Vitamin K Abstracts 3 - Bones


Dietary vitamin K intake is associated with bone quantitative ultrasound measurements but not with bone peripheral biochemical markers in elderly men and women

         (Bullo, Estruch et al. 2011) Download

BACKGROUND: Vitamin K may have a protective role against bone loss and osteoporotic fractures associated to aging, although data in humans are inconsistent and the mechanisms involved are still unknown. The main objective of the study was to assess the associations between vitamin K intake, bone density, bone structure quality and biochemical bone metabolism markers in elderly subjects. We also analyzed the relationship between changes in vitamin K intake and the evolution of bone quality markers after two years of follow-up. METHODS: Cross-sectional analysis was carried out on 365 elderly subjects, 200 of whom were also included in a 2-year longitudinal follow-up study. Usual dietary intakes were assessed using a semi-quantitative 137-item food frequency questionnaire (FFQ). Vitamin K intake was estimated using the USDA database. Bone biochemical markers were measured in a subset of 125 subjects. Quantitative ultrasound assessment (QUS) was performed at the calcaneus to estimate bone mineral density (BMD), speed of sound (SOS), broadband ultrasound attenuation (BUA) and the quantitative ultrasound index (QUI). RESULTS: Dietary intake of vitamin K was significantly associated with higher BMD and better QUS. No significant associations were found between vitamin K intake and bone biochemical markers. Those subjects who increased their vitamin K intake showed a lower loss of BMD, a lower decrease in SOS and a nonsignificant increase in BUA. CONCLUSIONS: High dietary vitamin K intake was associated with superior bone properties. Moreover, an increase in dietary vitamin K was significantly related to lower losses of bone mineral density and smaller increases in the porosity and elasticity attributed to aging, which helps to explain the previously described protective effect of vitamin K intake against osteoporotic fractures.

Vitamin K2 supplementation improves insulin sensitivity via osteocalcin metabolism: a placebo-controlled trial

         (Choi, Yu et al. 2011) Download

Vitamin K-dependent carboxylation of osteocalcin: friend or foe?

         (Gundberg, Lian et al. 2012) Download

Osteocalcin originates from osteoblastic synthesis and is deposited into bone or released into circulation, where it correlates with histological measures of bone formation. The presence of 3 vitamin K-dependent gamma carboxyglutamic acid residues is critical for osteocalcin's structure, which appears to regulate the maturation of bone mineral. In humans, the percentage of the circulating osteocalcin that is not gamma-carboxylated (percent ucOC) is used as a biomarker of vitamin K status. In contrast, when ucOC is not corrected for total osteocalcin, the interpretation of this measure is confounded by osteoblastic activity, independent of vitamin K. Observational studies using percent ucOC have led to the conclusion that vitamin K insufficiency leads to age-related bone loss. However, clinical trials do not provide overall support for the suggestion that vitamin K supplementation of the general population will reduce bone loss or fracture risk. More recently, results from in vitro and in vivo studies using animal models indicate that ucOC is an active hormone with a positive role in glucose metabolism. By inference, vitamin K, which decreases ucOC, would have a detrimental effect. However, in humans this hypothesis is not supported by the limited data available, nor is it supported by what has been established regarding osteocalcin chemistry. In summary, the specific function of osteocalcin in bone and glucose metabolism has yet to be elucidated.

Pleiotropic actions of vitamin K: protector of bone health and beyond?

         (Kaneki, Hosoi et al. 2006) Download

Vitamin K is a nutrient that was originally identified as an essential factor for blood coagulation. Recently, vitamin K has emerged as a potential protector against osteoporosis, atherosclerosis, and hepatocarcinoma. Accumulated evidence indicates that subclinical non-hemostatic vitamin K deficiency in extrahepatic tissues, particularly in bone and possibly in vasculature, exists widely in the otherwise healthy adult population. Vitamins K1 and K2 have been shown to exert protective effects against osteoporosis, although it is important that the beneficial effects will be further confirmed by large-scale, randomized, clinical trials. Increasing evidence implicates a role for vitamin K in calcification of arteries and atherogenesis. Moreover, the therapeutic potential of vitamin K2 as an antihepatoma drug has recently been highlighted. Most of the new biological functions of vitamin K in bone, vasculature, and hepatoma cells are considered attributable to promotion of gamma-carboxylation of glutamic acid residues in vitamin K-dependent proteins, which is shared by vitamins K1 and K2. In contrast, vitamin K2-specific, gamma-carboxylation-unrelated functions have also been demonstrated. Thus, biological differences between vitamins K1 and K2 and potential involvement of gamma-carboxylation-independent actions in the new roles of vitamin K remain open issues. Molecular bases of coagulation-unrelated pleiotropic actions of vitamin K and its implications in human health deserve further investigations.

