For many older adults with a diagnosis of osteoporosis, oral bisphosphonate drugs are the first line of treatment. While these drugs are typically safe, there have been reports of serious adverse events. In this population-based nested cohort study, we identified subjects in a Canadian province with universal health care coverage, who were newly dispensed a bisphosphonate drug. Although we found a relatively low rate of UGIBs overall, only 0.4% of the exposure cohort developing this rare event, older patients (> 80 years) were significantly more often affected.
Using logistic regression techniques, we found that older age was an independent risk factor for developing an UGIB within 120 days post bisphosphonate treatment; this relationship remained after controlling for sex, history of gastric ulcer disease, history of serious UGIB, NSAID, and PPI use. Regardless of age, patients who were male, had a past history of gastric ulcer, a more remote UGIB history, and used a PPI, were more likely to suffer a UGIB post bisphosphonate use. Interestingly, patients who had been dispensed NSAIDs concurrently were less likely to develop a UGIB within 120 days of bisphosphonate use.
Age, sex, and risk of UGIB
The incidence of UGIB (within 120 days of incident bisphosphonate use) was much higher for older subjects; in fact, patients > 80 years of age developed an UGIB two times more often when compared to those ≤ 80 years. This finding is congruent with UGIB (from any cause) in the general population where advanced age has consistently been identified as a risk factor for the increased incidence of UGIB and related mortality . While we recognize that older adults have multiple factors influencing their risk of GI bleeding, UGIB is thought primarily to be related to increased co-morbidity and the use of multiple medications in the older age group . Although we were unable to control for total medication counts per patient in our study, we postulate that the increased co-morbidity in the older group corresponded to an increase in medication use which potentially contributed to greater UGIB risk. Additional factors identified by other researchers include inactivity and disability, both of which have been associated with a higher risk of GI bleeding in older adults [37, 48]. Others have attributed the increased incidence to the increased use of NSAIDS in older adults, who are at greater risk of GI toxicity from these agents, as well as a higher prevalence of Helicobacter pylori and gastroesophageal reflux disease [49, 50]. Peptic ulcer disease is not only strongly associated with Helicobacter pylori infection and more common in older adults but is also well known as the most common cause of UGIB . We found that gastric ulcer disease was a strong independent predictor of UGIB; specifically, those with a past history of gastric ulcer disease were 90% more likely to develop an UGIB (within 120 days of incident bisphosphonate use) than those with no history of the disease.
In our study, we were concerned primarily with bisphosphonate medications and their association with UGIB in an older population. Esophagitis and gastropathy, described as mucosal injury to the esophagus and stomach respectively, can be caused by drugs such as bisphosphonates that are known to cause local effects on both areas of the GI tract . Although overt UGIB is an uncommon manifestation of esophagitis or gastropathy, these lesions are implicated as bleeding sources more frequently in the older adult, especially those 80 years and older .
We found that regardless of age, males had an approximately 70% increased risk of hospitalization for UGIB than females. This is consistent with previous studies, who have found approximately a two-fold increase in the incidence of UGIB, from any cause, in males than in females; however, mortality rates are similar in both sexes [32, 52]. In our study this was not unexpected as the male group was also found to have significantly more co-morbid disease, notably cardiovascular disease, and were more likely to have a past medical history of gastric ulcer disease both of which are associated with an increased risk of UGIB.
NSAIDs, PPIs, and risk of UGIB
Many studies, of various designs, have focused on NSAID use in relation to UGIBs; for the most part, findings over the last 15 years suggest that current users of NSAIDS have at least a 3 to 5 fold increased risk of UGIB . Contrary to these results, in our study we found that a prescription for a NSAID was the strongest negative predictor of UGIB; those who had been dispensed NSAIDs were two and a half times less likely to suffer a UGIB within 120 days of incident bisphosphonate use. Because of the known GI side effects associated with NSAID use, we initially speculated that perhaps patients, who were prescribed a NSAID, were healthier patients with fewer co-morbid conditions, thus less likely to develop a UGIB. We found that those with greater co-morbidities were significantly more likely to be dispensed a NSAID drug; therefore, the notion that those prescribed a NSAID were healthier did not stand. We did find an inverse relationship between NSAID use and past history of gastric ulcer disease; those with a gastric ulcer were less likely to have been dispensed a NSAID. For that reason, we postulated that the “protective” effect of NSAIDs may stem from their use in patients who do not have a history of gastric ulcer thus making users of NSAIDs perhaps less likely to develop a UGIB. The clinical significance of this finding, however, is unclear and caution in the interpretation of this finding is thus warranted.
