OSTEOPENIA AND BONE-REMODELING ABNORMALITIES IN WARFARIN-TREATED LAMBS

The physiologic role of osteocalcin (OC), a vitamin K-dependent protei n specific to bone, remains elusive. It has been shown that rats maint ained on chronic treatment with vitamin K1 and its antagonist warfarin exhibit a marked decrease in bone osteocalcin because noncarboxylated osteocalcin does not bind to bone hydroxyapatite. To assess the role of OC in bone remodeling, we applied the warfarin model to growing lam bs. We analyzed the bone changes after 3 months of concurrent warfarin and vitamin K1 treatment. Four groups of four lambs were constituted at birth and received daily a saline solution (control group, CT), 4 m g/kd/day of vitamin K1 (vitamin K group), 4 mg/kg/day of vitamin K1 75 or 150 mg/kg/day of warfarin (W75 and W150 group, respectively). In warfarin-treated animals, bone osteocalcin levels were decreased, bot h in the metaphysis (9% compared to controls) and the diaphysis (30% c ompared to controls) of the metacarpals. The fraction of noncarboxylat ed osteocalcin measured every month in the serum was significantly hig her in warfarin-treated lambs than in controls at each timing point (3 7.6 +/- 2.6% in W75 and 48.7 +/- 5.2% in W150 versus 14.4 +/- 3.8% in controls at 3 months). Compared to non-warfarin-treated animals (NW), the main histomorphometric parameters measured on the iliac crest afte r tetracycline double labeling were significantly reduced in the warfa rin-treated lambs: 12.2 +/- 5.2 versus 18.6 +/- 4.7% in NW (p < 0.03) for the cancellous bone area, which reflects the trabecular bone densi ty; 14.7 +/- 6.1 versus 21.0 +/- 3.6% in NW (p < 0.03) for the eroded perimeter, and 0.315 +/- 0.064 versus 0.561 +/- 0.23 mum3/mum2/day in NW (p < 0.02) for the tetracycline-based bone formation rate. In concl usion, the depletion of osteocalcin in the bone of lambs induced withi n 3 months a marked osteopenia that resulted from a decrease in resorp tion and a more pronounced decrease in bone formation. Our data sugges t that the presence of osteocalcin, the major gla-containing protein o f bone, may be important for the maintenance of a normal bone mass and remodeling of trabecular bone.