Differential effects of intermittent PTH(1–34) and PTH(7–34) on bone microarchitecture and aortic calcification in experimental renal failure

PTH(1–84) and PTH(7–84) are elevated in chronic kidney disease (CKD). These peptides, as their shorter analogs PTH(1–34) and PTH(7–34) both promote PTH receptor (PTH1R) internalization but only PTH(1–34) and PTH(1–84) activate the receptor. Here, we examined the effects of intermittent administration of PTH(1–34) and PTH(7–34) on mineral ion metabolism, bone architecture, and vascular calcification in rats with experimental CKD. CKD with or without parathyroidectomy (PTX) was established by 5/6 nephrectomy (NPX) in rats. Animals were divided into 4 groups: Sham PTX+ sham NPX (Sham); PTX+ sham NPX (PTX); Sham PTX+NPX (NPX); PTX+NPX (PTX/NPX). Rats were treated with single daily doses of 40 μg/kg PTH(1–34), PTH(7–34), or vehicle. Creatinine was higher in NPX and Ca lower in PTX and PTX/NPX groups than in Sham or NPX rats. Plasma phosphate was higher in PTX, NPX and PTX/NPX than in Sham rats. PTH(1–34) was more hypercalcemic than PTH(7–34) in PTX rats. Fractional bone volume in rats treated with PTH(1–34) increased significantly in all groups compared to that of vehicle treatment. In addition, trabecular number, thickness and volumetric bone density increased in rats treated with PTH(1–34). In contrast, PTH(1–34) diminished vascular calcification. Bone and renal PTH1R mRNA expression was reduced as much or more in PTX/NPX rats as in NPX alone, whereas PTH(7–34) had no effect on PTH1R expression. Renal but not bone PTH1R mRNA increased in response to PTH(1–34). These findings suggest that PTH(1–34) exerts greater hypercalcemic and anabolic effects in parathyroidectomized and/or nephrectomized rats than does PTH(7–34). There was no evidence for significant bone or vascular actions of PTH(7–34). We conclude that PTH(1–34) protects against vascular calcification and bone demineralization in experimental renal failure.