Relationship between vitamin K status, bone mineral density, and hs-CRP in young Korean women

         (Kim, Kim et al. 2010) Download

Vitamin K intake has been reported as an essential factor for bone formation. The current study was conducted under the hypothesis that insufficient vitamin K intake would affect inflammatory markers and bone mineral density in young adult women. The study was a cross-sectional design that included 75 women in their 20s. Physical assessments, bone mineral density measurements, 24-hr dietary recalls, and biochemical assessments for high sensitivity C-reactive protein (hs-CRP) and percentages of undercarboxylated osteocalcin (%ucOC) were performed. An analysis of vitamin K nutritional status was performed comparing first, second, and third tertiles of intake based on %ucOC in plasma. Vitamin K intake levels in the first, second, and third tertiles were 94.88 +/- 51.48 microg, 73.85 +/- 45.15 microg, and 62.58 +/- 39.92 microg, respectively (P < 0.05). The T-scores of the first and third tertiles were 1.06 and -0.03, respectively, indicating that bone mineral density was significantly lower in the group with lower vitamin K intake (P < 0.05). There was a tendency for different serum hs-CRP concentrations between the first (0.04 +/- 0.02) and third tertiles (0.11 +/- 0.18), however this was not statistically significant. Regression analysis was performed to identify the correlations between vitamin K nutritional status, inflammatory markers, and bone mineral density after adjusting for age and BMI. Serum hs-CRP concentrations were positively correlated with vitamin K deficiency status (P < 0.05). And bone mineral density, which was represented by speed, was negatively correlated with vitamin K deficiency status (P < 0.05). In conclusion, status of vitamin K affects inflammatory status and bone formation. Therefore, sufficient intake of vitamin K is required to secure peak bone mass in young adult women.

Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women

         (Knapen, Schurgers et al. 2007) Download

Vitamin K mediates the synthesis of proteins regulating bone metabolism. We have tested whether high vitamin K(2) intake promotes bone mineral density and bone strength. Results showed that K(2) improved BMC and femoral neck width, but not DXA-BMD. Hence high vitamin K(2) intake may contribute to preventing postmenopausal bone loss. INTRODUCTION: Vitamin K is involved in the synthesis of several proteins in bone. The importance of K vitamins for optimal bone health has been suggested by population-based studies, but intervention studies with DXA-BMD as a clinical endpoint have shown contradicting results. Unlike BMC, DXA-BMD does not take into account the geometry (size, thickness) of bone, which has an independent contribution to bone strength and fracture risk. Here we have tested whether BMC and femoral neck width are affected by high vitamin K intake. METHODS: A randomized clinical intervention study among 325 postmenopausal women receiving either placebo or 45 mg/day of vitamin K(2) (MK-4, menatetrenone) during three years. BMC and hip geometry were assessed by DXA. Bone strength indices were calculated from DXA-BMD, femoral neck width (FNW) and hip axis length (HAL). RESULTS: K(2) did not affect the DXA-BMD, but BMC and the FNW had increased relative to placebo. In the K(2)-treated group hip bone strength remained unchanged during the 3-year intervention period, whereas in the placebo group bone strength decreased significantly. CONCLUSIONS: Vitamin K(2) helps maintaining bone strength at the site of the femoral neck in postmenopausal women by improving BMC and FNW, whereas it has little effect on DXA-BMD.

Effects of vitamin K2 in hemodialysis patients with low serum parathyroid hormone levels

