Long-term Use of Oral Anticoagulants and the Risk of Fracture

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Abstract
OSTEOPOROSIS is a growing problem in postmenopausal women and elderly men.1 This same population has frequent indications for long-term anticoagulation,2 and warfarin sodium use is purportedly a strong risk factor for osteoporosis.3 The coumarins antagonize vitamin K through inhibition of the enzyme, vitamin K epoxide reductase. Vitamin K functions as a cofactor in the posttranslational γ-carboxylation of glutamic acid4 and, as a result of oral anticoagulant therapy, there is production of nonfunctional, undercarboxylated proteins, including osteocalcin and matrix Gla protein.5 Osteocalcin is considered an indicator of bone formation,6 while absence of matrix Gla protein is associated with severe osteopenia and fractures in a mouse model.7 The adverse effects of vitamin K deficiency and oral anticoagulants on young, rapidly growing bone have been well described both in animal models8,9 and in humans,10,11 but their effects on adult bone are uncertain. In postmenopausal women, low serum vitamin K12 and high levels of undercarboxylated osteocalcin13 correlate with low bone density. Likewise, 6 of 11 studies found decreased bone density in subjects exposed to long-term oral anticoagulants.14-24 However, a meta-analysis showed that oral anticoagulation was associated with a reduction of about 0.4 SD in bone density of the radius but no significant change in bone density of the hip or spine.25 High levels of undercarboxylated osteocalcin were shown to increase hip fracture risk almost 2-fold even after adjustment for femoral bone density.26 The most recent report found no increase in the risk of nontraumatic, nonvertebral fractures when self-reported warfarin users were compared with nonusers.24 However, the estimate was based on 15 fractures among 149 warfarin users, so statistical power was quite limited. To address this potentially important issue in more detail with longer follow-up of a larger sample of women, we performed a population-based retrospective cohort study to assess fracture risk following exposure to oral anticoagulants in comparison with fracture risk in the general population.