Published Research-Bone Globally it is estimated that 1 in 3 women and 1in 12 men over the age of 50 suffer from osteoporosis.   Bones remake themselves continually and contain completely new structures about every three years.  If anything interrupts the cycle of bone re-formation, the bone can weaken, develop fractures and/or break. Vitamin K is necessary for bone health.  Bones have proteins in them that are dependent on vitamin K.  Matrix Gla Protein is one of these proteins. You need to take vitamin K in high enough quantities to meet the basic needs of your body, with enough vitamin K left over for other parts of the body, like bones.  Koncentrated K is the only capsule on the market with enough vitamin K to help. Taking calcium directly is not recommended. Research shows that bone fractures are reduced when vitamin K levels are higher. High doses of vitamin K2, specifically MK4, are an approved treatment for osteoporosis in Japan.  Research shows that when taking a supplement of vitamin K, bone loss is reduced and fracture risk goes down.

The research offered below reflects the different lines of exploration on the impact of vitamin K on bone health.

Bone is a living tissue.  The skeleton renews itself in two ways:  bone modeling and bone remodeling. Bone modeling begins in fetal life and continues until skeletal maturity, taking place during growth and development in childhood.  It involves the formation of bone by osteoblasts or resorption of bone by osteoclasts on a given surface.  These processes are sequential and coordinated to shape the bone correctly (Allen & Burr, 2014).  The function of bone modeling is to increase bone mass and to maintain or reshape the bone in response to physiological stimuli (Clarke, 2008).

In contrast, bone remodeling occurs after the skeleton has reached maturity during adulthood, and is necessary to maintain structural integrity, bone volume and calcium and phosphate homeostasis (Feng & McDonald, 2011).  Remodeling repairs the bone by removing old and micro-damaged bone, replacing it with strong new bone.  First, cells called osteoclasts work to get rid of old, weakened bone.  They resorb old bone to make room for the creation of strong healthy bone.  Second, cells called osteoblasts, which are a form of immature bone cells, help produce a matrix composed of collagen that becomes mineralized and forms bone.  Continuous new bone matrix synthesis is followed by calcification of the newly formed bone. 

There is a continuous cycle of active bone formation and bone resorption, nominally taking about three to five years for complete bone remodeling.  Strong healthy bones require a certain nutritional diet, and without that diet, the cycle is interrupted, leading to things like a reduction in bone mass, changes in the distribution of bone, changes in the material properties of the remaining bone, an accumulation of damaged bone, and/or loss of the cortical micro-architecture making up the bone, all of which is damaging to bones.  

Bone Chemistry and Vitamin K

Vitamin K was best known for its function in the blood coagulation pathway, but a number of studies suggest that the K vitamins play an important role in bone metabolism and in the optimization of bone health (Weber, 2001; Ryan-Harshman et al, 2004).  Vitamin K (which is found mainly in leafy green vegetables) is required for a chemical modification of certain proteins with the process being called carboxylation.  During carboxylation, vitamin K reacts with glutamates in your body to produce the amino acid gamma-carboxyglutamate, or Gla, which activates the vitamin K-dependent proteins.  Once carboxylation takes place in your body through vitamin K, what remains are the byproducts of Gla -- vitamin K2 epoxide, vitamin K3 epoxide and water.  Gla then travels through the body to facilitate processes such as blood clotting and bone strengthening.  Vitamin K is the essential cofactor for the carboxylation of glutamate to gamma-carboxyglutamic acid (Gla), which activates the vitamin K–dependent Gla-containing proteins.  When vitamin K is low, or insufficient, then those proteins cannot be carboxylated, the chemical modification does not take place, they remain unactivated, and the processes of bone strengthening are interfered with.  Diseases like osteoporosis can result.

The identification of these vitamin K-dependent Gla proteins in the organic matrix of bone, boostered research on vitamin K and bone metabolism.  These proteins include bone-Gla protein (BGP), matrix-Gla protein (MGP), protein S, Gla-rich protein (GRP), periostin, and periostin-like factor PLF (Price, et al., 1976: Rani, et al.  2009:  Price, et al.  1983;  Maillard, et al.  1992; Couty, et al, 2009).  Three Gla-containing bone proteins, all synthesized by osteoblasts, have been identified: osteocalcin, matrix Gla protein, and protein S.  Osteocalcin is the most abundant noncollagenous protein in the bone.  All of these proteins are produced by osteoblasts and undergo activation via post translational carboxylation, meaning they require vitamin K to be available in high amounts. However, for many people, their dietary intake of vitamin K is too low for this activation to take place (Theuwissen, et al. 2012)
 

Bone Health and Vitamin K

The discovery of vitamin K-dependent proteins in bone has led to research on the role of vitamin K in maintaining bone health.  The research has shown that adequate amounts of vitamin K2 are needed in order to activate osteocalcin – the protein circulating in the blood, that is responsible for binding calcium ions to the matrix of bone, making bones stronger.  Vitamin K is also needed to activate Matrix Gla Protein (MGP), another protein circulating in the blood that is associated with the coming together of cartilage and bone.  

Significant and consistent conclusions emerge in the studies presented below, showing that bone fractures in both women and men are reduced in correlation with higher levels of vitamin K.  A deficiency of Vitamin K is associated with brittle bones, or osteoporotic fracture, and low bone mineral density (BMD) caused by high levels of under-carboxylated osteocalcin (Binkley, et al, 2000; Szulc, et al, 1996; Hart et al, 1984; Booth, Broe et al, 2003; Weber, 2001; Jaghsi, et al 2018).  Giri (et al, 2019) showed that supplementing with either 5 or 45 mg a day of MK4 reduced uncarboxylated osteocalcin to levels typical of healthy women.  

Vitamin K deficiency has been associated with features of osteoarthritis (Neogi et al, 2006; Oka et al, 2009; Ishii, et al, 2013; Misra et al, 2013; Volpe, 2015; Chin, 2020), as well as a loss of mobility (Shea et al, 2019) and overall physical performance (Azuma & Inoue, 2019).  There can also be deterioration of cartilage, join space narrowing and other changes (Malemud, 2015).  A recent study found that men and women with very low amounts of vitamin K intake were more likely to have articular cartilage and meniscus damage progression after three years (Shea et al, 2015).  Another study showed that subjects with vitamin K deficiency were found to have higher scores on the WOMAC scale, reflecting a more severe arthritic disease state (El-Brashy, et al 2016).  The ROAD study found low dietary intake of vitamin K was associated with joint space narrowing and osteophytosis in women (Muraki et al, 2014).

Studies of people with osteoarthritis (of the bone) showed lower levels of carboxylated matrix Gla protein in the tissues with arthritis, than in the tissue with normal cartilage (Wallin, et al, 2010).  And people with inflammatory arthritis had higher levels of uncarboxylated MGP compared to the non-inflammatory group (meaning they had low levels of vitamin K) (Rafel et al, 2014). Serum uncarboxylated MGP was reported to be lower in patients with knee OA than normal controls according to Bing (et al, 2015).  In general, MGP seems to be a potent calcification inhibitor in connective tissues (Nollet, et al, 2019).

Osteoporosis is defined as a metabolic bone disease characterized by low bone mass and micro-architectural deterioration of bone tissue, in which the bones gradually become less dense and become more likely to break.  In osteoporosis the net rate of bone resorption exceeds the rate of bone formation, resulting in a decrease in bone mass.  There is more osteoclast activity than osteoblast activity so your bone density decreases and you get osteoporosis.  Globally it is estimated that one in three women and one in twelve men over age 50 will suffer from osteoporosis in their lifetime (van Staa, et al., 2001).  In the United States, 10 million people have osteoporosis and 18 million have osteopenia, a milder condition that precedes osteoporosis (Cheung, et al., 2008).  A five-year prospective study found that all major bone fractures were associated with increased risk of death, especially in men (Center, et al.,  1999).  In both conditions, insufficient new bone is made and/or too much old bone is absorbed.  Although bone appears solid and unchanging, very little bone in the human body is more than ten years old.  Old bone is continually absorbed and new bone is built using Vitamin D, calcium, magnesium, phosphorous, and proteins. 
 

Bone Health, Age and Vitamin K

It is widely believed that bone loss occurs naturally as we age.  Alternatively, it is possible that bone loss reflects a reduction in the body’s processing of vitamin K as we age.  Changing levels of hormones due to age also control the flora, or healthy bacteria, present in the intestines.  The different floras affect how food is digested and therefore the amount of nutrients, including Vitamin K, which are absorbed through the intestinal walls (Woudstra, 2002; Drozdrowski, 2006; Yamaguchi, 2006).  As sex hormones control the depositing of these nutrients in the bones and therefore bone strength, the reductions in estrogen hormones in women is the leading cause of osteoporosis in women.  In men, an age-related decline in testosterone levels can cause osteoporosis.  Most people discover they have osteoporosis only when they break a bone, but the condition can be diagnosed and monitored using bone mineral density (BMD) scans. Research indicates that a low intake of vitamin K has been associated with an increased risk of hip fractures in the elderly (Kaneki et al, 2006; Booth et al, 2003; Apalset et al, 2011).  Insufficient vitamin K is also associated with osteoarthritis (Oka, et al, 2009; Ishii, et al, 2013; Misra, et al, 2013).

During adolescence the skeleton is most active in absorbing dietary calcium and building up the bone mass that will carry them throughout life.  Dietary intake of vitamin D, and vitamin K2 is critical during this life stage (Baucom et al, 2014).  And in children, inadequate vitamin K intake was correlated with negative bone parameters (Szmodis et al, 2019).

Research also suggests that osteoporosis is impacted by a reduction in the absorption of vitamin K, in concert with a concomitant reduction in the absorption of magnesium and a reduction in the production of vitamin D.  This synergy of vitamins K and D has been recognized in studies performed by the University of California (Kidd, 2010), along with a significant interaction with vitamin A which is produced by the liver on an as-needed basis. 

(Never take vitamin A as a supplement, just eat foods with Beta Carotene = = = let your liver make what you need). 

This synergy of vitamin K along with vitamin D has been demonstrated in clinical trials (Gallagher et al., 1979; Douglas, et al., 1995; Koshihara et al. 1996; Takahashi et al, 2001; Iwamoto et al, 2003; van Ballegooijen et al, 2019), and is associated with better lower-extremity knee function (Shea, et al 2017).  The mechanism likely involves mutual enhancement and potentiation of each vitamin’s effects on osteocalcin.  In light of the evidence, vitamins D and K should be used in conjunction to maximize the possible beneficial effects of each on bone health.  (Iwamoto, et al,  2004; Bolton-Smith et al, 2007; Braam, et al, 2009; Schwalfenberg et al, 2017; Kuang et al, 2020).  Schroder (et al, 2020) found that vitamin D induced a stiffer bone and MK4 a softer, more flexibone bone.  They concluded that combined administration of vitamin K2 and vitamin D could contribute to a stronger bone, overall.

Bones Weakened by Warfarin Treatments

The research has also explored the issues involved with bone loss associated with taking prescribed medications, such as warfarin.  Some prescribed medications, such as oral anticoagulants, warfarin (Coumadin), are known to be antagonists of vitamin K.  Warfarin creates a functional vitamin K deficiency, in its effort to inhibit blood clot formation, with all of the deleterious health consequences that cascade from there.  One of theses consequences is brittle bones or osteoporosis, through the inhibition of bone cell differentiation (Booth and Mayer, 2000; Simon et al.  2002; Jeong et al, 2011).  This and other serious side effects of warfarin give it one of the highest risk profiles of any medication (Phillips and Ansell, 2008) and requires that it be carefully managed for all people receiving the medication.  It is important for any person who is taking medication that interferes with vitamin K to consult with their physician and to consider taking a regular supplement of vitamin K to ensure they have enough to support basic bodily needs and so as to maintain a consistent level in concert with the medication. (Weibert et al., 1997; Crowther, 2002: Walker and Busey, 2008; NIHCC; Sconce and Kamali, 2006). 

Intake

Currently, the recommended daily intake (RDI) of vitamin K is based on the maintenance of normal blood coagulation (Beulens et al, 2013; Marles et al, 2017).  The National Academy of Medicine in the US has set the AI of vitamin K1 at 120 ug/day for adult men and 90 ug/day for adult women (National Research Council, 2000).  The World Health Organization and the Food and Agriculture Organization have set the recommended dosages for vitamin K1 at 65 ug/day for men and 55 ug/day for women, on the basis of 1 ug/day/kg body weight.  The European Commission has set the recommended daily allowance (RDA) for vitamin K at 75 ug/day for adult men and 65 ug/day for adult women (Tanaka et al, 2013).  Japan has set the AI of vitamin K at 75 ug/day for adult men and 65 ug/day for adult women by the Ministry of Health, Labor and Welfare in 2010 (Tanaka et al, 2013).

However, there is an ongoing debate on the optimal intake of vitamin K, based on the needs of extrahepatic tissues, and on the differences between the types of vitamin K and their action in the body.  Previous research has shown that, 65 ug/day is insufficient for the γ-carboxylation of osteocalcin (OC) (Inaba et al, 2015; Sato et al, 2020).  In that study, vitamin K intake from meals of all subjects was strictly controlled to an average of 72 ug/day, mainly with vitamin K1 and small amounts of MK-4 throughout the study.  They analyzed serum carboxylated OC (cOC) and undercarboxylated OC (ucOC), and determined the ratio of cOC/ucOC, a sensitive marker of vitamin K status in bone.  The ratio of cOC/ucOC significantly decreased after two weeks and decreased further by about 40% from baseline (Shearer et al, 1996).  Furthermore, cOC and ucOC concentrations continued to exhibit a tendency to decrease.  Because daily intake of 72 µg/day corresponds to 1.3 µg/day/kg body weight, the results demonstrated that the current RDIs of vitamin K set by many countries are insufficient for the γ-carboxylation of OC.   It also demonstrates that a relatively higher vitamin K intake is required for bone and vascular health [McCann & Ames, 2009]. As vitamin K accumulates mostly in the liver and is used for coagulation, a greater quantity is thought to be required for extrahepatic tissues [Inaba, Sato et al 2015). 

In 2015, the Japanese daily AI for vitamin K for adults was increased to 150 µg/day for both adult men and women. However, it is still unknown whether this level is sufficient for normal bone metabolism, as vitamin K1 from vegetables is poorly absorbed. 

