Proton Pump Inhibitors Use and Osteoporotic Fracture Risk in Older Women

Treatment with proton pump inhibitors is associated with increased risk for osteoporotic fracture compared with the use of histamine-2 receptor antagonists.

Treatment with proton pump inhibitors (PPIs) is associated with an increased risk for osteoporotic fracture compared with the use of histamine-2 receptor antagonists (H2RAs), according to study results published in Bone.

The use of PPIs has increased significantly in recent years, mainly for the treatment of gastroesophageal reflux disease and peptic ulcer disease. Although some studies have reported that PPI use may be associated with an increased risk for osteoporotic fracture, others did not show a similar association. As for H2RA use, the second most commonly used gastric acid suppressant, no association has been found with an increased risk for osteoporotic fracture.

The goal of the study was to directly compare the risk for osteoporotic fracture between PPI users and H2RA-only users.

The researchers used nationwide population-based study data from the South Korean National Health Insurance Services, focusing on older Korean women (aged ≥66 years) who had received treatment with PPIs or H2RAs. The case group included patients who developed osteoporotic fractures and the matched control group (1:5 ratio based on cohort entry date, follow-up duration, and baseline osteoporosis status) included patients who did not develop fractures during the follow-up period.

The study cohort included 8903 case and 44,515 control individuals, with a mean age at initiation of PPI or H2RA use of 66.59 and 66.61 years, respectively. Rheumatoid arthritis, chronic kidney disease, chronic obstructive pulmonary disease, Cushing syndrome, vitamin D deficiency, chronic liver disease, and diabetes mellitus were more prevalent in cases of osteoporotic fracture than in control individuals.

Any use of PPIs was associated with a 13% increased risk for osteoporotic fracture at any site (adjusted odds ratio [aOR], 1.13; 95% CI, 1.07-1.18) compared with the use of H2RAs only. This risk tended to increase with an increase in the cumulative duration of PPI use, with evidence of a 30% higher risk for fracture with PPI use for ≥1 year compared with H2RA use only (aOR, 1.30; 95% CI, 1.09-1.56; P <.001 for trend). The risk for fracture did not increase with increasing cumulative PPI dose.

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Recent use of PPI within the year prior but not remote use (not within the preceding year) was also associated with an increased fracture risk compared with H2RA-only use (aOR, 1.31; 95% CI, 1.23-1.38).

Moreover, this effect of PPI use on the risk for fracture did not differ according to major osteoporosis risk factors.

The researchers acknowledged several study limitations, including possible reverse causality, selection bias due to the relatively high rate of non participating women in the Korean health screening program, diagnosis of fractures based on claims data and not on medical records or imaging, and possible misclassification bias with regard to fracture type.

“The risk of osteoporotic fracture may be mitigated in women with gastrointestinal diseases who need acid inhibitor treatments and are at a high risk of osteoporotic fracture by prescribing PPI for minimal durations or replacing PPI with H2RA,” concluded the researchers.


Park JH, Song YM, Jung JH, Han K. Comparative analysis of the risk of osteoporotic fractures with proton pump inhibitor use and histamine-2 receptor antagonist therapy in elderly women: a nationwide population-based nested case-control study [published online February 29, 2020]. Bone. doi:10.1016/j.bone.2020.115306