Study Design |
Population |
Exclusion Criteria |
PPI Exposure |
Risk of Hip Fracture |
Risk of Other Fractures |
Dose-Response Relationship |
Nested case–control5 |
Patients aged ≥ 50 yrs from the UK GPRD (13,556 cases, 135,386 controls) |
Prior hip fracture |
Cumulative PPI use >1 yr |
AOR 1.44 (95% CI 1.30–1.59) |
NA |
Increasing risk of hip fracture with increasing cumulative duration of use and ADD: >1 yr: AOR 1.22 (95% CI 1.15–1.30) >2 yrs: AOR 1.41 (95% CI 1.28–1.56) >3 yrs: AOR 1.54 (95% CI 1.37–1.73) >4 yrs: AOR 1.59 (95% CI 1.39–1.80) ≤1.75 ADD: AOR 1.40 (95% CI 1.26–1.54) >1.75 ADD: AOR 2.65 (95% CI 1.80–3.90) |
Nested case–control6 |
Patients aged 50–79 yrs from UK GPRD (1098 cases, 10,923 controls) |
Major medical risk factors for hip fracture with OR > 2.0 |
Any PPI use |
RR 0.9 (95% CI 0.7–1.1) |
NA |
No dose-response relationship with the cumulative number of PPI prescriptions |
Nested case–control7 |
Adult members of Kaiser Permanente Northern California (33,752 cases, 130,471 controls) |
Prior hip fracture |
Cumulative PPI use ≥2 yrs |
OR 1.30 (95% CI 1.21–1.39) |
NA |
Increasing risk of hip fracture with increasing ADD but not with cumulative duration of use: <0.75 pills/day: OR 1.12 (95% CI 0.94–1.33) 0.75–1.49 pills/day: OR 1.30 (95% CI 1.19–1.42) ≥1.5 pills/day: OR 1.41 (95% CI 1.21–1.64) |
Case–control8 |
Fractures occurred in 2000 from the Danish national registry (124,655 cases, 373,962 controls) |
None |
Any PPI use; last use ≤1 yr ago |
AOR 1.45 (95% CI 1.28–1.65) |
Any fracture: AOR 1.18 (95% CI 1.12–1.43) Forearm: AOR 0.95 (95% CI 0.82–1.11) Spine: AOR 1.60 (95% CI 1.25–2.04) |
No dose-response relationship, stratified by the cumulative dose or ADD, in any fracture, hip fracture, spine fracture, or forearm fracture |
Case–control9 |
Patients aged≥ 50 yrs from a population database in Taiwan (1241 cases, 1241 controls) |
Prior hip, vertebral, or wrist fracture |
Any PPI use |
≤28 DDD: AOR 0.93 (95% CI 0.64–1.36) 29–70 DDD: AOR 1.40 (95% CI 0.91–2.15) >70 DDD: AOR 2.11 (95% CI 1.45–3.07)a |
NA |
Increasing risk of hip fracture with increasing cumulative dose; a similar dose-response trend was noted in patients with any PPI use in the past and those with any PPI use in ≤1 yr or ≤4 yrs preceding the index date |
Case–control10 |
Patients aged ≥ 50 yrs from a population database in Manitoba, Canada (15,792 cases, 47,289 controls) |
Receipt of osteoprotective drugs in the year before the fracture; residents of long-term care facilities |
Continuous PPI use ≥1 yr before fracture |
1–4 yrs use: NS ≥ 5 yrs use: AOR 1.62 (95% CI 1.02–2.59) |
Osteoporotic-related fractures: 1–6 yrs use: NS ≥ 7 yrs use: AOR 1.92(95% CI 1.16–3.18) |
Increasing risk of hip fracture with increasing duration of use after yr 5 ≥ 6 yrs use: AOR 2.49 (95% CI 1.33–4.67) ≥ 7 yrs use: AOR 4.55(95% CI 1.68–12.29) |
Prospective cohort11 |
Postmenopausal women in the WHI study (130,487 women) |
Prior hip fracture |
Current PPI use at baseline visit |
HR 1.00 (95% CI 0.71–1.40) |
Clinical spine: HR 1.47 (95% CI 1.18–1.82) Forearm/wrist: HR 1.26 (95% CI 1.05–1.51) Total fractures: HR 1.25 (95% CI 1.15–1.36) |
No dose-response relationship with increasing duration of PPI use in hip, spine, forearm/wrist, and total fracture |
Retrospective cohort12 |
