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Therapeutic Efficacy of 1,25-Dihydroxyvitamin D₃ and Calcium in Osteopenic Ovariectomized Rats: Evidence for a Direct Anabolic Effect of 1,25-Dihydroxyvitamin D₃ on Bone¹

Institute of Physiology, Physiological Chemistry, and Animal Nutrition, Ludwig Maximilians University, Munich 80539, Germany

Address all correspondence and requests for reprints to: Dr. Reinhold G. Erben, Institute of Animal Physiology, University of Munich, Veterinaerstrasse 13, D-80539 Munich, Germany. E-mail: r.erben{at}lrz.uni-muenchen.de

It is an important question for clinical therapy of osteoporosis with vitamin D metabolites whether these compounds exert their beneficial effects on the skeleton indirectly through an increase in intestinal calcium absorption or whether there is also a major direct component of action on bone. In this study, female 6-month-old Fischer rats were either 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 µg/kg·day) or high dose (0.1 µg/kg·day) 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃], or combinations of low and high dose 1,25-(OH)₂D₃ with the calcium supplement. By 3 months postsurgery, pretreatment OVX controls had lost 74% and 37% of tibial and vertebral cancellous bone, respectively. Two-way factorial ANOVA showed that a 3-month treatment of osteopenic OVX rats with 1,25-(OH)₂D₃ dose dependently increased vertebral and tibial cancellous bone mass (P < 0.001 and P = 0.021, respectively) and trabecular width (P < 0.001). Furthermore, 1,25-(OH)₂D₃ 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 excretion (P < 0.001). Calcium supplementation alone was without therapeutic effect, and there was no significant two-way interaction between the individual treatment effects of 1,25-(OH)₂D₃ and calcium on bone mass. These data indicate that the anabolic effects of 1,25-(OH)₂D₃ in osteopenic OVX rats are mediated through a direct activity on bone.

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