As vitamin K1, MK-4, and MK-7 have different intestinal absorption rates and blood half-lives in humans, their physiological activities are also considered to differ [Schurgers et al, 2002; Theuwissen et al 2012].  Thus, the RDIs for the different types of vitamin K2 should be established based on their relative activities. Vitamin K1 and MK-4 at their current RDIs are not sufficient for activation of OC. On the other hand, it is expected that MK-7 may promote bone health.  Among vitamin K homologs, MK-7 has been shown to have the highest bioavailability and the most significant effect on OC carboxylation in humans. 

Per Sato et al, (2020), “… a supplemental intake of 250-1000 ug/day of vitamin K1 activates OC“ (Binkley et al, 2002), which is higher than the current RDIs of vitamin K in most countries.  A markedly higher dose of MK-4 (600-1500 ug/day) is required to activate OC (Takeuchi et al, 2005; Nakamura et al, 2014) as it has been shown to have a very short half-life in humans (Schurgers et al, 2002) and it is poorly absorbed.  Nutritional doses of MK-4, such as the consecutive intake of 60 µg/day or a single intake of 420 μg, have shown to be ineffective (Sato, et al, 2012).   In contrast, MK-7 at doses around the current RDI (90–180 µg/day) promoted OC carboxylation (Brugge et al, 2011).  

In addition to OC carboxylation, which modulates the deposition of calcium in bone, MK-4 increases collagen accumulation [Ichikawa et al 2006; Sato, 2012]. We also confirmed that MK-7 increased collagen production using osteoblasts [48]. Collagen is essential to bone flexibility and elasticity, and occupies more than half the volume of bones. It is responsible for matrix production, the material on which calcium and other minerals accumulate. Therefore, along with bone minerals, collagen accumulation is critical for high-quality bone formation. Other than OC, many VKDPs, such as MGP, protein S, and periostin are produced in the bone matrix, suggesting a complex involvement of vitamin K and VKDPs in bones. 

Additionally, when higher doses over the RDA were used, it did not adversely affect the coagulation system in any way (Knapen et al, 2013). 

Prolonged supplementation of MK7 has been reported for 3 years, with no adverse effects of MK-7 has [Knapen et al 2015; Kaneki et al 2001). We found that an intake of 600 µg/day of MK-7 for one month did not affect biochemical parameters in serum and urine in healthy subjects. Safety of MK-7 has been reviewed by Marles et al., and its use in food for fortification purposes has been approved in many countries.  Sato ( et al, 2020) discusses the high efficacy of MK7 due to its higher bioavailability and longer half-life, and that it may promote bone health.  They recommend that MK7 and MK4 have distinct bioactivities and that recommended daily intake should be based on their different contributions to bone health.

Supplementing with vitamin K

High doses of menaquinones, specifically MK4, have been used as an approved treatment for osteoporosis in Japan since 1995.  A systematic review of clinical trials published in 2006 by Cockayne et al, concluded that the clinical findings to date suggest that supplementation with vitamin K1 and MK4 reduces bone loss as measured by bone mineral density (BMD).  Most of these trials used a high dose of MK4, which they defined as 45 mg. daily (Cockayne et al., 2006; Shea et al, 2007; Orimo et al, 2012; Jiang et al, 2014 ).  This dosage was determined as an optimal dose from a dose-finding study of MK4 in Japan, where the patients were administered daily doses of 15, 45, 90, and 135 mg (Iwamoto, 2014). 

A recent study utilizing a lower dose of MK4 (1.5 mg/day) also showed improved bone quality and no loss of BMD after one year, when compared to a control group  (Koitaya, 2014).  A systematic review of 18 studies in the literature showed that MK4 decreased the ratio of undercarboxylated osteocalcin/to osteocalcin and imporoved lumbar BMD when compared with placebo (Su, et al 2019).  Another review found positive evidence for the effects of MK4 on fracture incidence in postmenopausal women with osteoporosis (Iwamoto, 2014).  And doses of 5 mg up to 45 mg increased the amount of carboxylated osteocalcin in postmenopausal women (Giri et al, 2020).  Yuanyang (et al, 2019) found that bone mineral density (BMD) in the hip and waist of women with osteoporosis may be improved by vitamin K2 treatment, through supporting osteogenic activity and inhibiting both osteoclastic activity and expression of cathepsin K.  Based on a review of the research, it is recommended that eating natural sources of vitamin K2 as well as taking supplements can be an important strategy to prevent osteoporosis (Giammanco et al, 2012; Villa, et al, 2017; Capozzi et al, 2020). 

And doses of 5 mg up to 45 mg increased the amount of carboxylated osteocalcin in post menopausal women (Giri et al, 2020).  Another study showed that supplementing of at least 90 ug a day had a significant effect on reducing bone loss in postmenopausal women, while there was no benefit from combining with calcium (500 mg/day) and vitamin D (10ug a day) (Zhang et al, 2020).   

Based on a review of the research, it is recommended that eating natural sources of vitamin K2 as well as taking supplements can be an important strategy to prevent osteoporosis (Giammanco et al, 2012; Plaza et al, 2015; Villa, et al, 2017; Capozzi et al, 2020). 

A recent study investigated the effect of both vitamin K1 and MK7 on the bone health of postmenopausal women.  There were four intervention groups who received dairy products enriched with either calcium, vitamin D, vitamin K1 or vitamin K2 (MK7).  The results indicated that the women who received the vitamin Ks showed the most improved changes in bone metabolism and bone mass markers (Kanellakis, Moschinos et al 2012).   An animal study indicated that vitamin K treatment led to the healing of bone microfractures and beneficial effects on bone ultrastructure in osteoporotic mice (Rangel et al, 2018).

Glucocorticoids can harm endothelial cells and impair blood vessel functioning, as well as decreased the bone repair process.  Another study looked at osteonecrosis from glucocorticoids in rat models.  The glucocorticoid (medication for inflammation) had decreased the blood vessels and harmed the blood supply in the femoral head, leading to osteonecrosis.  They administered vitamin K2 and found that it significantly protected the blood supply and promoted vascularity.  (Zhang et al 2016).  They felt vitamin K2 could be a beneficial treatment for bones damaged from steroids.

It is believed that the vitamin K is used in the body according to the Triage Theory, whereas the liver takes it initially to ensure that blood clotting happens, and only what is left over becomes available to the other body tissues and various physiological functions that need it.   When vitamin K is insufficient, very little is left over and the other body tissues such as bone, go without and suffer the consequences.

The vitamin K intake of the general population may not be sufficient to guarantee the carboxylation needed to maintain osteocalcin activity (Bach, 1996; Yamauchi et al, 2010; Yamaguchi et al, 1999; Kim et al 2013) and the strong bones that activated osteocalcin can ensure.  It has been shown that low intake of vitamin K is associated with new-onset knee osteoarthritis and early osteoarthritis changes on MRIs (Misra et al 2013) and supplementing with MK4 led to a marked decrease in rhuematoid arthritis markers (Abdel-Rahman et al 2015) and can improve overall bone health (Akbari, et al, 2018).  In an animal study Okamoto (2008) found that MK4 suppressed the initiation of clinical arthritis in a dose dependent manner, and they felt that that MK4 was a new, non-toxic agent for the treatment of rheumatoid arthritis.  And recent work by Jeong (2019) investigated the differences in diversity and changes in specific bacterial taxa in microbiomes associated with early RA.  They found that genes related to the biosynthesis of menaquinone were enriched in healthy subjects, but not in early RA patients.

And ongoing research shows that vitamin K2 helps with the mineralization and differentiation of osteoblasts which help reduce osteoporosis (Zhang et al, 2017; Li et al, 2019).  In an animal study, Weng (et al, 2019) showed the administration of vitamin K2 plus parathyroid hormone increased the differentiation of osteoblasts and also had a synergistic effect on bone formation.

A new focus is on dental pulp stem cells.  Research indicated that MK4 has a significant effect on dental stem cells, helping them to differentiate into osteoblasts.  It was concluded that MK4 could enhance bone regeneration (Rsouli-Ghahroudi, et al, 2017).

And in an exciting announcement, there are plans to research methods to alter the gut microbiome in a way to bolster bone health (Guss et al, 2017; Jimenez, 2020).  A preliminary study of the microbiome and the functional capacity of the microbes, showed that disruption of the gut microbiome led to modifications in the genes responsible for synthesizing vitamin K and B, among other things.  Vitamin K content of the cecum, liver and kidneys were decreased by 32-66% compared to animals who had not been treated with antibiotics (Guss et al, 2020).

Research continues to be published that expands and explores the relationship between vitamin K and bone health.  The current findings indicate that vitamin K has a very beneficial impact on bone health, making it an extremely important supplement to take!  With adequate levels of vitamin K in our system, bone loss, and subsequent bone weakness may not occur (Chin, 2020). 

It is possible that with supplementation – taking the Koncentrated K capsule along with Vitamin D and Magnesium – one might be able to maintain healthy bone levels.
 

1970s

Johansen JS, Thomsen K, Christiansen C.  Plasma bone Gla protein in healthy adults.  Dependence on sex, age, and glomerular filtration.  Scand J Clin Lab Invest.  1974;47:345. 

Hauschka PV, Carr R.  Calcium-dependent alpha-helical structure in osteocalcin.  Biochemistry.  1975;21:2538-47. 

In 1974, identification of amino-γ-carboxy glutamic acid (Gla) in prothrombin as the product of vitamin K action unequivocally showed that vitamin K is a cofactor for posttranslational carboxylation of Gla residues. The Gla residues act as calcium-binding sites that are essential for normal hemostasis.  This was a tremendous discovery that helped highlight the significance of vitamin K in our bodies.

Hauschka PV, Lian JB, Gallop PM.  Direct identification of the calcium-binding amino acid, gamma-carboxyglutamate, in mineralized tissue.  Proc Natl Acad Scie.  1975;72:3925-29. 

Described a vitamin K-dependent bone-specific protein called bone Gla protein or osteocalcin.  The molecule is the most abundant noncallagenous protein in bone.  Osteocalcin has glutamic residues in its molecule and these are converted to g-carboxyglutamic acid (Gla) through post-translational modificationmediated by a vitamin K-dependent carboxylase. 

Price PA, Otsuka AA, Poser JW, Kristaponis J, Raman N.  Characterization of a gamma-carboxyglutamic acid-containing protein from bone.  Proc Natl Acad Sci USA.  1976;73:1447-51. 

Price PA, Poser JW, Raman N.  Primary structure of the gamma-carboxyglutamic acid-containing protein from bovine bone.  Proc Natl Acad Sci.  1976;73:3374-75. 

Gallagher JC, Riggs L, Eisman J, Hamstra A, Arnaud SB, Deluca HF.  Intestinal calcium absorption and serum vitamin D metabolites in normal subjects and osteoporotic patients:  Effect of age and dietary calcium.  J Clin Invest. 1979 September; 64(3): 729–36.

1980s

Armbrecht HJ, Zenser TV, Davis BB.  Effect of age on the conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 by kidney of rat.  J Clin Invest. 1980 November; 66(5): 1118–23.

Hauschka, PV.  Osteocalcin in developing bone systems.  In Suttie JW, editor.  Vitamin K Metabolism and Vitamin K-Dependent Proteins.  University Park Press; Baltimore, 1980.  p 227-36.

Lian JB, Glowacki JA, Glimcher MJ.  The occurrence of g-carboxyglutamic acid in elasmobranch endoskeleton.  In Suttie JW, editor.  Vitamin K Metabolism and Vitamin K-Dependent Proteins.  University Park Press; Baltimore, 1980.  p 263-68.

Poser JW, Esch FS, Ling NC Price PA.  Isolation and sequence of the vitamin K-dependent protein from human bone:  undercarboxylation of the first glutamic acid residue.  J Biol Chem.  1980;319:70. 

The gamma-carboxyglutamate-containing protein from human bone has been isolated from proteins released upon demineralization of bone.  The identification of glutamic acid at position 17 represents the first instance where a partially gamma-carboxylated glutamate has been found in a sequence position which is to the NH2-terminal side of a gamma-carboxyglutamate residue.

Price PA, Epstein DJ, Lothringer JW, Nishimoto SK, Poser JW, Williamson MK.  Structure and function of the vitamin K-dependent protein of bone.  In Suttie JW, editor.  Vitamin K Metabolism and Vitamin K-Dependent Proteins.  University Park Press; Baltimore, 1980.  p 219-26.

Brown MS, Kovanen PT, Goldstein JL.  Regulation of plasma cholesterol by lipoprotein receptors.  Science.  1981;212:628-35. 

Delmas PD, Stenner D, Wahner HW, Mann KG, Riggs BL.  Increase in serum bone gamma-carboxyglutamic acid protein with aging in women.  Implications for the mechanism of age-related bone loss.  J Clin Invest.  1983; 71:1316. 

Because it is unclear whether age-related bone loss results from increased bone resorption, decreased bone formation or both, we measured the serum level of bone Gla-protein (BGP), a specific marker for bone turnover, in 174 women, ages 30 to 94 years serum BGP increased linearly with aging.  This increase correlated inversely with concomitant decreases in bone mineral density at the lumbar spine, midradius, and distal radius. These data suggest that overall bone turnover increases in women with aging, and do not support the view that age-related bone loss results primarily from decreased bone formation.

Price PA, Urist MB, Otawara Y.  Matrix Gla protein, a new gamma-carboxyglutamic acid-containing protein which is associated with the organic matrix of bone.  Biochem Biophys Res commun.  1983:117;765-771. 

Epstein S, Poser JW, McClintock R, Johnston CC, Jr. Bryce G, Hui S.  Differences in serum bone Gla protein with age and sex.  Lancet. 1984;1:307. 

Serum bone Gla protein (BGP) was measured in 166 healthy men and women aged 30-90 years.  Serum BGP levels increased with age in both sexes and were higher in women than in men at all ages.  The most striking rise occurred in women after age 40-49.  BGP was significantly correlated positively with serum alkaline phosphatase and negatively with midshaft and distal bone mass in both sexes.  In women only, BGP levels were significantly positively related to levels of immunoreactive parathyroid hormone (iPTH).  When age was included in the multiple regression analysis, BGP was still correlated with alkaline phosphatase in both sexes and iPTH in women only.  Serum BGP levels were significantly higher in 13 osteoporotic patients than in age-matched controls. It is postulated that with increasing age vitamin D levels fall, causing a rise in iPTH and thus in bone turnover, which is reflected by a rise in BGP levels.

