{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T23:10:46Z","timestamp":1769123446100,"version":"3.49.0"},"reference-count":62,"publisher":"Bioscientifica","issue":"12","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ec.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,11,24]]},"abstract":"<jats:p>This retrospective study aimed to identify and characterize signals of ocular adverse events (AEs) related to bisphosphonates (BPs) using FDA adverse event reporting system (FAERS) data (Q1 2004 to Q3 2024) to inform future safety investigations. Disproportionality analysis was conducted utilizing the reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural network (BCPNN) methods to identify BP-related ocular AE signals. In addition, a modified ROR method was utilized to examine differences across gender and age. Among 6,965 ocular AE reports for five BPs (alendronate, zoledronate, pamidronate, risedronate, and ibandronate), 136 positive signals were identified, predominantly unlisted in drug labels. Notable risks included ocular inflammatory AEs (especially zoledronate) and novel risk signals such as cataract, glaucoma, and macular degeneration. Standardized MedDRA queries (SMQ) linked BPs to 11 eye disorders, with scleral disorders common to all five BPs and pamidronate involving the broadest SMQ categories. Ocular AEs for alendronate, zoledronate, and pamidronate exhibited age-related differences, while those for alendronate and zoledronate showed gender differences. This study identifies high-risk and novel ocular AEs related to BPs. These findings warrant further validation in future studies.<\/jats:p>","DOI":"10.1530\/ec-25-0482","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T17:50:42Z","timestamp":1764006642000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-10","source":"Crossref","is-referenced-by-count":1,"title":["Bisphosphonate-related ocular adverse events: a pharmacovigilance study based on the FAERS database"],"prefix":"10.1530","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2899-4073","authenticated-orcid":true,"given":"Yue","family":"Cui","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8157-3040","authenticated-orcid":true,"given":"Zhihui","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinglong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"416","reference":[{"key":"bib1","series-title":"Ocul Immunol Inflamm","first-page":"1995","article-title":"Bisphosphonates related ocular side effects: a case series and review of literature","volume":"30","author":"Gendelman O","year":"2021","unstructured":"Gendelman O\n, \nTripto \u2013 Shkolnik L\n, \nVered I\n, et al.\n Bisphosphonates related ocular side effects: a case series and review of literature. Ocul Immunol Inflamm 2021 30 1995\u20131999. (https:\/\/doi.org\/10.1080\/09273948.2021.1922705)"},{"key":"bib2","series-title":"Metabolism","article-title":"Extra-skeletal effects of bisphosphonates","volume":"110","author":"Panagiotakou A","year":"2020","unstructured":"Panagiotakou A\n, \nYavropoulou M\n, \nNasiri-Ansari N\n, et al.\n Extra-skeletal effects of bisphosphonates. Metabolism 2020 110 154264. (https:\/\/doi.org\/10.1016\/j.metabol.2020.154264)"},{"key":"bib3","series-title":"Bone","article-title":"Molecular mechanisms of action of bisphosphonates and new insights into their effects outside the skeleton","volume":"139","author":"Rogers MJ","year":"2020","unstructured":"Rogers MJ\n, \nM\u00f6nkk\u00f6nen J\n & \nMunoz MA\n\n. Molecular mechanisms of action of bisphosphonates and new insights into their effects outside the skeleton. Bone 2020 139 115493. (https:\/\/doi.org\/10.1016\/j.bone.2020.115493)"},{"key":"bib4","series-title":"J Ocul Pharmacol Therapeut","first-page":"3","article-title":"Ocular side effects of bisphosphonates: a review of literature","volume":"39","author":"Chartrand NA","year":"2023","unstructured":"Chartrand NA\n, \nLau C-K\n, \nParsons MT\n, et al.