We also found that those patients who had been dispensed a PPI medication were two times as likely to develop a UGIB post incident bisphosphonate use. As we used the prescription of a PPI as a proxy for the presence of GI disease, this finding was expected. Those who were at an increased risk, or who have already developed GI disease, are often prescribed drug therapy with either a histamine-2 (H2)–receptor antagonist (typically available as over the counter medications) or a PPI in order to provide mucosal protection . In other words, those patients using a bisphosphonate and a PPI likely had a greater underlying risk of an adverse GI event compared to those persons using a bisphosphonate alone; this would account for the observed increase in UGIB risk for concurrent users of the drugs . This was confirmed during post hoc analysis where we found significant positive relationship between PPI use and both a past history of gastric ulcer disease and past serious UGIB.
Comparison to previous research
Although a number of randomized controlled trials (RCTs) have reported higher rates of upper GI tract minor irritations in treatment groups (although not reaching statistical significance), there have been no reports of more serious upper GI tract adverse events such as UGIB [55–57]. RCTs typically follow a smaller group of highly selected individuals for a relatively short period of time and are designed primarily to investigate the fracture prevention efficacy of bisphosphonates. Unfortunately, there are few previous population based studies investigating the risk of UGIB associated with bisphosphonate drugs to compare our study results to [18–21].
This study, as with other studies based solely on administrative data, has some limitations that must be recognized. First, bisphosphonates are not only prescribed for the prevention and treatment of osteoporosis, but also for the treatment of certain malignancies and related malignancy complications as well as other serious conditions such as Paget’s disease of the bone. As we exclusively examined oral bisphosphonate preparations, we can be fairly certain that these drugs were not used to treat a malignancy or related complication such as hypercalcemia as these conditions are primarily treated with intravenous bisphosphonate infusions. Furthermore, a diagnosis of Paget’s disease is relatively rare (in comparison to a diagnosis of osteoporosis); moreover, we were interested in adverse events associated with new bisphosphonate use and as we controlled for co-morbidity, we did not think the primary therapeutic use of the drug would have changed the results of our study.
Second, the exposure cohort was compiled based on dispensation of bisphosphonate drugs and may not be an accurate reflection of actual drug consumption rates; therefore, we may have overestimated the use of bisphosphonates and perhaps have then underestimated UGIBs related to the new use of the drug (non-differential misclassification). This type of misclassification of exposure would bias the effect measure toward an apparent null effect. Third, due to the claims-based nature of the dataset, information related to other potentially confounding variables could not be assessed or controlled for. For example, we lacked data on other factors known to be related to UGIBs such as smoking and alcohol consumption, the use of over the counter medications such as NSAIDs (i.e. ibuprofen) and ASA, and the presence of un-diagnosed helicobacter pylori infections [32, 58]. Although the inclusion of these variables may have provided a more inclusive description of potential UGIB predictors, we do not believe that controlling for these variables would have altered the results of this study.
Thirdly, we based the outcome diagnosis of UGIB exclusively on discharge abstract coding and have no way of knowing if endoscopy was done and if done, where in fact the GI bleeding originated from (esophagus vs. stomach). We attempted to overcome this limitation by only including those patients who were diagnosed with a “serious” bleed; therefore, we are confident that diagnoses were confirmed in the clinical setting by endoscopy.
Lastly, we would be remiss if we did not acknowledge that the relationship between bisphosphonates and UGIBs may also be complicated by the known fact of an already increased prevalence of GI tract symptoms among older adults . In our study, we did not find differences in co-morbidity between those who developed a UGIB and those who did not. We did find that those who developed a UGIB were more likely to both have a concurrent past diagnosis of gastric ulcer disease as well as a remote history of UGIB. Taken together, this may have accounted for some of the decrease in observed risk in the group who did not develop a UGIB - even after controlling for these variables as confounders.
The strengths of this study include its population-based design, a large sample size, and its use of detailed data made possible by the use of a comprehensive linkable dataset including clinical and prescription drug information of most residents in the province. To our knowledge, this is one of the first comprehensive, population based studies of UGIB incidence associated with new oral bisphosphonate use. We used a strict case definition of UGIB, which has been previously validated; this strategy for identifying cases of UGIB (a rare event) was broad, reducing the likelihood that cases were missed . In addition, our study used a co-morbidity index that had been previously validated with the population and used sophisticated statistical analysis to control for potentially confounding variables. Given the longitudinal nature of the data, it was also possible to examine drug use as both an exposure (bisphosphonate) and an end-point (UGIB) thereby having the advantage of enough accumulated person-time of bisphosphonate exposure for detection of more rare GI associated adverse events. Taken together, these factors ought to contribute to a reliable estimate of the ORs for UGIBs within 120 days of incident bisphosphonate use.