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Proton Pump Inhibitors and Fracture Risk: a Review of Current Evidence and Mechanisms Involved

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Proton Pump Inhibitors and Fracture Risk: a Review of Current Evidence and Mechanisms Involved International Journal of Environmental Research and Public Health Review Proton Pump Inhibitors and Fracture Risk: A Review of Current Evidence and Mechanisms Involved Benjamin Ka Seng Thong , Soelaiman Ima-Nirwana and Kok-Yong Chin * Department of Pharmacology, Universiti Kebangsaan Malaysia Medical Centre, Cheras 56000, Malaysia; [email protected] (B.K.S.T.), [email protected] (S.I.-N.) * Correspondence: [email protected]; Tel.: +60-3-9145-9573 Received: 5 March 2019; Accepted: 30 April 2019; Published: 5 May 2019 Abstract: The number of patients with gastroesophageal problems taking proton pump inhibitors (PPIs) is increasing. Several studies suggested a possible association between PPIs and fracture risk, especially hip fractures, but the relationship remains contentious. This review aimed to investigate the longitudinal studies published in the last five years on the relationship between PPIs and fracture risk. The mechanism underlying this relationship was also explored. Overall, PPIs were positively associated with elevated fracture risk in multiple studies (n = 14), although some studies reported no significant relationship (n = 4). Increased gastrin production and hypochlorhydria are the two main mechanisms that affect bone remodeling, mineral absorption, and muscle strength, contributing to increased fracture risk among PPI users. As a conclusion, there is a potential relationship between PPIs and fracture risks. Therefore, patients on long-term PPI treatment should pay attention to bone health status and consider prophylaxis to decrease fracture risk. Keywords: bone; compression; omeprazole; osteoporosis; pantoprazole 1. Introduction Proton pump inhibitors (PPIs) are lipophilic weak bases (pKa 4.0–5.0) consisting of two components: a substituted pyridine and a benzimidazole. PPIs are synthesized as prodrugs and are converted to sulfenic acids or sulfenamides that bind to one or more cysteines of the gastric H+/K+-ATPase covalently in an acidic environment. There are several subtypes of proton pump inhibitors available in the market, such as esomeprazole, omeprazole, pantoprazole, lansoprazole, rabeprazole, ilaprazole, and dexlansoprazole. Although these PPIs have the same basis structure, they differ in pharmacokinetic and pharmacodynamic profile [1]. In clinical practice, PPIs are commonly used as acid-suppressive agents to treat multiple acid-related gastrointestinal disorders, such as peptic ulcer disease, Helicobacter pylori infection, dyspepsia, gastroesophageal reflux disease (GERD), and Zollinger Ellison syndrome [2–6]. Moreover, they also serve as prophylactic agents among users of non-steroidal anti-inflammatory drugs (NSAIDs) to prevent gastric ulcers and bleeding [7–9]. Overall, PPIs account for 95% of acid-suppressing drugs prescription due to their effectiveness [10]. In Australia, PPIs are the third most prescribed medications, equivalent to 6.9 million prescriptions in 2014 [11]. In the United States, there were 14.9 million patients receiving 157 million prescriptions of PPIs in the year 2012 [12]. Other than that, PPIs were one of the most frequently sold over-the-counter drug with $13 billion of global market value [13]. Long-term PPI therapy is reported to be associated with decreased bone mineral density (BMD) [14–16]. Reduction in BMD and deterioration of bone microstructure are characteristics of osteoporosis, a metabolic bone disease [17]. Osteoporosis ultimately leads to decreased bone strength and susceptibility to fracture [17]. Osteoporotic fracture is becoming a major health concern in the rapidly aging society, owing to the tremendous economic burden, mortality, and morbidity associated with it [18–21]. In fact, hip fracture Int. J. Environ. Res. Public Health 2019, 16, 1571; doi:10.3390/ijerph16091571 www.mdpi.com/journal/ijerph Int. J. Environ. Res. Public Health 2019, 16, 1571 2 of 17 is considered as the most common cause of elevated mortality and dependency in elderly patients. Approximately 1.6 million hip fracture cases are reported worldwide each year and the number will reach between 4.5 and 6.3 million by 2050 [20,22,23]. The risk of mortality in hip fracture patients is threefold higher than the general population [24]. In the United States, the estimated age-weighted and lifetime savings for surgical treatment of hip fractures was more than United States dollar (USD) 65,000 for a patient [25]. However, the extent of the problem of PPI-induced osteoporotic fracture is less known. There were several reviews on the relationship between PPI and fractures in the past [26–29], but they do not explore the mechanism underlying this relationship. Multiple longitudinal observational studies concluded in the recent five years shed new light on the relationship between PPIs and fracture risk. Therefore, this narrative review aimed to discuss the recent epidemiological findings pertaining to this topic and the possible underlying bone-weakening mechanism of PPIs. In reviewing the relationship between PPI and fracture risk, a literature search was performed using the keywords (“proton pump inhibitors” OR “*prazole” OR “acid suppress*”) AND (fracture OR bone) to identify original research articles indexed in PubMed, Scopus, and Web of Science. Only articles written in English, published between 2013–2018 were included. 