\n Ocular side effects of bisphosphonates: a review of literature. J Ocul Pharmacol Therapeut 2023 39 3\u201316. (https:\/\/doi.org\/10.1089\/jop.2022.0094)"},{"key":"bib5","series-title":"Indian J Ophthalmol","first-page":"1799","article-title":"Drug-induced uveitis: a review","volume":"68","author":"Agarwal M","year":"2020","unstructured":"Agarwal M\n, \nDutta Majumder P\n, \nBabu K\n, et al.\n Drug-induced uveitis: a review. Indian J Ophthalmol 2020 68 1799. (https:\/\/doi.org\/10.4103\/ijo.IJO_816_20)"},{"key":"bib6","series-title":"Expet Opin Drug Saf","first-page":"763","article-title":"Gender differences in adverse events related to osimertinib: a real-world pharmacovigilance analysis of FDA adverse event reporting system","volume":"23","author":"Li Z","year":"2023","unstructured":"Li Z\n, \nZou W\n, \nYuan J\n, et al.\n Gender differences in adverse events related to osimertinib: a real-world pharmacovigilance analysis of FDA adverse event reporting system. Expet Opin Drug Saf 2023 23 763\u2013770. (https:\/\/doi.org\/10.1080\/14740338.2023.2243220)"},{"key":"bib7","series-title":"J Ophthalmic Vis Res","first-page":"118","article-title":"Orbital inflammation caused by aminobisphosphonates","volume":"17","author":"Gonzalez Barlatay J","year":"2022","unstructured":"Gonzalez Barlatay J\n, \nPagano Boza C\n, \nHernandez Gauna GV\n, et al.\n Orbital inflammation caused by aminobisphosphonates. J Ophthalmic Vis Res 2022 17 118\u2013122. 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(https:\/\/doi.org\/10.1136\/bjophthalmol-2013-303355)"},{"key":"bib16","series-title":"Drugs Aging","first-page":"311","article-title":"Risk of cataract surgery and age-related macular degeneration after initiation of denosumab vs zoledronic acid for osteoporosis: a multi-database cohort study","volume":"37","author":"Lee H","year":"2020","unstructured":"Lee H\n, \nJin Y\n, \nRoh M\n, et al.\n Risk of cataract surgery and age-related macular degeneration after initiation of denosumab vs zoledronic acid for osteoporosis: a multi-database cohort study. Drugs Aging 2020 37 311\u2013320. (https:\/\/doi.org\/10.1007\/s40266-020-00745-2)"},{"key":"bib17","series-title":"Lancet Oncol","first-page":"339","article-title":"Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"20","author":"Gnant M","year":"2019","unstructured":"Gnant M\n, \nPfeiler G\n, \nSteger GG\n, et al.\n Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019 20 339\u2013351. (https:\/\/doi.org\/10.1016\/s1470-2045(18)30862-3)"},{"key":"bib18","series-title":"Eye","first-page":"1357","article-title":"Global and regional prevalence of age-related cataract: a comprehensive systematic review and meta-analysis","volume":"34","author":"Hashemi H","year":"2020","unstructured":"Hashemi H\n, \nPakzad R\n, \nYekta A\n, et al.\n Global and regional prevalence of age-related cataract: a comprehensive systematic review and meta-analysis. Eye 2020 34 1357\u20131370. 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The mechanisms of calcium homeostasis and signalling in the lens. Exp Eye Res 2009 88 226\u2013234. (https:\/\/doi.org\/10.1016\/j.exer.2008.10.025)"},{"key":"bib21","series-title":"Med Sci Monit","article-title":"A review of current clinical concepts in the pathophysiology, etiology, diagnosis, and management of hypercalcemia","volume":"28","author":"Tonon CR","year":"2022","unstructured":"Tonon CR\n, \nSilva TAAL\n, \nPereira FWL\n, et al.