Center for Advanced Orthopaedic Studies, Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA; Department of Orthopaedic Surgery, Harvard Medical School, Boston, MA, USA.
Center for Advanced Orthopaedic Studies, Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Bone. 2021 Mar;144:115801. doi: 10.1016/j.bone.2020.115801. Epub 2020 Dec 16.
Disuse osteoporosis can result from prolonged bed rest, paralysis, casts, braces, fractures and other conditions. Abaloparatide (ABL) is a PTHrP analog that increases bone density and strength by stimulating osteogenesis with limited effects on bone resorption. We examined skeletal responses to abaloparatide in young adult male rats with normal weight-bearing and with hindlimb unloading via a pelvic harness. Rats were allocated to four groups (10-12 per group): normal weight-bearing plus vehicle treatment (CON-VEH), normal weight-bearing plus ABL treatment (CON-ABL), hindlimb-unloading plus vehicle (HLU-VEH), or hindlimb-unloading plus ABL (HLU-ABL). Rats received ABL (25 μg/kg/day, s.c.) or vehicle throughout the 28-day unloading period and were then sacrificed, at which time HLU-VEH rats exhibited reduced bone formation and significant deficits in tibial, femoral, and vertebral bone mass compared with CON-VEH. ABL treatment increased serum osteocalcin in CON and HLU animals while having no effect on the osteoclast marker TRACP-5b. Longitudinal peripheral quantitative computed tomography (pQCT) indicated that ABL increased trabecular and cortical bone mass in the tibia. ABL was also associated with improved trabecular and cortical bone mass and architectural parameters at the femur, tibia, and vertebrae by μCT. Tibial histomorphometry indicated increased trabecular and endocortical bone formation with HLU-ABL versus HLU-VEH and with CON-ABL versus CON-VEH, and ABL was also associated with lower trabecular and endocortical osteoclast surfaces. Vertebral finite element analysis indicated higher ultimate load and stiffness for CON-ABL versus CON-VEH and for HLU-ABL versus HLU-VEH. In summary, ABL was associated with improved trabecular and cortical bone density and architecture in normal weight-bearing and hindlimb-unloaded rats, with higher bone formation and no difference in bone resorption. ABL was also associated with improved bone biomechanical parameters. These results provide rationale for investigating the ability of abaloparatide to prevent or treat disuse osteoporosis in humans.
废用性骨质疏松症可由长时间卧床、瘫痪、石膏固定、支具、骨折和其他疾病引起。阿巴洛肽（abaloparatide，ABL）是一种甲状旁腺素相关肽（PTHrP）类似物，它通过刺激成骨作用来增加骨密度和骨强度，而对骨吸收的影响有限。我们研究了 abaloparatide 对正常负重和通过骨盆吊带进行后肢去负荷的年轻成年雄性大鼠的骨骼反应。将大鼠分为四组（每组 10-12 只）：正常负重加 vehicle 处理（CON-VEH）、正常负重加 ABL 处理（CON-ABL）、后肢去负荷加 vehicle（HLU-VEH）或后肢去负荷加 ABL（HLU-ABL）。大鼠在 28 天去负荷期间每天接受 ABL（25μg/kg，皮下注射）或 vehicle 处理，然后处死，结果显示 HLU-VEH 大鼠的骨形成减少，胫骨、股骨和椎体骨量明显不足，与 CON-VEH 相比。ABL 治疗增加了 CON 和 HLU 动物的血清骨钙素，而对破骨细胞标志物 TRACP-5b 没有影响。纵向外周定量计算机断层扫描（pQCT）表明 ABL 增加了胫骨的小梁和皮质骨量。ABL 还通过 μCT 改善了股骨、胫骨和椎体的小梁和皮质骨量和结构参数。胫骨组织形态计量学分析表明，与 HLU-VEH 相比，HLU-ABL 增加了小梁和内皮质骨形成，与 CON-VEH 相比，CON-ABL 也增加了小梁和内皮质骨形成，ABL 还与较低的小梁和内皮质破骨细胞表面有关。椎体有限元分析表明，CON-ABL 与 CON-VEH 相比，HLU-ABL 与 HLU-VEH 相比，最终负载和刚度更高。总之，ABL 与正常负重和后肢去负荷大鼠的小梁和皮质骨密度和结构的改善有关，与骨形成增加而骨吸收无差异有关。ABL 还与改善的骨生物力学参数有关。这些结果为研究 abaloparatide 预防或治疗人类废用性骨质疏松症的能力提供了依据。
