Abaloparatide improves cortical geometry and trabecular microarchitecture and increases vertebral and femoral neck strength in a rat model of male osteoporosis
Abaloparatide improves cortical geometry and trabecular microarchitecture and increases vertebral and femoral neck strength in a rat model of male osteoporosis
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DOI：
10.1016/j.bone.2019.04.025
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发表时间：
2019-07-01
期刊：
影响因子：
4.1
通讯作者：
Lanske, Beate
中科院分区：
文献类型：
--
作者：
Besschetnova, Tatiana;Brooks, Daniel J.;Lanske, Beate
雄激素缺乏是男性骨质疏松症的主要原因，与骨吸收程度相关的骨形成水平不足导致骨质流失。Abaloparatide是一种骨合成代谢PTH受体激动剂，用于治疗绝经后骨质疏松的骨折高风险妇女，可增加雌激素缺乏动物的骨形成和骨强度，但不增加骨吸收。本研究考察了阿巴帕肽对雄性骨质疏松模型雄性睾丸切除（ORX）大鼠骨形成、骨量和骨强度的影响。四个月大的Sprague-Dawley大鼠接受ORX或假手术。8周后，假手术大鼠给予药体（生理盐水，n = 10）， ORX大鼠（n = 10/组）每日s.c.注射药体（Veh）或abalopar肽（ABL5或ABL25），剂量为5或25 pg/kg，连续8周，然后献祭。动态骨组织形态学测定表明，与Veh对照组相比，一个或两个abalopar肽组的胫骨骨干骨膜矿化表面、皮质内骨形成率（BFR）、皮质内骨形成率（BFR）和皮质厚度更高。与Veh相比，ABL25组的椎小梁BFR也更高，ABL25组的骨小梁成骨细胞表面更高，但破骨细胞表面没有增加。显微ct显示，与Veh相比，ABL25组的椎骨和股骨远端骨小梁体积和微结构均有所改善，ABL25组的股骨骨干皮质厚度更大，孔隙率未增加。生物力学测试表明，与Veh对照组相比，两组abalopaparty组具有更强的椎骨和股骨颈。这些发现为评估阿巴巴拉肽作为男性骨质疏松症的研究性治疗提供了临床前支持。
Androgen deficiency is a leading cause of male osteoporosis, with bone loss driven by an inadequate level of bone formation relative to the extent of bone resorption. Abaloparatide, an osteoanabolic PTH receptor agonist used to treat women with postmenopausal osteoporosis at high risk for fracture, increases bone formation and bone strength in estrogen-deficient animals without increasing bone resorption. This study examined the effects of abaloparatide on bone formation, bone mass, and bone strength in androgen-deficient orchiectomized (ORX) rats, a male osteoporosis model. Four-month-old Sprague-Dawley rats underwent ORX or sham surgery. Eight weeks later, sham-operated rats received vehicle (saline; n = 10) while ORX rats (n = 10/group) received vehicle (Veh) or abaloparatide at 5 or 25 pg/kg (ABL5 or ABL25) by daily s.c. injection for 8 weeks, followed by sacrifice. Dynamic bone histomorphometry indicated that the tibial diaphysis of one or both abaloparatide groups had higher periosteal mineralizing surface, intracortical bone formation rate (BFR), endocortical BFR, and cortical thickness vs Veh controls. Vertebral trabecular BFR was also higher in both abaloparatide groups vs Veh, and the ABL25 group had higher trabecular osteoblast surface without increased osteoclast surface. By micro-CT, the vertebra and distal femur of both abaloparatide-groups had improved trabecular bone volume and micro-architecture, and the femur diaphysis of the ABL25 group had greater cortical thickness with no increase in porosity vs Veh. Biomechanical testing indicated that both abaloparatide-groups had stronger vertebrae and femoral necks vs Veh controls. These findings provide preclinical support for evaluating abaloparatide as an investigational treatment for male osteoporosis.