Category Archives: MK-7

Vitamin K1 and K2 (MK-4, MK-7) Don’t Prevent Bone Loss in Rats Fed Adequate Nutrients


Vitamin K supplementation does not prevent bone loss in ovariectomized Norway rats.

Despite plausible biological mechanisms, the differential abilities of phylloquinone (PK) and menaquinones (MKn) to prevent bone loss remain controversial. The objective of the current study was to compare the effects of PK, menaquinone-4 (MK-4) and menaquinone-7 (MK-7) on the rate of bone loss in ovariectomized (OVX) Norway rats. A secondary aim was to compare the effects of vitamin K with those of bisphosphonates (BP) on bone loss.
Rats (n = 96) were randomized to 6 dosing groups [n = 16/group; Sham; OVX; OVX + BP (100 μg/kg/100 μg/mL saline sc); OVX + PK; OVX + MK-4; and OVX + MK-7] for 6 wk. Equimolar daily doses of 107 mg PK/kg, 147 mg MK-4/kg, and 201 mg MK-7/kg diet were provided.
BP significantly increased bone strength and bone mineral density (BMD) vs. OVX (P < 0.05). However, PK, MK-4 or MK-7 did not change bone strength or BMD compared to the OVX group. Whereas supplementation of PK, MK-4 and MK-7 increased serum and tibia concentrations of each respective form, PK concentrations were consistently higher despite equimolar intakes.
PK, MK-4, and MK-7 do not appear to prevent bone loss in OVX rats when administered concurrent with adequate intake of other nutrients.

Fu X, Moreines J, Booth SL
Nutr Metab (Lond) 2012
PMID: 22348311 | Free Full Text

In conclusion, supplementation of PK, MK-4 or MK-7 did not confer a beneficial effect on bone loss in ovariectomized Norway rats fed a diet that meets nutritional requirements for other nutrients, including calcium and vitamin D. This would suggest that equivocal findings in the literature regarding the effect of various forms of vitamin K on bone cannot be attributed to differences among the forms studied. These data are also consistent with a growing number of clinical studies that report no beneficial effect of vitamin K supplementation on bone loss in the elderly who are otherwise calcium and vitamin D-replete [1,18,19].

Review: Vitamin K Reviewed by European Vitamin K Experts


Beyond deficiency: potential benefits of increased intakes of vitamin K for bone and vascular health.

Vitamin K is well known for its role in the synthesis of a number of blood coagulation factors. During recent years vitamin K-dependent proteins were discovered to be of vital importance for bone and vascular health. Recommendations for dietary vitamin K intake have been made on the basis of the hepatic requirements for the synthesis of blood coagulation factors. Accumulating evidence suggests that the requirements for other functions than blood coagulation may be higher. This paper is the result of a closed workshop (Paris, November 2002) in which a number of European vitamin K experts reviewed the available data and formulated their standpoint with respect to recommended dietary vitamin K intake and the use of vitamin K-containing supplements.

Vermeer C, Shearer MJ, Zittermann A, Bolton-Smith C…
Eur J Nutr Dec 2004
PMID: 15309455 | Free Full Text

Accumulating evidence suggests that in many aspects arterial calcification mimics bone formation, which prompts interest in the effects of vitamin K on the vasculature. Previous population-based studies reported a significant reduction in aortic calcification with high vitamin K1 [62] and vitamin K2 intake [63], and a significant inverse correlation was found between vitamin K2 intake, and the incidence of both ischaemic heart disease and cardiovascular mortality [63]. Based on these findings the effect of treatment on arterial characteristics was monitored in the Maastricht osteostudy. These unpublished findings clearly demonstrated that supplementation with vitamin K1 can protect against vascular hardening and loss of arterial elasticity. High dose MK-4 also seems to have cholesterol lowering properties as shown in studies in rabbits [64] and humans [65].


Extremely high doses (45–90mg/day) of MK-4 have been used for the treatment of postmenopausal osteoporosis in Japan for several years [66, 67]. After the positive outcomes of the first clinical trials, the treatment is now used on a large scale; thus far, no adverse side-effects have been reported. A number of independent groups have claimed that this medication results in complete prevention of further bone loss in postmenopausal women, and in some women even a significant gain in BMD [68, 69]. The treatment was also reported to be successful in other groups at risk for bone loss such as haemodialysis patients and those treated with corticosteroids.


In considering the potential efficacy of pharmacological doses of MK-4 it should be noted that there is evidence for a secondary function of this analogue over and above its role in glutamate carboxylation. The available evidence (mainly from cell culture experiments) suggests that MK-4 (but not K1) may also be associated with production of interleukin-6, regulate the synthesis of PGE2 [83], or inhibit the mevalonate pathway in a comparable way to bisphosphonates [84], but at present only preliminary data exist.