Hart JP, Catterall A, Dodds RA, Klenerman L, Shearer MJ, Bitensky L, et al.  Circulating vitamin K1 levels in fractured neck of femur.  Lancet.  1984; 324:283. 

Used low circulating vitamin K1 to show the inverse association between vitamin K status and fracture risk. 

Cole DEC, Carpenter TO, Gundberg CM.  Serum osteocalcin levels in children with metabolic bone disease.  J Pediatr.  1985;106:770. 

They surveyed both normal children and patient populations to identify the effects of metabolic bone disease and impaired renal function on serum levels of osteocalcin, a vitamin K-dependent protein synthesized in bone.  Serum osteocalcin elevation coincided with the pubertal growth spurt.  In children with renal failure, osteocalcin was substantially increased, presumably because of diminished renal clearance of the protein.  Correlation between bone disease and serum osteocalcin was evident in a longitudinal study of one patient with renal failure. Children with various forms of rickets had elevated osteocalcin levels; hypoparathyroidism and osteoporosis were accompanied by variable changes.  Serum osteocalcin holds promise as a useful marker of subacute changes in bone metabolism.

Ettinger B, Genant HK, Cann CE.  Long-term estrogen replacement therapy prevents bone loss and fracture.  Ann Intern Med.  1985;102:319-24. 

To quantify the degree to which estrogen replacement therapy prevents postmenopausal osteoporosis, a retrospective study was done comparing the occurrence of fractures in 245 long-term estrogen users and 245 case-matched controls, followed for an average of 17.6 years.  Estrogen users showed significantly greater bone mineral: 54.2% greater spinal mineral (p less than 0.0002), 19.4% greater forearm mineral (p less than 0.0005), and 15.6% greater metacarpal cortical thickness (p less than 0.005).  Long-term estrogen replacement therapy confers significant protection against bone loss and fracture, highlighting the hormonal factor in changes in bone health.

Galli M, Canniggia M.  Osteocalcin in normal adult humans of different sex and age.  Horm Metab Res.  1985;17:165. 

Gundberg CM, Markowitz ME, Mizruchi M, Rosen JF.  Osteocalcin in human serum:  a circadian rhythm.  J Clin Endocrinol Metab.  1985;60:736. 

Hart JP, Shearer MJ, Klenerman L, Catterall A, Reeve J, Sambrook PN, et al.  Electrochemical detection of depressed circulating levels of vitamin K1 in osteoporosis.  J Clin Endocrinol Metab.  1985;60:1268-69.

Research showed that people with femoral neck fractures had low blood phylloquinone levels (vitamin K1).

Price P, Williamson M.  Primary structure of bovine matrix GLA protein, a new vitamin K-dependent bone protein.  J Biol Chem.  1985;260:14971-75.

Price PA.  Vitamin K dependent formation of bone Gla protein (osteocalcin) and its function.  Vitam Horm.  1985;42:64. 

Riis BJ, Krabbe S, Christiansen C, Catherwood BD, Deftos LJ.  Bone turnover in male puberty:  a longitudinal study.  Calcif Tissue Int.  1985;37:210. 

Stepan JJ, Tesarova A, Havranek T, Josi J, Formankova J, Pacovsky V.  Age and sex dependency of the biochemical indices of bone remodeling.  Clin Chim Acta.  1985;151:273. 

Farrugia W, Melick RA.  Metabolism of osteocalcin.  Calcif Tis Int.  1986;39:234. 

Price PA, Kaneda Y.  Vitamin K counteracts the effect of warfarin in liver but not in bone.  Thromb Res.  1987;46:121-31.

The research showed that there is a tissue-specific difference in the vitamin K supported carboxylation of vitamin K dependent proteins synthesized in the liver but not osteocalcin produced in bone. 

Yasumura S, Aloia JF, Gundberg CM, Yeh J, Vaswani An, Yuen K, LoMonte AF, et al.  Serum osteocalcin and total body calcium in normal pre-and postmenopausal women and postmenopausal osteoporotic patients.  J Clin Endocrinol Metab.  1987;64:681. 

Osteocalcin was measured in 51 normal pre- and 114 postmenopausal women and in 41 postmenopausal osteoporotic patients.  Total body calcium (TBCa) was determined in the same individuals.  Many of the perimenopausal nonosteoporotic women had increased osteocalcin values per their bloodwork, but 15 years or more after the menopause most of the women had serum osteocalcin levels in the normal range.  Osteoporotic women had a mean serum osteocalcin concentration that was significantly different from the respective values in normal and pre- and postmenopausal women (P < 0.001 for both variables in comparison to each group).  These data suggest that high serum osteocalcin levels, at least on a group basis, are an index of low skeletal mass.

Bitensky L, Hart JP, Catterall A, Hodges SJ, Pilkington MJ, Chayen J.  (1988) Circulating vitamin K levels in patients with fractures. J Bone Joint Surg BR. 1988;70:663–64.

One of the earlier studies that showed low vitamin K1 intake and low plasma vitamin K1 levels to be associated with low bone mineral density (BMD) and increased osteoporotic fracture risk in postmenopausal women.

Price PA.  Role of vitamin K-dependent proteins in bone metabolism.  In Olson RE, Beutler E, Broquist, HP, editors.  Ann Rev Nutri.  Palo Alto, CA: Annual Reviews Inc.; 1988. p. 565-83.

Describes matrix Gla-protein (MGP) the strongest vitamin K dependent inhibitor of tissue calcification presently known.

Soute, BAM, Ulrich, MMW, Knapen, MHJ, van Haarlem LJM, Vermeer C.  The quantification of gammacarboxyglutamic acid residues in plasma-osteocalcin.  Calcif Tissue Int 1988;43:184. 

Knapen MHJ, Hamulyak K, Vermeer C.  The effect of vitamin K supplementation on circulating osteocalcin (bone gla protein) and urinary calcium excretion.  Ann Intern Med. 1989;111:1001-5. 

Found that osteocalcin was undercarboxylated by 30% in postmenopausal women when compared with premenopausal women.  The postmenopausal women responded to phylloquinone supplementation with an increase in total and carboxylated osteocalcin and a decrease in urinary calcium and hydroxyproline. 

Price PA.  Gla-containing proteins of bone.  Connect Tissue Res.  1989;21:51-60. 

This study identified four vitamin K-dependent proteins (osteocalcin, matrix Gla protein, protein S, and Gas6) as components of bone matrix. 

1990s

Engelke JA, Hale JE, Suttie JW, Price PA.  Vitamin K-dependent carboxylase:   Utilization of decarboxylated bone Gla protein and matrix Gla protein as substrates.  Biochim Biophys Acta.  1991;1078:31-4. 

Hodges SJ, Pilkington MJ, Stamp TCB, Catterall A, Shearer MJ, Bitensky L, et al.  Depressed levels of circulating menaquinones in patients with osteoporotic fractures of the spine and femoral neck.  Bone.  1991;12:387-89. 

Vitamin K1 functions in the conversion of glutamate residues, present in certain bone peptides, into the active gamma-carboxyglutamate form.  We have shown previously that the circulating levels of vitamin K1 are depressed in osteoporotic patients.  However, it is known that menaquinones (vitamin K2) may be more effective than vitamin K1 in this conversion of the inactive to active form of glutamate residues.  A procedure for measuring such menaquinones has now demonstrated a marked deficiency of MK-7 and MK-8 in patients with osteoporotic fractures.  It is suggested that estimates of circulating levels of K1, MK-7, and MK-8 might provide a biochemical risk marker of osteoporotic fractures.

Plantalech L, Guilaumont M, Leclercq M, Delmas PD.  Impaired carboxylation of serum osteocalcin in elderly women.  J Bone Miner Res.  1991;6:1211-16. 

Measures of undercarboxylated OC, which reflects low activity of vitamin K, were associated with a higher incidence of femoral neck fractures. 

Maillard C, Berruyer M, Serre CM, Dechavanne M, Delmas PD.  Protein-S; a vitamin K-dependent protein is a bone matrix component synthesized and secreted by osteoblasts.  Endocrinology.  1992;130:1599-04. 

Orimo HM, Shiraki T, Fujita T, Onomura T, Inoue, Kushida K.  Clinical evaluation of menatetrenome in the treatment of involutional osteoprosis:  a double-blind multicenter comparative study with hydroxyl vitamin D.  J Bone Miner Res.  1992;7(Suppl 1):S122.

 

Akiyama Y, Hara K, Ohkawa I, Tajima T.  Effects of menatetrenone on bone loss induced by ovariectomy in rats.  Jpn J Pharmacol.  1993;62:145-53.  

In this study vitamin K2 inhibited bone loss.

Ferland G, Sadowski JA, O’Brien ME.  Dietary induced subclinical vitamin K deficiency in normal human subjects.  J Clin Invest.  1993 Apr;91(4):1761-68

Hara K, Akiyama Y, Ohkawa I, Tajima T.  Effects of menatetrenone on predonisolone-induced bone loss in rats.  Bone.  1993;14:813-18.

Vitamin k2 inhibited bone loss.

Hara K, Akiyama Y, Tajima T, Shiraki M.  Menatetrenone inhibits bone resorption partly through inhibition of PGE2 synthesis in vitro.  J Bone Miner Res.  1993;8:535-42. 

In vivo and in vitro studies show that vitamin K or its analogues can act directly on bone metabolism.  In this study, they reported that vitamin K2 inhibits bone resorption partly through the inhibition of prostaglandin E2 synthesis in organ culture.  Inhibiting bone resorption is desirable.

Hodges SJ, Akesson K, Vergnaud P, Obrant K, Delmas PD (1993) Circulating levels of vitamins K1 and K2 decreased in elderly women with hip fracture. J Bone Miner Res.  1993;8:1241–45.

Kapen MH, Jie KS, Hamulyak K, Vermeer C.  Vitamin K-induced changes in markers for osteoblast activity and urinary calcium loss.  Calcif. Tissue Int. 1993; 53:81-85. 

Szulc, P, Chapuy MC, Meunier PJ, Delmas PD.  Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women.  J Clin Invest.  1993;91(4): 1769-74.   

Circulating levels of undercarboxylated osteocalcin (ucOC) were found to be higher in post menopausal women than premenopausal women and markedly higher in women over the age of 70.  In a study of 195 institutionalized elderly women, the relative risk of hip fracture was six times higher in those who had elevated ucOC levels at the beginning of the study.  Undercarboxylation is an indicator of vitamin K deficiency. 

Price PA.  Vitamin K nutrition and postmenopausal osteoporosis.  J Clin Invest.  1993 April; 91(4): 1268.

Discusses the significant advances in the understanding of vitamin K nutrition in humans, and indicate that impaired synthesis of some vitamin K-dependent proteins may be far more prevalent in the human population than previously understood.

Akiyama Y, Hara K, Tajima T, Murota S, Morita I.  Effect of vitamin K2 (menatetrenone) on osteoclast-like cell formation in mouse bone marrow cultures.  Eur J Pharmacol.  1994;263:181-85.

The study showed that vitamin K2 inhibits osteoclast-like cell formation in vitro. 

Orimo H, Shiraki M, Hayashi Y, Hoshino T, Onaya T, Miyazaki S, Kurosawa H, Nakamura T, Ogawa N.  Effect of 1 alpha-hydroxy vitamin D3 on lumbar bone mineral density and vertebral fractures with postmenopausal osteoporosis.  Calcif Tissue Int.  1994;54:370-76. 

Szulc P, Arlot M, Chapuy MC, Duboeuf F, Meunier PJ, Delmas PD.  Serum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women.  J Bone Miner Res. 1994;9:1591-5. 

Research found that the incidence of hip fractures in aged women correlated directly with the increase in undercarboxylated osteocalcin and that bone mineral density (BMD) correlated negatively with the rise in under-carboxylated osteocalcin.  In other words, hip fractures increased as undercarboxylated osteocalcin increased.

Binkley NC, Suttie JW.  Vitamin K nutrition and osteoporosis.  J Nutr.  1995 Jul;125(7):1812-21.

A review that summarizes current knowledge regarding the possible role of vitamin K insufficiency in the pathogenesis of osteoporosis.

Douglas AS, Robins SP, Hutchison JD, Porter RW, Stewart A, Reid DM.  Carboxylation of osteocalcin in post-menopausal osteoporotic women following vitamin K and D supplementation.  Bone.  1995;17:15-20. 

The effect of vitamin supplements on bone metabolism indices in patients with osteoporosis was studied.  Over a two week period, vitamin supplements of K and K+D were given to 20 post-menopausal osteoporotic women with previous Colles fractures.  Osteoporosis was confirmed by bone mass measurements.  Vitamin K corrected the carboxylation defect in osteocalcin and while less marked 4 weeks later, the improvement was still detectable.  The result after K+D was similar.  The level of carboxylation became the same as in premenopausal women.

Hara K, Akiyama Y, Nakamura T, Murota S, Morita I.  The inhibitory effect of vitamin K2 (menatetrenone) on bone resorption may be related to its side chain. Bone.  1995;16:179-84.

Vermeer C, Jie KS, Knapen MH.  Role of vitamin K in bone metabolism.  Annu Rev Nutr.  1995;15:1-22.

Vitamin K supplementation of 1,000 mcg/day of phylloquinone (K1) for two weeks resulted in a decrease of ucOC (undercarboxylated osteocalcin) levels in postmenopausal women, as well as increases in several biochemical markers of bone formation.  The level of osteocalcin carboxylation has been proposed as an indicator of the nutritional state of bone with respect to vitamin K, with the level of ucOC going down as vitamin K levels increase. 

Bach AU, Anderson SA, Foley AL, Williams EC, Suttie JW.  Assessment of vitamin K status in human subjects administered “minidose” warfarin.  Am J Clin Nutr.  1996 Dec;64(6):894-902. 

Kameda T, et al. Vitamin K inhibits osteoclastic bone resorption by inducing osteoclast apoptosis.  Biochemical and Biophysical Research Communications.  1996;220:515-19. 

Kohlmeier M, Salomon A, Saupe J, Shearer MJ.  Transport of vitamin K to bone in humans.  The Journal of Nutrition.  1996;1570:27-32. 

Molecules with vitamin K activity are important for optimal bone health.  The major compound of this group in bone is vitamin K1 (phylloquinone), which is derived exclusively from plant foods in the diet.  Vitamin K1 is absorbed along with dietary fat from the small intestine and transported by chylomicrons in blood.  Vitamin K1 concentration in serum is linked to vitamin K status of bone.  The bone protein osteocalcin tends to be less completely carboxylated in people with low vitamin K concentrations in serum.  Many hemodialysis patients with a history of bone fractures have indications of poor vitamin K status.  The same patients also appear to have a greatly increased prospective bone fracture risk.

