{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T13:51:01Z","timestamp":1793109061927,"version":"4.5.0"},"reference-count":53,"publisher":"The Endocrine Society","issue":"5","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"EmPaTHy","award":["14\/FY2021\/G2\/01-A167"],"award-info":[{"award-number":["14\/FY2021\/G2\/01-A167"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>International guidelines recommend the use of oral bisphosphonates (oBP) for up to 5 years in the treatment of postmenopausal osteoporosis. However, benefits and risks of extending oBP therapy beyond this duration remain uncertain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>To determine the health outcomes (bone mineral density [BMD], fracture risk) and adverse effects (atypical fracture, osteonecrosis of the jaw [ONJ]) of extended oBP therapy beyond 5 years among postmenopausal women.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methodology<\/jats:title>\n                    <jats:p>A systematic search of Medline\u00a9, EMBASE\u00a9, and CINAHL\u00a9 was conducted from inception to 15 March 2024. Interventional and observational studies published in English were included. Two authors independently performed screening, quality appraisal using the NIH Quality Appraisal tool, and data extraction. The review followed PRISMA guidelines and was registered on PROSPERO (CRD42024475332). High heterogeneity precluded meta-analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Eleven studies (4 controlled trials, 7 observational) were included: 3 rated as good quality, 7 as fair, and 1 as poor. Extended oBP therapy beyond 5 years increased BMD at the hip (3\/3 studies), femoral neck (3\/3 studies) and lumbar spine (5\/5 studies). Prolonged oBP use reduced clinical vertebral fracture risk (1\/6 studies) but increased the risk of atypical fractures (3\/3 studies) and incomplete atypical femoral fractures (1\/1 study). None of the included studies assessed or reported ONJ.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Substantial heterogeneity and limited high-quality evidence preclude definitive conclusions regarding extended oBP use in postmenopausal women. While extended treatment may improve bone density and reduce vertebral fractures, it could also increase atypical fractures. Future high-quality studies are required to inform decisions regarding optimal treatment duration.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgag057","type":"journal-article","created":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T12:41:53Z","timestamp":1770468113000},"page":"e1226-e1238","source":"Crossref","is-referenced-by-count":2,"title":["Health and adverse events associated with extended oral bisphosphonates among postmenopausal women: a systematic review"],"prefix":"10.1210","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6314-201X","authenticated-orcid":false,"given":"Prawira","family":"Oka","sequence":"first","affiliation":[{"name":"Department of Research, SingHealth Polyclinics , Singapore 150167 ,","place":["Singapore"]},{"name":"SingHealth-Duke NUS Family Medicine Academic Clinical Program , Singapore 169857 ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1239-8215","authenticated-orcid":false,"given":"Aminath Shiwaza","family":"Moosa","sequence":"additional","affiliation":[{"name":"Department of Research, SingHealth Polyclinics , Singapore 150167 ,","place":["Singapore"]},{"name":"SingHealth-Duke NUS Family Medicine Academic Clinical Program , Singapore 169857 ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9596-7158","authenticated-orcid":false,"given":"Eileen Yi Ling","family":"Koh","sequence":"additional","affiliation":[{"name":"Department of Research, SingHealth Polyclinics , Singapore 150167 ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8320-1603","authenticated-orcid":false,"given":"Chirk Jenn","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Research, SingHealth Polyclinics , Singapore 150167 ,","place":["Singapore"]},{"name":"SingHealth-Duke NUS Family Medicine Academic Clinical Program , Singapore 169857 ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2026,2,10]]},"reference":[{"issue":"6","key":"2026042119565667900_dgag057-B1","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1001\/jama.285.6.785","article-title":"Osteoporosis prevention, diagnosis, and therapy","volume":"285","author":"NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy","year":"2001","journal-title":"JAMA"},{"issue":"1","key":"2026042119565667900_dgag057-B2","first-page":"9","article-title":"Primary osteoporosis in postmenopausal women","volume":"1","author":"Ji","year":"2015","journal-title":"Chronic Dis Transl Med"},{"issue":"1","key":"2026042119565667900_dgag057-B3","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1186\/s13018-021-02772-0","article-title":"The global prevalence of osteoporosis in the world: a comprehensive systematic review and meta-analysis","volume":"16","author":"Salari","year":"2021","journal-title":"J Orthop Surg