899 postmenopausal women, we documented 893 incident hip fractures over 565
786 person years of follow-up. In 2000, 6.7% of women regularly used a PPI, rising to 18.9% by 2008. Compared with participants who did not regularly use a PPI, regular users had a higher body mass index, were less physically active, consumed less alcohol, were more likely to have a history of osteoporosis, and were more likely to use hormone replacement therapy, thiazide diuretics, corticosteroids, or bisphosphonates (table 1).
Table 1 Baseline characteristics of 79 899 postmenopausal women enrolled in the Nurses’ Health Study according to use of proton pump inhibitors (PPIs) in 2000. Values are numbers (percentages) unless stated otherwise, and all variables (more ...)
The absolute risk of hip fracture among regular users of PPIs was 2.02 events per 1000 person years, compared with 1.51 events per 1000 person years among non-users. Compared with non-users, regular users of PPIs had a 35% increase in risk of hip fracture (age adjusted hazard ratio 1.35 (95% confidence interval 1.13 to 1.62)) (table 2). The relation remained largely unchanged even after adjusting for body mass index (hazard ratio 1.45 (1.21 to 1.73)) or intake of dietary and supplemental calcium (hazard ratio 1.35 (1.12 to 1.62)). After additionally accounting for other risk factors for fracture—including smoking status, physical activity, and history of osteoporosis—these risk estimates were not materially altered (hazard ratio 1.37 (1.14 to 1.64)). We also did not observe any change in risk after adjusting for concomitant use of drugs known to affect the risk of fracture, including hormone replacement, bisphosphonates, corticosteroids, and thiazide diuretics (fully adjusted multivariate hazard ratio 1.36 (1.13 to 1.63)).
Table 2 Risk of hip fracture according to use of proton pump inhibitors (PPIs) among 79 899 postmenopausal women enrolled in the Nurses’ Health Study
We first asked participants in the Nurses’ Health Study about PPI use in the 2000 questionnaire. We considered the possibility that women who reported use in 2000 had probably used PPIs for varying durations. Thus, we conducted an analysis in which we excluded women who reported use in 2000 and restricted the analysis to follow-up after 2002. Women who first reported PPI use in 2002 had a fully adjusted hazard ratio of hip fracture of 1.42 (1.14 to 1.76) compared with women who had not used PPIs. To test if the association between PPI use and fracture might be due to its effect on gastric acid suppression, we examined regular use of less potent acid suppressors, H2 blockers, in relation to risk of fracture after excluding participants who used PPIs. Compared with PPI use, regular use of H2 blockers was associated with a more modest risk of fracture (fully adjusted hazard ratio 1.23 (1.02 to 1.50) v non-use).
The risk of hip fracture associated with PPI use increased with the duration of use (Ptrend<0.01) (table 3). Compared with non-users, the fully adjusted hazard ratios of fracture were 1.36 (1.12 to 1.65) for women with two years’ use of PPIs, 1.42 (1.05 to 1.93) for four years’ use, and 1.55 (1.03 to 2.32) for six to eight years’ use. To assess consistent use, we focused our analyses on women who reported PPI use in two consecutive biennial follow-up questionnaires and compared the incidence of fracture among women who did not use PPIs in two consecutive intervals. Among consistent users, the fully adjusted hazard ratio of fracture was 1.42 (1.06 to 1.88).
Table 3 Risk of hip fracture according to duration of use of proton pump inhibitors (PPIs) among 79 899 postmenopausal women enrolled in the Nurses’ Health Study
We also considered time since stopping PPI use in relation to risk of fracture (table 4). Although risk persisted for women who stopped PPI use within two years, women who had stopped use more than two years previously had a fully adjusted hazard ratio of fracture of 1.10 (0.63 to 1.92), similar to that of women who had never used a PPI.
Table 4 Risk of hip fracture according to time since stopping use of proton pump inhibitors (PPIs) among 79 899 postmenopausal women enrolled in the Nurses’ Health Study
We evaluated potential differences in the influence of PPI use according to strata of known risk factors (table 5). The risk of hip fracture seemed to differ according to history of cigarette smoking (Pinteraction=0.03). Among women who either previously or currently smoked, the fully adjusted hazard ratio of fracture was 1.51 (1.20 to 1.91). In contrast, there was no significant association between PPI use and risk of fracture among women who never smoked (fully adjusted hazard ratio 1.06 (0.77 to 1.46)). The effect of PPIs was not modified by strata defined by age, body mass index, use of hormone replacement therapy, use of corticosteroids, history of osteoporosis, or intake of calcium (all Pinteraction>0.10).
Table 5 Risk of hip fracture according to use of proton pump inhibitors (PPI) in selected strata of 79 899 postmenopausal women enrolled in the Nurses’ Health Study
We considered the possibility that the observed association of PPIs with hip fracture could be related to the reason for taking the drug. In 2000 we collected detailed information about symptoms of acid reflux and heartburn from 16
478 participants through a supplementary questionnaire. Among these participants, the fully adjusted hazard ratio of fracture associated with regular use of PPIs was 1.45 (1.01 to 2.10) and was not materially altered after accounting for the reason for PPI use. Specifically, the fully adjusted hazard ratio of fracture was 1.53 (1.04 to 2.25) after adjusting for heartburn; 1.37 (0.94 to 2.02) after adjusting for acid reflux; and 1.39 (0.96 to 2.02) after adjusting for peptic ulcer disease. These effect estimates did not vary according to the participants’ case or control status (Pinteraction
=0.57). Moreover, in separate analyses, there were no independent associations between reported heartburn, acid reflux, or peptic ulcer disease and risk of hip fracture (data not shown). We also conducted several sensitivity analyses to confirm that our associations were robust (see appendix on bmj.com).
Finally, we performed a systematic review of our results with the 10 published epidemiological studies on risk of hip fracture with chronic use of PPIs (see table in appendix).3
There was moderate heterogeneity across studies (Qstatistic
=50.0, P=0.02). Among the 1
862 individuals included within the 11 studies, the pooled odds ratio of hip fracture associated with PPI use was 1.28 (1.19 to 1.37) using a random effects meta-analysis (figure). We observed similar results using a fixed effects meta-analysis (odds ratio 1.30 (1.25 to 1.36)). We also computed the pooled odds ratio with inclusion of only one of the three studies from the UK General Practice Research Database each in turn.3
Using a random effects meta-analysis, we found the pooled odds ratio of hip fracture associated with PPI use was 1.30 (1.20 to 1.40) including the study of Yang et al,3
1.27 (1.18 to 1.36) including de Vries et al,32
and 1.25 (1.15 to 1.37) including Kaye et al.16
Results of meta-analysis of our results with 10 published studies of risk of hip fracture with chronic use of a proton pump inhibitor (PPI). For the study by Yu et al,13 risk estimates were only provided for men and women separately