\n A review of current clinical concepts in the pathophysiology, etiology, diagnosis, and management of hypercalcemia. Med Sci Monit 2022 28 e935821. (https:\/\/doi.org\/10.12659\/msm.935821)"},{"key":"bib22","series-title":"Eye","first-page":"1160","article-title":"Risk of glaucoma with bisphosphonate use in patients with osteoporosis: a case-control study","volume":"39","author":"He B","year":"2024","unstructured":"He B\n, \nEtminan M\n, \nDarwich R\n, et al.\n Risk of glaucoma with bisphosphonate use in patients with osteoporosis: a case-control study. Eye 2024 39 1160\u20131164. (https:\/\/doi.org\/10.1038\/s41433-024-03574-4)"},{"key":"bib23","series-title":"Retin Cases Brief Rep","first-page":"552","article-title":"Bisphosphonate-induced bilateral anterior uveitis and choroidal effusions with secondary angle closure","volume":"15","author":"Thng ZX","year":"2021","unstructured":"Thng ZX\n, \nLi ZK\n & \nGan NY\n\n. Bisphosphonate-induced bilateral anterior uveitis and choroidal effusions with secondary angle closure. Retin Cases Brief Rep 2021 15 552\u2013555. (https:\/\/doi.org\/10.1097\/icb.0000000000000850)"},{"key":"bib24","series-title":"Drug Des Dev Ther","first-page":"1453","article-title":"Zoledronate upregulates MMP-9 and -13 in rat vascular smooth muscle cells by inducing oxidative stress","volume":"10","author":"Arun MZ","year":"2016","unstructured":"Arun MZ\n, \nReel B\n, \nSala-Newby G\n, et al.\n Zoledronate upregulates MMP-9 and -13 in rat vascular smooth muscle cells by inducing oxidative stress. Drug Des Dev Ther 2016 10 1453. (https:\/\/doi.org\/10.2147\/dddt.s103124)"},{"key":"bib25","series-title":"Am J Ophthalmol","first-page":"62","article-title":"Oral bisphosphonates and risk of wet age-related macular degeneration","volume":"168","author":"Mammo Z","year":"2016","unstructured":"Mammo Z\n, \nGuo M\n, \nMaberley D\n, et al.\n Oral bisphosphonates and risk of wet age-related macular degeneration. Am J Ophthalmol 2016 168 62\u201367. (https:\/\/doi.org\/10.1016\/j.ajo.2016.04.022)"},{"key":"bib26","series-title":"J Ophthalmol","first-page":"1","article-title":"Therapeutic effect of oral bisphosphonates on choroidal neovascularization in the human eye","volume":"2010","author":"Honda S","year":"2010","unstructured":"Honda S\n, \nNagai T\n, \nKondo N\n, et al.\n Therapeutic effect of oral bisphosphonates on choroidal neovascularization in the human eye. J Ophthalmol 2010 2010 1\u20137. (https:\/\/doi.org\/10.1155\/2010\/206837)"},{"key":"bib27","series-title":"BMJ Open Ophthalmol","article-title":"Zoledronic acid as adjuvant therapy in neovascular age-related macular degeneration: a randomised controlled pilot study","volume":"9","author":"Husum YS","year":"2024","unstructured":"Husum YS\n, \nMoe MC\n, \nFagerland MW\n, et al.\n Zoledronic acid as adjuvant therapy in neovascular age-related macular degeneration: a randomised controlled pilot study. BMJ Open Ophthalmol 2024 9 e001964. (https:\/\/doi.org\/10.1136\/bmjophth-2024-001964)"},{"key":"bib28","series-title":"Prog Retin Eye Res","first-page":"201","article-title":"The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD","volume":"60","author":"Datta S","year":"2017","unstructured":"Datta S\n, \nCano M\n, \nEbrahimi K\n, et al.\n The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD. Prog Retin Eye Res 2017 60 201\u2013218. (https:\/\/doi.org\/10.1016\/j.preteyeres.2017.03.002)"},{"key":"bib29","series-title":"Nat Rev Dis Primers","first-page":"31","article-title":"Age-related macular degeneration","volume":"7","author":"Fleckenstein M","year":"2021","unstructured":"Fleckenstein M\n, \nKeenan TDL\n, \nGuymer RH\n, et al.