Radius Health Inc., 950 Winter Street, Waltham, Massachusetts.
University of Michigan School of Dentistry, Phylon Pharma Services, Newbury Park, California.
J Orthop Res. 2019 Apr;37(4):812-820. doi: 10.1002/jor.24254. Epub 2019 Mar 21.
Fractures typically heal via endochondral and intramembranous bone formation, which together form a callus that achieves union and biomechanical recovery. PTHrP, a PTH receptor agonist, plays an important physiological role in fracture healing as an endogenous stimulator of endochondral and intramembranous bone formation. Abaloparatide, a novel systemically-administered osteoanabolic PTH receptor agonist that reduces fracture risk in women with postmenopausal osteoporosis, has 76% homology to PTHrP, suggesting it may have potential to improve fracture healing. To test this hypothesis, ninety-six 12-week-old male rats underwent unilateral internally-stabilized closed mid-diaphyseal femoral fractures and were treated starting the next day with daily s.c. saline (Vehicle) or abaloparatide at 5 or 20 µg/kg/d for 4 or 6 weeks (16 rats/group/time point). Histomorphometry and histology analyses indicated that fracture calluses from the abaloparatide groups exhibited significantly greater total area, higher fluorescence scores indicating more newly-formed bone, and higher fracture bridging scores versus Vehicle controls. Callus bridging score best correlated with callus cartilage score (r = 0.64) and fluorescence score (r = 0.67) at week 4, and callus area correlated with cartilage score (r = 0.60) and fluorescence score (r = 0.89) at Week 6. By micro-CT, calluses from one or both abaloparatide groups had greater bone volume, bone volume fraction, bone mineral content, bone mineral density, and cross-sectional area at both time points versus Vehicle controls. Destructive bending tests indicated greater callus maximum load and stiffness in one or both abaloparatide groups at both time points versus Vehicle controls. These results provide preliminary preclinical evidence for improved fracture healing with systemically-administered abaloparatide. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
骨折通常通过软骨内和膜内成骨愈合，两者共同形成一个骨痂，实现联合和生物力学恢复。甲状旁腺素相关蛋白（PTHrP）是一种甲状旁腺素受体激动剂，作为软骨内和膜内成骨的内源性刺激物，在骨折愈合中发挥着重要的生理作用。阿巴洛肽，一种新型的全身性骨合成甲状旁腺素受体激动剂，可降低绝经后骨质疏松症妇女的骨折风险，与 PTHrP 有 76%的同源性，表明它可能有改善骨折愈合的潜力。为了验证这一假说，96 只 12 周龄雄性大鼠接受单侧稳定的闭合股骨中段骨折，次日开始每天皮下注射生理盐水（载体）或阿巴洛肽 5 或 20µg/kg/d，持续 4 或 6 周（每组 16 只/时间点）。组织形态计量学和组织学分析表明，与载体对照组相比，阿巴洛肽组的骨折骨痂总面积更大，荧光评分更高，表明新骨形成更多，骨桥形成评分更高。骨痂桥接评分与骨痂软骨评分（r=0.64）和荧光评分（r=0.67）在第 4 周相关性最好，而骨痂面积与软骨评分（r=0.60）和荧光评分（r=0.89）在第 6 周相关性最好。通过微 CT，一个或两个阿巴洛肽组的骨痂在两个时间点的骨体积、骨体积分数、骨矿物质含量、骨密度和横截面积均大于载体对照组。破坏性弯曲试验表明，一个或两个阿巴洛肽组的骨痂在两个时间点的最大负荷和刚度均大于载体对照组。这些结果为系统给予阿巴洛肽可改善骨折愈合提供了初步的临床前证据。版权所有©2019 骨科研究协会。由 Wiley Periodicals, Inc. 出版。J Orthop Res.