2. The Relationship between PPIs and Fracture Risk 2.1. General Population Fracture risk in the general population using PPIs, such as children, young adults, men, elderly, and postmenopausal women, was explored in several studies [30–42]. In the case-control study of Freedberg et al. involving children (4–17 years; n = 87,071; 69.8% were cases) and young adults (18–29 years; n = 37,728; 30.2% were cases) in the United States (follow-up period: five years), a positive relationship between fracture risk and PPI exposure in young adults was found, with a body mass index (BMI)-adjusted odds ratio (aOR) of 1.39 (95% confidence interval (CI): 1.26–1.53) [41]. However, there was no significant relationship between PPI use and fracture risk in children in terms of cumulative exposure manner [41]. A dose-dependent effect of PPIs on fracture risk was suggested, whereby the effect was only observed in young adults but not in children [41]. The most common fracture sites were wrist (24.9%) and hand (20.5%) for children, and foot (12.4%) and hand (32.5%) for young adults [41]. However, the authors could not identify the etiology of the fracture, and the analysis was not stratified according to ethnicity [41]. In another study examining the positive relationship between PPIs and hip fracture risk among men of diverse ethnic background (70% non-Hispanic Caucasians) in the United States, the subjects were stratified based on age into 45–59 years (n = 999), 60–69 years (n = 1098), 70–79 years (n = 1969), and 80+ years (n = 2708) [32]. Subjects with the most recent use of omeprazole (aOR: 1.22; 95% CI: 1.02–1.47) and those with medication possession ratio (MPR) 80% (aOR: 1.33; 95% CI: 1.09–1.62) had ≥ an elevated risk of hip fracture [32]. Moreover, the authors suggested that patients on omeprazole for more than 2.5 months had an increased hip fracture risk [32]. They also demonstrated that cumulative exposure, frequency exposure, and duration of PPI use influenced fracture risk of the patients [32]. However, pantoprazole use was not significantly related to hip fracture risk after adjusting for other comorbidities [32]. This study benefited from the availability of electronic medical records in collecting data on medication use and fracture incidence. A limitation of note was that omeprazole and pantoprazole were the only generic ingredients investigated. Several studies focused on the relationship between PPIs and fracture among postmenopausal women [36,40,42]. A retrospective study conducted among Australian women (n = 1045, mean age = 76.5 2.6 for non-users and mean age = 77.5 2.5 for users) reported an increased ± ± fracture risk in patients taking PPIs 1 year or 1.5 standard daily doses [42]. Women with long-term ≥ ≥ PPI were two times more likely to experience a fracture (aOR: 2.07 (95% CI: 1.13–3.77)) [42]. Moreover, a significantly lower serum vitamin B12 level in PPI users was detected. This prompted the researchers Int. J. Environ. Res. Public Health 2019, 16, 1571 3 of 17 to suggest that patients on high-dose and longer-term PPI had an increased fall risk [42]. Additionally, an increase in fracture risk among postmenopausal women (n = 6917, mean age = 56.4, follow-up period = 14.4 years) using PPI was also reported by a Swedish retrospective study (aOR: 2.01 (95% CI: 1.31–3.08)) [40]. Moreover, PPI use was also reported to increase fracture risk in Australian elderly women (n = 1396, mean age = 78.2 years for PPI users; n = 1338, mean age = 78.3 years) [36]. Only patients on rabeprazole and multiple types of PPI were found to have increased fracture risk [36]. The relationship between PPIs and fracture risk in the elderly is debatable [30,37,39]. A data mining study utilizing the Food and Drug Administration (FDA) adverse event reporting system investigated 169,562 entries with PPI use [38]. The mean age of the PPI users with fracture was 65.3 years and a sex ratio (female to male) of 3.4. The fracture sites reported by PPI users were the thoracic cage and pelvic bone [38]. Ding et al. conducted a large retrospective cohort study (n = 25,276) with a follow-up period of five years using data from the Pharmaceutical Assistance Contract for the Elderly (PACE) program [39]. PPI users were 1.27 times more likely to experience a fracture, including major osteoporotic fracture, hip fracture, vertebral fracture, and other fractures compared to non-users [39]. In another cohort study, there was a significant increase in fracture risk (adjusted hazard ratio: 1.40; 95% CI: 1.11–1.77) among PPI-users (mean age of 67.6 years) after using PPIs for a decade [34].
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