\n Age-related macular degeneration. Nat Rev Dis Primers 2021 7 31. 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(https:\/\/doi.org\/10.1111\/aos.13899)"},{"key":"bib1","series-title":"Ocul Immunol Inflamm","first-page":"1995","article-title":"Bisphosphonates related ocular side effects: a case series and review of literature","volume":"30","author":"Gendelman O","year":"2021","unstructured":"Gendelman O\n, \nTripto \u2013 Shkolnik L\n, \nVered I\n, et al.\n Bisphosphonates related ocular side effects: a case series and review of literature. Ocul Immunol Inflamm 2021 30 1995\u20131999. (https:\/\/doi.org\/10.1080\/09273948.2021.1922705)"},{"key":"bib2","series-title":"Metabolism","article-title":"Extra-skeletal effects of bisphosphonates","volume":"110","author":"Panagiotakou A","year":"2020","unstructured":"Panagiotakou A\n, \nYavropoulou M\n, \nNasiri-Ansari N\n, et al.\n Extra-skeletal effects of bisphosphonates. Metabolism 2020 110 154264. (https:\/\/doi.org\/10.1016\/j.metabol.2020.154264)"},{"key":"bib3","series-title":"Bone","article-title":"Molecular mechanisms of action of bisphosphonates and new insights into their effects outside the skeleton","volume":"139","author":"Rogers MJ","year":"2020","unstructured":"Rogers MJ\n, \nM\u00f6nkk\u00f6nen J\n & \nMunoz MA\n\n. Molecular mechanisms of action of bisphosphonates and new insights into their effects outside the skeleton. Bone 2020 139 115493. (https:\/\/doi.org\/10.1016\/j.bone.2020.115493)"},{"key":"bib4","series-title":"J Ocul Pharmacol Therapeut","first-page":"3","article-title":"Ocular side effects of bisphosphonates: a review of literature","volume":"39","author":"Chartrand NA","year":"2023","unstructured":"Chartrand NA\n, \nLau C-K\n, \nParsons MT\n, et al.\n Ocular side effects of bisphosphonates: a review of literature. J Ocul Pharmacol Therapeut 2023 39 3\u201316. (https:\/\/doi.org\/10.1089\/jop.2022.0094)"},{"key":"bib5","series-title":"Indian J Ophthalmol","first-page":"1799","article-title":"Drug-induced uveitis: a review","volume":"68","author":"Agarwal M","year":"2020","unstructured":"Agarwal M\n, \nDutta Majumder P\n, \nBabu K\n, et al.\n Drug-induced uveitis: a review. Indian J Ophthalmol 2020 68 1799. (https:\/\/doi.org\/10.4103\/ijo.IJO_816_20)"},{"key":"bib6","series-title":"Expet Opin Drug Saf","first-page":"763","article-title":"Gender differences in adverse events related to osimertinib: a real-world pharmacovigilance analysis of FDA adverse event reporting system","volume":"23","author":"Li Z","year":"2023","unstructured":"Li Z\n, \nZou W\n, \nYuan J\n, et al.\n Gender differences in adverse events related to osimertinib: a real-world pharmacovigilance analysis of FDA adverse event reporting system. Expet Opin Drug Saf 2023 23 763\u2013770. (https:\/\/doi.org\/10.1080\/14740338.2023.2243220)"},{"key":"bib7","series-title":"J Ophthalmic Vis Res","first-page":"118","article-title":"Orbital inflammation caused by aminobisphosphonates","volume":"17","author":"Gonzalez Barlatay J","year":"2022","unstructured":"Gonzalez Barlatay J\n, \nPagano Boza C\n, \nHernandez Gauna GV\n, et al.\n Orbital inflammation caused by aminobisphosphonates. J Ophthalmic Vis Res 2022 17 118\u2013122. (https:\/\/doi.org\/10.18502\/jovr.v17i1.10176)"},{"key":"bib8","series-title":"N Z Med J","first-page":"83","article-title":"Drug-induced ocular inflammation","volume":"133","author":"Samalia P","year":"2020","unstructured":"Samalia P\n, \nSims J\n & \nNiederer R\n\n. Drug-induced ocular inflammation. N Z Med J 2020 133 83\u201394."