         (Nakashima, Yorioka et al. 2004) Download

In patients with adynamic bone disease, the bone contains few osteoblasts or osteoclasts and bone turnover is slow, so the risk of fracture is increased. The decrease of bone remodeling may also decrease the capacity of bone to buffer calcium, leading to an increase of the calcium x phosphate product and an increased risk of arterial calcification. Such findings emphasize that an effective treatment for adynamic bone disease is required. The present study investigated the influence of vitamin K2 (menatetrenone) on hemodialysis patients with low serum parathyroid hormone levels by using bone metabolism markers. The subjects were 32 hemodialysis patients (19 men and 13 women) aged from 27 to 76 years with an intact parathyroid hormone (PTH) level of less than 65 pg/ml and an intact osteocalcin level below 20 ng/ml. All patients received oral menatetrenone therapy (45 mg/day) for 12 months. To obtain control data on bone metabolism markers in hemodialysis patients with normal bone turnover, we selected 50 patients who had intact PTH levels within the range that maintains relatively normal bone turnover, that is, from 120 to 250 pg/ml. The baseline levels of all bone metabolism markers were significantly lower in our patients than in the normal PTH control group. There was a significant increase of gamma-carboxyglutamate (Gla) osteocalcin, bone alkaline phosphatase (B-ALP), tartrate-resistant acid phosphatase (TRACP), and cross-linked N-terminal telopeptide of type 1 collagen (NTx) levels after vitamin K2 administration. Type 1 procollagen carboxyterminal propeptide (P1CP) and intact osteocalcin both showed a significant increase after 12 months of treatment. Although there was no significant change of the alkaline phosphatase (ALP) level during the 12 months before the start of vitamin K2 therapy, there was a significant increase of alkaline phosphatase after vitamin K2 administration. Adjusted calcium, serum phosphate, and intact PTH showed no significant changes throughout the study. These changes of bone metabolism markers suggested that vitamin K2 therapy can improve bone remodeling in hemodialysis patients with low serum PTH levels.

Endocrine actions of osteocalcin

         (Patti, Gennari et al. 2013) Download

Osteocalcin is the most abundant noncollagenous protein of bone matrix. Once transcribed, this protein undergoes posttranslational modifications within osteoblastic cells before its secretion, including the carboxylation of three glutamic residues in glutamic acid, which is essential for hydroxyapatite binding and deposition in the extracellular matrix of bone. Recent provocative data from experimental observations in mice showed that the circulating undercarboxylated fraction of osteocalcin increases insulin secretion and sensitivity, lowers blood glucose, and decreases visceral fat in both genders, while it enhances testosterone production by the testes in males. Moreover, both total and undercarboxylated osteocalcins increase following physical activity with potential positive effects on glucose tolerance. Despite that these evidences have been only in part confirmed in humans, further prospective investigations are needed to definitively establish the endocrine role of osteocalcin both in the general population and cohorts of patients with diabetes or other metabolic disorders.

Bone health. New role for vitamin K?

         (Ryan-Harshman and Aldoori 2004) Download

OBJECTIVE: To assess growing evidence that vitamin K (phylloquinone) plays an important role in bone health and, subsequently, in prevention of osteoporotic fractures. QUALITY OF EVIDENCE: We searched MEDLINE from January 1972 to December 2002 using the key words vitamin K and bone health. We reviewed 30 articles that seemed relevant or had a human focus. All evidence can be categorized as level II. MAIN MESSAGE: Evidence suggests that dietary phylloquinone intake of <100 microg daily might not be optimal for bone health. Low intake of vitamin K could contribute to osteoporosis and subsequent fracture due to the undercarboxylation of osteocalcin. CONCLUSION: Family physicians need to be aware of the importance of encouraging adequate vitamin K intake, particularly among institutionalized elderly people, to prevent increased bone resorption. Further study is needed to determine the exact role of vitamin K in bone metabolism, and methods of assessing vitamin K requirements need to be standardized.

Vitamin K, circulating cytokines, and bone mineral density in older men and women

            (Shea, Dallal et al. 2008) Download

BACKGROUND: Vitamin K modulates cytokines involved in bone turnover, including interleukin-6 (IL-6) and osteoprotegerin in vitro. OBJECTIVE: The objective of this study was to assess 1) associations between measures of vitamin K status [plasma phylloquinone and serum percentage of undercarboxylated osteocalcin (%ucOC)] and IL-6, osteoprotegerin, and C-reactive protein (CRP) concentrations and 2) the effect of daily 500 mug phylloquinone supplementation for 3 y on cytokine concentrations. DESIGN: Concentrations of IL-6, osteoprotegerin, and CRP and bone mineral density (BMD) were measured at baseline and after 3 y of follow-up in 379 healthy men and women (60-81 y; 58.5% women) participating in a randomized trial that studied the effect of vitamin K supplementation on bone loss. RESULTS: Cross-sectionally, plasma phylloquinone was inversely associated with IL-6 and CRP, whereas serum %ucOC was inversely associated with IL-6. Osteoprotegerin was associated positively with plasma phylloquinone and inversely with %ucOC. No differences were observed in the 3-y change in IL-6, osteoprotegerin, and CRP concentrations between participants who received phylloquinone supplementation and those who did not. Overall, no association was observed between the 3-y changes in circulating cytokines and BMD. CONCLUSIONS: Poor vitamin K status was associated with high concentrations of cytokines involved in bone turnover, but vitamin K supplementation did not confer a decrease in cytokine concentrations. The healthy status of this cohort may explain a lack of effect of vitamin K supplementation on cytokine concentrations. This trial was registered with as NCT00183001.

