Vitamin K Deficiency From Long-Term Warfarin Anticoagulation Does Not Alter Skeletal Status in Male Rhesus Monkeys

Abstract

Vitamin K (K) inadequacy may cause bone loss. Thus, K deficiency induced by anticoagulants (e.g., warfarin) may be an osteoporosis risk factor. The skeletal impact of long-term warfarin anticoagulation was evaluated in male monkeys. No effect on BMD or bone markers of skeletal turnover was observed. This study suggests that warfarin-induced K deficiency does not have skeletal effects. Introduction:The skeletal role of vitamin K (K) remains unclear. It is reasonable that a potential role of vitamin K in bone health could be elucidated by study of patients receiving oral anticoagulants that act to produce vitamin K deficiency. However, some, but not all, reports find K deficiency induced by warfarin (W) anticoagulation to be associated with low bone mass. Additionally, epidemiologic studies have found W use to be associated with either increased or no change in fracture risk. Such divergent results may imply that human studies are compromised by the physical illnesses for which W was prescribed. Materials and Methods: To remove this potential confounder, we prospectively assessed skeletal status during long-term W anticoagulation of healthy nonhuman primates. Twenty adult (age, 7.4-17.9 yr, mean, 11.7 yr) male rhesus monkeys (Macaca mulatta) were randomized to daily W treatment or control groups. Bone mass of the total body, lumbar spine, and distal and central radius was determined by DXA at baseline and after 3, 6, 9, 12, 18, 24, and 30 mo of W treatment. Serum chemistries, urinary calcium excretion, bone-specific alkaline phosphatase, and total and percent unbound osteocalcin were measured at the same time-points. Prothrombin time and international normalized ratio (INR) were monitored monthly. Serum 25-hydroxyvitamin D was measured at the time of study conclusion. Results: W treatment produced skeletal K deficiency documented by elevation of circulating undercarboxylated osteocalcin (8.3% W versus 0.4% control, p < 0.0001) but did not alter serum markers of skeletal turnover, urinary calcium excretion, or BMD. Conclusions: In male rhesus monkeys, long-term W anticoagulation does not alter serum markers of bone turnover or BMD. Long-term W therapy does not have adverse skeletal consequences in primates with high intakes of calcium and vitamin D.

Bone and glucose metabolism: A two-way street

“…However, trials of vitamin K supplementation have generally failed to demonstrate an effect on fracture risk (88). Similarly, treatment with warfarin, a potent vitamin K antagonist that increases ucOC levels, has generally not been found to decrease BMD or bone strength in animal models (69, 89, 90). Clinical studies investigating warfarin use have had mixed results with some reporting increased risk of fracture (91, 92) or lower bone density (93, 94) but others reporting no discernable effect (95, 96).…”

VKORC1L1, an Enzyme Rescuing the Vitamin K 2,3-Epoxide Reductase Activity in Some Extrahepatic Tissues during Anticoagulation Therapy

“…Nevertheless, these various experiments were performed in rats receiving a vitamin K-depleted diet, and undercarboxylated OC in plasma and OC in bone are considered as very good markers of the deficiency in vit K. It is thus very difficult to interpret these experiences. Finally, the only in vivo study easily interpretable and close to human therapeutic conditions is the study performed on healthy nonhuman primates by Binkley et al (37). In this study, adult male rhesus monkeys received 1.5 mg/day menadione in the diet and 0.15 mg/kg/day warfarin (i.e.…”

Warfarin-induced impairment of cortical bone material quality and compensatory adaptation of cortical bone structure to mechanical stimuli

“…Warfarin has been suggested to increase fracture risk by impairing bone quality (Eastell 2006), but does not change bone turnover, which strongly affects bone quality, in humans (Knapen et al 2000) as well as in rats (Amizuka et al 2005) and rhesus monkeys (Binkley et al 2007). Our findings suggest that long-term use of warfarin weakens the rib and vertebra by impairing cortical bone material quality due to a marked decrease in osteocalcin content.…”