Oral Bisphosphonates and the Risk of Barrett's Esophagus
Oral Bisphosphonates and the Risk of Barrett's Esophagus
In this large, single-center, case–control study, mostly of male veterans, we found a significant association between previous or current use of oral bisphosphonates and the presence of BE. The use of oral bisphosphonates was associated with a greater than twofold increase in risk of BE than in control patients after adjustment for sex, age, race, PPI use, hiatal hernia, waist-to-hip ratio, H. pylori infection, and GERD symptoms. The association between oral bisphosphonates and BE was seen only among patients with frequent GERD symptoms, PPI use, or both.
BE is thought to develop from an inflammatory process caused by chronic gastroesophageal reflux contents leading to mucosal injury and DNA damage. Mediators of inflammation such as nuclear factor-κB have been linked to the induction of CDX genes that play an important role in the initiation of BE. Similarly, evidence suggests that bisphosphonate users develop esophagitis, esophageal erosions, and esophageal ulcers through direct topical injury, as esophageal biopsies have revealed foreign material consistent with the appearance of alendronate tablets. It is plausible that, through a common inflammatory process, oral bisphosphonates could be associated with BE.
The mechanisms underlying the association between BE and bisphosphonates are unknown. The nitrogen-containing bisphosphonates including alendronate and risedronate, which were used by subjects in this study, act by inhibiting the mevalonate pathway through farnesyl diphosphate synthase. The in vitro models of human epidermal keratinocytes exposed to alendronate or risedronate revealed suppression of epithelial cell growth via inhibition of farnesyl diphosphate synthase in the mevalonate to cholesterol pathway; the resulting reduction in cholesterol synthesis and geranylgeranylation suppresses cell growth by interfering with progression through the cell cycle. The inhibition of esophageal epithelial stem cells could potentiate the damage of gastroesophageal reflux and lead to inactivation of squamous differentiation and activation of columnar differentiation.
We observed that the association between bisphosphonate use and BE was modified by the presence of GERD symptoms, PPI use, and NSAID use. These factors could facilitate or inhibit the way oral bisphosphonates affect BE development. For example, there could be a potentiating effect for GERD, which is the most common risk factor for BE. PPIs are the primary antisecretory treatment for patients with GERD-related syndromes, and therefore they could a marker of GERD. NSAIDs have been studied in observational studies for a potentially protective effect against BE.
Bisphosphonates have come under the scrutiny of the FDA Advisory Committee for Reproductive Health Drugs and Drug Safety and Risk Management Committee in response to postmarketing reports of rare but serious adverse events, including esophageal cancer. A total of 34 cases were submitted to the FDA Adverse Event Reporting System of esophageal cancer of unspecified histological type in bisphosphonate users during 1998–2009. Histological analysis showed adenocarcinoma in 7 patients and squamous cell carcinoma in 1 patient. An additional 34 cases of esophageal cancer among bisphosphonate users were also reported from Europe and Japan. Histological analysis showed adenocarcinoma in six patients and squamous cell carcinoma in five patients. One patient from the United States and three patients from Europe and Japan concomitantly carried a diagnosis of BE. All cases reported in the United States and most cases in Europe and Japan involved alendronate as the suspect bisphosphonate. The bisphosphonate use in our study was predominantly alendronate (89%) rather than risedronate (11%). Animal models have shown that risedronate, a pyridinyl bisphosphonate, induces less gastric damage compared with the primary amino bisphosphonates including pamidronates.
Subsequently, population-based studies conducted in the United Kingdom, Denmark, and Taiwan have arrived at conflicting results regarding the use of bisphosphonates and esophageal cancer. Green et al. showed an increased risk between oral bisphosphonates and esophageal cancer, whereas the other three studies concluded that oral bisphosphonates were not likely risk factors for esophageal cancer. Only one study by Cardwell et al., conducted among 46,036 bisphosphonate users, reported on prior BE diagnosis, but rates of BE were low, accounting for 0.5% of the study participants, with only 1 patient developing cancer.
It is unknown how bisphosphonate use influences adenocarcinoma risk in BE. A recent study conducted of a national VA cohort of patients with BE found that oral bisphosphonates were not associated with an increased risk of esophageal adenocarcinoma, but this study was limited by only 2 cases (of 116 total cases) being exposed to oral bisphosphonates. This is further complicated by growing evidence that bisphosphonates demonstrate antitumor activity through inhibition of the mevalonate pathway that has been implicated in various aspects of tumor development and progression.