Vitamin K2 stimulates osteoblastogenesis and suppresses osteoclastogenesis by suppressing NF-kappaB activation

         (Yamaguchi and Weitzmann 2011) Download

Several bone protective factors are reported to exhibit stimulatory activities on bone formation coupled with inhibitory effects on bone resorption; one such factor is vitamin K2. Vitamin K species [K1 (phylloquinone) and K2 (menaquinone)] have long been associated with bone protective activities and are receiving intense interest as nutritional supplements for the prevention or amelioration of bone disease in humans. However, the mechanisms of vitamin K action on the skeleton are poorly defined. Activation of the nuclear factor kappaB (NF-kappaB) signal transduction pathway is essential for osteoclast formation and resorption. By contrast, NF-kappaB signaling potently antagonizes osteoblast differentiation and function, prompting us to speculate that NF-kappaB antagonists may represent a novel class of dual anti-catabolic and pro-anabolic agents. We now show that vitamin K2 action on osteoblast and osteoclast formation and activity is accomplished by down-regulating basal and cytokine-induced NF-kappaB activation, by increasing IkappaB mRNA, in a gamma-carboxylation-independent manner. Furthermore, vitamin K2 prevented repression by tumor necrosis factor alpha (TNFalpha) of SMAD signaling induced by either transforming growth factor ss (TGFss) or bone morphogenetic protein-2 (BMP-2). Vitamin K2 further antagonized receptor activator of NF-kappaB (RANK) ligand (RANKL)-induced NF-kappaB activation in osteoclast precursors. Our data provide a novel mechanism to explain the dual pro-anabolic and anti-catabolic activities of vitamin K2, and may further support the concept that pharmacological modulation of NF-kappaB signal transduction may constitute an effective mechanism for ameliorating pathological bone loss and for promoting bone health.


Bullo, M., R. Estruch, et al. (2011). "Dietary vitamin K intake is associated with bone quantitative ultrasound measurements but not with bone peripheral biochemical markers in elderly men and women." Bone 48(6): 1313-8. [PMID: 21447413]

Choi, H. J., J. Yu, et al. (2011). "Vitamin K2 supplementation improves insulin sensitivity via osteocalcin metabolism: a placebo-controlled trial." Diabetes Care 34(9): e147. [PMID: 21868771]

Gundberg, C. M., J. B. Lian, et al. (2012). "Vitamin K-dependent carboxylation of osteocalcin: friend or foe?" Adv Nutr 3(2): 149-57. [PMID: 22516722]

Kaneki, M., T. Hosoi, et al. (2006). "Pleiotropic actions of vitamin K: protector of bone health and beyond?" Nutrition 22(7-8): 845-52. [PMID: 16815498]

Kim, M., H. Kim, et al. (2010). "Relationship between vitamin K status, bone mineral density, and hs-CRP in young Korean women." Nutr Res Pract 4(6): 507-14. [PMID: 21286409]

Knapen, M. H., L. J. Schurgers, et al. (2007). "Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women." Osteoporos Int 18(7): 963-72. [PMID: 17287908]

Nakashima, A., N. Yorioka, et al. (2004). "Effects of vitamin K2 in hemodialysis patients with low serum parathyroid hormone levels." Bone 34(3): 579-83. [PMID: 15003806]

Patti, A., L. Gennari, et al. (2013). "Endocrine actions of osteocalcin." Int J Endocrinol 2013: 846480. [PMID: 23737779]

Ryan-Harshman, M. and W. Aldoori (2004). "Bone health. New role for vitamin K?" Can Fam Physician 50: 993-7. [PMID: 15317231]

Shea, M. K., G. E. Dallal, et al. (2008). "Vitamin K, circulating cytokines, and bone mineral density in older men and women." Am J Clin Nutr 88(2): 356-63. [PMID: 18689371]

Yamaguchi, M. and M. N. Weitzmann (2011). "Vitamin K2 stimulates osteoblastogenesis and suppresses osteoclastogenesis by suppressing NF-kappaB activation." Int J Mol Med 27(1): 3-14. [PMID: 21072493]