Abstract Disclosure: J.C. Lo: None. M. Chandra: None. M.M. Khan: None. L.D. Carbone: None. E.A. Garcia: None. G.H. Tabada: None. D. Low: None. R.L. Hui: None. Introduction: Bisphosphonate (BP) drugs remain one of the first line therapies for fracture prevention, but treatment patterns have changed since BPs were first approved for osteoporosis. This study examines trends among adults initiating oral BP in a large US healthcare system over a 25-year period (1988-2022) and in each successive 5-year period. Methods: The study cohort comprised adults aged 50-89y who initiated alendronate, risedronate or oral ibandronate during 1998-2022 in an integrated healthcare delivery system, excluding those with select bone disorders, multiple myeloma, secondary metastatic cancer, end stage renal disease, and receipt of intravenous BP. Covariates included age (proportion age <65y), sex, race and ethnicity, and prior fracture (diagnosed within 5 years) using electronic health record data. Demographic trends and fracture status were examined across time periods. The chi-squared test and Cochrane-Armitage test for trend were used to examine differences and trends. This report extends findings from an earlier report of women initiating oral BP during 2004-2012 in the same healthcare population. Results: Among 208,780 adults (86% women) who initiated BP, including 26,646 (1998-2002, 35% <65y), 44,726 (2003-2007, 35% <65y), 34,005 (2008-2012, 24% <65y), 35,248 (2013-2017, 19% <65y), and 38,743 (2018-2022, 17% <65y) women and 2348 (1998-2002, 28% <65y), 4895 (2003-2007, 26% <65y), 5172 (2008-2012, 17% <65y), 5331 (2013-2017, 13% <65y), and 11,666 (2018-2022, 5% <65y) men in each 5-year period. Over time, an increasing proportion were age ≥65y (p<0.001 for trend), with larger numbers of older adults in later years partly reflecting initiatives targeting secondary fracture prevention (since 2008 for women, 2015 for men) and BMD screening (since 2011 for women, 2017 for men). Among women initiating BP, the proportion with prior fracture increased from 24-30% (pre-2008) to 43-45% (post-2008), partly reflecting secondary fracture prevention initiatives for women. For men, this proportion increased from 33% (1998-2002) to 42% (2003-2007), 47% (2008-2012), and 54% (2013-2017), but fell to 36% (2018-2022) after BMD screening initiatives began in 2017 for older men (primary prevention efforts). Racial and ethnic diversity in treatment also increased, comparing 1988-2002 (75.2% White, 2.5% Black, 8.6% Hispanic, 12.7% Asian/Pacific Islander) to 2018-2022 (61.5% White, 2.9% Black, 12.2% Hispanic, 21.1% Asian/Pacific Islander, p<0.001 for overall differences and % non-White). Conclusions: In a primary care population of adults initiating oral BP, a larger proportion in later years were age >65y, including larger numbers both with and without fracture coinciding with initiatives for fracture prevention. Among those initiating BP, the relative proportions with prior fracture in each period were likely influenced by primary or secondary prevention efforts. Presentation: 6/2/2024