1,25-Dihydroxy-19-nor-vitamin D(2), a vitamin D analog with reduced bone resorbing activity in vitro.
1,25-Dihydroxy-19-nor-vitamin D(2) (19-norD(2)), a new analog of 1,25(OH)(2)D(3), suppresses parathyroid hormone in renal failure patients and in uremic rats but has less calcemic activity than 1,25(OH)(2)D(3). Although 19-norD(2) has high affinity for the vitamin D receptor and similar pharmacokinetics to those of 1,25(OH)(2)D(3), it has much less bone resorbing activity in vivo. The intrinsic activity of 19-norD(2) on osteoclastogenesis and activation of bone resorption in mouse bone marrow cultures was examined to determine the mechanism involved. 19-norD(2) and 1,25(OH)(2)D(3) (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-norD(2), as measured by pit-forming assays, was reduced 62% compared with 10 nM 1,25(OH)(2)D(3)-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-norD(2) in cultures was approximately 20% greater than 1, 25(OH)(2)D(3), not enough to account for the different effects on bone resorption. The VDR levels were identical in cultures that were treated with 19-norD(2) and 1,25(OH)(2)D(3). In summary, 19-norD(2) is less effective than 1,25(OH)(2)D(3) 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-norD(2) compared with 1,25(OH)(2)D(3).
Holliday
L Shannon
LS
Department of Medicine, Division of Nephrology and Hypertension, and Department of Anatomy & Cell Biology, University of Florida College of Medicine, Gainesville, Florida.
Gluck
Stephen L
SL
Department of Medicine, Division of Nephrology and Hypertension, and Department of Anatomy & Cell Biology, University of Florida College of Medicine, Gainesville, Florida.
Slatopolsky
Eduardo
E
Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
Brown
Alex J
AJ
Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D001862:Bone Resorption / Q000473:pathology*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects* / Q000473:pathology
C083610:1,25-dihydroxy-19-norvitamin D3; D002117:Calcitriol