular disease, peptic ulcer disease, renal failure, among others. There were 13,556 hip fracture cases and 135,386 controls. PPI use for more than 1 year was associated with a significantly increased risk of hip fracture (adjusted Hazard Ratio = 1.44, 95% CI, 1.30-1.59; NNTH/person-years = 1266; 944-1856). The associated risk was further increased among patients taking higher doses of PPI and with increasing duration of use. Histamine 2 receptor antagonist therapy (e.g. ranitidine, cimetidine) did not significantly increase hip fracture risk.