Any risks associated with relatively high consumption of either K1 or K2 appear minimal, with intakes up to 1 mg/d K1 and 45 mg/d MK-4 often having been used without observed adverse events. Two possible exceptions exist. Firstly a potential problem relates to interference with oral anticoagulants. However, a systematic dose-response study among subjects on oral anticoagulant treatment demonstrated that the stability of anticoagulation was not significantly affected by vitamin K supplements at doses below 100 μg/day [14]. Secondly, preliminary studies have suggested that high vitamin K1 supplementation (i. e. above 1 mg/day) can contribute to periodontal disease via a bacterial mechanism on gingival tissue (S. Hodges, unpublished data).



MK-7 Suppresses Osteoblast Proliferation and Enhances RANKL In Vitro


Menaquinone-7 regulates the expressions of osteocalcin, OPG, RANKL and RANK in osteoblastic MC3T3E1 cells.

Epidemiological studies show that dietary intake of natto, which contains significant amount of vitamin K(2), reduces the risk of bone formation loss. However, many confounding factors, such as calcium and isoflavone, are found in natto, because it is made from soybeans. In this study, the direct effects of MK-7, a vitamin K(2) analogue, were assessed in osteoblasts. Osteoblastic MC3T3E1 cells were cultured with or without MK-7 for 10 days and the number of cells was calculated. The cell count was not different between MK-7 treated cells and control cells for 1, 2, and 4 days. However, it was significantly suppressed in MK-7 treated cells at 10 days, suggesting that MK-7 suppressed cell proliferation. Real-time PCR analysis showed that mRNAs of osteocalcin (OC), osteoprotegerin (OPG), and the receptor activator of the NFkappaB ligand (RANKL) were induced after MK-7 administration to the culture medium. RANK mRNA expression was also enhanced by MK-7 administration. Immunocytochemical analysis showed that MK-7 increased the protein levels of OC and RANKL. RANK protein was also enhanced, but this induction was suppressed by anti-RANK antibody administration. This suppression was recovered when anti-RANK antibody and MK-7 were administered. These observations suggest that MK-7 may directly affect MC3T3E1 cells and stimulate osteoblastic differentiation, not proliferation. Katsuyama H, Otsuki T, Tomita M, Fukunaga M… Int. J. Mol. Med. Feb 2005 PMID: 15647836

MK-7 does some bad things. This says it supresses poliferation of osteoblasts, and enhances RANKL. This is in vitro and there were positive effects as well. This is interesting, but in vivo studies would be good to look at.

Review: Vitamin K and Bone Health 1998-2008


Update on the role of vitamin K in skeletal health.

A protective role for vitamin K in bone health has been suggested based on its role as an enzymatic cofactor. In observational studies, vitamin K insufficiency is generally associated with lower bone mass and increased hip fracture risk. However, these findings are not supported in randomized controlled trials (RCT) of phylloquinone (vitamin K(1)) supplementation and bone loss at the hip in the elderly. This suggests that increased vegetable and legume intakes may simultaneously improve measures of vitamin K status and skeletal health, even though the mechanisms underlying these improvements may be independent of each other. Menaquinone-4 (vitamin K(2)), when given at pharmacological doses, appears to protect against fracture risk and bone loss at the spine. However, there are emerging data that suggest the efficacy of vitamin K supplementation on bone loss is inconclusive.

Shea MK, Booth SL
Nutr. Rev. Oct 2008
PMID: 18826451 | Free Full Text

This is a great review of the different forms of Vitamin K and their benefits for bone. The full study includes a table listing many studies dated from 1998 to 2008 with their outcomes. I highly recommend reading the full text.

MK-4 in doses of 45 mg/d is used as a pharmacological treatment for osteoporosis in Japan, so there are numerous randomized control studies that have assessed the efficacy of MK-4 supplementation on skeletal health. Such doses cannot be attained from the diet, regardless of the form of vitamin K consumed. Phylloquinone from the diet is converted to MK-4 in certain tissues, including bone, but the proportion of phylloquinone that is converted is not known and no dose-dependent data are available for this conversion.


