The Effects of Warfarin on Bone Metabolism

Introduction Bone is a metabolically active organ which has a permanent renewal in the life cycle. This constant renewal is necessary for maintaining the structural integrity and supplying the metabolic functions of the bone as a reservoir for calcium, phosphate, and magnesium (1). In addition, bone is structured by inorganic minerals such as calcium and phosphorus and the organic matrix. Approximately 90%-95% of the bone matrix is of type I collagen (1). The osteocalcin is considered a significant non-collagenous protein which plays an essential role in bone metabolism. Further, osteocalcin, which is known as the gamma-carboxy glutamic acid of the bone is a marker of bone formation whose carboxylation is dependent on vitamin K (2-4). Osteocalcin is a marker for a bone formation which is produced by the osteoblasts and plays an important role in the accumulation of bone minerals such as calcium which are involved in bone mineralization and calcium ion homeostasis (5). Furthermore, alkaline phosphatase is another marker for monitoring the activity of the bone metabolism which is a tetrameric glycoprotein and its serum level reflects the activities of bone metabolism (6,7). Moreover, warfarin is one of the most effective oral anticoagulant drugs prescribed to stabilize the international normalized ratio (INR). Totally, 99% of this drug binds to the albumin after oral absorption while only 1% becomes inactive by CYP2C9 liver enzyme and excretes in the bile. Warfarin exposes its anticoagulation effect by competitive inhabitation of vitamin K epoxide reductase enzyme complex which is responsible for recycling the restored vitamin K (K1H2) needed for gamma-carboxylation (8-12). The K1H2 is a required co-factor for the gamma-glutamyl carboxylase enzyme and is converted into inactive metabolite and epoxide vitamin K1 for conversion of glutamic to gammacarboxy glutamic. Then, once again the inactive form of vitamin K is restored in the vitamin K cycle by VKORC1 liver enzyme to the active co-factor for the enzyme carboxylase. Warfarin inhibits this enzyme and reduces the restored vitamin K1 and activated coagulation factors delaying the blood clotting. It is suggested that vitamin K2 may play an important role in maintaining the health levels of the bone mineral density. The strong relationship between a lack of vitamin K2 and bone health disorders is proven by both clinical and laboratory studies. The osteocalcin is not converted from the inactive mode to activated carboxyl mode and thus calcium cannot be placed in the bone without the presence of vitamin K2 Abstract Objectives: Osteocalcin which is s non-collagenous protein plays an important role in bone metabolism and its carboxylation depends on vitamin K. In addition, warfarin inhibits vitamin K epoxide reductase complex and has an anticoagulant effect and therefore interrupts the activity of osteocalcin. Accordingly, this study aimed to estimate the effects of warfarin on bone metabolism. In other words, it was attempted to evaluate the changes in serum levels of bone metabolism in warfarin-taking patients and find the relationship between the inhibition of vitamin K metabolism by warfarin and their synergistic effects on bone metabolism. Materials and Methods: A total of 72 individuals were selected including healthy controls (n = 36) and patients (n = 36) who referred to clinical laboratories of Tabriz after consuming warfarin. Nearly 5 ml blood samples were collected and non-carboxylated osteocalcin experiments, parathyroid hormone (PTH), vitamin D3, calcium, phosphorus, magnesium, and alkaline phosphatase were performed for all the samples of each group. Results: In this study, non-carboxylated osteocalcin, PTH, and international normalized ratio (INR) increased significantly in the case group while increasing of Mg2+ was non-significant in this group. However, vitamin D3, Ca2+, alkaline phosphatase (ALP), and P demonstrated a significant decrease in the case group compared to the control group. Conclusions: In general, the consumption of warfarin leads to bone and vessel wall damages, causing cardiovascular diseases.