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

Vitamin K for Osteoporosis: Clinical Studies

The relationship between dietary vitamin K intake and bone status has been investigated in several epidemiologic ( Table 1 ) and intervention studies ( Table 2 ). These studies suggest that vitamin K deficiency causes reductions in BMD and increases the risk of fractures, resulting from the undercarboxylation of osteocalcin. Low intakes of vitamin K have been associated with an increased risk of hip fractures. In a study of 72,327 women, vitamin K intakes (assessed through the use of a food-frequency questionnaire) were inversely related to the risk of hip fracture.[38] The adjusted relative risk (RR = 0.70; 95% confidence interval [CI], 0.53-0.93) of hip fracture was 30% less in the women from the top four quintiles of vitamin K intake (>109 µg daily) compared with women from the lowest quintile (<109 µg daily). This finding is supported by a study of 888 men and women from the Framingham Heart Study.[39] Patients with the highest quartile of vitamin K intake (median, 254 µg daily) had a 65% lower adjusted RR (RR = 0.35; 95% CI, 0.13-0.94) of hip fracture than did those in the lowest quartile of intake (median, 56 µg daily).

Undercarboxylated Osteocalcin and Bone Health

Numerous studies have shown that an association exists among undercarboxylated serum osteocalcin, BMD, and fracture rate.[40,41,42,43,44] In a study of 359 independently-living women, increased levels of undercarboxylated osteocalcin were associated with increased risk of hip fracture, with an odds ratio of 1.9 (95% CI, 1.2-3.0).[40] In a series of reports involving institutionalized elderly women, a strong correlation was found between undercarboxylated serum osteocalcin levels and the subsequent risk of hip fracture.[41] Women with abnormally high undercarboxylated osteocalcin concentrations (>1.65 ng/mL) had a RR between 3.1 (99.9% CI, 1.7-6.0; p < 0.001)[42] and 5.9 (99.9% CI, 1.5-22.7; p < 0.001) times higher than those with normal undercarboxylated osteocalcin levels (<1.65 ng/mL). Knapen et al.[43] conducted a cross-sectional study of 212 women and found a strong inverse correlation (adjusted RR = 0.5-0.7) between serum undercarboxylated osteocalcin levels and BMD in postmenopausal women. In a trial of 141 postmenopausal women, the percentage of carboxylated osteocalcin to total osteocalcin was measured.[44] The value of that variable was positively correlated with BMD of the lumbar spine (r = 0.32, p < 0.005) and femoral neck (r = 0.25, p < 0.005).

Hodges et al.[45] demonstrated that depressed serum levels of phylloquinone and menaquinone (for the latter, most notably MK-7 and MK-8) are found in patients with osteoporotic fractures and suggested that serum levels of phylloquinone and menaquinone can serve as markers for osteoporotic fracture risk.

Vitamin K, Osteocalcin Carboxylation, and Bone Health

A number of clinical studies have been conducted investigating the effect of vitamin K administration on the carboxylation of osteocalcin, BMD, and fracture rates.[29,36,46,47] Various dosages of both phylloquinone and menaquinone have been used in clinical trials; however, in all studies, undercarboxylated osteocalcin levels declined significantly with vitamin K supplementation. In a study to determine the prevalence of suboptimal carboxylation of osteocalcin in healthy North American adults, Binkley et al.[29] conducted a single-blind, placebo-controlled trial with 219 healthy young and elderly adults. The treatment group received 1 mg of phytonadione daily for two weeks. At the end of the study, patients receiving phytonadione had a significant decrease in the mean percentage of undercarboxylated osteocalcin, from 7.6% to 3.4% (p < 0.001), without significant differences when stratified by age or sex. In a randomized, open-label, controlled trial of 241 Japanese postmenopausal osteoporotic women, the treatment group received 45 mg of menaquinone daily for two years.[46] At the end of the study, the undercarboxylated serum osteocalcin concentrations in the treatment group were significantly lower than in the control group (1.6 ± 0.1 ng/mL and 3.0 ± ng/mL, respectively) (p < 0.0001). In addition, the occurrence of fracture in the treatment group was significantly lower than in the control group (χ2 = 10.935, p = 0.0273). In a smaller, randomized, open-label study of Japanese osteoporotic women, Miki et al.[47] found that undercarboxylated serum osteocalcin levels could be reduced in as little as two weeks. The treatment group received 45 mg of menaquinone (specifically MK-4) plus 200 mg of calcium daily. The control group received only 200 mg of calcium daily. After two weeks, the mean ± S.D. serum undercarboxylated osteocalcin concentrations in the treatment group declined from a baseline value of 2.8 ± 0.9 ng/mL to 1.7 ± 0.5 ng/mL (p < 0.05). No significant changes occurred in the control group over the same period.