As reviewed in an earlier volume of this journal,60 studies indicate a therapeutic dose (45 mg/day) of MK-4 has a beneficial effect on spine or metacarpal BMD and fracture61–76 (Table 2). There is also improvement in bone turnover, as measured by circulating markers of bone formation and bone resorption, in response to MK-4 supplementation studies.71,72,76,77 In a separate systematic review and analysis of randomized clinical trials assessing the influence of vitamin K supplementation on hip fracture, Cockayne et al.78 concluded that supplementation with MK-4 for longer than 6 months reduces risk for hip and vertebral fracture. Included in that analysis were 12 studies that used daily doses of 45 mg/d of MK-4. As discussed by the authors, several of the studies used for the meta-analysis lacked sufficient sample size,64–66,70,73,79 were non-placebo-controlled intervention trials,70–74,76,77,80 and/or used concurrent treatment with calcium and/or vitamin D.62,69,75,76

It was subsequently disclosed that a large unpublished surveillance study conducted in Japan (n > 3000) did not find a protective effect of MK-4 supplementation (45 mg/day) on bone loss and fracture in the elderly, and that inclusion of this study may have altered the results of the meta-analysis.81 More recently, two placebo-controlled studies with large sample sizes reported no protective effect of 45 mg/d of MK-4 on hip BMD.59,67 Prior to these two publications, the majority of MK-4 supplementation studies did not report hip BMD as an outcome (Table 2). Given the heterogeneous quality of the studies used and considering the null findings of more recent, larger, placebo-controlled trials and unpublished surveillance data, prior systematic reviews and meta-analyses may need to be revisited.


Review: Phytochemicals for Bone Osteoporosis


Regulatory mechanism of food factors in bone metabolism and prevention of osteoporosis.

Aging induces a decrease in bone mass, and osteoporosis with its accompanying decrease in bone mass is widely recognized as a major public health problem. Bone loss with increasing age may be due to decreased bone formation and increased bone resorption. Pharmacologic and nutritional factors may prevent bone loss with aging, although chemical compounds in food and plants which act on bone metabolism are poorly understood. We have found that isoflavones (including genistein and daidzein), which are contained in soybeans, have a stimulatory effect on osteoblastic bone formation and an inhibitory effect on osteoclastic bone resorption, thereby increasing bone mass. Menaquinone-7, an analogue of vitamin K(2) which is abundant in fermented soybeans, has been demonstrated to stimulate osteoblastic bone formation and to inhibit osteoclastic bone resorption. Of various carotenoids, beta-cryptoxanthin, which is abundant in Satsuma mandarin (Citrus unchiu MARC), has a stimulatory effect on osteoblastic bone formation and an inhibitory effect on osteoclastic bone resorption. The supplementation of these factors has a preventive effect on bone loss induced by ovariectomy in rats, which are an animal model of osteoporosis, and their intake has been shown to have a stimulatory effect on bone mass in humans. Factors with an anabolic effect on bone metabolism were found in extracts obtained from wasabi leafstalk (Wasabi japonica MATSUM), the marine alga Sargassum horneri, and bee pollen Cistus ladaniferus. Phytocomponent p-hydroxycinnamic acid was also found to have an anabolic effect on bone metabolism. Food chemical factors thus play a role in bone health and may be important in the prevention of bone loss with increasing age.

Yamaguchi M
Yakugaku Zasshi Nov 2006
PMID: 17077614 | Free Full Text

MK-7 at 360mcg for a Year Does Not Benefit Postmenopausal Norwegian Women


Vitamin K2 supplementation does not influence bone loss in early menopausal women: a randomised double-blind placebo-controlled trial.

Vitamin K2 may preserve bone strength and reduce fracture risk. In this randomised double-blind placebo-controlled trial among healthy postmenopausal Norwegian women, 1 year supplementation of vitamin K2 in the form of Natto capsules had no effect on bone loss rates. Japanese studies indicate that vitamin K2 (menaquinone-7 (MK-7)) intake may preserve bone strength, but this has not been documented in Europeans. The aim of this study was to assess the effect of MK-7 on bone mineral density (BMD) changes in postmenopausal Norwegian women.
Three hundred thirty-four healthy women between 50 and 60 years, 1-5 years after menopause, were recruited to a randomised double-blind placebo-controlled trial. The participants were randomly assigned into two groups, one receiving 360 microg MK-7 in the form of Natto capsules and the other the same amount of identical-looking placebo capsules containing olive oil. BMD was measured at total hip, femoral neck, lumbar spine and total body at baseline and 12 months together with serum levels of bone-specific alkaline phosphatase, Crosslaps, total osteocalcin (N-mid OC), carboxylated (cOC) and under-carboxylated osteocalcin (ucOC).
After 12 months, there were no statistical differences in bone loss rates between the groups at the total hip or any other measurement site. Serum levels of cOC increased and ucOC decreased in the treatment versus the placebo group (p < 0.001).
MK-7 taken as Natto over 1 year reduced serum levels of ucOC but did not influence bone loss rates in early menopausal women.

Emaus N, Gjesdal CG, Almås B, Christensen M…
Osteoporos Int Oct 2010
PMID: 19937427

360mcg is a fairly high dose, and they took it for a good long time. This is very disappointing  for MK-7.

Vitamin K2 MK-7 Decreases Bone Loss in Postmenopausal Women


Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women.