Kohlmeier M, Saupe J, Drossel HJ Shearer MJ.  Variation of phylloquinone (vitamin K1) concentrations in hemodialysis patients.  Thromb. Haemost. 1996;74:1252-1254. 

Koshihara Y, Hoshi K, Ishibashi H, Shiraki M.  Vitamin K2 promote 1,25(OH)2 vitamin D3-induced mineralization in human periosteal osteoblasts.  Calcif Tissue Int.  1996;59:466-473. 

The study reported that vitamin K2 enhances human osteoblast-induced mineralization with or without vitamin D3.

Shearer MJ, Bach A, Kohlmeier M.  Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K with special reference to bone health.  J Nutr.  1996;126:1181S-1186S. 

Shiraki M, Kushida K, Yamazaki K, nagai T, Inoue T, Orimo H.  Effects of 2 years’ treatment of osteoporosis with 1-alpha-hydroxy vitamin D3 on bone mineral density and incidence of fracture:  A placebo-controlled, double-blind prospective study.  Endocr J.  1996;43:211-220.

Szulc P, Chapuy M-C, Meunier PJ, Delmas PD.  Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture:  a three year follow up study.  Bone.  1996;18:487-488. 

A clear rationale for ensuring optimal dietary intake of vitamin K is the evidence that a high circulating level of undercarboxylated osteocalcin is an independent risk predictor of bone fractures.  Undercarboxylation of osteocalcin has been reported to be associated with an increased risk of fracture, and oral supplementation with vitamin K1 as well as K2 can correct undercarboxylation of osteocalcin. 

Booth SL.  Skeletal functions of vitamin K-dependent proteins:  not just for clotting anymore.  Nutr Rev. 1997:55(7):282-84. 

Osteocalcin and matrix Gla protein (MGP) are two vitamin K-dependent proteins present in bone and cartilage.  Transgenic mice models were recently developed to isolate the function of each of these proteins.  While osteocalcin-deficient mice have increased bone formation, MGP-deficient mice have abnormal calcification leading to osteopenia, fractures, and premature death owing to arterial calcification.

Hussain MM, Goldberg IJ, Weisgraber KH, Mahley RW, Innerarity TL.  Uptake of chylomicrons by the liver, but not by the bone marrow, is modulated by lipoprotein lipase activity.  Arterioscler Thromb Vasc Biol.  1997;17:1407-13. 

This study describes the bone marrow as an organ of major quantitative relevance in chylomicron uptake in rodents and mammals, but more information is needed on which bone cells participate in the uptake process. 

Kohlmeier M, Saupe J, Shearer MJ, Schaefer K, Asmus G.  Bone health of adult hemodialysis patients is related to vitamin K status.  Kitney Int.  1997;51:1218-21.  

Their data indicates that suboptimal vitamin K nutriture in hemodialysis patients is associated both with increased bone fracture risk and with a high prevalence of hyperparathyroidism.

Koshihara Y, Hoshi K.  Vitamin K2 enhances osteocalcin accumulation in the extracellular matrix of human osteoblasts in vitro.  Journal of Bone and Mineral Research.  1997;12:431-38. 

Shearer JM.  The roles of vitamins D and K in bone health and osteoporosis prevention.  Proc Nutri Soc.  1997;56(3):915-37.

Although vitamin K deficiency would seem the most likely cause of elevated blood ucOC, investigators have also documented an inverse relationship between measures of vitamin D nutritional status and ucOC levels, as well as a significant lowering of ucOC by vitamin D supplementation. 

Sokoll LJ, Booth SL, O’Brien ME, Davidson KW, Tsaioun KI, Sadowski JA.  Changes in serum osteocalcin, plasma phylloquinone, and urinary gamma-carboxyglutamic acid in response to altered intakes of dietary phylloquinone in human subjects.  Am J Clin Nutr.  1997;65:779-84. 

Vergnaud P, Garnero P, Meunier PJ, Greart G, Kamihagi K, Delmas PD.  Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women:  the EPIDOS Study.  J Clin Endocrinal Metabl.  1997;82(3):719-24.
In a large sample of 7,500 elderly women living independently, circulating ucOC was also predictive of fracture risk. 

Booth, SL, Suttie JW.  Dietary intake and adequacy of vitamin K.  J Nutr.  1998;128(5):785-88.

Reliable measurements of vitamin K content in foods are now available, and data from 11 studies of vitamin K intake indicate that the mean intake of young adults is ∼80 μg phylloquinone/d and that older adults consume ∼150 μg/d.  The vitamin K concentration in most foods is very low (<10 μg/100 g), and the majority of the vitamin is obtained from a few leafy green vegetables and four vegetable oils (soybean, cottonseed, canola and olive) that contain high amounts.  Limited data indicate that absorption of phylloquinone from a food matrix is poor.  Menaquinones absorbed from the diet or the gut appear to provide only a minor portion of the human daily requirement.

Boskey AL, Gadaleta S, Gundherg C, Doty SR, Ducy P, Karsenty G.  Fourier transform infrared microspectroscopic analysis of bones of osteocalcin-deficient mice provides insight into the function of osteocalcin.  Bone.  1998;23:187-96.

Cracium AM, Wolf J, Knapen MH, Brouns F, Vermeer C.  Improved bone metabolism in female elite athletes after vitamin K supplementation.  Int J Sports Med.  1998; 19:479-84. 

In female elite athletes strenuous exercise may result in hypoestrogenism and amenorrhoea.  As a consequence a low peak bone mass and rapid bone loss are often seen in relatively young athletes.  In postmenopausal women, increased intake of vitamin K may result in an increase of serum markers for bone formation, a decrease of urinary markers for bone resorption, and a decrease in urinary calcium loss.  In the present paper we report an intervention study among eight female athletes.  All participants received vitamin K supplementation (10 mg/day) during one month, and various bone markers were measured before and after treatment.  At baseline the athletes not using oral contraceptives were biochemically vitamin K-deficient as deduced from the calcium binding capacity of the circulating bone protein osteocalcin.  In all subjects increased vitamin K was associated with an increased calcium-binding capacity of osteocalcin. In the low-estrogen group vitamin K supplementation induced a 15 - 20 % increase of bone formation markers and a parallel 20 - 25 % decrease of bone resorption markers.  This shift is suggestive for an improved balance between bone formation and resorption.

Gundberg CM, Nieman SD, Abrams S, Rosen H.  Vitamin K status and bone health:  An analysis of methods for determination of undercarboxylated osteocalcin.  J Clin Endocrinol metab.  1998;83:3258-66.

Jamal, SA, Browner, WS, Bauer DC, Cummings SR.  Warfarin use and risk for osteoporosis in elderly women.  Study of Osteoporotic Fractures Research Group.  Ann Intern Med. 1998;128(10):829-32.  

This reported no association between long term warfarin treatment and fracture risk.

Knapen MHJ, Nieuwenhuijzen Kruseman AC,Wouters RSME, Vermeer C.  Correlation of serum osteocalcin fractions with bone mineral density in women during the first 10 years after menopause.  Calcif Tissue Int.  1998;63:375-79. 

Lamon-Fava S, Sadowski JA, Davidson KW, O’Brien ME, McNamara JR, Schaefer EJ.  Plasma lipoproteins as carriers of phylloquinone (vitamin K1) in humans.  Am J Clin Nutr.  1998;67:1226-131. 

Their study shows that vitamin K remains associated with chylomicron remnants to a percentage in the fasting state and is not transferred to other carriers in the blood other than lipoproteins.  The primary dietary form of vitamin K is phylloquinone (vitamin K1).  The chylomicron remnants carry 70-90% of vitamin K in the blood, with minor proportions being bound to LDL and high-density liproteins (HDL).

Orimo H, Shiraki M,, Tomita A, Morii A, Fujita T, Ohata M.  Effects of menatetrenone on the bone and calcium metabolism in osteoporosis:  A double-blinded placebo-controlled study.  J Bone Miner Metab.  1998;16:106-12. 

Metacarpal bone mineral density (BMD) is increased in osteoporosis through the administration of vitamin K2.  Higher doses of MK4 were given (45mg a day) results in increased bone mass as well as decreased hip fracture. 

Price PA, Faus SA, Williamson MK.  Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves.  Arterioscler Thromb Vasc Biol.  1998;18:1400-7. 

Sato Y, Honda Y, Kuno H, aoizumi K.  Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin E-and K-deficient stroke patients.  Bone.  1998;23:291-96. 

Vermeer C, Knapen MH, Schurgers LJ.  Vitamin K and metabolic bone disease.  J Clin Pathol.  1998 June;51(6):424-6.

Without doubt vitamin K is essential for the biosynthesis of three abundant bone proteins.  In cell culture systems, vitamin K may have an additional role, namely the regulation of cell growth.  Vitamin K status should be considered in relation to individual tissues, not to the whole organism.  Whereas nutritional vitamin K deficiency of the liver is very rare in humans, biochemically detectable vitamin K deficiency of bone tissue is quite common, notably in the elderly.  This will result in increased serum levels of undercarboxylated osteocalcin, which is associated with low bone mass and increased fracture risk.

Brody, T.  Nutritional biochemistry.  2^nd ed.  San Diego:  Academic Press; 1999.

Carabello PJ, Heit JA, Atkinson EJ, Silverstein MD, O’Fallon WM, Castro MR, et al.  Long term use of oral anticoagulants and the risk of fracture.  Arch Intern Med.  1999;159(15):1750-56.

Vitamin K participates in bone metabolism.  Oral anticoagulants antagonize vitamin K, meaning that the use of oral anticoagulants may interfere with bone metabolism and also increase the risk of osteoporosis.  This study found a significantly higher risk of rib and vertebral fractures in warfarin users compared to nonusers. 

Center JR, Nguyen TV, Schneider D, et al.  Mortality after all major types of osteoporotic fracture in men and women:  An observational study.  Lancet.  1999;353:878-82. 

A five-year prospective study on fracture and mortality rate in men and women age 60 and older found all major fractures were associated with increased mortality, especially in men. 

Feskanich D, Weber P, Willett WC, Rockett H, Booth SL, Colditz, GA.  Vitamin K intake and hip fractures in women:  A prospective study.  Am J Clin Nutr. 1999;69(1):74-9.     

The Nurses Health Study followed more than 72,000 women for ten years.  Women whose vitamin K intakes were in the lowest quintile (1/5) had a 30% higher risk of hip fracture than women with vitamin K intakes in the highest four quintiles. 

Iwamoto I, Kosha S, Noguchi S, Murakami M, Fujino T, Tsutomu D, et al. A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D, and estrogen-progestin therapy.  Maturitas.  1999;31:161-64.

Olson BR, Reginato AM, Wang W.  Bone development.  Ann Rev Cell and Dev Biol.   1999;16:191-20.

Yamaguchi M, Taguchi H, Gao YH, Igarashi A, Tsukamoto Y.  Effect of vitamin K2 (menaquinone-7) in fermented soybean (natto) on bone loss in ovariectomized rats.  J Bone Mineral Metab.  1999;17(1):23-9.

This study investigated the effect of dietary vitamin K2 (MK7) on bone loss in ovariectomized rats.  They were given MK4 or MK7 for 24 days, which caused an increased in the concentrations in both blood levels and in the femur bones. When they were given a diet of natto with or without MK7 for 77 days, they also showed a significant increase in the femoral bone for MK4.  They concluded that the intake of dietary MK7 has a preventive effect on the typical bone loss caused by the removal of ovaries.  

2000s

Binkley NC, Krueger DC, Engelke JA, Foley AL, Suttie JW.   Vitamin K supplementation reduces serum concentrations of under-gamma-carboxylated osteocalcin in healthy young and elderly adults.  Am J Clin Nutr.  2000;72:1523-28. 

Data shows that low serum (blood level) concentrations of either phylloquinone (vitamin K1) or under-carboxylated osteocalcin are associated with low BMD (bone mineral density) and increased risk for osteoporotic fracture, indicating that taking vitamin K1 or K2 supplements can strengthen bones. 

Booth SL, Mayer J. Warfarin use and fracture risk.  Nutr Rev.  2000;58:20-2. 

Booth SL, Tucker KL, Chen H, Hannan MT, Gagnon DR, Cupples LA, et al.  Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women.  Am J Clin Nutr.  2000;71(5): 1201-8.

A study of over 800 elderly men and women, followed in the Framingham Heart Study for seven years, found that men and women with dietary vitamin K intakes in the highest quartile (1/4) had a 65% lower risk of hip fracture than those with dietary vitamin K intakes in the lowest quartile (approximately 250 micrograms/day vs. 50 mcg/day of vitamin K.

Koivu-Tikkanen TJ, Schurgers LJ, Thijssen HH, Vermeer C.  Intestinal, hepatic, and circulating vitamin K levels at low and high intakes of vitamin K in rats.  British Journal Nutri.  2000 Feb;83(2):185-90. 

Assessed how high doses of dietary vitamin K influence the intestinal profile of K-vitamins in vitamin K-deficient rats.  Data suggested that menaquinone-4 may be converted into menaquinone-8 (but not into other menaquinones) via a metablic pathway which has not been reported previously.

Luukinen H, Kakonen S-M, Petterson K, Koski K, Laippala P, Lovgren T, et al.  Strong prediction of fractures among older adults by the ratio of carboxylated to total serum osteocalcin.  J Bone Miner Res. 2000;1:2473-8. 

Used elevated circulating levels of the bone Gla-protein osteocalcin to show the inverse association between vitamin K status and fracture risk, where low vitamin K status was associated with higher risk of fracture. 

National Research Council. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc; National Academy Press: Washington, DC, USA, 2000; pp. 162–196. 

Olson R.  Osteoporosis and vitamin K intake.  Am J Clin Nutr.  2000;71:1031-2.

Research supports the role of vitamin K in the retardation of bone loss in elderly persons. 

Shiraki M, Shiraki Y, Aoki C, Miura M.  Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis.  Journal of Bone and Mineral Research.  2000; 15(3):515-21.

