Decreased axial and peripheral bone density in patients taking long-term warfarin

Impaired vitamin K metabolism is associated with under-carboxylation of the non-collagenous bone-matrix protein osteocalcin, which is required in its fully carboxylated state for normal bone formation. Post-menopausal women have under-carboxylation of osteocalcin which increases with age and is marked in the elderly. A similarly marked degree of impaired carboxylation occurs during coumarin therapy, and a key question is whether this may lead to accelerated loss of bone mass which is clinically important. We measured axial and peripheral bone mineral density (BMD) in 40 male patients on warfarin and 40 controls individually matched for age, disease and other drug therapy. A consistent trend for reduced BMD at all sites was observed in the warfarin-treated patients. This was particularly marked in the cancellous bone at the distal radius (9% reduction, p = 0.023) and at the cancellous rich lumbar spine site (10.4% reduction, p < 0.004). No significant relationship was observed between warfarin dose, International Normalized Ratio (INR) or duration of therapy and bone density. Because of the biochemical similarity, this study provides a new lead on post-menopausal osteoporosis, and supports the hypothesis that impaired carboxylation of osteocalcin plays a role in the pathogenesis of bone loss in the elderly through deficiency in vitamin K metabolism.