Daily or intermittent calcitriol administration during growth hormone therapy in rats with renal failure and advanced secondary hyperparathyroidism

Abstract

Growth hormone (GH) improves growth in children with chronic renal failure. The response to GH may be affected by the degree of secondary hyperparathyroidism and concurrent treatment with vitamin D. Forty-six rats underwent 5/6 nephrectomy (Nx) and were given a high-phosphorus diet (Nx-Phos) to induce advanced secondary hyperparathyroidism and divided into the following groups: (1) Nx-Phos (n = 10) received saline, (2) GH at 10 IU/kg per d (Nx-Phos+GH; n = 9), (3) GH and daily calcitriol (D) at 50 ng/kg per d (Nx-Phos+GH+daily D; n = 8), (4) GH and intermittent D (three times weekly) at 350 ng/kg per wk (Nx-Phos+GH+int D; n = 9), and (5) intact-control (n = 10). Serum parathyroid hormone (PTH) levels were elevated in Nx-Phos, but IGF-I levels did not change with growth hormone. Body length, tibial length, and growth plate width did not increase with either GH or calcitriol. Proliferating cell nuclear antigen staining, PTH/PTHrP receptor, bone morphogenetic protein-7, and fibroblast growth factor receptor-3 expression increased with GH alone or with intermittent calcitriol but were slightly diminished during daily calcitriol administration. GH enhanced IGF-I, IGF binding receptor-3, and GH receptor but declined with daily and intermittent calcitriol. Overall, there was no improvement in body length, tibial length, and growth plate width at the end of GH therapy, but selected markers of chondrocyte proliferation and chondrocyte differentiation increased, although these changes were attenuated by calcitriol. The combination of GH and calcitriol that is frequently used in children with renal failure and secondary hyperparathyroidism require further studies to evaluate the optimal dose and frequency of administration to increase linear growth and prevent bone disease.