title: The effect of dose and type of proton pump inhibitor use on risk of fractures and osteoporosis treatment in older Australian women: A prospective cohort study.
abstract: OBJECTIVE
  Proton pump inhibitors (PPIs) are among the most prescribed medications worldwide, however, there is growing concern regarding potential negative effects on bone health. The aim was to examine the effect of dose and type of PPI use on subsequent use of osteoporosis medication and fractures in older Australian women.
  
  
  METHODS
  Data were included from 4432 participants (born 1921-26) in the 2002 survey of the Australian Longitudinal Study on Women's Health. Medication data were from the national pharmaceutical administrative database (2003-2012, inclusive). Fractures were sourced from linked hospital datasets available for four major States of Australia. Competing risk regression models used PPI exposure as a time-dependent covariate and either time to first osteoporosis medication prescription or fracture as the outcome, with death as a competing risk.
  
  
  RESULTS
  Of the 2328 PPI users and 2104 PPI non-users, 827 (36%) and 550 (26%) became users of osteoporosis medication, respectively. PPI use was associated with an increased risk of subsequent use of osteoporosis medication (adjusted sub-hazard ratio [SHR]=1.28; 95% confidence interval [CI]=1.13-1.44) and subsequent fracture (SHR=1.29, CI=1.08-1.55). Analysis with PPI categorized according to defined daily dose (DDD), showed some evidence for a dose-response effect (osteoporosis medication: <400 DDD: SHR=1.23, CI=1.06-1.42 and ≥400 DDD: SHR=1.39, CI=1.17-1.65, compared with non-users; SHRs were in the same range for fractures). Esomeprazole was the most common PPI prescribed (22.9%). Analysis by type of PPI use showed an increased subsequent risk for: (1) use of osteoporosis medication for rabeprazole (SHR=1.51, CI=1.08-2.10) and esomeprazole (SHR=1.48, CI=1.17-1.88); and (2) fractures for rabeprazole (SHR=2.06, CI=1.37-3.10). Users of multiple types of PPI also had increased risks for use of osteoporosis medication and fractures.
  
  
  CONCLUSIONS
  An appropriate benefit/risk assessment should be made when prescribing PPIs, especially for esomeprazole and rabeprazole, as osteoporosis and fracture risks were increased in this cohort of elderly females subsequent to PPI prescription.
authors: The University of Queensland, School of Public Health, Brisbane, QLD 4006, Australia; VU University Amsterdam, Faculty of Medicine, Amsterdam 1081 BT, Netherlands.
authors: Mariëlle M C
authors: MMC
authors: van der Hoorn
authors: The University of Queensland, School of Pharmacy, Brisbane, QLD 4072, Australia.
authors: Susan E
authors: SE
authors: Tett
authors: VU University Medical Center, Department of Internal Medicine, Amsterdam 1007 MB, Netherlands.
authors: Oscar J
authors: OJ
authors: de Vries
authors: The University of Queensland, School of Public Health, Brisbane, QLD 4006, Australia.
authors: Annette J
authors: AJ
authors: Dobson
authors: The University of Queensland, School of Public Health, Brisbane, QLD 4006, Australia; The University of Queensland, School of Human Movement and Nutrition Sciences, Brisbane, QLD 4072, Australia. Electronic address: g.peeters@uq.edu.au.
authors: G M E E Geeske
authors: GMEEG
authors: Peeters
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D015331:Cohort Studies; D064098:Esomeprazole / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D050723:Fractures, Bone / Q000139:chemically induced / Q000209:etiology*; D006801:Humans; D008137:Longitudinal Studies; D015663:Osteoporosis, Postmenopausal / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology*; D011446:Prospective Studies; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D064750:Rabeprazole / Q000008:administration & dosage / Q000009:adverse effects; D012307:Risk Factors
chemical_list: D050071:Bone Density Conservation Agents; D054328:Proton Pump Inhibitors; D064750:Rabeprazole; D064098:Esomeprazole
keywords: Esomeprazole; Fractures; Omeprazole; Osteoporosis medication; Proton pump inhibitors