Res"},{"issue":"1","key":"2026042119565667900_dgag057-B4","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1186\/s13018-019-1226-6","article-title":"Mortality after osteoporotic hip fracture: incidence, trends, and associated factors","volume":"14","author":"Guzon-Illescas","year":"2019","journal-title":"J Orthop Surg Res"},{"issue":"3","key":"2026042119565667900_dgag057-B5","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1111\/j.1532-5415.1997.tb00941.x","article-title":"The economic cost of hip fractures in community-dwelling older adults: a prospective study","volume":"45","author":"Brainsky","year":"1997","journal-title":"J Am Geriatr Soc"},{"key":"2026042119565667900_dgag057-B6","first-page":"937","article-title":"A systematic review of the outcomes of osteoporotic fracture patients after hospital discharge: morbidity, subsequent fractures, and mortality","volume":"10","author":"Nazrun","year":"2014","journal-title":"Ther Clin Risk Manag"},{"issue":"1","key":"2026042119565667900_dgag057-B7","doi-asserted-by":"crossref","first-page":"37","DOI":"10.11005\/jbm.2017.24.1.37","article-title":"The efficacy of bisphosphonates for prevention of osteoporotic fracture: an update meta-analysis","volume":"24","author":"Byun","year":"2017","journal-title":"J Bone Metab"},{"issue":"7","key":"2026042119565667900_dgag057-B8","doi-asserted-by":"crossref","first-page":"2272","DOI":"10.1210\/jc.2012-1027","article-title":"Benefits and risks of bisphosphonate therapy for osteoporosis","volume":"97","author":"Khosla","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2026042119565667900_dgag057-B9","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1210\/jc.2009-0852","article-title":"Effect of osteoporosis treatment on mortality: a meta-analysis","volume":"95","author":"Bolland","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"issue":"15","key":"2026042119565667900_dgag057-B10","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1056\/NEJMoa1708322","article-title":"Romosozumab or alendronate for fracture prevention in women with osteoporosis","volume":"377","author":"Saag","year":"2017","journal-title":"N Engl J Med"},{"issue":"1","key":"2026042119565667900_dgag057-B11","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1007\/s11657-022-01061-5","article-title":"UK clinical guideline for the prevention and treatment of osteoporosis","volume":"17","author":"Gregson","year":"2022","journal-title":"Arch Osteoporos"},{"key":"2026042119565667900_dgag057-B12","doi-asserted-by":"publisher","first-page":"472","DOI":"10.5694\/mja2.52637","article-title":"2024 Royal Australian College of General Practitioners and Healthy Bones Australia guideline for osteoporosis management and fracture prevention in postmenopausal women and men over 50 years of age","volume-title":"Med J Aust","author":"Wong","year":"2025"},{"issue":"2","key":"2026042119565667900_dgag057-B13","doi-asserted-by":"crossref","first-page":"224","DOI":"10.7326\/M22-1034","article-title":"Pharmacologic treatment of primary osteoporosis or low bone mass to prevent fractures in adults: a living clinical guideline from the American College of Physicians","volume":"176","author":"Qaseem","year":"2023","journal-title":"Ann Intern Med"},{"key":"2026042119565667900_dgag057-B14","author":"International Osteoporosis Foundation"},{"key":"2026042119565667900_dgag057-B15","author":"Agency for Care Effectiveness"},{"issue":"9","key":"2026042119565667900_dgag057-B16","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.4065\/83.9.1032","article-title":"Bisphosphonates: mechanism of action and role in clinical practice","volume":"83","author":"Drake","year":"2008","journal-title":"Mayo Clin Proc"},{"issue":"11","key":"2026042119565667900_dgag057-B17","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1097\/GME.0000000000000757","article-title":"Long-term bisphosphonates: primum non nocere","volume":"23","author":"Ott","year":"2016","journal-title":"Menopause"},{"issue":"12","key":"2026042119565667900_dgag057-B18","doi-asserted-by":"crossref","first-page":"e2025190","DOI":"10.1001\/jamanetworkopen.2020.25190","article-title":"Bisphosphonate treatment beyond 5 years and hip fracture risk in older women","volume":"3","author":"Izano","year":"2020","journal-title":"JAMA Netw Open"},{"key":"2026042119565667900_dgag057-B19","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.bone.2013.09.023","article-title":"Update on long-term treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review","volume":"58","author":"Eriksen","year":"2014","journal-title":"Bone"},{"issue":"8","key":"2026042119565667900_dgag057-B20","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1056\/NEJMoa1916525","article-title":"Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates","volume":"383","author":"Black","year":"2020","journal-title":"N Engl J Med"},{"issue":"1","key":"2026042119565667900_dgag057-B21","doi-asserted-by":"crossref","first-page":"10892","DOI":"10.1038\/s41598-023-37944-x","article-title":"Atypical femur fracture associated with common anti-osteoporosis