The strengths of our study include a large sample size and the accurate endoscopic and histologic definition of cases and controls. All patients completed a comprehensive survey before the EGD to capture several potential confounders. Oral bisphosphonate use was ascertained by filled prescriptions in the electronic pharmacy records and supplemented by self-report information in all cases and controls. Exposure to the medication was based on prescriptions that were actually filled. Finally, corroborating the known associations between BE and older age, male sex, white race, GERD symptoms, and waist-to-hip ratio confers internal validity to the new observation related to bisphosphonates.
However, our study has several limitations. It was conducted at a single-center VA medical center, where patients are likely to be older men, which may limit the generalizability of the results. Patients who were enrolled in this study may have received bisphosphonates from non-VA pharmacies, although studies have shown that veterans who use the VA healthcare system tend to disproportionately or exclusively use VA pharmacy services. There are no data as to whether oral bisphosphonates were taken according to directions, which require patients to remain upright for at least 30 min after ingestion, or as to the actual ingestion of medications, given that compliance with oral bisphosphonates is already known to be suboptimal. Of the 54 patients with a filled bisphosphonate prescription, only 6 reported taking alendronate on the self-reported survey. This could indicate a high percentage of noncompliance, although we believe that using the electronic pharmacy data for filled (dispensed) prescription is a more accurate and complete method for ascertaining medications use than self-report. Polypharmacy, which is quiet high among older veteran patients, likely contributed to the inaccuracy of self-report information in this study. Although we conducted a survey with an extensive questionnaire to document potential confounders, we cannot rule out other residual confounding from unmeasured or poorly measured variables. For example, the BE cases in this study were more likely than controls to have a long history of GERD symptoms. Oral bisphosphonate use may have worsened existing symptoms, leading to presentation to a physician and subsequent recruitment for a research endoscopy and the possible introduction of a selection bias.
In conclusion, among 285 veterans with denitive BE and 1,618 controls, we found a significant association between oral bisphosphonate use and an increased risk of BE, especially among patients with GERD symptoms, those on PPI treatment, or those not taking NSAIDs. This is the first published study on this association. Additional studies are needed to further examine this association, as it could suggest an increased risk of esophageal cancer in oral bisphosphonate users.
Discussion
In this large, single-center, case–control study, mostly of male veterans, we found a significant association between previous or current use of oral bisphosphonates and the presence of BE. The use of oral bisphosphonates was associated with a greater than twofold increase in risk of BE than in control patients after adjustment for sex, age, race, PPI use, hiatal hernia, waist-to-hip ratio, H. pylori infection, and GERD symptoms. The association between oral bisphosphonates and BE was seen only among patients with frequent GERD symptoms, PPI use, or both.
BE is thought to develop from an inflammatory process caused by chronic gastroesophageal reflux contents leading to mucosal injury and DNA damage. Mediators of inflammation such as nuclear factor-κB have been linked to the induction of CDX genes that play an important role in the initiation of BE. Similarly, evidence suggests that bisphosphonate users develop esophagitis, esophageal erosions, and esophageal ulcers through direct topical injury, as esophageal biopsies have revealed foreign material consistent with the appearance of alendronate tablets. It is plausible that, through a common inflammatory process, oral bisphosphonates could be associated with BE.
The mechanisms underlying the association between BE and bisphosphonates are unknown. The nitrogen-containing bisphosphonates including alendronate and risedronate, which were used by subjects in this study, act by inhibiting the mevalonate pathway through farnesyl diphosphate synthase. The in vitro models of human epidermal keratinocytes exposed to alendronate or risedronate revealed suppression of epithelial cell growth via inhibition of farnesyl diphosphate synthase in the mevalonate to cholesterol pathway; the resulting reduction in cholesterol synthesis and geranylgeranylation suppresses cell growth by interfering with progression through the cell cycle. The inhibition of esophageal epithelial stem cells could potentiate the damage of gastroesophageal reflux and lead to inactivation of squamous differentiation and activation of columnar differentiation.
We observed that the association between bisphosphonate use and BE was modified by the presence of GERD symptoms, PPI use, and NSAID use. These factors could facilitate or inhibit the way oral bisphosphonates affect BE development. For example, there could be a potentiating effect for GERD, which is the most common risk factor for BE. PPIs are the primary antisecretory treatment for patients with GERD-related syndromes, and therefore they could a marker of GERD. NSAIDs have been studied in observational studies for a potentially protective effect against BE.
