Proton Pump Inhibitors May Compromise Antifracture Efficacy of Alendronate in Elderly Patients

Elderly patients who receive proton pump inhibitors (PPIs) while using alendronate, an oral bisphosphonate typically prescribed to reduce the risk of osteoporotic fractures, may have poorer response to alendronate. According to a population-based cohort study conducted by Danish researchers, the diminished efficacy of alendronate in patients using a PPI was dose dependent and most pronounced regarding hip fracture risk [Arch Intern Med. 2011;171(11):998-1004]. PPIs are commonly used to treat gastrointestinal tract complaints in the elderly, and the authors suggested substituting histamine H2-receptor blockers or parenteral therapies in patients taking oral bisphosphonates. The study population comprised 38,088 Danish men (n=6431) and women (n=31,657) aged ≥35 years (mean, 70.4 years) who filled their first prescription for alendronate from 1996 through 2005. Information was obtained from Denmark’s National Hospital Discharge Register and the National Prescription Database. Individuals who previously used alendronate or other osteoporosis therapies were excluded. The date of the first alendronate prescription was designated as the index date. Data were collected on use of PPIs, histamine H2-receptor blockers, and oral glucocorticoids and fracture history. The 18% of patients prescribed one of these agents in the 12 months before the index date were classified as baseline users, whereas the 26% of patients given one of these drugs within the first 36 months of initiating alendronate were considered concurrent users. Omeprazole and esomeprazole were the PPIs most often prescribed. Authors calculated defined daily dose (DDD) of PPI to determine whether degree of exposure affected fracture risk. The study’s primary outcome was hip fracture (neck or intertrochanteric femur); secondary outcomes included fractures of the spine, forearm, or humerous. The cohort included 10,177 current or prior PPI users and 27,911 non-PPI users. Overall, 2071 individuals experienced a hip fracture and 1110 had a major osteoporotic non-hip fracture during the study. Poorer alendronate adherence, as indicated by a lower medication possession ratio (MPR), increased the risk of hip and other fractures. For patients with a 100% MPR, hip fractures were less frequent in those aged <70 years compared with those aged ≥70 years (hazard ratio [HR], 0.53 vs 0.71, respectively). Sex did not correlate with hip fracture risk. Of the 10,177 PPI users, 594 patients (5.8%) had hip fractures compared with 1477 (5.3%) non-PPI users. The rate of hip fractures per 1000 patient-years was 15.8 in the non-PPI arm versus 17.4 in the PPI group. Hip fracture risk among non-PPI users whose MPR suggested complete alendronate adherence was reduced significantly from baseline, by 39% (HR, 0.61; 95% confidence interval [CI], 0.52-0.71; P<.001). In contrast, hip fracture risk only declined 19% for concurrent PPI and alendronate users (HR, 0.81; 95% CI, 0.64-1.01; P=.06), which was not significant. Alendronate’s efficacy was compromised far more in PPI users aged ≥70 years, who had an HR of 0.96 for hip fracture compared with 0.62 for nonusers aged ≥70 years, 0.60 for nonusers aged <70 years, and 0.42 for PPI users aged <70 years. Patients with a DDD of the PPI >360 saw no reduction in hip fracture risk with alendronate, whereas the drug’s protectiveness against hip fracture was undiminished among patients with a DDD of the PPI between 1 and 359. PPI use did not weaken alendronate’s protection against non-hip osteoporotic fractures. Use of histamine H2-receptor blockers did not affect response to alendronate, whereas oral glucocorticoid use correlated with significantly improved response. The study is limited by the fact that it is observational, with no placebo arm. The authors noted they were unable to verify whether patients used medications as prescribed, had fractures treated outside a hospital setting, or had other risk factors for fracture. Despite these limitations, they said the study has “important strengths,” including its large patient population and completeness of follow-up data. According to the authors, other studies have associated PPI use with osteoporotic fracture, but are inconclusive as to whether the relationship is causal. Although high concentrations of PPIs have been shown to inhibit osteoclast resorption, the authors believe the inhibitory effects of these drugs on calcium and vitamin B12 are more likely responsible for the increased risk of osteoporotic fracture, along with the greater prevalence of Helicobacter infection among PPI users. “Support for causality is provided by the finding of a pronounced dose-response relationship, by the impact of current but not past PPI use, and also to some extent by the absence of similar effects by histamine H2-receptor blockers when addressed in the same way,” they said. The authors said use of PPIs at common doses resulted in “pronounced blunting of the antifracture efficacy of alendronate,” with its effectiveness against hip fracture cut in half. “This is a concern given the widespread use of both oral bisphosphonates and PPIs in elderly patients,” they concluded, and called for additional research to explore the mechanism of interaction between this class of drugs and PPIs.