This prospective study examined the relationships between acid-suppressive medication use and skeletal outcomes in two large cohorts, of men and of women, which had similar design and included community dwellers older than 65. After adjustment for potential confounding factors, use of PPIs in men was associated with mildly lower hip bone density. There was also a suggestion of increased bone loss in men and women who used PPIs but we did not observe statistically significant differences. Analysis of fracture outcomes showed that use of PPIs conferred a 34% increased risk of non-spine fracture in the cohort of women. Among men who were not taking calcium supplements, there was a 49% greater risk of non-spine fracture compared to those not taking PPIs. Men taking calcium supplements did not have an increased risk of non-spine fracture associated with PPI use.
Based on our non-spine fracture data in the SOF cohort, we estimated the PPI number-needed-to-harm (NNH) is such that one extra non-spine fracture would be expected for every 10 women treated for 5 years with a PPI. While this represents a small individual risk, the widespread use of these medications is such that the population attributable fraction is 3.6%. This means that 3.6% of non-spine fractures in women of this age group could potentially be attributed to use of PPIs. This attributable fraction may become significantly higher given the ever-widening popularity of these medications. Within the time frame of our study, use of acid-suppressive medications within our two cohorts increased by 50%, reflecting the general trend during this time of greater availability and popularity of the proton pump inhibitors in particular. In addition, individuals that initiate PPI treatment tend to remain on the medication for many years, if not the remainder of their lifespans.(2
Two case-control studies utilizing national health administrative databases have been reported on this topic. However, neither of the two previous studies examined bone density measurements or interaction with calcium intake. Vestergaard et. al. performed a Denmark study which found an 18% increase in any fracture and 45% increase in hip fracture for men and women who had used PPIs in the past year(12
). Yang et. al. completed a more recent study within the United Kingdom, which also demonstrated an increase in hip fracture risk among users of PPIs(13
). Increasing duration and dose of PPI therapy conferred higher risks of fracture. In addition, they found that the association between PPI use and fracture was more pronounced in men (OR 1.78, CI 1.42-2.22 in men; OR 1.36, CI 1.22-1.53 in women, p=0.04). By contrast, we did not see any effect of PPI use on hip fracture risk. The Denmark study was unable to control for several confounding factors such as BMI and physical activity. Removing these covariates from our fracture analysis did not change our estimates of fracture risk (data not shown). Therefore the reason for this discrepancy is not known, though it may be that our current study is underpowered to see a direct effect on hip fractures and we lack other information such as duration of medication usage to look for time-dependent effects. Nevertheless, the mild increase in overall non-spine fracture risk within the SOF cohort of women is qualitatively similar to these published population-wide case control studies. This is similar also to the observed non-spine fracture risk among the men not taking calcium supplements in the MrOS cohort.
Three independent studies now suggest that use of PPIs in vivo confers a mild increased risk of fractures. This is despite in vitro biochemical studies of PPIs that have suggested potential antiresorptive properties by functioning at osteoclast-specific proton pumps(28
). A possible mechanism to explain this increase in fracture risk may be via the decreased absorption of calcium in users of acid-suppressive medications. Achlorhydia is associated with decreased absorption of certain forms of calcium(30
). Several recent studies have demonstrated that hypochlorhydia due to short-term omeprazole use is also associated with impaired intestinal calcium absorption. In one study, participants who were administered a short course of omeprazole had decreased serum calcium and urinary calcium levels as compared to placebo(6
). Another recently reported short-term trial found that, compared to placebo, omeprazole use reduced the fractional absorption of calcium from 9.1% to 3.5%(7
). Therefore, it is conceivable that decreased calcium absorption is the mechanism by which PPIs increase fracture risk. If so, individuals with low baseline calcium intake would be at even higher risk for hypocalcemia with PPI use. Interestingly, our data does suggest that men with lower intake of calcium who used PPIs had heightened susceptibility to fractures, which is consistent with this hypothesis. Conversely, sufficient levels of calcium supplementation might mitigate the adverse skeletal effects of PPI use.
Whether H2RA use increases fracture risk is still unclear. Grisso et al. first reported an increased risk of fracture for cimetidine users(11
). The Denmark study found a dose dependent decrease in fracture risk with H2RAs(12
), while the UK study reported a dose dependent increase in fractures with H2RAs(13
). Our present analysis did not find a statistically significant effect upon fracture in men or women using H2RAs. Theoretically, H2RAs are less effective than PPIs at promoting an acidic gastric environment, and therefore would have less of a detrimental effect upon calcium absorption. Thus we would expect a weaker association with fracture rates, which may be hard to discern given the mild effect seen with the more potent PPIs. Further analysis is hampered by diminishing numbers of participants who are prescribed H2RAs in the face of the increasing popularity of PPIs.
Our study should be interpreted with the following limitations in mind. We are reporting the results of two separate cohorts and therefore direct comparisons between men and women are not possible. However, the design of MrOS was based upon the SOF study and therefore they share many similarities. Vertebral fracture data was unavailable and the number of non-spine fractures was limited. Thus we may not have had enough power to detect true effects of acid suppressive medications on fracture risk, especially for hip fractures.
Finally, a main limitation of our study lies in the assessment of acid-suppressive medication use, but all of the difficulties in assessment would have biased the results to the null. First of all, we only assessed use of medications in the 4 weeks prior to the clinic visits and thus we may have underestimated the number of actual users of acid-suppressive medications. In addition, nonprescription medications were not documented in MrOS during the baseline visit. We may be underestimating baseline use of H2RAs, but the first over-the-counter PPI was not FDA approved until a year after our baseline visit. We did collect nonprescription medication data on subsequent follow-up MrOS visits which was incorporated into the analysis. Regrettably, we have limited data on dose and duration of medication usage, but inclusion of short-term users in addition to chronic users would again bias our results to the null. Lastly, increasing numbers of participants were started on acid suppression during the study due to increasing indications and popularity. We attempted to adjust for this by analyzing the fracture outcomes in a time dependent manner, such that participants could switch medication categories during the follow-up visit, and subsequent fractures would be analyzed according to the new category.
In summary, we observed that PPI use is associated with mildly decreased bone density in men. These bone density differences were not seen in women and a statistically significant effect on rate of bone loss was not observed in either cohort. Nevertheless, we found that use of acid-suppressive medications is associated with a modest increase in non-spine fracture risk in women, and perhaps also in men with low calcium intake. Along with previously published studies, this data suggests that PPIs may have unintended negative skeletal effects, although they are likely minor on the individual level. Further studies are warranted to better elucidate the connection between acid-suppressive medications and skeletal outcomes.