Elsevier

Annals of Epidemiology

Volume 24, Issue 4, April 2014, Pages 286-290
Annals of Epidemiology

Original article
Proton-pump inhibitor use and hip fractures in men: a population-based case-control study

https://doi.org/10.1016/j.annepidem.2014.01.004Get rights and content

Abstract

Purpose

To estimate the association between proton-pump inhibitor (PPI) use and hip fracture.

Methods

We conducted a case-control study of 6774 pairs of men aged 45 years or older, matched on age, race, and medical center. Cases sustained incident hip fractures in 1997–2006. Fracture date was index date for each case-control pair. PPI exposure was identified from electronic pharmacy records, 1991–2006. PPI use was measured as (1) ever versus never; (2) adherence; (3) duration; and (4) recentness. Omeprazole and pantoprazole were analyzed separately using conditional logistic regression, adjusted for comorbidities. Nonusers were the referent group.

Results

Eight hundred ninety-six (13.2%) cases and 713 (10.5%) controls used omeprazole before index date (matched odds ratio [OR], 1.13; 95% confidence interval [CI], 1.01–1.27). Greatest adherence (medication possession ratio > 80%) (OR, 1.33; 95% CI, 1.09–1.62), highest tertile of duration (OR, 1.23; 95% CI, 1.02–1.48), and recent use (OR, 1.22; 95% CI, 1.02–1.47) were associated with hip fracture. Six hundred ninety-four (10.2%) cases and 576 (8.5%) controls had used pantoprazole (OR, 1.10; 95% CI, 0.97–1.24). Longest duration (OR, 1.25; 95% CI, 1.02–1.53) and most recent use (OR, 1.38; 95% CI, 1.12–1.71) were associated with hip fracture. Our study suggests that PPI use and hip fractures are associated, with risk increasing with longer duration and more recent use.

Introduction

Proton-pump inhibitor (PPI) medications, introduced in 1989 and used for the treatment of gastroesophageal reflux disease, ulcers, Helicobacter pylori, and other gastrointestinal conditions, are among the most commonly prescribed drugs worldwide [1]. As these agents are often used to treat chronic conditions, many patients could be on these medications for extended periods. In addition, in some clinical instances, use of doses higher than the defined daily dose may be recommended for periods. Use of antisecretory medications may negatively affect bone metabolism and reduce bone mineral density via impaired calcium absorption [2] or induction of secondary hyperparathyroidism [3]. Either of these possible mechanisms of reduced bone mineral density could theoretically be amplified by the use of acid inhibitors for long durations and/or at high dosages.

Hip fractures are among the most important possible negative outcomes of reduced bone density and osteoporosis, resulting in considerable morbidity and mortality [4]. Over the past several years, a number of studies have examined the possible association between long-term use of PPIs and hip fractures in older adults. Although a small number of studies have not observed any apparent increases in hip fracture risk with the use of PPIs [5], [6], [7], several studies have demonstrated such associations [8], [9], [10], [11], [12], [13], [14], [15], and recently published meta-analyses have also reported pooled results suggesting the presence of an association [11], [16], [17], [18], [19], [20], [21]. The apparent heterogeneity of results may be at least partially attributable to variations in study methodologies and handling of multiple possible confounding factors, with exposure definitions and ascertainment being particularly variable. Regardless, the question of whether PPI use and subsequent increases in hip fracture risk are associated remains open.

With an aim of providing additional information that might help resolve this question, we conducted a population-based case-control study of men enrolled in a large integrated care system to assess the possible associations of hip fracture and use of the two most commonly prescribed PPIs, omeprazole and pantoprazole, using pharmacy dispense records to measure exposure in three different ways: prescription adherence, duration of use, and recentness of use.

Section snippets

Study design, setting, subjects

This population-based case-control study was conducted within the Southern California region of Kaiser Permanente (KPSC), using methods that have been previously described [22]. KPSC is a large integrated health care system serving a racially, ethnically, and socioeconomically diverse population of approximately 3.5 million people. Based on geographic proximity, all KPSC members are assigned to one of the 14 medical centers and also receive outpatient services from among approximately 200

Results

Over the 10-year study period, 6774 men were identified as having an incident hip fracture and were matched to 6774 men without evidence of fracture in the EHR, for a total study sample of 13,548 men. Approximately 69% of men were aged older than 70 years (Table 1). The majority of the study group was non-Hispanic white (70%). Hip fracture cases tended to have greater overall burden of comorbidity than control subjects, with 51% of case subjects having a Charlson Index score 3 or higher

Discussion

Our study suggests that omeprazole use (any vs. none) is associated with a modest increase in risk of hip fracture. In addition, patients who use the medication for more than 2.5 months or within 7 days of index date are at increased risk for hip fractures compared with nonusers. Moreover, greater medication adherence was associated with higher fracture risk. Greater adherence to a prescribed regimen over time results in greater exposure to the medication in terms of both frequency of exposure

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