Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-ku, Sapporo, 060-8638, Japan.
Chitose Institute of Science and Technology, Chitose, Japan.
Osteoporos Int. 2017 Apr;28(4):1481-1490. doi: 10.1007/s00198-016-3861-7. Epub 2016 Dec 8.
This study showed that bisphosphonate was safe and effective for the treatment of bone disorders in stage 4 chronic kidney disease (CKD) rats. Intermittent teriparatide therapy showed an anabolic action on bone even under secondary hyperparathyroidism conditions without having an adverse effect on mineral metabolism in late-stage CKD.
Patients with late-stage CKD are at high risk for fragility fractures. However, there are no consensus on the efficacy and safety of osteoporosis medications for patients with late-stage CKD. In the present study, we aimed to examine the efficacy and safety of alendronate (ALN) and teriparatide (TPD) for treating bone disorder in late-stage CKD with pre-existing secondary hyperparathyroidism using a rat model of CKD.
Male 10-week-old Sprague-Dawley rats were subjected to a 5/6 nephrectomy or sham surgery and randomized into the following four groups: sham, vehicle (saline subcutaneous (sc) daily), ALN (50 μg/kg sc daily), and TPD (40 μg/kg sc daily). Medications commenced at 24 weeks of age and continued for 4 weeks. Micro-computed tomography, histological analysis, infrared spectroscopic imaging, and serum assays were performed.
Nephrectomized rats developed hyperphosphatemia, secondary hyperparathyroidism (SHPT), and high creatinine, equivalent to CKD stage 4 in humans. ALN suppressed the bone turnover and increased the degree of mineralization in cortical bone, resulting in an improvement in the mechanical properties. TPD further increased the bone turnover and significantly increased the degree of mineralization, micro-geometry, and bone volume, resulting in a significant improvement in the mechanical properties. Both ALN and TPD had no adverse effect on renal function and mineral metabolism.
BP is safe and effective for the treatment of bone disorders in stage 4 CKD rats. Intermittent TPD therapy showed an anabolic action on bone even under SHPT conditions without having an adverse effect on mineral metabolism in late-stage CKD.
本研究旨在使用 CKD 大鼠模型，研究阿仑膦酸钠（ALN）和特立帕肽（TPD）治疗伴有继发甲状旁腺功能亢进的晚期 CKD 患者骨病的疗效和安全性。
雄性 10 周龄 Sprague-Dawley 大鼠接受 5/6 肾切除术或假手术，并随机分为以下 4 组：假手术组、 vehicle（生理盐水每日皮下注射）组、ALN（50μg/kg 每日皮下注射）组和 TPD（40μg/kg 每日皮下注射）组。药物治疗于 24 周龄开始，持续 4 周。进行 micro-computed tomography、组织学分析、红外光谱成像和血清检测。
肾切除大鼠出现高磷血症、继发甲状旁腺功能亢进（SHPT）和高肌酐，相当于人类的 CKD 4 期。ALN 抑制了骨转换并增加了皮质骨的矿化程度，从而改善了力学性能。TPD 进一步增加了骨转换，显著增加了矿化程度、微结构和骨量，从而显著改善了力学性能。ALN 和 TPD 均对肾功能和矿物质代谢无不良影响。
BP 对治疗 4 期 CKD 大鼠的骨病是安全有效的。间歇性 TPD 治疗在继发甲状旁腺功能亢进的情况下对骨骼具有合成代谢作用，而对晚期 CKD 矿物质代谢无不良影响。
