{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:50:42Z","timestamp":1792601442075,"version":"4.5.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T00:00:00Z","timestamp":1730937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>This study analyzed the FDA\u2019s Adverse Event Reporting System (FAERS) data to investigate the correlation between oral bisphosphonates (BPs) and oesophageal adverse events (AEs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We systematically extracted data on adverse reactions to oral alendronate, risedronate, and ibandronate from the FAERS database, covering the period from the 2004 Q1 to the 2023 Q4. The role_code of AEs mainly includes primary suspect (PS), secondary suspect (SS), concomitant (C), and interaction (I). This study targeted reports with a role_code of \u201cPS.\u201d According to the FDA deduplication rule, the latest FDA_DT is selected when the CASEID is the same, and the higher PRIMARYID is selected when the CASEID and FDA_DT are the same. Our analysis leveraged four statistical methods, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS), to assess the relationship between oral bisphosphonates and oesophageal AEs. The Kaplan-Meier method was utilized to evaluate the cumulative incidence of oesophageal toxicity, while the log-rank test examined the temporal onset profiles of these toxicities. Additionally, the Pearson chi-squared test was employed to identify any significant differences in mortality and hospitalization rates associated with the oesophageal AEs caused by these medications.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The FAERS database had 41,590 AE reports for oral BPs, with 3,497 (8.41%) related to oesophageal AEs. Our findings indicate that oral BPs are disproportionately associated with an increased incidence of gastrointestinal system AEs at the system organ class (SOC) level. The adverse events identified at the preferred terms (PTs) level encompassed conditions such as gastroesophageal reflux disease, oesophagitis, and oesophageal pain. A significant divergence in the cumulative incidence of oesophageal AEs was observed among patients treated with the three different oral bisphosphonates, as confirmed by the log-rank test (<jats:italic>p<\/jats:italic> &amp;lt; 0.0001). Hospitalization rates varied significantly among patients receiving different BPs (<jats:italic>p<\/jats:italic> &amp;lt; 0.05), but no significant difference in mortality rates was found.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The study establishes a significant link between oral BPs and oesophageal toxicity, highlighting the need for further research into the mechanisms of BP-induced oesophageal toxicity and potential preventive measures.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1473756","type":"journal-article","created":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T04:43:25Z","timestamp":1730954605000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Disproportionality analysis of oesophageal toxicity associated with oral bisphosphonates using the FAERS database (2004\u20132023)"],"prefix":"10.3389","volume":"15","author":[{"given":"Lin","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhicheng","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huangrong","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiafeng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuo","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,11,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"906","DOI":"10.3748\/wjg.v22.i3.906","article-title":"Bisphosphonates as potential adjuvants for patients with cancers of the digestive system","volume":"22","author":"Ang","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1007\/s11914-017-0401-0","article-title":"Long-Term bisphosphonate therapy in osteogenesis imperfecta","volume":"15","author":"Biggin","year":"2017","journal-title":"Curr. Osteoporos. Rep."},{"key":"B3","doi-asserted-by":"publisher","first-page":"25","DOI":"10.5455\/medarh.2017.71.25-28","article-title":"Risk factors for osteoporosis in postmenopausal women","volume":"71","author":"Bijelic","year":"2017","journal-title":"Med. Arch."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1399","DOI":"10.1093\/annonc\/mdg367","article-title":"Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases","volume":"14","author":"Body","year":"2003","journal-title":"Ann. Oncol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1001\/jama.2010.1098","article-title":"Exposure to oral bisphosphonates and risk of esophageal cancer","volume":"304","author":"Cardwell","year":"2010","journal-title":"Jama"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1676","DOI":"10.1056\/NEJM200310233491721","article-title":"Renal failure with the use of zoledronic acid","volume":"349","author":"Chang","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"115784","DOI":"10.1016\/j.bone.2020.115784","article-title":"Bisphosphonates for the treatment of fibrous dysplasia of bone","volume":"143","author":"Chapurlat","year":"2021","journal-title":"Bone"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2306","DOI":"10.1111\/j.1572-0241.2001.04034.x","article-title":"Effect of hyoscine N-butylbromide on gastroesophageal reflux in normal subjects and patients with gastroesophageal reflux disease","volume":"96","author":"Ciccaglione","year":"2001","journal-title":"Am. J. Gastroenterol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"115570","DOI":"10.1016\/j.bone.2020.115570","article-title":"Bisphosphonates and breast cancer - from cautious palliation to saving lives","volume":"140","author":"Coleman","year":"2020","journal-title":"Bone"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.4065\/77.10.1031","article-title":"Oral bisphosphonates and upper gastrointestinal tract problems: what is the evidence?","volume":"77","author":"Cryer","year":"2002","journal-title":"Mayo Clin. Proc."