drugs in FDA adverse event reporting system","volume":"13","author":"Xiao","year":"2023","journal-title":"Sci Rep"},{"issue":"4","key":"2026042119565667900_dgag057-B22","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1111\/odi.12632","article-title":"Time to onset of bisphosphonate-related osteonecrosis of the jaws: a multicentre retrospective cohort study","volume":"23","author":"Fung","year":"2017","journal-title":"Oral Dis"},{"issue":"33","key":"2026042119565667900_dgag057-B23","doi-asserted-by":"crossref","first-page":"8722","DOI":"10.1073\/pnas.1704460114","article-title":"Atypical fracture with long-term bisphosphonate therapy is associated with altered cortical composition and reduced fracture resistance","volume":"114","author":"Lloyd","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026042119565667900_dgag057-B24","doi-asserted-by":"crossref","first-page":"471035","DOI":"10.1155\/2014\/471035","article-title":"Bisphosphonate associated osteonecrosis of the jaw: an update on pathophysiology, risk factors, and treatment","volume":"2014","author":"Rasmusson","year":"2014","journal-title":"Int J Dent"},{"issue":"1","key":"2026042119565667900_dgag057-B25","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1002\/jbmr.2708","article-title":"Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research","volume":"31","author":"Adler","year":"2016","journal-title":"J Bone Miner Res"},{"key":"2026042119565667900_dgag057-B26","author":"Agency for Care Effectiveness, Ministry of Health, Singapore"},{"issue":"2","key":"2026042119565667900_dgag057-B27","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s00198-020-05557-z","article-title":"The osteoporosis treatment gap in patients at risk of fracture in European primary care: a multi-country cross-sectional observational study","volume":"32","author":"McCloskey","year":"2021","journal-title":"Osteoporos Int"},{"issue":"1","key":"2026042119565667900_dgag057-B28","doi-asserted-by":"crossref","first-page":"37","DOI":"10.7326\/M19-0533","article-title":"Long-term drug therapy and drug discontinuations and holidays for osteoporosis fracture prevention: a systematic review","volume":"171","author":"Fink","year":"2019","journal-title":"Ann Intern Med"},{"issue":"8","key":"2026042119565667900_dgag057-B29","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1002\/jbmr.1893","article-title":"Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis","volume":"28","author":"Gedmintas","year":"2013","journal-title":"J Bone Miner Res"},{"key":"2026042119565667900_dgag057-B30","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"The BMJ"},{"key":"2026042119565667900_dgag057-B31","volume-title":"Principles of Bone Biology","author":"Bilezikian","year":"2008"},{"key":"2026042119565667900_dgag057-B32","author":"Veritas Health Innovation"},{"key":"2026042119565667900_dgag057-B33","author":"National Institute of Health"},{"issue":"8","key":"2026042119565667900_dgag057-B34","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1359\/JBMR.040326","article-title":"Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the fracture intervention trial long-term extension","volume":"19","author":"Ensrud","year":"2004","journal-title":"J Bone Miner Res"},{"issue":"5","key":"2026042119565667900_dgag057-B35","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1002\/jbmr.11","article-title":"Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial","volume":"25","author":"Schwartz","year":"2010","journal-title":"J Bone Miner Res"},{"issue":"9","key":"2026042119565667900_dgag057-B36","first-page":"3109","article-title":"Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women*","volume":"85","author":"Tonino","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"issue":"24","key":"2026042119565667900_dgag057-B37","doi-asserted-by":"crossref","first-page":"2927","DOI":"10.1001\/jama.296.24.2927","article-title":"Effects of continuing or stopping alendronate after 5 years of treatment the fracture intervention trial long-term extension (FLEX): a randomized trial","volume":"296","author":"Black","year":"2006","journal-title":"JAMA"},{"issue":"12","key":"2026042119565667900_dgag057-B38","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1056\/NEJMoa030897","article-title":"Ten years\u2019 experience with alendronate for osteoporosis in postmenopausal women","volume":"350","author":"Bone","year":"2004","journal-title":"N Engl J Med"},{"issue":"3","key":"2026042119565667900_dgag057-B39","doi-asserted-by":"crossref","first-page":"2309499019875262","DOI":"10.1177\/2309499019875262","article-title":"Incomplete atypical femoral fractures after bisphosphonate use in postmenopausal women","volume":"27","author":"Canbek","year":"2019","journal-title":"J Orthop Surg"},{"issue":"9","key":"2026042119565667900_dgag057-B40","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1111\/jgs.14911","article-title":"Long-term oral bisphosphonate therapy and fractures in older women: the women's health initiative","volume":"65","author":"Drieling","year":"2017","journal-title":"J