Department of Transplant Surgery, Tokai University School of Medicine, Isehara, Japan.
Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, 143 Shimo-Kasuya, Isehara, 259-1193, Japan.
J Bone Miner Metab. 2020 Jul;38(4):501-510. doi: 10.1007/s00774-020-01095-0. Epub 2020 Mar 5.
High-turnover bone disease is a major consequence of SHPT and may explain the high risk for fracture in patients with advanced chronic kidney disease (CKD). Bisphosphonates suppress bone turnover and improve bone strength, but their effects have not been fully characterized in advanced CKD with severe SHPT. Bisphosphonates also increase 1,25-dihydroxyvitamin D levels in normal and uremic rats, but the underlying mechanism remains to be determined.
We investigated the skeletal and mineral metabolic effects of RIS, a pyridinyl bisphosphonate, in rats with severe SHPT induced by 5/6 nephrectomy plus a high phosphate diet.
Nephrectomized rats developed severe SHPT, along with hyperphosphatemia, low 1,25-dihydroxyvitamin D, and markedly increased FGF23. Moreover, these rats exhibited characteristic features of high-turnover renal osteodystrophy, including increased indices of trabecular bone turnover, decreased cortical bone thickness, inferior cortical biomechanical properties, and a prominent increase in peritrabecular fibrosis. RIS treatment increased bone volume and partially attenuated trabecular bone remodeling, cortical bone loss, and mechanical properties, whereas it produced a marked improvement in peritrabecular fibrosis along with a corresponding decrease in osteogenic gene markers. RIS treatment also suppressed the elevation of FGF23, which was associated with increased 1,25-dihydroxyvitamin D.
In a rat model of severe SHPT, treatment with RIS partially attenuated histological manifestations of high-turnover bone disease. RIS treatment also suppressed the elevation of FGF23, which may explain the increased 1,25-dihydroxyvitamin D production during the treatment.
高转换率骨病是甲状旁腺功能亢进症的主要后果，可能解释了晚期慢性肾脏病（CKD）患者骨折风险高的原因。双膦酸盐抑制骨转换并改善骨强度，但它们在伴有严重甲状旁腺功能亢进症的晚期 CKD 中的作用尚未完全确定。双膦酸盐还增加了正常和尿毒症大鼠 1,25-二羟维生素 D 的水平，但潜在的机制仍有待确定。
我们研究了一种吡啶基双膦酸盐 RIS 在 5/6 肾切除加高磷饮食诱导的严重 SHPT 大鼠中的骨骼和矿物质代谢作用。
肾切除大鼠发生严重的甲状旁腺功能亢进症，伴有高磷血症、低 1,25-二羟维生素 D 和显著增加的 FGF23。此外，这些大鼠表现出高转换率肾性骨营养不良的特征性特征，包括增加的小梁骨转换指数、皮质骨厚度降低、皮质骨生物力学特性降低以及骨小梁周围纤维化明显增加。RIS 治疗增加了骨量并部分减轻了小梁骨重塑、皮质骨丢失和机械性能，同时显著改善了骨小梁周围纤维化，并相应降低了成骨基因标志物。RIS 治疗还抑制了 FGF23 的升高，这与 1,25-二羟维生素 D 的增加有关。
在严重 SHPT 的大鼠模型中，RIS 治疗部分减轻了高转换率骨病的组织学表现。RIS 治疗还抑制了 FGF23 的升高，这可能解释了治疗期间 1,25-二羟维生素 D 产量的增加。
