Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, 060-8638, Japan.
Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
J Bone Miner Metab. 2019 Mar;37(2):256-263. doi: 10.1007/s00774-018-0930-3. Epub 2018 May 2.
Despite preclinical studies demonstrating the effectiveness of teriparatide for skeletal repair in small animals, inconclusive data from clinical trials have raised questions regarding the optimal teriparatide dosing regimen for bone repair. To address this, we assessed the effect of teriparatide frequency and dose on long-bone healing using a mouse femur osteotomy/fracture model. Eight-week-old male ICR mice were subjected to open femur osteotomies, then randomized into following five groups (n = 8 per group): vehicle; low dose/high frequency: 3 μg/kg/dose, 3 times/day; low dose/low frequency: 9 μg/kg/dose, 1 time/day; high dose/high frequency: 9 μg/kg/dose, 3 times/day; high dose/low frequency: 27 μg/kg/dose, 1 time/day. Skeletal repair was assessed by microcomputed tomography, mechanical testing, and histology 4 weeks after surgery. High-dose and/or high-frequency teriparatide treatment increased callus bone volume but failed to have a significant impact on the biomechanical recovery of fractured femurs, possibly because of impaired cortical shell formation in fracture calluses. Meanwhile, low-dose/low-frequency teriparatide therapy enhanced callus bone formation without interfering with cortical shell formation despite a lesser increase in callus bone volume, leading to significant two and fourfold increases in ultimate load and stiffness, respectively. Our findings demonstrate that administering teriparatide at higher doses and/or higher frequencies raises fracture callus volume but does not always accelerate the biomechanical recovery of fractured bone, which points to the importance of finding the optimal teriparatide dosing regimen for accelerating skeletal repair.
尽管临床前研究表明特立帕肽在小动物骨骼修复方面具有有效性,但临床试验的不确定数据引发了人们对特立帕肽治疗骨骼修复的最佳剂量方案的质疑。为了解决这个问题,我们使用小鼠股骨切开/骨折模型评估了特立帕肽的频率和剂量对长骨愈合的影响。将 8 周龄雄性 ICR 小鼠进行开放性股骨切开术,然后随机分为以下五组(每组 n=8):载体;低剂量/高频率:3μg/kg/剂量,每日 3 次;低剂量/低频率:9μg/kg/剂量,每日 1 次;高剂量/高频率:9μg/kg/剂量,每日 3 次;高剂量/低频率:27μg/kg/剂量,每日 1 次。手术后 4 周,通过 microCT、力学测试和组织学评估骨骼修复情况。高剂量和/或高频率的特立帕肽治疗增加了骨痂骨量,但对骨折股骨的生物力学恢复没有显著影响,这可能是由于骨折骨痂中皮质壳形成受损。同时,低剂量/低频率的特立帕肽治疗增强了骨痂骨形成,尽管骨痂骨量增加较少,但不干扰皮质壳形成,导致最终负荷和刚度分别显著增加了 2 倍和 4 倍。我们的研究结果表明,给予特立帕肽更高的剂量和/或更高的频率会增加骨折骨痂体积,但并不总是加速骨折骨的生物力学恢复,这表明找到最佳的特立帕肽剂量方案以加速骨骼修复非常重要。