Am Geriatr Soc"},{"key":"2026042119565667900_dgag057-B41","doi-asserted-by":"crossref","first-page":"201","DOI":"10.2147\/TCRM.S10136","article-title":"Seven years\u2019 experience with alendronate in postmenopausal Japanese women with osteoporosis","volume":"6","author":"Iwamoto","year":"2010","journal-title":"Ther Clin Risk Manag"},{"issue":"11","key":"2026042119565667900_dgag057-B42","doi-asserted-by":"crossref","first-page":"3251","DOI":"10.1007\/s00198-017-4169-y","article-title":"Predisposing factors associated with atypical femur fracture among postmenopausal Korean women receiving bisphosphonate therapy: 8 years\u2019 experience in a single center","volume":"28","author":"Koh","year":"2017","journal-title":"Osteoporos Int"},{"issue":"6","key":"2026042119565667900_dgag057-B43","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1007\/s00223-004-0286-7","article-title":"Seven years of treatment with risedronate in women with postmenopausal osteoporosis","volume":"75","author":"Mellstr\u00f6m","year":"2004","journal-title":"Calcif Tissue Int"},{"issue":"6","key":"2026042119565667900_dgag057-B44","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/S0002-9343(97)00278-7","article-title":"Cyclical etidronate in the treatment of postmenopausal osteoporosis: efficacy and safety after seven years of treatment","volume":"103","author":"Miller","year":"1997","journal-title":"Am J Med"},{"issue":"8","key":"2026042119565667900_dgag057-B45","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1001\/jama.2011.190","article-title":"Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women","volume":"305","author":"Park-Wyllie","year":"2011","journal-title":"JAMA"},{"issue":"7","key":"2026042119565667900_dgag057-B46","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1089\/jwh.2015.5617","article-title":"The association between long-term bisphosphonate use and the risk of fracture among women aged 50 or older with osteoporosis","volume":"25","author":"Wang","year":"2016","journal-title":"J Womens Health"},{"issue":"2","key":"2026042119565667900_dgag057-B47","doi-asserted-by":"crossref","first-page":"279","DOI":"10.2147\/CIA.S2134","article-title":"Bisphosphonates in the management of postmenopausal osteoporosis-optimizing efficacy in clinical practice","volume":"3","author":"Bock","year":"2008","journal-title":"Clin Interv Aging"},{"issue":"4","key":"2026042119565667900_dgag057-B48","first-page":"CD003376","article-title":"Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women","volume":"4","author":"Wells","year":"2024","journal-title":"Cochrane Database Syst Rev"},{"issue":"4","key":"2026042119565667900_dgag057-B49","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1002\/jbmr.1501","article-title":"Bone micromechanical properties are compromised during long-term alendronate therapy independently of mineralization","volume":"27","author":"Bala","year":"2012","journal-title":"J Bone Miner Res"},{"issue":"11","key":"2026042119565667900_dgag057-B50","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1002\/jbmr.253","article-title":"Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research","volume":"25","author":"Shane","year":"2010","journal-title":"J Bone Miner Res"},{"issue":"2","key":"2026042119565667900_dgag057-B51","doi-asserted-by":"crossref","first-page":"224","DOI":"10.7326\/M22-1034","article-title":"Pharmacologic treatment of primary osteoporosis or low bone mass to prevent fractures in adults: a living clinical guideline from the American College of Physicians","volume":"176","author":"Qaseem","year":"2023","journal-title":"Ann Intern Med"},{"issue":"5","key":"2026042119565667900_dgag057-B52","doi-asserted-by":"crossref","first-page":"382","DOI":"10.14740\/jocmr2970w","article-title":"Gender disparities in osteoporosis","volume":"9","author":"Alswat","year":"2017","journal-title":"J Clin Med Res"},{"issue":"13","key":"2026042119565667900_dgag057-B53","doi-asserted-by":"crossref","first-page":"2988","DOI":"10.3390\/jcm10132988","article-title":"Comparison of the effect of oral versus intravenous bisphosphonate administration on osteoclastogenesis in advanced-stage medication-related osteonecrosis of the jaw patients","volume":"10","author":"Kim","year":"2021","journal-title":"J Clin Med"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgag057\/66847588\/dgag057.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/111\/5\/e1226\/66847588\/dgag057.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/111\/5\/e1226\/66847588\/dgag057.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T23:57:09Z","timestamp":1776815829000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/111\/5\/e1226\/8472052"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,10]]},"references-count":53,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,2,10]]},"published-print":{"date-parts":[[2026,4,22]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgag057","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,5]]},"published":{"date-parts":[[2026,2,10]]}}}