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Long\u2010term use has been associated with the development of atypical femur fractures (AFFs) and osteonecrosis of the jaw (ONJ). Drug holidays seek to reduce the risk of insufficiency fractures (AFFs) while maintaining durable effects of long\u2010term treatment in the prevention of fragility fracture. Guidelines suggest that BP drug holidays be considered after 3 to 5\u2009years. However individual factors impacting this decision and outcomes are unclear. This review examines key factors in the planning of a safe BP drug holiday and surrogate markers of fracture risk in patients discontinuing treatment. Fifteen randomized control trials and 19 real\u2010world studies were included, including nationwide prospective studies from several countries. Increases in bone turnover markers (BTMs) and reductions in bone mineral density (BMD) were generally observed during BP drug holidays. Resurgent bone turnover was problematic in high\u2010risk patients in whom fractures recurred as early as 12\u2009months following a drug holiday. Risk factors for holiday\u2010related fractures included older age, low hip BMD, underweight, low medication adherence, and prevalent\/incident fractures. Zoledronic acid conferred the most durable reduction in fractures, particularly after six annual infusions. Five years of alendronate was insufficient in preventing vertebral fractures in high\u2010risk patients embarking on a drug holiday. Relatively faster offset of antiresorptive effect was seen in risedronate users with more frequent fractures than alendronate during a drug holiday. Studies directly counterbalancing effects of long\u2010term treatment on AFF risk versus drug holiday outcomes in the same population were lacking. In the absence of persistently high fracture risk and following a specific treatment duration dependent on the BP used, drug holidays are safe and mitigate the risk of AFF. However, anti\u2010resorptive effects diminish over time; ongoing monitoring and careful planning of BP resumption is necessary. \u00a9 2022 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10629","type":"journal-article","created":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T22:55:15Z","timestamp":1649717715000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Bisphosphonate Drug Holidays: Evidence From Clinical Trials and Real\u2010World Studies"],"prefix":"10.1093","volume":"6","author":[{"given":"Mawson","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Diabetes and Endocrinology Westmead Hospital  Westmead NSW Australia"},{"name":"Faculty of Medicine and Health University of Sydney  Sydney 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