According to research published early online in the British Medical Journal (BMJ), regular use of proton pump inhibitors (PPIs) may be associated with an increased risk of hip fracture among postmenopausal women; this risk appears to increase with duration of use, and may be more pronounced in those with a history of smoking.

The authors note that concern has grown over the potential association between long-term use of PPIs and bone fractures.  It is thought that these medicines may inhibit calcium absorption, directly interfere with osteoclast function or induce hypergastrinaemia, resulting in reductions in bone mineral density (BMD) related to hyperparathyroidism.  Although previous research into this possible association has been conducted, the studies have had important limitations, including a retrospective design, lack of control for important confounders, and lack of information on duration of PPI use.

The purpose of the current study was to examine the association between PPI use and risk of hip fracture among postmenopausal women using data from the US prospective Nurses’ Health Study – this collects detailed information on dietary and lifestyle factors and therefore permitted analysis in the context of potential confounders.  The study included 79,899 postmenopausal women who had provided data on the use of PPIs and other risk factors every two years since 2000, with no history of cancer or hip fracture previously reported, and who were followed up to June 2008.  Participants were not questioned regarding the specific PPI or the dose used.    
 

The main outcome measure was incident hip fracture.  The following findings are reported:

• A total of 893 hip fractures were reported during 565,786 person years of follow-up.

• The absolute risk of hip fracture was 2.02 events per 1000 person years for regular users of PPIs and 1.51 events per 1000 person years among non-users (fully adjusted multivariate hazard ratio (HR) 1.36; 1.13 to 1.63).

• The risk of hip fracture associated with PPI use increased with the duration of use (P trend <0.01). Consistent use (reported PPI use in two consecutive biennial follow-up questionnaires) was associated with a fully adjusted HR of fracture of 1.42 (1.06 to 1.88), compared to non-use for two consecutive intervals.

• Compared with PPI use, regular use of H2 blockers was associated with a more modest risk of fracture compared to non-use (fully adjusted HR 1.23; 1.02 to 1.50).

• Women who had stopped PPI use more than two years previously had a fully adjusted HR of fracture of 1.10 (0.63 to 1.92), similar to that of women who had never used a PPI.

• The relation between PPI use and fracture differed by smoking history (P interaction = 0.03).  PPI use was associated with a >50% increase in risk of fracture among current and former smokers (multivariate HR 1.51; 95% CI 1.20 to 1.91), whereas there was no association in women who never smoked (multivariate HR 1.06; 0.77 to 1.46).

• A meta-analysis of these results with 10 prior studies found a pooled odds ratio of hip fracture associated with PPI use of 1.30 (1.25 to 1.36).

The authors acknowledge several limitations to their study, including its observational nature, the lack of information on PPI use prior to 2000, a lack of specific information on specific PPI used or the dose, reliance on self-reported history of fracture, and a lack of information on bone mineral density.  They comment however that their results are reasonable in magnitude, in line with previous findings, and biologically plausible. 

They conclude that their results, “considered in the context of a systematic review of prior studies, provide compelling evidence of a significant association between PPI use and fracture. Furthermore, in view of the steadily growing prevalence of regular PPI use, our estimates of an absolute increase in risk of five hip fractures per 10,000 person years associated with PPI use suggest the potential for a high burden of fractures attributable to PPIs across the population.”  They say that the need for long-term use of PPIs, especially among smokers, should be carefully evaluated. 

The Royal Pharmaceutical Society spokesperson on gastroenterology medicines has issued a response to these findings – please see the link below for details.