Bolland, Mark JNisa, ZaynahMellar, AnnaGasteiger, ChiaraPinel, VeronicaMihov, BorislavBastin, SonjaGrey, AndrewReid, Ian RGamble, GregHorne, Anne2026-05-192026-05-192025-10-18Journal of Clinical Endocrinology and Metabolism (JCEM), ISSN: 0021-972X (Print); 1945-7197 (Online), Oxford University Press, 111(4), e1080-e1087. doi: 10.1210/clinem/dgaf5690021-972X1945-7197http://hdl.handle.net/10292/21126CONTEXT: We recently reported that zoledronate given once at baseline or twice (every 5y) reduced fracture risk over 10y. OBJECTIVE: We assessed whether the effects of zoledronate differ over time or across important baseline variables, and how they relate to changes in bone mineral density (BMD) over time. DESIGN: 10y, prospective, randomized, double-blind, placebo-controlled trial, from 2012 to 2023. SETTING: Clinical research centre. PARTICIPANTS: 1054 post-menopausal women, aged 50-60y, with BMD T-score at the lumbar spine, femoral neck or total hip between 0 and -2.5. INTERVENTION: Either 5-yearly 5mg zoledronate (zol-zol), 5mg zoledronate infusion at baseline and placebo at 5y (zol-placebo), or 5-yearly placebo (placebo-placebo). MAIN OUTCOME MEASURES: Morphometric vertebral fractures, major osteoporotic and any fractures. RESULTS: Morphometric vertebral fractures were not reduced in years 0-5 following zoledronate but were reduced in years 5-10 by 58% (95% CI 21-77%) (zol-zol) and 57% (21%-77%) (zol-placebo). For any fracture and major osteoporotic fracture, similar temporal patterns were observed. There were no interactions between treatment effect and baseline variables (including age, body mass index, BMD, falls or fracture history, and estimated fracture risk) or between treatment effect and changes in BMD with zoledronate. CONCLUSIONS: Fracture reductions with single dose or 5-yearly zoledronate appear greater in years 5-10 than years 0-5. The risk reductions are broadly consistent across this cohort and independent of baseline or change in BMD. This suggests that routine BMD monitoring may not be necessary for low-risk women considering the option of less frequent zoledronate for long-term fracture risk reduction.© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society. Note: This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.https://creativecommons.org/licenses/by/4.0/bone mineral densityfracturepostmenopausal womenzoledronatebone mineral densityfracturepostmenopausal womenzoledronate32 Biomedical and Clinical Sciences3202 Clinical SciencesWomen's HealthAgingClinical Trials and Supportive ActivitiesClinical ResearchPhysical Injury - Accidents and Adverse EffectsOsteoporosis6.1 PharmaceuticalsMusculoskeletalInjuries and accidents1103 Clinical Sciences1114 Paediatrics and Reproductive MedicineEndocrinology & Metabolism3202 Clinical sciencesHumansFemaleZoledronic AcidMiddle AgedBone Density Conservation AgentsBone DensityDouble-Blind MethodOsteoporotic FracturesProspective StudiesOsteoporosis, PostmenopausalSpinal FracturesTreatment OutcomeFollow-Up StudiesDrug Administration ScheduleHumansOsteoporosis, PostmenopausalSpinal FracturesTreatment OutcomeDrug Administration ScheduleFollow-Up StudiesProspective StudiesDouble-Blind MethodBone DensityMiddle AgedFemaleBone Density Conservation AgentsOsteoporotic FracturesZoledronic AcidHumansFemaleZoledronic AcidMiddle AgedBone Density Conservation AgentsBone DensityDouble-Blind MethodOsteoporotic FracturesProspective StudiesOsteoporosis, PostmenopausalSpinal FracturesTreatment OutcomeFollow-Up StudiesDrug Administration ScheduleJournal ArticleOpenAccess10.1210/clinem/dgaf569