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Abstract
Although active vitamin D is used in certain countries for the treatment of osteoporosis,
the risk of causing hypercalcemia/hypercalciuria means that there is only a narrow
therapeutic window, and this has precluded worldwide approval. The results of our
previous animal studies have suggested that the therapeutic effect of active vitamin
D on bone loss after estrogen deficiency can be dissociated at least partly from its
effect of enhancing intestinal calcium absorption and suppressing parathyroid hormone
(PTH) secretion. To test this, we compared the effects of ED-71, a hydroxypropoxy
derivative of 1alpha,25-dihydroxyvitamin D3, with orally administered alfacalcidol,
on bone mineral density (BMD) and the bone remodeling process as a function of their
effects on calcium metabolism and PTH, in a rat ovariectomy (ovx) model of osteoporosis.
ED-71 increased bone mass at the lumbar vertebra to a greater extent than alfacalcidol,
while enhancing calcium absorption (indicated by urinary calcium excretion) and decreasing
serum PTH levels to the same degree as alfacalcidol. ED-71 lowered the biochemical
and histological parameters of bone resorption more potently than alfacalcidol, while
maintaining bone formation markers. These results suggest that active vitamin D exerts
an antiosteoporotic effect by inhibiting osteoclastic bone resorption while maintaining
osteoblastic function, and that these anticatabolic/anabolic effects of active vitamin
D take place independently of its effects on calcium absorption and PTH. The demonstration
that ED-71 is more potent in these properties than alfacalcidol makes it an attractive
candidate as an antiosteoporotic drug.