},{"key":"B11","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1097\/00045391-199605000-00009","article-title":"Calcium Channel blockers and the gastrointestinal tract","volume":"3","author":"Findling","year":"1996","journal-title":"Am. J. Ther."},{"key":"B12","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1007\/s40264-023-01345-w","article-title":"Challenges and opportunities in accessing and analysing FAERS data: a call towards a collaborative approach","volume":"46","author":"Giunchi","year":"2023","journal-title":"Drug Saf."},{"key":"B13","doi-asserted-by":"publisher","first-page":"c4444","DOI":"10.1136\/bmj.c4444","article-title":"Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort","volume":"341","author":"Green","year":"2010","journal-title":"Bmj"},{"key":"B14","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/1471-2474-11-68","article-title":"Adverse events, bone mineral density and discontinuation associated with generic alendronate among postmenopausal women previously tolerant of brand alendronate: a retrospective cohort study","volume":"11","author":"Grima","year":"2010","journal-title":"BMC Musculoskelet. Disord."},{"key":"B15","doi-asserted-by":"publisher","first-page":"821","DOI":"10.18433\/j3vw2f","article-title":"Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications","volume":"16","author":"Harirforoosh","year":"2013","journal-title":"J. Pharm. Pharm. Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"106601","DOI":"10.1016\/j.intimp.2020.106601","article-title":"Colitis following the use of immune checkpoint inhibitors: a real-world analysis of spontaneous reports submitted to the FDA adverse event reporting system","volume":"84","author":"Hu","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1177\/2168479013514236","article-title":"A review of statistical methods for safety surveillance","volume":"48","author":"Huang","year":"2014","journal-title":"Ther. Innov. Regul. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"836357","DOI":"10.3389\/fpubh.2022.836357","article-title":"Association between blood lead level with high blood pressure in US (NHANES 1999-2018)","volume":"10","author":"Huang","year":"2022","journal-title":"Front. Public Health"},{"key":"B19","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1177\/0962280211430681","article-title":"Slope estimation for informatively right censored longitudinal data modelling the number of observations using geometric and Poisson distributions: application to renal transplant cohort","volume":"24","author":"Jaffa","year":"2015","journal-title":"Stat. Methods Med. Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1111\/j.1572-0241.1999.988_k.x","article-title":"Different effects of an oral anticholinergic drug on gastroesophageal reflux in upright and supine position in normal, ambulant subjects: a pilot study","volume":"94","author":"Koerselman","year":"1999","journal-title":"Am. J. Gastroenterol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1196\/annals.1365.036","article-title":"Bisphosphonates","volume":"1092","author":"Lambrinoudaki","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.bonr.2016.06.001","article-title":"Association of gastrointestinal events with osteoporosis treatment initiation and treatment compliance in Germany: an observational study","volume":"5","author":"Modi","year":"2016","journal-title":"Bone Rep."},{"key":"B23","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1007\/s00198-014-2925-9","article-title":"Oral bisphosphonates and upper gastrointestinal toxicity: a study of cancer and early signals of esophageal injury","volume":"26","author":"Morden","year":"2015","journal-title":"Osteoporos. Int."},{"key":"B24","doi-asserted-by":"publisher","first-page":"S38","DOI":"10.5152\/tjg.2017.11","article-title":"P\u0131narba\u015f\u0131 \u015eim\u015fek B: which drugs are risk factors for the development of gastroesophageal reflux disease?","volume":"28","author":"Mungan","year":"2017","journal-title":"Turk J. Gastroenterol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1007\/s00198-020-05498-7","article-title":"Upper gastrointestinal safety of oral bisphosphonate in hospitalized patients","volume":"32","author":"Nguyen","year":"2021","journal-title":"Osteoporos. Int."},{"key":"B26","doi-asserted-by":"publisher","first-page":"135","DOI":"10.26442\/00403660.2019.08.000228","article-title":"Gastroesophageal reflux disease and esophagitis associated with the use of drugs: the modern state of the problem","volume":"91","author":"Osadchuk","year":"2019","journal-title":"Ter. Arkh"},{"key":"B27","doi-asserted-by":"publisher","first-page":"96","DOI":"10.14310\/horm.2002.1226","article-title":"Bisphosphonate-associated adverse events","volume":"8","author":"Papapetrou","year":"2009","journal-title":"Horm. (Athens)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.humpath.2007.01.014","article-title":"Pathological effects of drugs on the gastrointestinal tract: a review","volume":"38","author":"Parfitt","year":"2007","journal-title":"Hum. Pathol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1080\/14740338.2020.1799975","article-title":"A real-world disproportionality analysis of FDA Adverse Event Reporting System (FAERS) events for baricitinib","volume":"19","author":"Peng","year":"2020","journal-title":"Expert Opin. Drug Saf."