Three cohort, five case-control and three nested case-control studies were included in the review. The total number of patients was in excess of 700,000 (study sizes ranged from approximately 760 to 390,000, where reported). No randomised controlled trials were identified. Study quality scores ranged from 4 to 9 (out of 9) in case-control studies and from 7 to 8 in cohort studies.
Proton-pump inhibitors were found to increase fracture risk (adjusted OR 1.29, 95% CI 1.18 to 1.41; Ι²=69.8%; 10 studies). This increase was found for all types of study and levels of study quality. There was an increased risk of hip fracture (OR 1.31, 95% CI 1.11 to 1.54; nine studies) and vertebral fracture risk (OR 1.56, 95% CI 1.31 to 1.85; three studies), but no association with other types of fracture. There was no evidence of a differential effect due to dose or sex.
Histamine-2 receptor antagonists were not associated with fractures overall (OR 1.10, 95% CI 0.99 to 1.23; Ι²=86.3%; seven studies). An association was identified in the two cohort studies (OR 1.08, 95% CI 1.02 to 1.13) and in two nested case-control studies (OR 1.20, 95% CI 1.13 to 1.28), but not in other case-control studies. A significant association was found in the three high-quality studies (OR=1.13, 95% CI 1.05 to 1.21), but not the low-quality studies. There was no evidence of a differential effect due to type of fracture or dose.
Further subgroup and sensitivity analyses were reported.
There was no evidence of publication bias in any meta-analysis.