We have investigated whether low-dose vitamin K2 supplements (menaquinone-7, MK-7) could beneficially affect bone health. Next to an improved vitamin K status, MK-7 supplementation significantly decreased the age-related decline in bone mineral density and bone strength. Low-dose MK-7 supplements may therefore help postmenopausal women prevent bone loss.
Despite contradictory data on vitamin K supplementation and bone health, the European Food Safety Authorities (EFSA) accepted the health claim on vitamin K’s role in maintenance of normal bone. In line with EFSA’s opinion, we showed that 3-year high-dose vitamin K1 (phylloquinone) and K2 (short-chain menaquinone-4) supplementation improved bone health after menopause. Because of the longer half-life and greater potency of the long-chain MK-7, we have extended these investigations by measuring the effect of low-dose MK-7 supplementation on bone health.
Healthy postmenopausal women (n = 244) received for 3 years placebo or MK-7 (180 μg MK-7/day) capsules. Bone mineral density of lumbar spine, total hip, and femoral neck was measured by DXA; bone strength indices of the femoral neck were calculated. Vertebral fracture assessment was performed by DXA and used as measure for vertebral fractures. Circulating uncarboxylated osteocalcin (ucOC) and carboxylated OC (cOC) were measured; the ucOC/cOC ratio served as marker of vitamin K status. Measurements occurred at baseline and after 1, 2, and 3 years of treatment.
MK-7 intake significantly improved vitamin K status and decreased the age-related decline in BMC and BMD at the lumbar spine and femoral neck, but not at the total hip. Bone strength was also favorably affected by MK-7. MK-7 significantly decreased the loss in vertebral height of the lower thoracic region at the mid-site of the vertebrae.
MK-7 supplements may help postmenopausal women to prevent bone loss. Whether these results can be extrapolated to other populations, e.g., children and men, needs further investigation.

Knapen MH, Drummen NE, Smit E, Vermeer C…
Osteoporos Int Sep 2013
PMID: 23525894

Review: Vitamin K and Bone Health


Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K with special reference to bone health.

Vitamin K occurs in nature as a series of compounds with a common 2-methyl- 1,4 naphthoquinone nucleus and differing isoprenoid side chains at the 3 position. They comprise a single major plant form, phylloquinone with a phytyl side chain and a family of bacterially synthesized menaquinones (MKs) with multiprenyl side chains. The major dietary source to humans is phylloquinone for which the chief food contributors are green, leafy vegetables followed by certain vegetable oils (soybean, rapeseed and olive oils). Recent analyses by high pressure liquid chromatography are now providing a wide-ranging database of phylloquinone in foods. Menaquinones are found in moderate concentrations in only a few foods such as cheeses (MK-8 and MK-9). A wider spectrum of MKs is synthesized by the gut microflora, and their intestinal absorption probably accounts for most of the hepatic stores, particularly those with very long side chains (MKs-10-13) synthesized by members of the genus Bacteroides. The site of absorption of floral MKs is not known, but reasonable concentrations are found in the terminal ileum where bile salt-mediated absorption is possible. Both phylloquinone and menaquinones are bioactive in hepatic gamma-carboxylation but long-chain MKs are less well absorbed. Liver stores of vitamin K are relatively small and predominantly MKs-7-13. The hepatic reserves of phylloquinone (approximately 10% of the total) are labile and turn over at a faster rate than menaquinones. Trabecular and cortical bone appear to contain substantial concentrations of both phylloquinone and menaquinones. A majority (approximately 60-70%) of the daily dietary intake of phylloquinone is lost to the body by excretion, which emphasizes the need for a continuous dietary supply to maintain tissue reserves.

Shearer MJ, Bach A, Kohlmeier M
J. Nutr. Apr 1996
PMID: 8642453 | Free Full Text

At the present time the human requirements for vitamin K are based solely on its classical function in coagulation being listed as a Recommended Dietary Allowance (RDA) in the United States (Suttie 1992) and a Safe and Adequate Intake in the United Kingdom (Department of Health Report 1991). In both cases these requirements were set at a value of 1 mcg/kg/d. If, as argued by Vermeer et al. and Kohlmeier et al. in this volume, vitamin K is important to bone health and its requirements for this bone function are greater than for its hepatic function, a great challenge to researchers and future committees alike is to determine whether these putative extra demands can be quantified more precisely. Finally, it should be noted that the concept of reexamining the optimal intake of a vitamin with respect to the extra health benefits, which may be conferred by giving amounts over and above those required to protect against the originally discovered deficiency disease, is not new. There is already a recognition of the newer and often unexpected roles played by several other vitamins including in some cases the beneficial effects of extra intakes (Sauberlich and Machlin 1992).