Involvement of Vitamin D

It appears that adequate levels of both vitamins D and K may have additive effects in improving bone health. Many studies have investigated the combined effects of vitamins D and K.[12,36,44,48,49] An excellent review on the additive effects of vitamin D3 and menaquinone was recently published by Iwamoto and colleagues.[50] 1,25 (OH)2 D3 is the most active vitamin D3 metabolite and promotes intestinal absorption of calcium, reduces serum levels of parathyroid hormone, and activates the synthesis of osteocalcin.[49,51,52,53]

In a three-year, randomized, double-blind trial of 155 postmenopausal women, Braam et al.[36] found that vitamin D and phytonadione had a complementary effect on the attenuation of bone loss. Participants were divided into three groups: (1) placebo, (2) vitamin D and mineral (8 µg of vitamin D, 500 mg of milk-derived calcium, 150 mg of magnesium, and 10 mg of zinc daily), and (3) vitamin D, mineral, and phytonadione (same as vitamin D and mineral group plus 1 mg of phytonadione daily). After three years, patients who received vitamin D, minerals, and phytonadione demonstrated a 1.7% reduction (95% CI, 0.35-3.44%) in bone loss from the femoral neck (absolute bone loss of 3.3%) compared with the placebo group (absolute bone loss of 5.0%) and a 1.3% reduction (95% CI, 0.10-3.41%) compared with those receiving only vitamin D and mineral supplements (absolute bone loss of 4.6%). No significant differences were observed among the three groups with respect to changes in BMD of the lumbar spine.

In a two-week, single-blind study, 20 postmenopausal, osteoporotic women were given either 1 mg of phytonadione daily or 1 mg of phytonadione plus 400 IU of vitamin D2 daily.[48] The mean carboxylation level of osteocalcin was corrected to pre-menopausal levels (~72%) in both groups, but the addition of vitamin D2 had no effect on study results. The percentage of carboxylated osteocalcin increased from 57% before treatment to 73% after treatment (p < 0.001). A similar finding was reported in a study conducted by Takahashi et al.[49] In that open-label trial of 113 osteoporotic women with femoral hip or vertebral fractures and 91 premenopausal and postmenopausal women without fractures or osteoporosis, participants were randomized to receive menaquinone (45 mg daily), vitamin D3 (1 µg daily), or menaquinone (45 mg daily) plus vitamin D3 (1 µg daily) for four weeks. Significant decreases occurred in undercarboxylated serum osteocalcin levels in the menaquinone only (p = 0.0001) and the menaquinone plus vitamin D3 (p = 0.0018) groups but not in women treated with vitamin D3 only.

In a randomized, double-blind study investigating the effects of vitamin D3 and phytonadione in postmenopausal women, Schaafsma et al.[44] found that a daily intake of 80 µg of phytonadione was necessary to reach premenopausal percentages of carboxylated osteocalcin. At the end of the study, improvements in the percentage of carboxylated osteocalcin were seen in both the phytonadione-treated group with normal BMD (p = 0.001) and the phytonadione-treated group with low BMD (p ≤ 0.0001), compared with the control group, who received no phytonadione. Surprisingly, the percentage of carboxylated osteocalcin also increased in those receiving vitamin D3 only (p ≤ 0.006). Another randomized, open-label study supporting the combined effects of vitamin D3 and menaquinone on BMD in osteoporotic women was conducted by Iwamoto et al.[12] Ninety-two postmenopausal women with osteoporosis were given vitamin D3 (0.75 µg), menaquinone (45 mg daily), vitamins D3 (0.75 µg daily) plus menaquinone (45 mg daily), or calcium (2 g daily). After two years, BMD increased significantly in the vitamin D3- and menaquinone-treated groups, compared with the calcium-treated group (p < 0.05 and p < 0.001, respectively). However, the most significant increase in BMD was seen in the vitamin D3 plus menaquinone group (p < 0.0001).

Menaquinone was also found to have a synergistic effect when administered with postmenopausal hormone therapy.[54] Hormone therapy is known to increase BMD for two to three years after menopause and maintain it thereafter. For some women taking hormone therapy, the increase in BMD reaches a plateau and then declines. A combined administration of menaquinone (45 mg of MK-4 daily) and hormone therapy was investigated in 10 women who had declining BMD levels. The mean ± S.D. rate of change in their BMD increased significantly, from -2.4% ± 2.5% to 6.7% ± 2.9% (p < 0.03) after 12 months of combination therapy.

Two recent studies have provided dose-response data on phytonadione that indicate that current dietary intake recommendations may be inadequate. Binkley et al.[32] conducted a single-blind, placebo-controlled trial to identify the lowest dosage of phytonadione needed to maximally carboxylate osteocalcin. One-hundred healthy adults age 19-36 years were randomly assigned to receive placebo or 250, 375, 500, or 1000 µg of phytonadione daily for two weeks. The percentage of undercarboxylated serum osteocalcin decreased with increasing dosages (p < 0.0001), with the greatest reduction occurring in those who received 1000 µg daily. In an 84-day depletion and repletion study, 21 older women received a phylloquinone-restricted diet (18 µg daily), followed by a stepwise repletion of 86, 200, and 450 µg of phytonadione.[33] Various markers of vitamin K status were evaluated to measure participants' response. The carboxylation of prothrombin was restored to prestudy levels with an intake of 200 µg daily. However, carboxylated osteocalcin remained below normal levels after supplementation of up to 450 µg of phytonadione daily. The efficacy of phytonadione and menaquinone supplementation in the treatment of osteoporosis is currently under study in the United States.[55]


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