A total of 241 osteoporotic patients were enrolled in a 24 month randomized study.  The control group received 45 mg/day orally vitamin K2.  Vitamin K2 clearly maintained lumbar BMD for two years, and the incidence of clinical fractures in the control was higher than the vitamin K2 treated group, suggesting that vitamin K2 treatment effectively prevents the occurrence of new fractures. 

Booth SL, Lichtenstein AH, O’Brien-Morse M, McKeown NM, Wood RJ, et al.  Effects of a hydrogenated form of vitamin K on bone formation and resorption.  Am J Clin Nutr.  2001;74:783-90. 

Bostrom K, Tsao D, Shen S, Wang y, Demer LL.  Matrix GLA protein modulates differentiation induced by bone morphogenetic protein-2 in C3H10T1/2 cells.  J Biol Chem.  2001;276:14044-52. 

They propose the mechanism that MGP inhibits calcification by binding to one of the bone morphogenic protens, BMP-2 to regulate osteogenesis.

Iwamoto J, Takeda T, Ichimura S.  Effect of menatetrenone on bone mineral density and incidence of vertebral fractures in postmenopausal women with osteoporosis:  a comparison with the effect of etidronate.  J. Orthop Sci. 2001:6(6):487-92. 

In Japan, intervention trials in hemodialysis patients and osteoporotic women using very high pharmacologic doses (45mg/day) of menatetrenone (MK4) have reported significant reductions in the rate of bone loss. 

Kaneki M, Hodges SJ, Hosoi T, Jufiwara S, Lyons A, Crean SI, et al.  Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2:  possible implications for hip-fracture risk.  Nutrition.  2001;17:315-21. 

Schoon EJ, Muller MC, Vermeer C, Schurgers LJ, Brummer RJ, Stockbrugger RW.  Low serum and bone vitamin K status in patients with longstanding Crohn’s disease: another pathogenetic factor of osteoporosis in Crohn’s disease?  Gut, 2001 Apr;48(4):473-7.  

Found poor vitamin K status to be associated with low bone mineral density in longstanding Crohn’s disease, meaning that taking more vitamin K would help improve bone mineral density. 

Takahashi M, Naitou K, Ohishi T,  Kushida K, Miura M.  Effect of vitamin K and/or D on under-carboxylated and intact osteocalcin in osteoporotic patients with vertebral or hip fractures. Clin Endocrinol. 2001; 54:219-24.

In a 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 D 3 (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. 

 

Reid DM, Macdonald HM.  Nutrition and bone:  Is there more to it than just calcium and vitamin D?  Q J Med.  2001;94:53-6.  

Discusses possible role of vitamin K in bone health. 

van Staa TP, Dennison EM, Leufkens HG, Cooper C.  Epidemiology of fractures in England and Wales.  Bone, 2001;29:517-22. 

Watkins BA, Li Y, Seifert MF.  Lipids as modulators of bone remodeling.  Curr Opin Clin Nutr Metab Care.  2001;4:105-110.

Dietary lipids or fats play an important role in bone formation.  These include essential fatty acids, polyunsaturated fatty acids, and lipophilic vitamins.  In this context, vitamin K is of particular interest, as it only stays with lipoproteins. 

Weber P.  Vitamin K and bone health.  Nutrition, 2001;17:880-87.

The research suggests a key role for vitamin K nutrition in optimizing of bone health.

Zitterman A, Effects of Vitamin K on calcium and bone metabolism.  Curr Opin Clin Nutr Metab Care.  2001 Nov;4(6):483-7.

Per their analysis, many of the recent studies show that vitamin K2 is the most effective form of vitamin K for calcium and bone health.

Binkley N, Krueger D, Engelke JA, Crenshaw T, Suttie JW.  Vitamin K supplementation does not affect ovariectomy-induced bone loss in rats.  Bone.  2002;30:897-900. 

Binkley NC, Krueger DC, Kawahara TN, Engelke JA, Chappell RJ, Suttie JW.  A high phylloquinone intake is required to achieve maximal osteocalcin gamma-carboxylation. Am J Clin Nutr.  2002;76:1055–60. 

The researchers conducted a single-blind, placebo-controlled trial to identify the lowest dosage of vitamin K1 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 vitamin K1 daily for two weeks.  The percentage of undercarboxylated serum osteocalcin (ucOC) decreased with increasing dosages ( p < 0.0001), with the greatest reduction occurring in those who received 1000 µg daily.  A decline in usOC means that vitamin K levels had increased.

Booth SL, Lichtenstein AH, Dallal GE.  Phylloquinone absorption from phylloquinone-fortified oil is greater than from a vegetable in younger and older men and women.  The Journal of Nutrition.  2002;132:2609-12. 

Newman P, Bonello F, Wierzbicki AS, Lumb P, Savidge GF, Shearer MJ.  The uptake of lipoprotein-borne phylloquinone (vitamin K1) by osteoblasts and osteoblast-like cells:  Role of heparin sulfate proteoglycans and apolipoprotein E.  J Bone Miner Res.  2002;17:426-33.

This study provides evidence that human osteoblast-like cells are able to take up lipoproteins and vitamin K, but the underlying molecular mechanisms have yet to be identified. 

Sato I, Ohtani Y, Yamada Y, Saitoh S, Harada H.  Difference in the metabolism of vitamin K between liver and bone in vitamin K-deficient rats.  Br. J Nutr. 2002 Apr;87(4):307-14.  

The results suggested that the turnover of vitamin K in the bone is slower than that in the liver, and that intake of a larger amount of vitamin K is required for its accumulation in the bone than in the liver.  Furthermore the effect of MK7 on prothrombin time was higher than with K1 or MK4.

Schurgers, L.J.; Vermeer, C. Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochim Biophys Acta. 2002;1570,27–32.

Simon RR, Beaudin SM, Johnston M., et al.  Long-term treatment with sodium warfarin results in decreased femoral bone strength and cancellous bone volume in rats.  Thromb Res.  2002;105:353-58. 

Woudstra T, Thomson AB.  Nutrient absorption and intestinal adaptaion with ageing.  Best Pract Res Clin Gastroenterol. 2002 Feb;16(1):1-15.

Malabsorption of carbohydrates, lipids, amino acids, minerals and vitamins have been described in the elderly.  The ability of the intestine to adapt may be impaired in the elderly and this may lead to further malnutrition.  Dietary manipulation may prove to be useful to enhance the needed intestinal absorption with ageing.  There is an age-associated increase in the prevalence of dyslipidaemia as well as diabetes.  These conditions may benefit from nutritional intervention targeted at reducing the absorption of some nutrients.  With the continued characterization of the proteins involved in sterol and fatty acid absorption, therapeutic interventions to modify absorption may become available in the future.

Zebboudj A, Imura M, Bostrom K.  Matrix GLA protein, a regulatory protein for bone morphogenetic protein-2.  J Biol Chem.  2002;277:4388-94. 

Abrams SA.  Normal acquisition and loss of bone mass.  Horm Res.  2003;60:71-76. 

Braam LA, Knapen MH, Geusens P, Brouns F, Vermeer C.  Factors affecting bone loss in female endurance athletes: a two-year follow-up study. Am J Sport Med. 2003;31:889–95. 

Booth S.  Dietary vitamin K and bone health.  In:  New SA, Bonjour JP, editors.  Nutritional aspects of bone health.  Cambridge:  Royal Society of Chemistry; 2003. p. 323-38.  

Booth SL, Broe KE, Gagnon DR, Tucker KL, Hannan MT, McLean RR, et al.  Vitamin K intake and bone mineral density in women and men.  Am J Clin Nutr. 2003;77:512–16.

Braam LA, Knapen MH, Geusens P, Brouns F, Hamulyák K, Gerichhausen MJ, et al.  Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age.  Calcif Tissue Int.  2003;73(1):21-26. 

Long-term trials of phylloquinone supplementation at doses attainable by dietary intake (200-1000mcg/day) have found significant correlations between taking Vitamin D, K2, and a mineral supplement, and a 35% reduction in bone loss when compared with placebo after a period of 36 months. 181 postmenopausal women between the ages of 50 and 60 years of age were given daily supplements, including 1 mg/d of K1.  After three years the groups receiving vitamin K had less bone loss at the femoral neck but not at the lumbar spine.

Iwamoto J, Takeda T, Ichimura S. Treatment with vitamin D3 and/or vitamin K2 for postmenopausal osteoporosis.  Keio J Med. 2003; 52:147-50.

Lou LZ, Xu L.  Vitamin K and osteoporosis.  Zhongguo Yi Xue Ke Xue Yuan Xue Bao.  2003 Jun; 25(3):346-9.

Vitamin K is a cofactor for carboxylase activity and can facilitate and influence osteocalcin to increase the formation of bone.  There is also evidence that vitamin K can regulate calcium balance and bone metabolism.  There is a consistent line of evidence in human epidemiologic and intervention studies that clearly demonstrate that vitamin K can reduce fracture rates to improve bone health.  Research is needed on how much more vitamin K should be included in human diets. 

Tabb MM, Sun A, Zhou C, Grun F, Errandi I, Romero K, Pham H, et al.  Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR.  Journal of Biological Chemistry.  2003;278:43919-927. 

Booth SL, Broe KE, Peterson JW, Cheng DM, Dawson-Hughes B, et al.  Associations between vitamin K biochemical measures and bone mineral density in men and women.  J Clin Endocrin Metab.  2004;89:4904–09.

Found that low dietary vitamin K intake is associated with low bone mineral density. 

Ishida Y, Kawai S.  Comparative efficacy of hormone replacement therapy, etidronate, calcitonin, alfacalcidol and vitamin K in postmenopausal women with osteoporosis:  The Yamaguchi osteoporosis prevention study.  Am J Med.  2004;117:549-555.

Treatment with vitamin MK4 reduces risk of fracture.

Iwamoto J, Takeda T, Sato Y.  Effects of vitamin K2 on osteoporosis.  Current Pharmaceutical Design.  2004;10:2557-76. 

This article reviews the evidence on vitamin K2, which is essential to carboxylate or activate osteocalcin.  Evidence suggests that K2 enhances osteocalcin assumulation in osteoblasts in bone.  Clinically, K2 sustains the lumbar bone mineral density and prevents fractures in patients with glucocorticoid-induced osteoporosis, increases the metacarpal BMD in patients with cerebrovascular disease, and sustains the lumbar BMD in patients with osteoporosis induced by liver dysfunction.  Further studies are needed to confirm the efficacy of vitamin K2 in the treatment of osteoporosis.

Mercola J, Droege R.  10 Important facts about vitamin K that you need to know. 2004.  Available:  http://products.mercola.com/vitamin-k/  Accessed 17 Aug 2012.

Ryan-Harshman M, Aldoori W. Bone health. New role for vitamin K? Can Fam Physician. 2004;50:993–997.

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. 

Schilling AF, Schinke T, Muench C, Gebauer M, Priemel M, Niemeier A, et al.  Increased bone formation in mice lacking apolipoprotein E.  J Bone Miner Res.  2004;20:274-282. 

Vermeer C, Shearer MJ, Zitterman A, Bolton-Smith C, Szulc P, Hodges S, et al.  Beyond deficiency:  Potential benefits of increased intakes of vitamin K for bone and vascular health.  Eur J Nutr.  2004;43:325-35. 

Adams J, Pepping J.  Vitamin K in the treatment and prevention of osteoporosis and arterial calcification.  Am J Health Syst Pharm.  2005;62:1574-81. 

Several studies suggest that concurrent use of menaquinone (K2) and vitamin D may substantially reduce bone loss.  Several epidemiologic and intervention studies have found that vitamin K deficiency causes reductions in bone mineral density and increases the risk of fractures.  The results of two dose-response studies have indicated that the amount of vitamin K needed for optimal gamma-carboxylation of osteocalcin is significantly higher than what is provided through diet alone and that current dosage recommendations should be increased to optimize bone mineralization.  Few adverse effects have been reported from oral vitamin K. 

Harke JM, Krueger K, Gemar D, Checovich M, Zeldin S, Engelke R, et al.  Vitamin K treatment reduces undercarboxyled osteocalcin but does not alter bone turnover or density in postmenopausal North American Women.  ASBMR Annual Meeting; 2005.

This group studied 381 postmenopausal women and found that neither vitamin K1 (1 mg/d) nor vitamin K2 (45 mg/d) supplementation for 2 years affected BMD at the lumbar spine or total hip. 

Katsuyama H, Otsuki T, Tomita M, Fukunaga M, Fukunaga T, Suzuki N, et al.  Menaquinone-7 regulates the expressions of osteocalcin.  OPG.  RANKL and RANK in osteoblastic MC3T3E1 cells.  Int J. Mol Med.  2005;15:231-36. 

Laize V, Martel P, Viegas CSB, Price PA, Cancela ML. Evolution of matrix, and bone gamma-carboxyglutamic acid proteins in vertebrates.  J Biol Chem.  2005;280:26659-668.

Plaza SM, Lamson DW.  Vitamin K2 in bone metabolism and osteoporosis.  Alt Med Rev.  2005;10(1):24-35. 

This article covers the influence of vitamin K2 on bone formation and bone loss.  Studies confirm the effectiveness of vitamin K2 for decreased BMD from a variety of causes, including postmenopausal osteoporosis, Parkinson’s disease, use of leuprolide or prednisolone, biliary cirrhosis, stroke inactivity and anorexia.  The recommendation is that more people take vitamin K2 regularly and at higher doses as it has beneficial activity far beyond osteoporosis.

Niemeier A, Kassem M, Toedter K, Wendt D, Ruether W, Beisiegel U, et al.  Expression of LRP1 by human osteoblasts:  A mechanism for the delivery of lipoproteins and vitamin K1 to bone.  J of Bone and Min Res.  2005;20(2);283-93.

Clinical and experimental data is accumulating showing the importance of dietary fats and fat soluble vitamins like vitamin K1 for bone formation.  Chylomicrons (CM) are triglyceride-rich lipoproteins which are synthesized in the intestine and function as carriers of dietary fats and fat-soluble vitamins.  This study provides evidence that osteoblasts  and specific cell receptors LDLR play a role in the uptake of vitamin K.  Dietary vitamin K is an essential co-factor of the gamma-carboxylation of bone matrix proteins.

Sato Y, Kanoko T, Satoh K, Iwamoto J.  Menatetrenone and vitamin D2 with calcium supplements prevent non-vertebral fracture in elderly women with Alzheimer’s disease.  Bone.  2005:36;61-68. 

