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. G rowth hormone (GH) is a potent mitogenic agent that is frequently used to increase linear growth in children with chronic renal failure. The growth response, however, remains suboptimal in children who are maintained on chronic dialysis therapy compared with predialysis patients who are on conservative medical treatment (1). Causative factors that may contribute to the poor response to GH in dialysis children include a greater degree of GH insensitivity, increased severity of secondary hyperparathyroidism, differences in skeletal histology, concurrent treatment with vitamin D, and high doses of calcium salts.GH stimulates proliferation in various types of cells, including chondrocytes and osteoblasts, and increases collagen production either directly by binding to the GH receptor (GHR) or indirectly by increasing hepatic and local IGF-I production (2-4). Calcitriol (1,25-dihydroxyvitamin D 3 ) is used on a regular basis to maintain normocalcemia, control the development and progression of secondary hyperparathyroidism, and prevent renal bone disease in pediatric patients with chronic renal failure. Studies have shown that calcitriol exerts a dose-dependent antiproliferative effect on chondrocytes and osteoblasts (5). Mehls et al. (6) demon...

Paricalcitol versus calcitriol treatment for hyperparathyroidism in pediatric hemodialysis patients

“…As reported previously in adults and children, growth hormone increases endogenous parathyroid hormone and higher doses of vitamin D analogues may be required to control the SHPT [25][26][27].…”

Growth after renal transplantation

“…This increase did not persist over time after a long-lasting treatment with rhGH in patients with Turner syndrome [83]. Transient increases in alkaline phosphatase activity, serum phosphate concentration [70] or even PTH concentration [68] have been observed in randomized controlled trials, but rhGH did not induce an increased incidence of renal osteodystrophy; however, overt renal osteodystrophy may blunt the response to rhGH [84]. …”

Intermittent or daily administration of 1-alpha calcidol for nephrectomised infants on peritoneal dialysis?

“…No additional illnesses were reported that could account for this. Previous studies have shown that calcitriol exerts a dose-dependent antiproliferative effect on chondrocytes and osteoblasts [31], while Sanchez et al, studying the effect of growth hormone (GH) on bone in uraemic rats with either intermittent or daily administrations of calcitriol [32], found that the medication attenuated the effect of the GH-induced increase in insulin-like growth factor (IGF)-I, IGF-binding protein (IGFBP)-3 and GH receptor (GHR) protein expression on chondrocytes in the growth plate. In addition, growth hormone increased PTH/parathyroid hormone-related protein (PTHrP) receptor protein expression more when administered with intermittent calcitriol than with daily calcitriol.…”