Clin Ther. 2026 Oct 19:S0149-2918(26)00353-X. doi: 10.1016/j.clinthera.2026.09.014. Online ahead of print.
ABSTRACT
PURPOSE: After a fragility fracture, subsequent fracture risk is highest during the first 6 to 12 months and remains elevated for 1 to 2 years. Anti-osteoporosis therapies differ in onset, persistence, discontinuation kinetics, and safety constraints, yet guidelines rarely operationalize treatment timing within this imminent-risk period. This narrative review examines temporal mismatch between post-fracture risk and treatment effect and proposes a time-matched secondary fracture prevention framework.
METHODS: We conducted an argument-driven narrative review using a structured, non-systematic search of PubMed/MEDLINE and Google Scholar from January 2000 through July 26, 2026. English-language guidelines, pivotal randomized trials, systematic reviews/meta-analyses, and implementation or health-services studies relevant to secondary fracture prevention were included, with priority given to 2024 to 2026 publications. Selection was purposive; no formal risk-of-bias assessment or pooled statistical analysis was performed.
FINDINGS: The evidence base comprised 103 publications and one trial-registry record. Subsequent fractures consistently clustered within the first 12 to 24 months after an index fracture. A pooled meta-analysis of bisphosphonate trials in postmenopausal osteoporosis estimated 12.4 months (95% CI, 6.3 to 18.4 months) to prevent one nonvertebral fracture per 100 treated women; this population-level estimate is not a drug-specific onset threshold and was not derived specifically from recent-fracture patients. Several injectable antiresorptive and bone-forming therapies show early fracture-risk reduction in pivotal trials, but treatment choice must remain safety qualified. In particular, romosozumab requires cardiovascular risk assessment because of the imbalance in serious cardiovascular events observed in ARCH and current labeling restrictions. Rare medication-related osteonecrosis of the jaw and denosumab-associated hypocalcemia in advanced chronic kidney disease are additional counseling and monitoring considerations. Treatment cessation is also time-sensitive, especially for denosumab because delayed dosing or discontinuation without follow-on therapy can lead to rebound bone turnover and vertebral fractures.
IMPLICATIONS: Secondary fracture prevention may be improved by initiating appropriate therapy promptly after the index fracture, matching treatment characteristics to the period of highest risk, planning sequential therapy from the outset, and minimizing delivery delays. The framework is hypothesis-generating and should not override drug-specific contraindications, local labeling, or individualized benefit-risk assessment. Prospective studies should test whether explicitly time-matched care reduces early re-fracture compared with conventional risk-stratified treatment.
PMID:42897034 | DOI:10.1016/j.clinthera.2026.09.014