Takeuchi, A.; Masuda, Y.; Kimura, M.; Marushima, R.; Matsuoka, R.; Hasegawa, M.; Takahara, M.; Onuki, M. Minimal effective dose of vitamin K2 (menaquinone-4) on serum osteocalcin concentration in Japanese subjects and safety evaluation of vitamin K2 supplemented in calcium tablet. J. Jpn. Soc. Clin. Nutr. 2005;26:254–260.

Cockayne S, Adamson J. Lanham-New S, Shearer MJ, Gilbody S, Torgerson DJ.  Vitamin K and the prevention of fractures:  systematic review and meta-analysis of randomized controlled trials.  Arch Intern Med.  2006;166(12);1256-61. 

A meta analysis of seven Japanese randomized controlled trials associated Menatetrenone-4 (MK4) supplementation with increased BMD (bone mineral density) and reduced fracture incidence.  Daily supplementation with vitamin K2 (45 mg of menaquinone 4) consistently reduced hip, vertebral, and all nonvertebral fractures.  The analysis reported that MK4 supplementation lowered risk for vertebral fractures by 60%, hip fractures by 77%, and nonvertebral fractures by 81%; all associations were statistically significant.  Six of the individual trials employed 45 mg of menatetrenone (MK4) daily, while one trial used 15 mg of menatetrenone daily.

Drozdowski L, Thomson AB.  Aging and the intestine.  World J Gastroenterrol.  2006 Dec 21;12(47):7578-84. 

Over the lifetime of the animal, there are many changes in the function of the body's organ systems.  In the gastrointestinal tract there is a general modest decline in the function of the esophagus, stomach, colon, pancreas and liver.  In the small intestine, there may be subtle alterations in the intestinal morphology, as well as a decline in the uptake of fatty acids and sugars.  The age-associated malabsorption of nutrients that occurs with aging may be one of the several factors which contribute to the malnutrition that occurs with aging.

Gage, BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF.  Risk of osteoporotic fracture in elderly patients taking warfarin:  Results from the National Registry of Atrial Fibrillation 2.  Arch Intern Med.  2006;166(2):241-46.  

This study in elderly patients with atrial fibrillation reported that long-term warfarin treatment was associated with a significantly higher risk of osteoporotic fracture in men but not in women.

Ichikawa T, Horie-Inoue K, Ikeda K, Blumberg B, Inoue S.  Steroid, and xenobiotic receptor S. X. R. mediates vitamin K2-activated transcription of extracellular matrix-related genes and collagen accumulation in osteoblastic cells.  J Biol Chem.  2006;281:16927-934. 

Ikeda Y, et al.  Intake of fermented soybeans, Natto, is associated with reduced bone loss in postmenopausal women:  Japanese population-based osteoporosis (JPOS) study.  J Nutr Vol.  2006;136:1323-28. 

Iwamoto J, Takeda T, Sato Y.  Menatetrenone (vitamin K2) and bone quality in the treatment of postmenopausal osteoporosis.  Nutr rev.  2006;64:509-17.

Kaneki M, Hosoi T, Ouchi Y, Orimo H.  Pleitropic actions of vitamin K:  Protector of bone health and beyond?  Nutrition. 2006; 22(7):845-52. 

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, atheroslerosis, and hepatocarcinoma.  Accumulated evidence indicates that vitamin K deficiency in tissues, particularly in bone and in vasculature exists widely in the otherwise healthy adult population.  Biological differences between vitamins K1 and K2 and potential involvement of gamma carboxylation – independent actions in the new roles of vitamin K remain to be investigated. 

Kaneki M.  Protective effects of vitamin K against osteoporosis and its pleiotropic actions.  Clinc Calcium.  2006 Sep;16(9):1526-34.

Vitamin K has emerged as a potential protector against osteoporosis and hepatocarcinoma.  Accumulated evidence indicates that subclinical non-hemostatic vitamin K deficiency in extrahepatic tissues, particularly in bone, exists widely in the otherwise healthy adult population.  Both vitamin K1 and K2 have been shown to exert protective effects against osteoporosis.  Moreover, therapeutic potential of vitamin K2 as an anti-hepatoma drug has been highlighted, including the anti-oxidant property.

Kruger MC, Booth CL, Coad J, Schollum LM, Kuhn-Sherlock B, Shearer, MJ.  Effect of calcium fortified milk supplementation with or without vitamin K on biochemical markers of bone turnover in premenopausal women.  Nutrition. 2006;22:1120–28. 

Martini LA, Booth SL, Saltzman E, do Rosaio Dias E, de Oliverie Latorre M, Wood RJ.  Dietary phylloquinone depletion and repletion in postmenopausal women:  Effects on bone and mineral metabolism.  Osteoporosis Int.  2006;17:929-35.
Vitamin K treatment may reduce bone resorption.

McLean RR, Booth SL, Kiel DP, Broe KE, Gagnon DR, Tucker KL, et al.  Association of dietary and biochemical measures of vitamin K with quantitative ultrasound of the heel in men and women.  Osteoporos Int.  2006;17:600-7.

Neogi T, Booth SL, Zhang YQ, Jacques PF, Terkeltaub R, Aliabadi P, et al.  Low vitamin K status is associated with osteoarthritis in the hand and knee.  Arthritis Rheum.  2006 Apr;54(4):1255-61.
Insufficient vitamin K can result in abnormal cartilage and bone mineralization. Furthermore, osteophyte growth, seen in osteoarthritis, may be a vitamin K dependent process. This study found that vitamin K deficiency is associated with radiographic features of osteoarthritis.  As the levels of vitamin K in the blood rose, the prevalence for hand osteoarthritis decreased.  These observational data support the hypothesis of an association between low plasma levels of K and increased prevalence of osteoarthritis manifestations in the hand and knee. 

Rejnmark, L, Vertergaard P, Charles P, Hermann AP, Brot C, Eiken P, et al.  No effect of vitamin K1 intake on bone mineral density and fracture risk in perimenopausal women.  Osteoporos Int.  2006; 17(8):1122-32.

Did not find a relationship between dietary vitamin K intake and measures of bone strength, BMD, or fracture incidence. 

Tsugawa N, Shiraki M, Suhara Y, Kamao M, Tanaka K, Okano T.  Vitamin K status of healthy Japanese women:  Age-related vitamin K requirement for gamma-carboxylation of osteocalcin.  Am J Clin Nutr.  2006 Feb;83(2):380-6. 

Vitamin K deficiency is associated with low bone mineral density and increased risk of bone fracture.  Phylloquinone K1 and menaquinone 4 (MK4) and 7 (MK7) are generally observed in human plasma.  This study measured the circulating concentrations of K1, MK4 and MK7 in women in association with bone metabolism.  On average, MK7 and MK4 were the highest and lowest respectively, in all age groups.  If gamma carboxylation is related to the prevention of fracture or bone mineral loss, circulating vitamin K concentrations in elderly people should be kept higher than those in young people.

Yamaguchi M.  Regulatory mechanism of food factors in bone metabolism and prevention of osteoporosis.  Yakugaku Zasshi.  2006;126(11):1117-37.

Aging induces a decrease in bone mass and osteoporosis is widely recognized as a major public health problem.  Pharmacological and nutritional factors may prevent age-related bone loss.  Carotenoids and isoflavones, contained in soybeans, have a stimulatory effect on osteoblastic bone foramtion and an inhibitory effect on osteoclastic bone resorption, increasing bone mass.  MK7, which is abundant in fermented soy beans, stimulates bone formation and inhibits bone loss.  Food chemical factors do play a role in bone health and supplementing intake with additional vitamins may be important in the prevention of bone loss, as one ages.

Yao Y, Zebboudj A, Shao E, Perez M, Bostrom K.  Regulation of bone morphogenetic protein-4 by matrix GLA protein in vascular endothelial cells involves activin-like kinase receptor 1.  J Biol Chem.  2006;281:33921-930.

Binkley N, Krueger D, Engelke JA, Suttie JW.  Long-term warfarin treatment does not alter skeletal status in male rhesus monkeys.  J. Bone Miner res.  2007;22:695-700. 

Bolton-Smith C, McMurdo ME, Paterson CR, Mole PA, Harvey JM, Fenton ST, et al.  Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.  J Bone Min Res.  2007;22:509-19. 

244 postmenopausal women were randomized to receive placebo, vitamin K1 (200 ug/d), vitamin D3(400 iu) plus calcium (1,000mg/d), or vitamins K1 and D plus calcium.  After 2 years, there was no significant difference in BMD at any site between groups; however the group taking the combined vitamins K, D, and calcium showed a 1.6% increase in BMD at the ultradistal radius site compared to baseline. 

Booth SL.  Vitamin K status in the elderly.  Curr Opin Clin Nutr Metab Care.  2007;10:20-3. 

The first meta-analysis evaluating the data on the role of vitamin K and bone health concluded that increased intakes of vitamin K are warranted to reduce bone loss and fracture risk among the elderly. 

Ichikawa T, Horie-Inoue K, Ikeda K, Blumberg B, Inoue S.  Vitamin K2 induces phosphorylation of protein kinase A and expression of novel target genes in osteoblastic cells.  Journal of Molecular Endocrinology.  2007;39:239-47. 

Igarashi M, et al.  Vitamin K induces osteoblast differentiation through Pregnane x receptor-mediated transcriptional control of the msx2 gene.  Molecular and Cellular Biology.  2007;27:7947-54. 

Kitchin B, Morgan SL.  Not just calcium and vitamin D:  other nutritional considerations in osteoporosis.  Current Rheumatology Reports.  2007Apr;9(1):85-92.

Vitamin K and vitamin B-12 are important nutritional considerations to consider for reducing risk of fracture by increasing bone mineral density as well as improving bone microarchitecture. 

Knapen MH, Schurgers, LJ, Vermeer C.  Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women.  Osteoporos Int.  2007;18(7):963-72. 

This study found that supplemental menatetrenone improved measures of bone strength compared to placebo.  The dose was 45mg/day in the three year placebo-controlled intervention trial in 325 postmenopausal women.  Suggests that vitamin K1 affects bone geometry and bone quality rather than bone density, and whether there are differences in the effects of vitamins K1 and K2 on bone remains to be determined. 

Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, et al.  Endocrine regulation of energy metabolism by the skeleton.  Cell.  2007;130:456-69. 

Pearson, DA.  Bone health and osteoporosis:  the role of vitamin K and potential antagonism by anticoagulants.  Nutri Clin Pract.  2007 Oct;22(5):517-44.

A thorough literature review on vitamin K, osteocalcin and their role in bone metabolism and osteporosis indicate that vitamin K has a positive effect on bone mineral density and decreases fracture risk.  Given that typical dietary intakes of vitamin K are below the levels associated with better bone mineral density and reduced fracture risk, the issue of increasing dietary intakes, supplementation and/or fortification arise.  Also discuss the long-term therapy adversely affects vertebral BMD and fracture risk. 

Sconce, E., Avery, P., Wynne, H. & Kamali, F.  Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin.  Blood.  2007;109:2419-23.

Shea MK, Booth SL.  Role of vitamin K in the regulation of calcification.  Inter. Congresson Ser.2007;1297:165-178.

There is strong evidence of a protective effect of MK4 in pharmacological doses on age-related bone loss and fracture risk.  This effect appears to be enhanced by vitamin D supplementation.

Shearer MJ, Cockrayne R, Adamson J, Lanham-New SA, Gilbody S & Torgerson DJ (2007)  Vitamin K and bone health.  Arch Intern Med.  2007;167: 94-95. 

Sugiyama T.  Possible involvements of vitamin K in bone quality.  Arch Intern med.  2007;167:93. 

Tamura T, Morgan SL, Takimoto H.  Vitamin K and the prevention of fractures.  Arch Intern Med.  2007;167:94. 

Tsugawa N, Okano T.  Serum vitamin K concentration and nutrition.  Clin Calcium.  2007 Nov;17(11):1717-26.

Low dietary vitamin K intake or status has been shown to be associated with low bone mineral density and increased hip fracture risk.  Review of studies that suggest that there can be a vitamin K insufficiency in bone, even while there is sufficient vitamin K for blood coagulation and review the factors which affect blood circulation of vitamin K.  . 

Booth SL, Dallal G, Shea MK, Gundberg C, Peterson JW, Dawson-Hughes B.  Effect of vitamin K supplementation on bone loss in elderly men and women.  J Clin Endrocrinol Metab.  2008;93:1217-23.

Randomized 452 healthy men and women between 60 and 80 years of age to receive a multivitamin that contained either 500 ug/d of vitamin K1 or no vitamin K1 plus a daily calcium (600 mg) and vitamin # (400 iu) supplement.  After three years they did not find any differences in BMD at the femoral neck, lumbar spine, or total body between the two groups. 

Bugel S.  Vitamin K and bone health in adult humans.  Vitam Horm.  2008;78:393-416.

Vitamin K is a coenzyme for glutamate carboxylase which mediates the conversion to Gla.  This carboxylation of the Gla proteins is essential for the proteins to attract calcium.  The beset known of the bone related proteins is osteocalcin (OC).  A number of studies have shown that vitamin K insufficiency is associated with low bone mineral density (BMD) and increased fractures.  Vitamin K supplementation has been shown to improve the bone turnover profile.  The bodily requirements for vitamin K might need to be set higher in order to meet the needs for bone health. 

Cheung AM, Tile L, Lee Y, Tomlinson G, Hawker G, Scher J, et al. Vitamin K supplementation in postmenopausal women with osteopenia (ECKO Trial): A randomized controlled trial.  PLoS Med.  2008 Oct;5(10): e196. doi:10.1371

The study was conducted to determine whether daily high dose vitamin K1 supplementation safely reduces bone loss, bone turnover, and fractures.  Their study showed that 5 mg of vitamin K1 supplementation daily for 2-4 years protected against clinical fractures and cancers.  Over the 4 year period, fewer women in the vitamin K group had fractures (nine versus twenty women in the placebo group), and fewer had cancer (three versus twelve).  Finally, vitamin K supplementation was well tolerated over the 4 year period and adverse health effects were similar in the two treatment groups.

 

Allen MR, Burr DB. Bone Modeling and Remodeling. Basic and Applied Bone Biology Chapter. 2014;4:75–90. 

Ferron M, Hinoi E, Karsenty G, Ducy P.  Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice.  Proc Natl Acad Sci USA.  2008; 105:5266-70. 

Heiss C, Hoesel LM, Wehr U, Wenisch S, Drosse I, Alt V, et al.  Diagnosis of osteoporosis with vitamin K as a new biochemical marker.  Vitam Horm.  2008;78:417-34.

