a Orthopaedics, Department of Clinical and Experimental Medicine, Faculty of Health Sciences , Linköping University , Linköping , Sweden.
Acta Orthop. 2018 Dec;89(6):674-677. doi: 10.1080/17453674.2018.1523771. Epub 2018 Oct 18.
Background and purpose - Teriparatide accelerates fracture healing in animals and probably in man. Abaloparatide is a new drug with similar although not identical effects on the teriparatide receptor. Given at 4 times the teriparatide dose in a human osteoporosis trial, abaloparatide increased bone density more than teriparatide, and both reduced fracture risk. We investigated in mice whether abaloparatide stimulates fracture healing, and if it does so with the suggested dose effect relation (4:1). Patients and methods - In a validated mouse model for metaphyseal healing (burr hole with screw pull-out), 96 mice were randomly allocated to 11 groups: control (saline), teriparatide or abaloparatide, where teriparatide and abaloparatide were given at 5 different doses each. In a femoral shaft osteotomy model, 24 mice were randomly allocated to 3 groups: control (saline), teriparatide (15 µg/kg) or abaloparatide (60 µg/kg). Each treatment was given daily via subcutaneous injections. Results were evaluated by mechanical testing and microCT. Results - In the metaphyseal model, a dose-dependent increase in screw pull-out force could be seen. In a linear regression analysis (r = 0.78) each increase in ln(dose) by 1 (regardless of drug type) was associated with an increase in pull-out force by 1.50 N (SE 0.18) (p < 0.001). Changing drug from teriparatide to abaloparatide increased the force by 1.41 N (SE 0.60; p = 0.02). In the diaphyseal model, the callus density was 23% (SD 10), 38% (SD 10), and 47% (SD 2) for control, for teriparatide and abaloparatide respectively. Both drugs were significantly different from controls (p = 0.001 and p = 0.008), but not from each other. Interpretation - Both drugs improve fracture healing, but in these mouse models, the potency per µg of abaloparatide seems only 2.5 times that of teriparatide, rather than the 4:1 relation chosen in the clinical abaloparatide-teriparatide comparison trial.
背景与目的-特立帕肽可加速动物骨折愈合，可能对人类也有作用。阿巴洛肽是一种新药，对特立帕肽受体具有相似（但不完全相同）的作用。在骨质疏松症临床试验中，阿巴洛肽以特立帕肽 4 倍剂量给药，其增加骨密度的作用强于特立帕肽，且均降低了骨折风险。我们在小鼠中研究了阿巴洛肽是否能刺激骨折愈合，如果能，其作用是否符合建议的剂量效应关系（4:1）。患者和方法-在一种经验证的骺板愈合小鼠模型（骨钻加螺钉拔出）中，96 只小鼠被随机分配至 11 组：对照组（生理盐水）、特立帕肽或阿巴洛肽，其中特立帕肽和阿巴洛肽各有 5 个不同剂量。在股骨干骨折模型中，24 只小鼠被随机分配至 3 组：对照组（生理盐水）、特立帕肽（15 µg/kg）或阿巴洛肽（60 µg/kg）。每组均通过皮下注射每日给药。通过机械测试和 microCT 评估结果。结果-在骺板模型中，螺钉拔出力随剂量增加而增加。在线性回归分析（r = 0.78）中，ln（剂量）每增加 1，螺钉拔出力增加 1.50 N（SE 0.18）（p < 0.001）。将药物从特立帕肽改为阿巴洛肽可使力增加 1.41 N（SE 0.60；p = 0.02）。在骨干模型中，对照组、特立帕肽组和阿巴洛肽组的骨痂密度分别为 23%（SD 10）、38%（SD 10）和 47%（SD 2）。与对照组相比，两种药物均有显著差异（p = 0.001 和 p = 0.008），但彼此之间无差异。解释-两种药物均改善了骨折愈合，但在这些小鼠模型中，阿巴洛肽每微克的效价似乎仅为特立帕肽的 2.5 倍，而不是临床阿巴洛肽-特立帕肽比较试验中选择的 4:1 关系。