Bisphosphonates have come under the scrutiny of the FDA Advisory Committee for Reproductive Health Drugs and Drug Safety and Risk Management Committee in response to postmarketing reports of rare but serious adverse events, including esophageal cancer. A total of 34 cases were submitted to the FDA Adverse Event Reporting System of esophageal cancer of unspecified histological type in bisphosphonate users during 1998–2009. Histological analysis showed adenocarcinoma in 7 patients and squamous cell carcinoma in 1 patient. An additional 34 cases of esophageal cancer among bisphosphonate users were also reported from Europe and Japan. Histological analysis showed adenocarcinoma in six patients and squamous cell carcinoma in five patients. One patient from the United States and three patients from Europe and Japan concomitantly carried a diagnosis of BE. All cases reported in the United States and most cases in Europe and Japan involved alendronate as the suspect bisphosphonate. The bisphosphonate use in our study was predominantly alendronate (89%) rather than risedronate (11%). Animal models have shown that risedronate, a pyridinyl bisphosphonate, induces less gastric damage compared with the primary amino bisphosphonates including pamidronates.
Subsequently, population-based studies conducted in the United Kingdom, Denmark, and Taiwan have arrived at conflicting results regarding the use of bisphosphonates and esophageal cancer. Green et al. showed an increased risk between oral bisphosphonates and esophageal cancer, whereas the other three studies concluded that oral bisphosphonates were not likely risk factors for esophageal cancer. Only one study by Cardwell et al., conducted among 46,036 bisphosphonate users, reported on prior BE diagnosis, but rates of BE were low, accounting for 0.5% of the study participants, with only 1 patient developing cancer.
It is unknown how bisphosphonate use influences adenocarcinoma risk in BE. A recent study conducted of a national VA cohort of patients with BE found that oral bisphosphonates were not associated with an increased risk of esophageal adenocarcinoma, but this study was limited by only 2 cases (of 116 total cases) being exposed to oral bisphosphonates. This is further complicated by growing evidence that bisphosphonates demonstrate antitumor activity through inhibition of the mevalonate pathway that has been implicated in various aspects of tumor development and progression.
The strengths of our study include a large sample size and the accurate endoscopic and histologic definition of cases and controls. All patients completed a comprehensive survey before the EGD to capture several potential confounders. Oral bisphosphonate use was ascertained by filled prescriptions in the electronic pharmacy records and supplemented by self-report information in all cases and controls. Exposure to the medication was based on prescriptions that were actually filled. Finally, corroborating the known associations between BE and older age, male sex, white race, GERD symptoms, and waist-to-hip ratio confers internal validity to the new observation related to bisphosphonates.
However, our study has several limitations. It was conducted at a single-center VA medical center, where patients are likely to be older men, which may limit the generalizability of the results. Patients who were enrolled in this study may have received bisphosphonates from non-VA pharmacies, although studies have shown that veterans who use the VA healthcare system tend to disproportionately or exclusively use VA pharmacy services. There are no data as to whether oral bisphosphonates were taken according to directions, which require patients to remain upright for at least 30 min after ingestion, or as to the actual ingestion of medications, given that compliance with oral bisphosphonates is already known to be suboptimal. Of the 54 patients with a filled bisphosphonate prescription, only 6 reported taking alendronate on the self-reported survey. This could indicate a high percentage of noncompliance, although we believe that using the electronic pharmacy data for filled (dispensed) prescription is a more accurate and complete method for ascertaining medications use than self-report. Polypharmacy, which is quiet high among older veteran patients, likely contributed to the inaccuracy of self-report information in this study. Although we conducted a survey with an extensive questionnaire to document potential confounders, we cannot rule out other residual confounding from unmeasured or poorly measured variables. For example, the BE cases in this study were more likely than controls to have a long history of GERD symptoms. Oral bisphosphonate use may have worsened existing symptoms, leading to presentation to a physician and subsequent recruitment for a research endoscopy and the possible introduction of a selection bias.
In conclusion, among 285 veterans with denitive BE and 1,618 controls, we found a significant association between oral bisphosphonate use and an increased risk of BE, especially among patients with GERD symptoms, those on PPI treatment, or those not taking NSAIDs. This is the first published study on this association. Additional studies are needed to further examine this association, as it could suggest an increased risk of esophageal cancer in oral bisphosphonate users.
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