Patients with osteoporosis have been shown to have decreased levels of vitamin K.  Further, regular intake of vitamin K may increase bone mineral density (BMD), thereby lowering the fracture risk.  This review focuses on the significance and importance of vitamin K for bone metabolism. 

Loveridge N, Lanham-New SA.  Bones and ageing.  In:  Mathers J, Buttriss J, editors.  British Nutrition Foundation Taskforce on Nutritional Aspects of Ageing.  London:  Blackwell Publishing; 2008.   

Morishita M, Nagashima M, Wauke K, Takahashi H, Takenouchi K.  Osteoblast inhibitory effects of vitamin K2 alone or in combination with etidronate or risedronate in patients with rheumatoid arthritis:  2-year results.  Journal of Rheumatology.  2008;35;407-13. 

Okamoto H.  Vitamin K and rheumatoid arthritis.  IUBMB life.  2008 Jun;60(6):355-61. 

The study investigated the effect of MK4 on the proliferation of rheumatoid synovial cells and the development of arthritis in collagen-induced arthritis.  The results indicated that MK4 inhibited the proliferation of fibroblast like synoviocytes and inhibited the development of arthritis in a dose dependent manner.  They conclude that MK4 may represent a new agent for the treatment rheumatoid arthritis.

Phillips KW, Ansell J.  Outpatient management of oral vitamin K antagonist therapy:  defining and measuring high-quality management.  Expert Rev Cardiovasc Ther.  2008;6(10):57-70. 

Recommend the addition of oral doses of vitamin K to help maintain an optimal ratio of warfarin to efficacy.

van Summeren MJ, van Coeverden SC, Schurgers LJ, Braam LA, Noirt F, Uiterwaal CS, et al.  Vitamin K status is associated with childhood bone mineral content.  Br J Nutr.  2008;100:852-58.

Vitamin K contributes to bone health.  In children, the significance of vitamin K in bone-mass acquisition is less well known.  This longitudinal study looked at whether biochemical indicators of vitamin K status are related to gains in bone mineral content and markers of bone metabolism in peripubertal children.  307 healthy children, mean age 11 years, were measured for bone mineral content, lumbar spine and femoral neck measurements at baseline and then two years later.  They found a substantial difference in vitamin K status.  An improvement in vitamin K status over 2 years was associated with a marked increase in total body bone mineral content, and higher bone mass.  It was hypothesized that the high levels of ucOC result from an imbalance between dietary intake and the metabolic requirement for vitamin K during growth.  And that an adequate vitamin K status during puberty may contribute to a higher peak bone mass and prevent osteoporosis in later life. 

Viegas CS, Simes DC, Laize V, Williamson MK, Price PA, Cancela ML.  Gla-rich protein (GRP) a new vitamin K-dependent protein identified from sturgeon cartilage and highly conserved in vertebrates.  J Biol Chem.  2008;283:36655-65.

Walker MB, Bussey HI.  Vitamin K and warfarin:  What you should know [Internet].  St. Antonio (TX):  Clotcare (US);2004 May, updated 2008 January [cited 2012 Dec 17].  [about 2 screens].  Available from http://www.clotcare.com/vitaminkandwarfarin.aspx  

Yaegashi Y, Onoda T, Tanno K, Kuribayashi T, Sakata K, & Orimo H.  Association of hip fracture incidence and intake of calcium, magnesium, vitamin D, and vitamin K.  European Journal of Epidemiology.  2008;23(3):219-25.

The study analyzed the association between hip fracture incidence in 12 regional blocks in Japan and dietary intake of four key nutrients:  calcium, magnesium, vitamin K, and vitamin K.  They found a significant correlation between hip fracture incidence and vitamin K intake. 

Atkins GJ, Welldon KJ, Wijenayaka AR, Bonewald I, Findlay DM.  Vitamin K promotes mineralization, osteoblast to osteocyte transition and an anti-catabolic phenotype by gamma-carboxylation-dependent and –independent mechanisms.  Am J Physio Cell Physiol.  2009 Dec;297(6):358-67.

This study provides compelling evidence that vitamin K modulates structural parameters and cell effectors of bone strength.  Vitamin K promotes collagen accumulation, cell-matrix interactions, matrix mineralization, mineral maturation, and osteocyte differentiation by gamma carboxylation dependent and independent michenanisms. 

Binkley N, Harke J, Krueger D, Engelke J, Vallarta-Ast N, et al.  Vitamin K treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density, or geometry in healthy postmenopausal North American women.  J of Bone and Min Res.  2009;24:983-91. 

381 postmenopausal women received phylloquinone (1 mg daily), MK4 (45 mg daily) or a placebo over twelve months, along with 1000 IU of vitamin D and 600 mg of calcium.  There was no effect on lumbar spine or proximal femur BMD or proximal femur geometric parameters. 

Coen G, Ballanti P, Silvestrini G, Mantella D, Manni M, Di Giulio S, et al.  Immunohistochemical localization, and mRNA expression of matrix Gla protein and fetuin-A in bone biopsies of hemodialysis patients.  Virchows Arch.  2009;454:263-71. 

Coutu DL, Wu JH, Monette A, Rivard GE, Blostein MD, Galipeau J.  Periostin, a member of a novel family of vitamin K-dependent proteins is expressed by mesenchymal stromal cells.  J Biol Chem.  2008;283:17991-18001. 

Inoue T, Fujita T, Kishimoto H, Makino T, Nakamura T, Sato T, et al.  Randomized controlled study on the prevention of osteoporotic fractures (OF study): a phase IV clinical study of 15-mg menatetrenone capsules.  J Bone Miner Metab.  2009;27:66-75. 

An open-label study with blinded evaluation was performed to compare the preventive effect of a calcium supplement alone (monotherapy) or calcium supplement plus menatetrenone (MK4) (combined therapy) on fracture in osteoporotic postmenopausal women aged 50 years or older.  There was a lower risk of new vertebral fractures in patients who received combined therapy.  The results suggested that menatetrenone may prevent vertebral fractures in patients with more advanced osteoporosis.  The lower incidence rate of clinical fractures in our combined therapy group compared with our monotherapy group, even though the difference was not significant, also suggests that vitamin K2 may provide an additional therapeutic benefit by reducing the risk of nonvertebral fractures. 

Iwamoto J, Sato Y, Takeda T, Matsumoto H.  High-dose vitamin K supplementation reduces fracture incidenced in postmenopausal women:  a review of the literature.  Nutrition Research.  2009;29:221-28. 

The objective of the present review of the literature was to evaluate the effect of vitamin K supplementation on the skeleton of postmenopausal women. High-dose vitamin K(1) and vitamin K(2) supplementation improved indices of bone strength in the femoral neck and reduced the incidence of clinical fractures.

Kassi E, Papavassiliou AG.  A possible role of osteocalcin in the regulation of insulin secretion:  human in vivo evidence?  J Endocrinol.  2009;199:151-53. 

Oka H, Akune T, Muraki S, En-yo Y, Yoshida M, Saika A, Sasaki S, et al.  Association of low dietary vitamin K intake with radiographic knee osteoarthritis in the Japanese elderly population:   dietary survey in a population-based cohort of the ROAD study.  J Orthop Sci.  2009 Nov;14(6):687-92.

This study sought to identify dietary nutrients associated with knee osteoarthritis in the Japanese elderly in the ROAD study (Research on Osteoarthritis Against Disability).  719 participants in a rural cohort.  Among the dietary factors, only vitamin K intake was shown to be inversely associated with the prevalence of knee arthritis.  The prevalence for arthritis decreased with vitamin K intake.  They concluded that low dietary vitamin K intake is a risk factor of knee arthritis and vitamin K may have a protective role, and might lead to a disease-modifying treatment.

Rani S, Barbe M, Barr A, Litvin J.  Periostin-like-factor and periostin in an animal model of work-related musculoskeletal disorder.  Bone.  2009;44:502-12. 

Rubinacci A.  Expanding the functional spectrum of vitamin K in bone.  Focus on:  “Vitamin K promotes mineralization, osteoblast to osteocyte transition, and an anti-catabolic phenotype by carboxylation-dependent and –independent mechanisms.”  American Journal of Physiology Cell Physiology.  2009 Dec;297(6):1336-38. 

For 40 years, research focused on vitamin K's role in blood coagulation, and its mechanism of action remained undetermined.  In 1974, identification of amino-γ-carboxy glutamic acid (Gla) in prothrombin as the product of vitamin K action unequivocally showed that vitamin K is a cofactor for posttranslational carboxylation of Gla residues. The Gla residues act as calcium-binding sites that are essential for normal hemostasis.  Subsequent discoveries of other Gla proteins involved in blood coagulation, such as factors VII, IX, and X synthesized in the liver as well as proteins C, S, and Z, gave further insight into vitamin K's action in hemostasis.  The identification of Gla proteins in the organic matrix of bone boosted research on vitamin K and bone metabolism; these proteins include bone-Gla protein (BGP), matrix-Gla protein (MGP), protein-S, Gla-rich protein (GRP), periostin, and periostin-like factor (PLF).  The vitamin K’s ability to promote collagen accumulation, cell-matrix interactions, matrix mineralization, mineral maturation, and osteocyte differentiation (all determining factors of bone quality) are relevant to bone health. 

 

Stevenson M, Lloyd-Jones M, Papaioannou D.  Vitamin K to prevent fractures in older women:  systematic review and economic evaluation.  Health Technol. Assess.  2009 Sep;12(45):iii-xi, 1-134. 

The review aimed to determine the clinical and cost-effectiveness of vitamin K in preventing osteoporotic fractures in post menopausal women.  The study compared vitamin K with alendronate(Fosomax), risedronate (Actonel), and strontium ranelate (Protelos), pharmaceuticals prescribed for osteoporosis.  The review found that vitamin K and alendronate were markedly more cost-effective than either risedronate  or strontium ranelate.  Additionally, women receiving either Fosomax or Actonel had adverse upper gastrointestinal events.  A systematic review has indicated that bisphosphonates are associated with an increased risk of osteonecrosis (bone death) of the jaw.  The analyses suggest that vitamin K1  is the most cost-effective and safe intervention, with a call for more randomly controlled trials to be conducted. 

Suhara Y, Wada A, Okana T.  Elucidation of the mechanism producing menaquinone-4 in osteoblastic cells.  Bioorg. Med Chem Lett.  2009;19:1054-57. 

van Summeren MJ, Braam LA, Lilien MR, Schurgers LJ, Kuis W, Vermeer C.  The effect of menaquinone-7 (vitamin K2) supplementation on osteocalcin carboxylation in healthy prepubertal children.  Br J Nutr.  2009 Oct;102(8):1171-8.

Vitamin K contributes to bone health, probably through its role as cofactor in the carboxylation of osteocalcin.  Intervention studies in adults have demonstrated that markedly higher osteocalcin carboxylation is obtained by intakes of vitamin K well above the current recommended dietary intake. However, the relationship between increased vitamin K2 intake and enhanced osteocalcin carboxylation has never been shown in healthy children.  The objective was to study the effect of 45 microg menaquinone-7 (MK-7; one of the vitamin K2 species) on the circulating levels of undercarboxylated osteocalcin (ucOC) and carboxylated osteocalcin (cOC) in healthy prepubertal children.  These findings demonstrate that in healthy, prepubertal children, modest supplementation with MK-7 increases how much MK-7 is circulating in the blood stream, and also increases osteocalcin carboxylation.

2010s

Emaus N, Gjesdal CG, Almas B, Christensen M, Grimsgaard AS, Berntsen GKR, et al.  Vitamin K2 supplementation does not influence bone loss in early menopausal women: a randomized double-blind placebo-controlled trial.  Osteoporosis International.  Oct 2010;21(10):1731-1740.

Vitamin K may preserve bone strength and reduce fracture risk.  In this study 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 (MK7) intake may preserve bone strength, but this has not been documented in Europeans.  334 women between 50-60 years, 1-5 years after menopause received a low dose of 360 ug of MK7 or identical capsules containing olive oil.  After one year, there was no statistical differences in bone loss rates between the groups.  Serum levels of cOC increased and ucOC decreased in the treatment groups.  It is likely that the dose was too low to make a difference in twelve months.

Forli L, Bollerslev J, Simonsen S, Isaksen GA, Kvamsdal KE, Godang K, et al.  Dietary vitamin K2 supplement improves bone status after lung and heart transplantation.  Transplantation.  2010 Feb 27;89(4):458-64.

Osteoporosis is a problem after transplantation.  Studies indicate that vitamin K plays a role in optimal bone health.  The aim of this randomized, double blind, prospective longitudinal study was to investigate the effect of a dietary supplement with vitamin K2 (180 micrograms menaquinone-7) on bone mass, the first year after lung and heart transplantation.  35 lung and 59 heart recipients received vitamin K2 or placebo.  One year of vitamin K2 supplement suggested a favorable effect on lumbar spine bone mineral density with a different response in lung and heart recipients.  Bone mass was higher in the vitamin K2 group and the bone mineral concentration was greater in patients with the lung transplant.  Vitamin D status should receive more attention for transplant patients.

Kidd PM.  Vitamins D and K as pleiotropic nutrients:  Clinical importance to the skeletal and cardiovascular systems and preliminary evidence for synergy.  Altern Med Rev.  2010 Sep;15(3):199-222. 

Vitamins D and K are lipid-phase nutrients that are endowed with versatile homeostatic capacities at the organ, tissue, and cellular levels. Their metabolic and physiologic roles overlap considerably, as evidenced in the bone and cardiovascular systems.  At least 17 tissues likely synthesize 1 alpha,25D, and 35 tissues carry the vitamin D receptor (VDR).  Vitamin K-dependent (VKD) proteins play key roles in many tissues throughout the body.  This review updates vitamin D and K skeletal and cardiovascular benefits and evidence for their synergy of action in human populations.  Vitamin K1 (phylloquinone) is more abundant in foods but less bioactive than the vitamin K2‚ menaquinones (especially MK-4, menatetrenone).  Menadione (vitamin K3) has minimal K activity.

Kim M, Kim H, Sohn C.  Relationship between vitamin K status, bone mineral density and hs-CRP in young Korean women. Nutr Res Pract.  2010 Dec;4(6):507-14.

