Proton Pump Inhibitor Use, H 2-Receptor Antagonist Use, and Risk of Incident Clinical Vertebral Fracture in Women

Calcif Tissue Int. 2018 Oct;103(4):380-387. doi: 10.1007/s00223-018-0432-2. Epub 2018 May 12.


The few prospective studies examining the relation between proton pump inhibitor (PPI) use and risk of vertebral fracture (VF) suggest a higher risk, but the magnitude of the association has been inconsistent. Moreover, no prospective studies have examined the association between substantially longer duration of PPI use and VF risk. Our objective was to determine the association between PPI use, H2RA use, and incident clinical VF in women. We conducted a prospective study in 55,545 women participating in the Nurses' Health Study. PPI and H2RA use was assessed by questionnaire every 4 years. Self-reports of VF were confirmed by medical record. Our analysis included 547 incident VF cases (2002-2014). The multivariate adjusted relative risk (MVRR) of VF for women taking PPIs was 1.29 (95% CI 1.04-1.59) compared with non-users. Longer duration of PPI use was associated with higher VF risk (MVRR 1.16 [0.90-1.49] for < 4 years; 1.27 [0.93-1.73] for 4-7.9 years; 1.64 [1.02-2.64] for ≥ 8 years; ptrend = 0.01). The MVRR of VF for women taking H2RAs was 1.22 (0.90-1.67) compared with non-users. Longer duration of H2RA use was not associated with VF risk (MVRR 1.16 [0.88-1.53] for < 4 years; 0.98 [0.60-1.59] for ≥ 4 years; ptrend = 0.72). PPI use is independently associated with a modestly higher risk of VF and the risk increases with longer duration of use. There was no statistically significant association between H2RA use and VF risk. Our findings add to the growing evidence suggesting caution with PPI use, particularly with longer duration of use.

Keywords: H2-receptor antagonist; Nurses’ health study; Prospective study; Proton pump inhibitor; Vertebral fracture.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Cohort Studies
  • Female
  • Histamine H2 Antagonists / adverse effects*
  • Humans
  • Incidence
  • Middle Aged
  • Prospective Studies
  • Proton Pump Inhibitors / adverse effects*
  • Risk Factors
  • Spinal Fractures / epidemiology*
  • Surveys and Questionnaires


  • Histamine H2 Antagonists
  • Proton Pump Inhibitors