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1617","DOI":"10.1007\/s00198-014-2647-z","article-title":"Alendronate, a bisphosphonate, increased upper and lower gastrointestinal bleeding: risk factor analysis from a nationwide population-based study","volume":"25","author":"Peng","year":"2014","journal-title":"Osteoporos. Int."},{"key":"B31","doi-asserted-by":"publisher","first-page":"115887","DOI":"10.1016\/j.bone.2021.115887","article-title":"Bisphosphonates in inflammatory rheumatic diseases","volume":"146","author":"Peris","year":"2021","journal-title":"Bone"},{"key":"B32","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1111\/ger.12590","article-title":"Oral bisphosphonates: adverse effects on the oral mucosa not related to the jaw bones. A scoping review","volume":"39","author":"Psimma","year":"2022","journal-title":"Gerodontology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"115465","DOI":"10.1016\/j.bone.2020.115465","article-title":"Bisphosphonates in the management of Paget's disease","volume":"138","author":"Ralston","year":"2020","journal-title":"Bone"},{"key":"B34","first-page":"1261","article-title":"Bisphosphonates in the prevention and treatment of bone metastases","volume":"17","author":"Ramaswamy","year":"2003","journal-title":"Oncol. (Williston Park)"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1735","DOI":"10.1002\/cncr.11701","article-title":"Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial","volume":"98","author":"Rosen","year":"2003","journal-title":"Cancer"},{"key":"B36","first-page":"127","article-title":"Effect of diazepam on the lower esophageal sphincter. A double-blind controlled study","volume":"73","author":"Rushnak","year":"1980","journal-title":"Am. J. Gastroenterol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"115933","DOI":"10.1016\/j.bone.2021.115933","article-title":"Bisphosphonates in dentistry: historical perspectives, adverse effects, and novel applications","volume":"147","author":"Sedghizadeh","year":"2021","journal-title":"Bone"},{"key":"B38","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1186\/s12891-018-2101-z","article-title":"Effect of bisphosphonates on periprosthetic bone loss after total knee arthroplasty: a meta-analysis of randomized controlled trials","volume":"19","author":"Shi","year":"2018","journal-title":"BMC Musculoskelet. Disord."},{"key":"B39","doi-asserted-by":"publisher","first-page":"2705","DOI":"10.1111\/cns.14215","article-title":"Cardiac adverse events associated with quetiapine: disproportionality analysis of FDA adverse event reporting system","volume":"29","author":"Shu","year":"2023","journal-title":"CNS Neurosci. Ther."},{"key":"B40","doi-asserted-by":"publisher","first-page":"608","DOI":"10.3109\/13697137.2014.995164","article-title":"Adherence to oral bisphosphonates: 30 more minutes in dosing instructions matter","volume":"18","author":"Vytrisalova","year":"2015","journal-title":"Climacteric"},{"key":"B41","doi-asserted-by":"publisher","first-page":"750458","DOI":"10.3389\/fnins.2021.750458","article-title":"Mapping the BCPNN learning rule to a memristor model","volume":"15","author":"Wang","year":"2021","journal-title":"Front. Neurosci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"e007133","DOI":"10.1136\/bmjopen-2014-007133","article-title":"Bisphosphonates and evidence for association with esophageal and gastric cancer: a systematic review and meta-analysis","volume":"5","author":"Wright","year":"2015","journal-title":"BMJ Open"},{"key":"B43","doi-asserted-by":"publisher","first-page":"c4506","DOI":"10.1136\/bmj.c4506","article-title":"Oral bisphosphonates and oesophageal cancer","volume":"341","author":"Wysowski","year":"2010","journal-title":"Bmj"},{"key":"B44","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1016\/j.pharep.2018.03.011","article-title":"Bisphosphonates: future perspective for neurological disorders","volume":"70","author":"Zameer","year":"2018","journal-title":"Pharmacol. Rep."},{"key":"B45","doi-asserted-by":"publisher","first-page":"735466","DOI":"10.3389\/fcvm.2021.735466","article-title":"Cardiovascular toxicity of carfilzomib: the real-world evidence based on the adverse event reporting system database of the FDA, the United States","volume":"8","author":"Zhai","year":"2021","journal-title":"Front. Cardiovasc Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1111\/j.1442-2050.2009.00972.x","article-title":"Drug-induced esophagitis","volume":"22","author":"Zografos","year":"2009","journal-title":"Dis. Esophagus"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1473756\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T04:43:31Z","timestamp":1730954611000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1473756\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,7]]},"references-count":46,"alternative-id":["10.3389\/fphar.2024.1473756"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1473756","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,7]]},"article-number":"1473756"}}