Proton pump inhibitors (PPI) are widely-prescribed medications. PPI exposure may be associated with lower trabecular bone score (TBS), but has not shown a consistent effect on bone mineral density (BMD). We hypothesized that abdominal obesity, which is associated with both gastroesophageal disease and PPI use, could confound the relationship between PPI use and TBS. We assessed the effect of PPI use on TBS (primary measurement) and BMD (secondary measurements) before and after adjustment for sagittal abdominal diameter (SAD), a DXA-derived measure of abdominal soft-tissue thickness. The study population comprised 60 930 individuals (90.3% women, mean age 65.7 yr) that included 11 340 (18.6%) with PPI use in the preceding 12 mo. PPI exposure was categorized from medication persistence ratio (MPR) as non-use (referent), minimal (MPR 0.01-0.25), mild (MPR 0.26-0.5), moderate (MPR 0.51-0.75) and high use (MPR 0.76-1). When logistic regression models were minimally-adjusted for age, sex and scanner, increasing PPI use versus non-use was associated with progressively increasing odds ratios (ORs) for TBS in the lowest tertile (minimal 1.11 [95% CI 1.02-1.22], mild 1.18 [1.04-1.34], moderate 1.34 [1.17-1.53], high 1.41 [1.31-1.52]) but inversely with osteoporotic BMD (minimal 0.97 [0.89-1.06], mild 0.85 [0.75-0.97], moderate 0.82 [0.72-0.94]), high 0.76 [0.70-0.82]). SAD was greater in PPI users than non-users. After further adjustment for SAD, PPI use was not associated with lower TBS or BMD. Similar patterns were seen in men and women, and for longer durations of PPI use. Among 4742 with a second DXA (mean interval 3.4 yr), PPI use was not associated with more rapid TBS or BMD loss compared to non-users. In conclusion, PPI use is associated with greater SAD, an indicator of abdominal obesity. SAD and other clinical variables have a confounding effect on TBS and BMD measurements. When fully-adjusted, PPI exposure did not significantly decrease TBS or BMD.