Effects of new vitamin D analogues on parathyroid function in chronically uraemic rats with secondary hyperparathyroidism

Abstract

Treatment with calcitriol or its analogue, alfacalcidol often leads to hypercalcaemia, hyperphosphataemia or both in patients which chronic renal failure and advanced secondary hyperparathyroidism. We tested three new vitamin D analogues (CB 1093, EB 1213, GS 1725) in an attempt to identify potentially non hypercalcaemic compounds, capable of decreasing plasma parathyroid hormone (PTH) concentration. Male Wistar AF rats aged 12-14 weeks were fed a synthetic, phosphate-rich diet and underwent either sham surgery (control) or a standard two-step 5/6th nephrectomy. Four weeks later, renal function was mildly decreased in the latter. Chronic renal failure rats were then divided into six groups, with 8-10 rats in each group. They received daily 1.p. injections, from days 0 to 4, of either placebo, calcitriol, or one of the following three active vitamin D analogues: CB1093, 0.25 micrograms; EB1213, 0.25 or 1.25 micrograms; and GS1725, 0.025 micrograms/kg body weight per day, respectively. Sham-operated rats received no drug. On day 5, arterial blood was sampled and rats were sacrificed. At predefined dosage schedules, all three compounds significantly decreased plasma immunoreactive PTH levels (except EB1213 at low dose). The decrement was somewhat less marked than that obtained with calcitriol, at the dose of 0.25 micrograms/kg b.w. per day. However, calcitriol induced a marked increase in plasma calcium and phosphate concentrations at that dose, whereas vitamin D analogues led to a more modest increase in plasma calcium level, and none to a worsening of hyperphosphataemia. CB1093 treatment was even associated with a significant decrease in plasma phosphate level. All three calcitriol analogues tested are promising as non-hypercalcaemic agents in the treatment of uraemic secondary hyperparathyroidism. However, more prolonged administration to uraemic rats of calcitriol analogues with slightly modified dosage schedules and of calcitriol with lower non-hypercalcaemic dose is required for an optimal comparison before considering clinical trials.