1,25-dihydroxyvitamin D-3 as well as its analogue OCT lower blood calcium through inhibition of bone resorption in hypercalcemic rats with continuousparathyroid hormone-related peptide infusion

The effects of 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] and its analogue 22-oxa-1,25(OH)(2)D-3 (22-oxacalcitriol) (OCT) on calcium and bone metaboli sm were examined in an animal model of hypercalcemia with continuous infusi on of parathyroid hormone-related peptide (PTHrP), to determine whether act ive vitamin D could counteract the skeletal action of PTHrP in addition to its reported effect in suppressing the production of PTHrP in cancer cells. Parathyroid glands were removed from 8-week-old Sprague-Dawley rats to eli minate the confounding effects of endogenous PTH. Animals were then continu ously infused with human PTHrP(1-34) at a constant rate via osmotic minipum ps for 2 weeks, and at the same time treated orally or intravenously with O CT or 1,25(OH)(2)D-3 four to nine times during the a-week period. Under the se conditions, OCT and, surprisingly, 1,25(OH)(2)D-3 alleviated hypercalcem ia in a dose-dependent manner. 1,25(OH)(2)D-3 and OCT suppressed the urinar y excretion of deoxypyridinoline, although they did not affect renal calciu m handling, suggesting that the antihypercalcemic effect is attributable to the inhibition of bone resorption, These active vitamin D compounds also c ounteracted the effects of PTHrP at the proximal renal tubules, as reflecte d by a decrease in phosphate excretion. Histomorphometric analysis of bone revealed a dose-related decrease in parameters of bone resorption, These re sults suggest that 1,25(OH)(2)D-3 as well as OCT has the potential to allev iate hypercalcemia, at least in part, through the inhibition of bone resorp tion in hypercalcemic rats with constant PTHrP levels. We propose that the main function of active vitamin D in high bone-turnover states is to inhibi t bone resorption, and this may have important implications for the underst anding of the role of active vitamin D in the treatment of metabolic bone d iseases, such as osteoporosis.