Vitamin K in the Treatment and Prevention of Osteoporosis and Arterial Calcification

Jamie Adams; Joseph Pepping


Am J Health Syst Pharm. 2005;62(15):1574-1581. 

In This Article

Arterial Calcification

Similarity to Bone Metabolism

Arterial calcification was once thought to be a passive process that occurred in response to tissue injury. Evidence now suggests that it is an active, cell-controlled process that shares many similarities with bone metabolism.[3,21,56,57] Arterial calcification occurs at two sites in the vessel wall: the media and the intima. Medial calcification is known as Mönckeberg's arteriosclerosis. Unlike intimal calcification, Mönckeberg's arteriosclerosis occurs independently of atherosclerosis.[21,58,59] Although the cells involved differ depending on the site of calcification, MGP is expressed at both sites.[3] The connection between MGP and vascular calcification has been documented by both cell culture and animal studies. Human cell studies have shown that normal vascular smooth muscle cells express MGP and, at sites of calcification, it is substantially upregulated.[56,58,60] This may be a physiological attempt to minimize calcification and tissue damage.[21,61] In an animal cell study, it was found that endochondral calcification triggered by warfarin could be inhibited by an overexpression of MGP.[15] Animal studies of MGP-deficient mice and warfarin-treated rats provide strong evidence that MGP is a potent inhibitor of vascular calcification.[14,18] Extensive arterial calcification was found in animals that do not express MGP and those that could not carboxylate it. Assuming that the VKD γ-carboxylation of MGP is essential for its inhibitory effect on calcification, vitamin K deficiency may be a risk factor for vascular calcification.

Clinical Studies

Concurrent arterial calcification and osteoporosis have been called the "calcification paradox"[3] and occur frequently in postmenopausal women.[6] However, only a few human studies investigating the connection between these two diseases have been published. In a study of 45 postmenopausal women with normal and low BMD, an inverse relationship was found between BMD and coronary calcification.[5] The mean ± S.D. total coronary calcium score (a measure of calcification) was significantly higher in all arteries of the women with low BMD than in the control group (221.7 ± 355.4 and 41.9 ± 83.1, respectively) (p < 0.025). In a nine-year, population-based study of 236 women, progression of atherosclerotic calcification was associated with increasing bone loss.[6] Women with progressive aortic calcification had an average loss of metacarpal bone density of 7.2 mm2%, compared with 5.6 mm2% in women without progressive aortic calcification (p < 0.05). In two studies by Jie et al.,[7,8] a correlation was found between vitamin K status and mineralization of both bone and vessel walls. In a population-based study, vitamin K status, osteocalcin levels, and aortic calcifications were assessed in 113 postmenopausal women.[8] The presence of aortic calcification was associated with lower bone mass and a marginal vitamin K status. There was a 7% difference in the bone mass between women with and without aortic calcification (mean difference, 3.2 mm2; 95% CI, -0.2 to 6.5 mm2; p = 0.06). In another cohort study, 113 postmenopausal women with aortic calcifications were found to consume approximately 42.9 µg less dietary vitamin K than participants without aortic calcification (95% CI, -6.6 to 92.5 µg).[7] These women also had a 0.32-ng/mL higher adjusted undercarboxylated osteocalcin level (95% CI, 0.03-0.61 ng/mL) and lower hydroxyapetite-binding capacity than those women without aortic calcification.

In a population study of 4500 elderly patients, an inverse relationship was demonstrated between dietary intake of menaquinone and aortic calcification, myocardial infarction, and sudden cardiovascular death.[62]

The most convincing data to date were recently reported by Braam et al.[63] In this three-year, randomized, placebo-controlled trial of 181 healthy, Caucasian postmenopausal women, daily supplementation with 1 mg of phytonadione (plus 8 µ g of vitamin D3 and minerals [500 mg of calcium, 150 mg of magnesium, and 10 mg of zinc per day]) inhibited the loss of carotid artery elasticity, compared with those receiving placebo and those in the vitamin D3 plus minerals group (-13.2 kPa; 95% CI, -35.8 to -5.3) (p < 0.01). No significant differences in arterial elasticity were noted between the placebo group and the vitamin D3 plus minerals group. In this study, no significant differences were observed in carotid artery intima-media thickness between the three study groups.

Interestingly, no prospective interventional studies have been published investigating menaquinone deficiency as a risk factor for arterial calcification or whether supplementation with menaquinone affects arterial elasticity, arterial calcification, or intima-media thickness.


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