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 pharmacokinetic s to those of 1,25(OH)(2)D-3, it has much less bone resorbing activity in v ivo. The intrinsic activity of 19-norD(2) on osteoclastogenesis and activat ion of bone resorption in mouse bone marrow cultures was examined to determ ine the mechanism involved. 19-norD(2) and 1,25(OH)(2)D-3 (10 nM) were equi valent in stimulating the formation and maintenance of large multinucleated , tartrate-resistant acid phosphatase-positive cells. However, the amount o f 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-s timulated osteoclasts (P < 0.05). This difference could not be attributed t o enhanced catabolism or to downregulated vitamin D receptor. The rate of d egradation of 19-norD(2) in cultures was approximately 20% greater than 1,2 5(OH)(2)D-3, not enough to account for the different effects on bone resorp tion. The VDR levels were identical in cultures that were treated with 19-n orD(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 re ason for this difference is not clear but seems to involve the late maturat ion and/or activation of osteoclasts as the number of pits produced by each tartrate-resistant acid phosphatase-positive cell is reduced under stimula tion by 19-norD(2) compared with 1,25(OH)(2)D-3.