1,25-Dihydroxyvitamin D3 as Well as Its Analogue OCT Lower Blood Calcium Through Inhibition of Bone Resorption in Hypercalcemic Rats with Continuous Parathyroid Hormone–Related Peptide Infusion

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  • Ko-Ichi Endo
    Pharmaceutical Research Laboratory, Chugai Pharmaceutical Co. Ltd., Shizuoka and Tokyo, Japan
  • Kyoko Katsumata
    Pharmaceutical Research Laboratory, Chugai Pharmaceutical Co. Ltd., Shizuoka and Tokyo, Japan
  • Michinori Hirata
    Pharmaceutical Research Laboratory, Chugai Pharmaceutical Co. Ltd., Shizuoka and Tokyo, Japan
  • Toshimi Masaki
    Product Research Laboratory, Chugai Pharmaceutical Co. Ltd., Shizuoka and Tokyo, Japan
  • Noboru Kubodera
    Pharmaceutical Research Laboratory, Chugai Pharmaceutical Co. Ltd., Shizuoka and Tokyo, Japan
  • Toshitaka Nakamura
    Department of Orthopedic Surgery, University of Occupational and Environmental Health School of Medicine, Kita-Kyushu, Japan
  • Kyoji Ikeda
    Department of Geriatric Research, National Institute for Longevity Sciences, Aichi, Japan
  • Etsuro Ogata
    Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

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<jats:title>Abstract</jats:title> <jats:p>The effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and its analogue 22-oxa-1,25(OH)2D3 (22-oxacalcitriol) (OCT) on calcium and bone metabolism were examined in an animal model of hypercalcemia with continuous infusion of parathyroid hormone–related peptide (PTHrP), to determine whether active 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 eliminate the confounding effects of endogenous PTH. Animals were then continuously infused with human PTHrP(1–34) at a constant rate via osmotic minipumps for 2 weeks, and at the same time treated orally or intravenously with OCT or 1,25(OH)2D3 four to nine times during the 2-week period. Under these conditions, OCT and, surprisingly, 1,25(OH)2D3 alleviated hypercalcemia in a dose-dependent manner. 1,25(OH)2D3 and OCT suppressed the urinary excretion of deoxypyridinoline, although they did not affect renal calcium handling, suggesting that the antihypercalcemic effect is attributable to the inhibition of bone resorption. These active vitamin D compounds also counteracted the effects of PTHrP at the proximal renal tubules, as reflected by a decrease in phosphate excretion. Histomorphometric analysis of bone revealed a dose-related decrease in parameters of bone resorption. These results suggest that 1,25(OH)2D3 as well as OCT has the potential to alleviate hypercalcemia, at least in part, through the inhibition of bone resorption in hypercalcemic rats with constant PTHrP levels. We propose that the main function of active vitamin D in high bone-turnover states is to inhibit bone resorption, and this may have important implications for the understanding of the role of active vitamin D in the treatment of metabolic bone diseases, such as osteoporosis.</jats:p>

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