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1,25-Dihydroxy-19-nor-vitamin D₂, a Vitamin D Analog with Reduced Bone Resorbing Activity In Vitro

L. SHANNON HOLLIDAY^*, STEPHEN L. GLUCK^*, EDUARDO SLATOPOLSKY and ALEX J. BROWN

^* Department of Medicine, Division of Nephrology and Hypertension, and Department of Anatomy & Cell Biology, University of Florida College of Medicine, Gainesville, Florida
Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.

Correspondence to Dr. Alex J. Brown, Department of Internal Medicine, Renal Division, 660 South Euclid, Washington University School of Medicine, St. Louis, MO 63110. Phone: 314-362-8232; Fax: 314-362-8237; E-mail: abrown{at}imgate.wustl.edu

Abstract. 1,25-Dihydroxy-19-nor-vitamin D₂ (19-norD₂), a new analog of 1,25(OH)₂D₃, suppresses parathyroid hormone in renal failure patients and in uremic rats but has less calcemic activity than 1,25(OH)₂D₃. Although 19-norD₂ has high affinity for the vitamin D receptor and similar pharmacokinetics to those of 1,25(OH)₂D₃, it has much less bone resorbing activity in vivo. The intrinsic activity of 19-norD₂ on osteoclastogenesis and activation of bone resorption in mouse bone marrow cultures was examined to determine the mechanism involved. 19-norD₂ and 1,25(OH)₂D₃ (10 nM) were equivalent in stimulating the formation and maintenance of large multinucleated, tartrate-resistant acid phosphatase-positive cells. However, the amount of bone resorbed by osteoclasts stimulated by 10 nM 19-norD₂, as measured by pit-forming assays, was reduced 62% compared with 10 nM 1,25(OH)₂D₃-stimulated osteoclasts (P < 0.05). This difference could not be attributed to enhanced catabolism or to downregulated vitamin D receptor. The rate of degradation of 19-norD₂ in cultures was approximately 20% greater than 1,25(OH)₂D₃, not enough to account for the different effects on bone resorption. The VDR levels were identical in cultures that were treated with 19-norD₂ and 1,25(OH)₂D₃. In summary, 19-norD₂ is less effective than 1,25(OH)₂D₃ in stimulating mouse marrow osteoclasts to resorb bone. The reason for this difference is not clear but seems to involve the late maturation and/or activation of osteoclasts as the number of pits produced by each tartrate-resistant acid phosphatase-positive cell is reduced under stimulation by 19-norD₂ compared with 1,25(OH)₂D₃.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673