We found that use of proton pump inhibitors increased the risk of hip fracture after 5 or more years of continuous exposure. The risk of any osteoporotic fracture was increased after at least 7 years of continuous exposure to proton pump inhibitors. Patients with less than 6 years of continuous exposure were not at significantly increased risk of an osteoporosis-related fracture compared to controls, and they were not at increased risk of hip fracture with 4 or fewer years exposure. Although many of our odds ratios were between 1 and 2, which suggests a modest increase in the relative odds of a fracture, osteoporotic fractures are common occurrences associated with substantial morbidity and mortality, particularly with increasing age. Therefore, relatively small increases in the relative risk of a fracture may have pertinent effects on the absolute risk of events and their associated costs to the individual and society. The calculated odds ratios for exposure to proton pump inhibitors are also similar in size to those for other established osteoporotic-fracture risk factors, such as smoking, low body mass index and excessive alcohol intake.20
Our findings are consistent with those in a recent study by Yang and colleagues.15
They reported that patients with hip fractures were 1.21 times more likely than matched controls to have been prescribed a proton pump inhibitor for more than 1 year and 1.59 times more likely to have used a proton pump inhibitor for 4 or more years. Patients with hip fractures were also 2.65 times more likely than controls to have used proton pump inhibitors at doses more than 1.75 times the standard dose.15
Although we did not find a significant increase in hip fractures or overall osteoporosis-related fractures among patients with less than 5 or 7 years, respectively, of continuous proton pump inhibitor exposure, our long-term results are consistent with these data.
In contrast to the study by Yang and colleagues,15
we only found an increase in the overall risk of fracture among patients who had 7 or more years of exposure to proton pump inhibitors, and an increase in the risk of hip fracture with 5 or more years of exposure. This is not surprising because bone mineralization and resorption takes place over many years, and the effect of a drug that has a subtle effect on bone mineralization may require several years of exposure before it has a measurable effect on clinical outcomes. It is possible that the finding of a significantly increased risk of fracture among patients with 1 or more years exposure by Yang and colleagues may have been because this cohort included many patients who had been using proton pump inhibitors for up to 15 years. Therefore, if a significant proportion of patients in their study cohort had extended exposure to proton pump inhibitors, those patients may have been responsible for a disproportionate share of the fracture burden. However, the study by Yang and colleagues15
does not comment on the distribution of the duration of exposure to proton pump inhibitors within the cohort with 1 or more years of exposure.
The mechanism by which extended use of proton pump inhibitors increases the risk of fracture is unknown; however, it is most likely due to the acid-inhibiting effects of proton pump inhibitors accelerating the rate of bone mineral loss. This is consistent with proton pump inhibitor exposure being more strongly associated with hip fracture than with the combined outcomes of hip, spine and wrist fractures because low bone mineral density is much more strongly associated with hip fracture than with the combined outcomes of hip, spine and wrist fractures.19
Although the precise effect of acid inhibition on bone mineral density over time is uncharacterized, there are several physiologic mechanisms by which use of proton pump inhibitors could affect bone mineral metabolism. First, the ability of the small intestine to absorb ingested calcium salts is dependent on solubility, and the solubility of calcium salts is pH dependent.21
Calcium carbonate, which is the most common calcium salt found in dietary supplements, is relatively insoluble at high pH levels, which could potentially hinder its absorption.22
Conversely, in vitro, proton pump inhibitors inhibit bone resorption, and in vivo, proton pump inhibitors decrease urinary excretion of calcium, likely because of inhibition of vacuolar H+
/ATPases found on osteoclast cell membranes.23
Therefore, further research is required to determine the precise effect of long-term use of proton pump inhibitors on bone mineral metabolism.
Our study suggests that the risk of osteoporosis-related fracture increases with the duration of exposure to proton pump inhibitors. This has specific implications for patients with long-term exposure. Because many of the common indications for proton pump inhibitor therapy are not self-limiting,24
a substantial portion of proton pump inhibitor use is of indefinite duration. Furthermore, use has been increasing in recent years, likely because of a number of factors, including increasing affordability with the emergence of generic and over-the-counter formulations, and an increasing reluctance to give cyclooxygenase-2 inhibitors as a gastroprotective strategy for people taking nonsteroidal anti-inflammatory drugs.25
These factors may promote the long-term use of proton pump inhibitors, leaving patients at increased risk of osteoporosis-related fractures. Conversely, there is evidence that these medications are frequently given to patients with no obvious indication,26,27
and other studies have suggested that many long-term proton pump inhibitor users can be stepped-down to less intensive therapies without recurrence of symptoms.28,29
Because evidence also suggests that use of proton pump inhibitors may be associated with an increased risk of enteric infections such as Clostridium difficile
and community acquired pneumonia,30,31
clinicians must be increasingly vigilant in ensuring that proton pump inhibitors are used sparingly and only when absolutely indicated. However, there will remain a subset of patients for whom continuation of long-term therapy is necessary because of an underlying high-risk of gastrointestinal bleeding, recalcitrant symptoms or complications of gastroesophageal reflux disease, including peptic strictures and erosive esophagitis. Further study is required to determine whether there are pharmacologic strategies, including the use of calcium supplementation, bisphosphonates or estrogen analogues, that can mitigate the risk of fracture.32,33,34
Our study has some limitations that deserve further discussion. First, owing to the lack of anthropomorphic data and information about the use of over-the-counter calcium supplements, vitamin D supplements, tobacco and alcohol in our data set, we were unable to control for the possible confounding effects of these factors. We were also unable to determine whether increased fracture risk from proton pump inhibitors is related to reduced bone density or increased risk for falls; however, to our knowledge, there is no evidence that proton pump inhibitors increase falls. Second, as with any observational study, there may be unrecognized differences between cases and controls that can confound the results. Finally, fractures that do not lead to a physician interaction (which includes many vertebral fractures) cannot be identified. However, given the comprehensiveness of the Population Health Research Data Repository and its previous use for determining risk factors for osteoporotic fractures, we are confident that it is unlikely that these limitations had a profound effect on our results.
In conclusion, we detected an association between long-term (≥ 7 years) exposure to proton pump inhibitors and osteoporosis-related fractures. We also found an association between hip fractures and 5 or more years exposure to proton pump inhibitors. However, short-term use did not appear to increase fracture risk. Further study is required to examine the effect of acid inhibition on calcium absorption and bone mineral metabolism, specifically to determine the effect of acid inhibition on bone mineral density over time. As well, further research is needed to examine the role of osteoprotective medications for patients who require long-term proton pump inhibitor therapy. Lastly, as with any medication, we recommend that proton pump inhibitors be used only in clinical situations where they are necessary and in which they have been proven to be efficacious.
@@ See related commentary by Richards and Goltzman, page 306