INTERMITTENT VERSUS CONTINUOUS ADMINISTRATION OF 1,25-DIHYDROXYVITAMIN-D(3) IN EXPERIMENTAL RENAL HYPERPARATHYROIDISM

Conflicting results have been reported regarding the efficacy of intermittent versus continuous administration of 1,25(OH)2D3 in renal secondary hyperparathyroidism. To address this issue we examined sham-operated control rats and hyperparathyroid rats with subtotal (5/6) nephrectomy (Nx). The Nx animals (20 to 22 animals per group) were subjected to three treatment protocols: (i) solvent treatment (Nx-solvent); (ii) two i.p. injections of 35 pmol 1,25(OH)2D3 on days 0 and 4 (Nx-bolus); and (iii) continuous infusion of 70 pmol 1,25(OH)2D3 over six days via osmotic minipump (Nx-infusion). All measurements were performed six days after start of treatment. As compared to sham-operated controls, the pre-pro-PTH/beta-actin mRNA ratio was 2.04-fold higher in Nx-solvent. Both modes of administration of 1,25(OH)2D, resulted in inhibition of PTH mRNA concentrations relative to Nx-solvent. The pre-pro-PTH/beta-actin mRNA ratio was, however, significantly lower (P < 0.05) in Nx-bolus than in Nx-infusion (Nx-bolus 1.26 higher than sham-operated controls; Nx-infusion 1.65 higher than sham-operated controls). Aminoterminal PTH (N-PTH) serum concentrations were higher in Nx-solvent (52 +/- 4 pg/ml) than in sham-operated controls (32 +/- 3 pg/ml, P < 0.01). N-PTH concentrations in Nx-bolus (38 +/- 4 pg/ml) were significantly lower than in Nx-solvent (P < 0.01) and in Nx-infusion (46 +/- 4 pg/ml, P < 0.05). Parathyroid gland weight (mug/g body wt) was higher in Nx-solvent (1.30 +/- 0.08 pg/ml) than in sham-operated controls (0.79 +/- 0.04 pg/ml, P < 0.02). Again, parathyroid weight was lower in Nx-bolus (0.99 +/- 0.014 pg/ml, P < 0.05 vs. Nx-solvent) than in Nx-infusion (1.16 +/- 0.06 pg/ml). Differential effects of bolus versus infusion treatment were not explained by changes in serum calcium or phosphate. Analysis of the 1,25(OH)2D3 concentration time-profile showed higher peak concentrations in bolus-treated animals (170 to 200 pg/ml after 8 hr) than in infusion-treated animals (125 to 130 pg/ml after 48 hr). The time-averaged mean increase in 1,25(OH)2D3 serum concentrations was, however, higher in infusion-treated animals (42.3 pg/ml/24 hr) than in bolus-treated animals (26.0 pg/ml/24 hr). We conclude that the stimulation of parathyroid gland function in experimental uremia is more effectively suppressed when the same total dose of 1,25(OH)2D3 is given by intermittent bolus administration than by continuous infusion. Our results are compatible with the notion that the 1,25(OH)2D3 concentration time-profile, that is, the 1,25(OH)2D3 peak concentration, is an important determinant of the response of parathyroid glands to 1,25(OH)2D3.