We found that current PPI use was associated with a 1.2-fold increased risk of hip/femur fracture. Higher daily dosages (>1.75 DDD), male gender, and use of oral corticosteroids further increased the risk. The highest increase of risk was observed within the year after initiation of acid suppressants, and attenuated with prolonged use. This finding, does not support a causal effect of PPIs on bone, but suggests the presence of unmeasured distortion, such as selection bias and/or residual confounding.
The key finding of this study is that the increased risk of hip/femur fracture among current acid suppressant users is probably not causal. As far as we know, PPIs and H2RAs do not increase the risk of falling. Therefore, if a causal relationship exists, fracture risk should increase only after long-term exposure (at least 6–12 months to alter bone mineral density). However, the smoothing spline regression plots (Fig. ) did not provide evidence for a duration of use effect. Furthermore, acid suppression in the stomach caused by PPIs is significant greater and lasts longer compared with H2RAs [1
]. Thus, if impaired calcium absorption caused by acid suppression is associated with an increased risk of fracture, this should be most abundant with PPI use. Nevertheless, prolonged H2RA use (instead of PPI use) of >36 months yielded a higher AOR of 1.30 (95% CI 0.94–1.81) compared to PPI use with an AOR of 1.09 (95% CI 0.81–1.47). These results support the alternative hypothesis that the observed association is flawed due to unknown distortion, instead of an increased fracture risk caused by impaired calcium absorption. Consequently, these results do not support the hypothesis that acid suppression is associated with an increased risk of fracture.
Clinical studies showed conflicting results regarding calcium uptake and osteoclastic pump inhibition in users of PPIs [21
]. When studying calcium uptake along with a meal, Graziani et al. and Hardy et al. [3
] found that calcium uptake was decreased in hypochlorhydric subjects, whereas other studies did not observe any effect [23
]. Only during fasting conditions calcium uptake was decreased among patients using PPIs [2
] and among achlorhydric patients [23
]. Furthermore, some in vitro [6
] and in vivo [5
] studies suggested that PPIs could inhibit the osteoclastic proton pump and thereby reduce bone resorption. Conversely, short-term omeprazole treatment did not alter osteoclast or osteoblast function in paediatric users [27
]. Moreover, no significant differences were observed in BMD among postmenopausal women using acid suppressants (PPIs and H2RA), while in men, even lower cross-sectional bone masses were observed [28
]. In addition, the most recent study performed by Targownik et al. [29
] showed that both chronic PPI use and high daily doses of PPIs were not associated with osteoporosis or accelerated BMD loss.
Several observational studies that investigated the association between duration of acid suppressant use and fracture risk found discrepant results as well [8
]. Both Yang et al. and Targownik et al. [8
] found that fracture risk increased with longer durations of PPI use. In contrast, members of our group found results which are similar to the present study (i.e. PPI use for a duration ≤1 year is associated with the highest fracture risk) using the same database as Yang et al. [11
]. Moreover, our sensitivity analysis, in which we resembled the definitions of Yang et al., did not support a duration-of-use effect. Additionally, Kaye et al. [12
] who also used the GPRD database did not find any association between the number of PPI prescriptions and hip fracture. The reasons for these discrepancies remain unclear.
There are alternative explanations for the small, overall 1.2-fold increased risk among current users of acid suppressants. These include the inability of the current and previous studies, to measure (or only partially measure) alcohol consumption, smoking history and low body mass index. All these factors are associated with an increased risk of fracture [30
]. Besides, PPIs are often used for the eradication of Helicobacter pylori
], which may be associated with an increased risk of osteoporosis [34
]. In addition, PPIs are associated with the onset of Clostridium difficile
], which may be an alternative explanation for the increased risk of fracture. Finally, celiac disease, which is associated with the onset of reflux oesophagitis [36
], has recently been associated with an increased risk of both osteoporosis and fracture [37
]. Nevertheless, we were unable to fully adjust for these three potential confounders, because PHARMO RLS has missing data of diagnoses determined outside the hospital.
Our study has several strengths. As we used a population-based design, our study represents the entire population of the Netherlands. It has a large study size and the average period of follow-up exceeded 4 years. Furthermore, written dosage instructions allowed us to discriminate between different average daily doses of PPIs and H2RAs and concomitant use of average daily dosages of oral glucocorticoids. The main limitation of our study is the inability to adjust for residual confounding. No information was present in the PHARMO RLS about low body mass index, alcohol consumption, smoking, celiac disease, C. difficile
and H. pylori
eradication. These potential confounders could have overestimated the observed increased fracture risk. Conversely, no information was present about the use of over-the-counter drugs like calcium and vitamin D supplements, which decrease this risk [4
]. Yet, according to our knowledge, the trend observed in the spline showing the recency of use (Fig. ) would be similar, even after adjustments for these potential confounders. In addition, although not confirmed by clinical trials, current literature suggests that non-steroidal anti-inflammatory drugs inhibit bone formation [39
]. For this reason, our analyses were adjusted for the use of these drugs in the 6 months before the index date. Finally, data collection for this study ended on the 31st of December 2002. Addition of more recent data would probably identify more long-term PPI users, which would add more power to the duration of use results.
In conclusion, our findings show that there is probably no causal relationship between PPI use and hip fracture risk. The observed association may be the result of unmeasured distortions: although current use of PPIs was associated with a 1.2-fold increased risk of hip/femur fracture, the positive association was attenuated with longer durations of continuous use. Our findings do not support that discontinuation of PPIs decreases risk of hip fracture in elderly patients.