Concurrent warfarin treatment further reduces bone mineral levels in 1,25-dihydroxyvitamin D3-treated rats

Weanling rats on a normal diet mobilized bone calcium in response to 11 daily injections of 125 ng of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3)/100 g, body weight. This effect was most evident in the tibial midshaft, where calcium levels were reduced by 38% compared to untreated controls. Calcium levels were reduced by only 13% in the proximal tibial metaphysis, a region formed by longitudinal growth during the 11-day experiment. The concurrent daily administration of the vitamin K antagonist warfarin dramatically increased calcium mobilization from the tibial metaphysis of 1,25-(OH)2D3-treated rats. Compared to rats which received 1,25-(OH)2D3 alone, the calcium content of the tibial metaphysis in rats treated with 1,25-(OH)2D3 plus warfarin was reduced by 40.4% (p less than 0.001) and the total dry weight was reduced by 35.0% (p less than 0.001). There was no effect of warfarin on bone calcium content or dry weight in the absence of 1,25-(OH)2D3 treatment. These observations indicate that a component of the steroidal hormone action of 1,25-(OH)2D3 on bone may be mediated by increased synthesis of a vitamin K-dependent protein. The action of this vitamin K-dependent protein would oppose net calcium loss in the tibial metaphysis of 1,25-(OH)2D3-treated rats. This vitamin K-dependent protein may be the bone Gla protein, the only bone specific protein whose synthesis is known to be increased by 1,25-(OH)2D3.