THERAPEUTIC EFFICACY OF 1-ALPHA,25-DIHYDROXYVITAMIN D-3 AND CALCIUM IN OSTEOPENIC OVARIECTOMIZED RATS - EVIDENCE FOR A DIRECT ANABOLIC EFFECT OF 1-ALPHA,25-DIHYDROXYVITAMIN D-3 ON BONE

It is an important question for clinical therapy of osteoporosis with vitamin D metabolites whether these compounds exert their beneficial e ffects on the skeleton indirectly through an increase in intestinal ca lcium absorption or whether there is also a major direct component of action on bone. In this study, female 6-month-old Fischer rats were ei ther ovariectomized (OVX) or sham operated. One month before surgery, all rats were placed on a diet containing 0.25% calcium and were kept on this diet throughout the study. Beginning 3 months post-OVX, groups of OVX rats orally received vehicle, a calcium supplement, low dose ( 0.025 mu g/kg.day) or high dose (0.1 mu g/kg.day) 1 alpha,25-dihydroxy vitamin D-3 [1,25-(OH)(2)D-3], or combinations of low and high dose 1, 25-(OH)(2)D-3 with the calcium supplement. By 3 months postsurgery, pr etreatment OVX controls had lost 74% and 37% of tibial and vertebral c ancellous bone, respectively. Two-way factorial ANOVA showed that a 3- month treatment of osteopenic OVX rats with 1,25-(OH)(2)D-3 dose depen dently increased vertebral and tibial cancellous bone mass (P < 0.001 and P = 0.021, respectively) and trabecular width (P < 0.001). Further more, 1,25-(OH)(2)D-3 increased serum calcium (P = 0.028) and urinary calcium excretion (P < 0.001) and reduced serum PTH levels (P < 0.001) , osteoclast numbers (P < 0.001), and urinary collagen cross-links exc retion (P < 0.001). Calcium supplementation alone was without therapeu tic effect, and there was no significant two-way interaction between t he individual treatment effects of 1,25-(OH)(2)D-3 and calcium on bone mass. These data indicate that the anabolic effects of 1,25-(OH)(2)D- 3 in osteopenic OVX rats are mediated through a direct activity on bon e.