Houchen Lyu1, Kazuki Yoshida2, Sizheng S Zhao3, Jie Wei4, Chao Zeng5, Sara K Tedeschi2, Benjamin Z Leder6, Guanghua Lei7, Peifu Tang8, Daniel H Solomon9. 1. National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, General Hospital of Chinese PLA, Beijing, China, Xiangya Hospital of Central South University, Changsha, China, and Brigham and Women's Hospital, Boston, Massachusetts (H.L.). 2. Brigham and Women's Hospital, Boston, Massachusetts (K.Y., S.K.T.). 3. Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom (S.S.Z.). 4. Health Management Center, Xiangya Hospital of Central South University, Changsha, China (J.W.). 5. Xiangya Hospital of Central South University, Changsha, China (C.Z.). 6. Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (B.Z.L.). 7. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, and Hunan Key Laboratory of Joint Degeneration and Injury, Changsha, China (G.L.). 8. National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, General Hospital of Chinese PLA, Beijing, China (P.T.). 9. Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (D.H.S.).
Abstract
BACKGROUND: Denosumab is effective for osteoporosis, but discontinuation leads to rapid reversal of its therapeutic effect. OBJECTIVE: To estimate the risk for fracture among users of denosumab who delayed subsequent doses compared with users who received doses on time. DESIGN: Population-based cohort study. SETTING: The Health Improvement Network U.K. primary care database, 2010 to 2019. PATIENTS: Persons aged 45 years or older who initiated denosumab therapy for osteoporosis. MEASUREMENTS: Observational data were used to emulate an analysis of a hypothetical trial with 3 dosing intervals: subsequent denosumab injection given within 4 weeks after the recommended date ("on time"), delay by 4 to 16 weeks ("short delay"), and delay by more than 16 weeks ("long delay"). The primary outcome was a composite of all fracture types at 6 months after the recommended date. Secondary outcomes were major osteoporotic fracture, vertebral fracture, hip fracture, and nonvertebral fracture. RESULTS: Investigators identified 2594 patients initiating denosumab therapy. The risk for composite fracture over 6 months was 27.3 in 1000 for on-time dosing, 32.2 in 1000 for short delay, and 42.4 in 1000 for long delay. Compared with on-time injections, short delay had a hazard ratio (HR) for composite fracture of 1.03 (95% CI, 0.63 to 1.69) and long delay an HR of 1.44 (CI, 0.96 to 2.17) (P for trend = 0.093). For vertebral fractures, short delay had an HR of 1.48 (CI, 0.58 to 3.79) and long delay an HR of 3.91 (CI, 1.62 to 9.45). LIMITATION: Dosing schedules were not randomly assigned. CONCLUSION: Although delayed administration of subsequent denosumab doses by more than 16 weeks is associated with increased risk for vertebral fracture compared with on-time dosing, evidence is insufficient to conclude that fracture risk is increased at other anatomical sites with long delay. PRIMARY FUNDING SOURCE: National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation.
BACKGROUND:Denosumab is effective for osteoporosis, but discontinuation leads to rapid reversal of its therapeutic effect. OBJECTIVE: To estimate the risk for fracture among users of denosumab who delayed subsequent doses compared with users who received doses on time. DESIGN: Population-based cohort study. SETTING: The Health Improvement Network U.K. primary care database, 2010 to 2019. PATIENTS: Persons aged 45 years or older who initiated denosumab therapy for osteoporosis. MEASUREMENTS: Observational data were used to emulate an analysis of a hypothetical trial with 3 dosing intervals: subsequent denosumab injection given within 4 weeks after the recommended date ("on time"), delay by 4 to 16 weeks ("short delay"), and delay by more than 16 weeks ("long delay"). The primary outcome was a composite of all fracture types at 6 months after the recommended date. Secondary outcomes were major osteoporotic fracture, vertebral fracture, hip fracture, and nonvertebral fracture. RESULTS: Investigators identified 2594 patients initiating denosumab therapy. The risk for composite fracture over 6 months was 27.3 in 1000 for on-time dosing, 32.2 in 1000 for short delay, and 42.4 in 1000 for long delay. Compared with on-time injections, short delay had a hazard ratio (HR) for composite fracture of 1.03 (95% CI, 0.63 to 1.69) and long delay an HR of 1.44 (CI, 0.96 to 2.17) (P for trend = 0.093). For vertebral fractures, short delay had an HR of 1.48 (CI, 0.58 to 3.79) and long delay an HR of 3.91 (CI, 1.62 to 9.45). LIMITATION: Dosing schedules were not randomly assigned. CONCLUSION: Although delayed administration of subsequent denosumab doses by more than 16 weeks is associated with increased risk for vertebral fracture compared with on-time dosing, evidence is insufficient to conclude that fracture risk is increased at other anatomical sites with long delay. PRIMARY FUNDING SOURCE: National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation.
Authors: S De Vincentis; D Domenici; A Ansaloni; G Boselli; G D'Angelo; A Russo; E Taliani; V Rochira; M Simoni; B Madeo Journal: J Endocrinol Invest Date: 2022-05-19 Impact factor: 5.467
Authors: Athanasios D Anastasilakis; Stergios A Polyzos; Maria P Yavropoulou; Natasha M Appelman-Dijkstra; Charikleia Ntenti; Stylianos Mandanas; Athanasios Papatheodorou; Polyzois Makras Journal: Calcif Tissue Int Date: 2021-01-02 Impact factor: 4.333