Subjects aged ≥ 65 yrs from two prospective studies conducted in the U.S. (5339 women, 5755 men) |
History of bilateral hip replacement |
Current PPI use, included use ≤4 wks before baseline visit |
Women: RH 1.16 (95% CI 0.80–1.67) Men: RH 0.62 (95% CI 0.26–1.44) |
Nonspine fracture: Women: RH 1.34 (95% CI 1.10–1.64) Men: RH 1.21 (95% CI 0.91–1.62) |
NA |
Retrospective cohort13 |
Postmenopausal women from a prospective study conducted in Europe (1211 women) |
Baseline use of bisphosphonates or raloxifene |
Current omeprazole use, included use ≤1 yr before baseline visit |
NA |
Vertebral fracture: RR 3.10 (95% CI 1.14–8.44) |
NA |
Prospective cohort14 |
Postmenopausal women who presented to two Japanese hospitals for evaluation and treatment of osteoporosis and upper gastrointestinal disorders (75 women) |
Diabetes mellitus, thyroid disorder, metabolic bone diseases, drugs or hormones that affect bone and gastrointestinal mucosa (e.g., bisphosphonates) |
RRE patients required >6 mo of PPI therapy |
NA |
RRE patients had more episodes of vertebral fracture than patients without RE: 2.50 ± 2.60 vs 1.11 ± 1.68, p=0.009 |
NA |
Retrospective cohort15 |
Patients aged ≥ 35 yrs who began new treatment with alendronate from a Danish national registry (38,088 patients) |
Prior treatment with any antiosteoporotic drug; emigrated before end of study |
Any concurrent PPI use during first 36 mo of alendronate therapy |
Alendronate user/PPI nonuser: HR 0.61 (95% CI 0.52–0.71) Alendronate user/PPI user: HR 0.81 (95% CI 0.64–1.01) Interaction p<0.05 |
Interaction between PPI use and treatment response to alendronate for spine, humerus, or forearm fracture: NS |
Greater attenuation of the treatment response to alendronate with increasing cumulative dose of PPIs: 1–359 DDD: HR 0.63 (95% CI 0.55–0.72) 360–719 DDD: HR 1.00 (95% CI 0.70–1.45) >720 DDD: HR 1.24 (95% CI 0.71–2.18) |
Case–control16 |
Adult patients in Dutch PHARMO population database (6763 cases, 26,341 controls) |
None |
Current PPI use within 30 days before the fracture; recent, past, and distant use of PPI |
Current use: AOR 1.20 (95% CI 1.04–1.40) Recent use: AOR 0.96 (95% CI 0.83–1.12) Past use: AOR 0.97 (95% CI 0.74–1.26) Distant past use: AOR 1.24 (95% CI 1.08–1.43) |
NA |
Current users with the highest ADD of PPI had the largest AOR, but no consistent trend with lower doses: <1.00 DDD: AOR 1.21 (95% CI 0.93–1.57) 1.00–1.75 DDD: AOR 1.12 (95% CI 0.88–1.42) >1.75 DDD: AOR 1.35 (95% CI 1.02–1.77); Increasing continuous duration of current PPI therapy did not increase fracture risk |
Retrospective cohort17 |
Patients aged ≥ 40 yrs from UK GPRD who received a PPI (228,121 patients) |
Paget's disease or cancer |
Current PPI use compared with past PPI use as control group |
Without concomitant bisphosphonates: ARR 1.22 (95% CI 1.10–1.37) |
Any fracture: ARR 1.15 (95% CI 1.10–1.20) Osteoporotic: ARR 1.16 (95% CI 1.09–1.24) Radius/ulna: ARR 1.09 (95% CI 0.98–1.20) Vertebral: ARR 1.40 (95% CI 1.11–1.78) |
Increasing risk of osteoporotic and hip fractures with increasing DDD but not with increasing duration of current PPI use: Hip fracture: <1.0 DDD: ARR 1.13 (95% CI 0.98–1.31) Hip fracture: 1.0–1.75 DDD: ARR 1.27 (95% CI 1.12–1.45) Hip fracture: >1.75 DDD: ARR 1.45 (95% CI 1.06–1.99) |