},{"key":"bib9","series-title":"Cureus","article-title":"Acute iridocyclitis associated with intravenous zoledronic acid: a case report","volume":"15","author":"Ankireddypalli AR","year":"2023","unstructured":"Ankireddypalli AR\n & \nSibley S\n\n. Acute iridocyclitis associated with intravenous zoledronic acid: a case report. Cureus 2023 15 e43162. (https:\/\/doi.org\/10.7759\/cureus.43162)"},{"key":"bib10","series-title":"Can Med Assoc J","first-page":"E431","article-title":"Inflammatory ocular adverse events with the use of oral bisphosphonates: a retrospective cohort study","volume":"184","author":"Etminan M","year":"2012","unstructured":"Etminan M\n, \nForooghian F\n & \nMaberley D\n\n. Inflammatory ocular adverse events with the use of oral bisphosphonates: a retrospective cohort study. Can Med Assoc J 2012 184 E431\u2013E434. (https:\/\/doi.org\/10.1503\/cmaj.111752)"},{"key":"bib11","series-title":"Osteoporos Int","first-page":"499","article-title":"Incidence of ocular side effects with intravenous zoledronate: secondary analysis of a randomized controlled trial","volume":"26","author":"Patel DV","year":"2014","unstructured":"Patel DV\n, \nBolland M\n, \nNisa Z\n, et al.\n Incidence of ocular side effects with intravenous zoledronate: secondary analysis of a randomized controlled trial. Osteoporos Int 2014 26 499\u2013503. (https:\/\/doi.org\/10.1007\/s00198-014-2872-5)"},{"key":"bib12","series-title":"Eye","first-page":"538","article-title":"Clinical features, treatment, and prognosis of zoledronic acid-induced uveitis","volume":"39","author":"Wu Z","year":"2025","unstructured":"Wu Z\n, \nSun W\n, \nZhou Y\n, et al.\n Clinical features, treatment, and prognosis of zoledronic acid-induced uveitis. Eye 2025 39 538\u2013543. (https:\/\/doi.org\/10.1038\/s41433-024-03586-0)"},{"key":"bib13","series-title":"N Engl J Med","first-page":"737","article-title":"Gamma\/delta T-cell stimulation by pamidronate","volume":"340","author":"Kunzmann V","year":"1999","unstructured":"Kunzmann V\n, \nBauer E\n & \nWilhelm M\n\n. Gamma\/delta T-cell stimulation by pamidronate. N Engl J Med 1999 340 737\u2013738. (https:\/\/doi.org\/10.1056\/nejm199903043400914)"},{"key":"bib14","series-title":"J Immunol","first-page":"560","article-title":"Major role of \u03b3\u03b4 T cells in the generation of IL-17+ uveitogenic T cells","volume":"183","author":"Cui Y","year":"2009","unstructured":"Cui Y\n, \nShao H\n, \nLan C\n, et al.\n Major role of \u03b3\u03b4 T cells in the generation of IL-17+ uveitogenic T cells. J Immunol 2009 183 560\u2013567. (https:\/\/doi.org\/10.4049\/jimmunol.0900241)"},{"key":"bib15","series-title":"Br J Ophthalmol","first-page":"1074","article-title":"Pro-inflammatory and anti-angiogenic effects of bisphosphonates on human cultured retinal pigment epithelial cells","volume":"97","author":"Or C","year":"2013","unstructured":"Or C\n, \nCui J\n, \nMatsubara J\n, et al.\n Pro-inflammatory and anti-angiogenic effects of bisphosphonates on human cultured retinal pigment epithelial cells. Br J Ophthalmol 2013 97 1074\u20131078. (https:\/\/doi.org\/10.1136\/bjophthalmol-2013-303355)"},{"key":"bib16","series-title":"Drugs Aging","first-page":"311","article-title":"Risk of cataract surgery and age-related macular degeneration after initiation of denosumab vs zoledronic acid for osteoporosis: a multi-database cohort study","volume":"37","author":"Lee H","year":"2020","unstructured":"Lee H\n, \nJin Y\n, \nRoh M\n, et al.\n Risk of cataract surgery and age-related macular degeneration after initiation of denosumab vs zoledronic acid for osteoporosis: a multi-database cohort study. Drugs Aging 2020 37 311\u2013320. 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