Vitamin K has been reported as an essential factor for bone formation.  Maximal bone mass is achieved during the twenties, meaning that it is important to maintain a healthy skeletal structure during that time.  This study examined whether insufficient vitamin K intake would affect inflammatory markers and bone mineral density (BMD) in young adult women.  75 women in their twenties were studied, showing that the level of C Reactive Protein was positively correlated with vitamin K deficiency status.  Also bone mineral density was negatively correlated with vitamin K status, meaning the higher the level of vitamin K in your system, the better your BMD was.  They concluded that vitamin K status affects inflammatory status and bone formation and that sufficient intake of vitamin K is required to secure peak bone mass in young adult women.

Tsugawa N, Okano T.  Vitamin K and fracture.  Clin Calcium.  2010 Sep;20(9):1334-40.

Recent studies suggest that there is potential vitamin K insufficiency in bone, even when there is sufficient vitamin K found in blood levels.  Includes a review of the relationship between vitamin K status and fracture.

Wallin R, Schurgers LJ, Loeser RF.  Biosynthesis of the vitamin K-dependent matrix Gla protein (MGP) in chondrocytes:  a fetuin-MGP protein complex is assembled in vesicles shed from normal but not from osteoarthritic chondrocytes.  Osteoarthritis Cartilage.  2010 Aug;18(8):1096-103. 

This study looked at MGP and the formation of a fetuin-MGP protein complex was altered in the cartilage of folks with osteoarthritis.  They found significantly less carboxylated MGP in arthritic tissues when compared to those with normal cartilage.  This was correlated with significantly less vitamin K-dependent gamma carboxylase activity.  They concluded that the absence of carboxylated MGP and carboxylated MGP-fetuin complex in osteoarthritic cells and vesicles may be an important mechanism for the increased mineralization of the cartilage.

Yamauchia M, Yamaguchi T, Nawata K, TAkaoka S, Sugimoto T.  Relationships between undercarboxylated osteocalcin and vitamin K intakes, bone turnover, and bone mineral density in healthy women.  Clin Nutr.  2010;29:761-65.  

Low vitamin K intakes and high levels of uncarboxylated osteocalcin (ucOC) are risk factors for hip fractures.  This study enrolled 221 healthy women and examined BMD, uNTX, and nutrient intakes.  They found that vitamin K intakes were significantly and negatively correlated with ucOC.

Apalset EM, Gjesdal CG, Eide GE, Tell GS.  Intake of vitamin K1 and K2 and risk of hip fractures:  the Hordaland Health Study.  Bone. 2011 Nov;49(5):990-5.

This study investigated the association between intake of vitamins K1 and K2 and the subsequent risk of hip fracture in a general population sample, as well as the potential effect of apoliprotein E gene (Apoe).  They studied almost 3000 men and women in western Norway.  Participants with the lowest intake of vitamin K1 had an increased risk of suffering a hip fracture.  Vitamin K2 intake was not associated with hip fracture risk, and the presence of the Apoe 4 gene did not increase the risk of hip fracture.  They concluded that a low intake of vitamin K was associated with an increased risk of hip fractures.  

Brugè, F.; Bacchetti, T.; Principi, F.; Littarru, G.P.; Tiano, L. Olive oil supplemented with menaquinone-7 significantly affects osteocalcin carboxylation. Br J Nutr. 2011;106:1058–1062.

Feng X, McDonald JM. Disorders of bone remodeling. Annual review of pathology. 2011;6:121–45. 

Jeong HM, Cho DH, Jin YH, Chung JO, Chung MY, et al.  Inhibition of osteoblastic differentiation by warfarinf and 18-α-glycyrrhetinic acid.  Archives of Pharmacal Res.  2011;34(8):1381-7.

Anticoagulation therapy with vitamin K antagonists such as warfarin is widely used to prevent and treat stroke in patients with chronic atrial fibrillation or mechanical heart valves. Because vitamin K is an essential factor for carboxylation of osteocalcin, vitamin K antagonists might cause bone loss.  Several studies show that bone mineral density is decreased and fracture risk is increased with warfarin therapy. Here we investigated whether warfarin has an inhibitory effect on osteoblastic differentiation using an osteoblastic cell line (C2C12). These results suggest that warfarin and AGA (18-α-glycyrrhetinic acid), a GJC inhibitor, have an inhibitory effect on osteoblastic differentiation.

Sato Y, Honda Y, Umeno K, Hayashida N, Iwamoto J, Takeda U, Matsumoto H.  The prevention of hip fracture with menatetrenone and risedronate plus calcium supplementation in elderly patients with Alzheimer disease:  A randomized controlled trial.  The Karume medical journal.  2011;57(4):117-24. 

A high incidence of fractures is an important problem for patients with Alzheimers.  A total of 231 elderly patients were randomly assigned to daily treatment with 45 mg of menatetrenone or a placebo once weekly and followed for twelve months.  During the study period, bone mineral density in the treatment group increased by 5.7 % and increased by 2.1 % in the control group.  The medications were well tolerated and the vitamin K was effective in reducing the risk of fracture.

Vermeer C, Theuwissen, E.  Vitamin K, osteoporosis and degenerative diseases of ageing.  Menopause International, 2011 March;17(1):19-23. 

During recent years, new Gla-containing proteins have been discovered and the vitamin K-dependent carboxylation is also essential for their function.  However it seems our dietary vitamin K intake is too low to support the carboxylation of some of the Gla-Proteins.

Fang Y, Hu C, Tao X, Wan Y, Tao F.  Effect of vitamin K on bone mineral density:  a meta-analysis of randomized controlled trials.  J Bone Mineral Metab.  2012;30:60-8.

This article is a systematic review of randomly controlled trials on vitamin K and bone health.  Subgroup analysis in the most recent meta-analysis on vitamin K and bone health revealed that K2 but not K1 supplementation had favorable effects on lumbar spine bone mineral density (BMD).  Vitamin K supplementation was shown to be efficacious in increasing BMD at the lumbar spine, but not the femoral neck.

Fu X, Moreines, J, Booth, SL.  Vitamin K supplementation does not prevent bone loss in ovariectomized Norway rats.  Nutr. Metab.  2012;9:12. 

Supplementation of Pk, MK4 or MK7 did not confer a beneficial effect on bone loss in ovariectomized Norway rats fed a diet that meets nutritional requirements for calcium and vitamin D. 

Gajic-Veljanoski O, Bayoumi, AM, Tomlinson G, Khan K, Cheung AM.  Vitamin K supplementation for the primary prevention of osteoporotic fractures:  is it cost-effective and is future research warranted.  Osteoporosis.  Published online March 8, 2012. 

Lifetime supplementation with vitamin K, vitamin D2 and calcium is likely to reduce fractures and increase survival in postmenopausal women.  They developed a microsimulation model to quantify the cost-effectiveness of various interventions to prevent fractures in 50 year old postmenopausal women without osteoporosis.  They compared no supplementation, vitamin D3 with calcium, vitamin K2 with vitamin D3 and calcium at the same doses.  The results indicated that adding vitamin K2 to vitamin D3 with calcium, reduced the lifetime probability of at least one fracture by 25%, and discounted costs by thousands of dollars.  They concluded that lifetime supplementation with vitamin K, vitamin D3 and calcium is likely to reduce fractures and increase survival in postmenopausal women. 

Giammanco M, Di Majo D, Leto G, Flandina C, Piaza M, Guardia M.  The role of vitamin K in bone remodeling and osteoporosis.  J Food Res. 2012;1(4):106-23.

Vitamin K has been shown to regulate important biological functions such aas bone mineralization, calcium homeostasis, apoptosis, cell growth and signal transduction.  In particular the protective effects of vitamin K on bone tissue are of clinical relevance.   

Important information to know when you are taking: Warfarin (Coumadin) and Vitamin K [Internet].  Bethesda (MD): National Centers of Clinical Important Drug and Food Information (US);2012 Sept 5 [cited 2012 Dec 17].[about 3 screens].  Available from:  http://www.cc.nih.gov/ccc/patient_education/drug_nutrient/coumadin1.pdf

Kanellakis S, Moschinos G, Tenta R, Schaafsma A, van den Heuvel E GHM, Papaionnau N, et al.  Changes in parameters of bone metabolism in postmenopausal women following a 12-month intervention period using dairy products enriched with calcium, vitamin D, and phylloquinone (vitamin K1) or Menaquinone-7 (vitamin K2):  The Postmenopausal Healthy Study II.  Calcif Tissue Int.  2012;90 apr:251-62.

This study examined the effect of dairy products enriched with calcium, vitamin D3, phylloquinone (vitamin K1), or menaquinone-7 (vitamin K2) on parameters of bone metabolism in postmenopausal women following a 12 month intervention.  All intervention groups had significant increases in total body BMD, compared to the control group, while only the K1 and K2 groups, showed significant increases in lumbar spine bone mineral density (BMD).  The groups who received vitamin K1 or K2 took doses of 100 ug daily.  The study revealed more favorable changes in bone metabolism and bone mass indices for the two vitamin K supplemented groups.     

Karsenty G, Oury F.  Biology without walls:  The novel endocrinology of bone.  Annu Rev Physiol. 2012;74:87-105.

Lijima H, Shinzaki S, Takehara T.  The importance of vitamins D and K for the bone health and immune function in inflammatory bowel disease.  Curr Opin Clin Nutr Metab Care.  2012 Nov;15(6):635-40. 

Vitamin D and vitamin K are suggested to be involved in the suppression of inflammation and modulation of disease activity in bone metabolism and inflammatory bowel diseases.

Matusomoto T, Miyakawa T, Yamamoto D.  Effects of vitamin K on the morphometric and material properties of bone in the tibiae of growing rats.  Metabolism.  2012 (Mar);61(3):407-14.

Suboptimal vitamin K nutriture is evident during rapid growth.  This study aimed to determine whether vitamin K2 (MK4) supplementations is beneficial to bone structure and bone tissue in growing rats.  The results showed a positive effect on bone formation, with increased mineral crystallinity, collagen maturity and hardness.  It appears that MK4 supplementation during growth enhances bone quality.    

Miki T, Masaki H.  New approved markers of bone turnover for osteoporosis in Japan.  Clinical Calcium.  2012 Jun;22(6):877-83. 

Described the unique value of uncarboxylated osteocalcin (ucOC) as a marker of bone turnover, as it reflects vitamin K insufficiency for bone.

Naito K, Watari T, Obayashi O, Katsube S, Nagaoka I, Kaneko K.  Relationship between serum undercarboxylated osteocalcin and hyaluronan levels in patients with bilateral knee osteoarthritis.  International Journ of Mol Med.  2012 May;29(5):756-60.

Serum undercarboxylated osteocalcin (ucOC) is a marker for vitamin K metabolism (deficiency).  This study investigated the serum levels of ucOC with bilateral knee osteoarthritis and the findings suggest that vitamin K metabolism may be associated with synovitis in patients with knee osteoarthritis and that serum ucOC could be a marker for knee osteoarthritis.

Orimo H, Nakamura T, Hosoi T, Iki M, Uenishi K, Endo N, Ohta H, Shiraki M, Sugimoto T, Suzuki T, Soen S, Nishizawa Y, Hagino H, Fukunaga M, Fujiwara S. Japanese 2011 guidelines for prevention and treatment of osteoporosis—executive summary. Archives of Osteoporosis. 2012;7:3–20. 

Sato T.  Vitamin K2 and bone quality.  Vitam Trace Elem.  2012:S6. doi:10.4172/2167-0390.S6-001

Vitamin K is a cofactor required for important vitamin K-dependent proteins.  Additionally K2 induces collagen accumulation in the bone matrix, and promotes bone quality and bone strength.  It doesn’t necessary increase bone mineral density.  It is believed that MK7 at nutritional doses will promote bone health.

Sato, T.; Schurgers, L.J.; Uenishi, K. Comparison of menaquinone-4 and menaquinone-7 bioavailability in Japanese. Nutr. J. 2012;11:93.

Theuwissen, E.; Cranenburg, E.C.; Knapen, M.H.; Magdeleyns, E.J.; Teunissen, K.J.; Schurgers, L.J.; Smit, E.; Vermeer, C. Low-dose menaquinone-7 supplementation improved extra-hepatic vitamin K status, but had no effect on thrombin generation in healthy subjects. Br J Nutr. 2012;108:1652–1657.

Beulens, J.W.J.; Booth, S.L.; van den Heuvel, E.G.H.M.; Stoecklin, E.; Baka, A.; Vermeer, C. The role of menaquinones (vitamin K2) in human health. Br. J. Nutr. 2013, 110, 1357–1368. 

Ishii Y, Noguchi H, Takeda M, Sato J, Yamamoto N, Wakabayashi H, et a.  Distribution of vitamin K2 in subchondral bone in osteoarthritic knee joints.  Knee Surg Sports Traumatol Arthrose.  2013;21:1813-1818.

This study evaluated the distribution of vitamin K2 in harvested bones obtained during knee surgery in patients with osteoarthritis, medial and lateral femoral and tibia condyles (protuberance at the end of some bones).  As vitamin K regulates bone turnover in patients with osteoporosis, it could have multiple effects on cartilage and bone.  The results suggested that vitamin K2 might affect bone turnover.  Medial bone showing advanced arthritis had lower vitamin K2 levels, while lateral condyles showing less advanced arthritis contained more vitamin K2.  Gender and age were not correlated with vitamin K2 locality.

Kim M, Na W, Sohn C.  Vitamin K1 (phylloquinone) and K2 (menaquinone-4) supplementation improves bone formation in a high-fat, diet-induced obese mice.  J Clin Biochem Nutr.  2013 Sep;53(2):108-13.

Several reports suggest that obesity is a risk factor for osteoporosis.  Typically there is a lower bone density in the obese population.  Vitamin K plays an important role in improving bone metabolism.  In this study, K1 and K2 supplementation were studied for their effect on the biochemical markers of bone turnover and on the microstructure of bones, in obese mice. Mice were fed a 10% fat or a 45% high fat diet with and without K1 and K2.  Vitamin K status was measured via osteocalcin, which was higher in the high fat diet and K2 group.  Supplementation with vitamin K seemed to prevent bone loss in a high fat diet and obese state.  It appears the vitamin K modulated osteoblast and osteoclast activities, balanced bone metabolism, and prevented bone loss.  It also appeared that the vitamin K decreased the excessive increase in body weight for those mice on the high fat diet.  Further studies are needed to explore this effect in humans.

Knapen MHJ, Drummen NE, Smit E, Vermeer C, Theuwissen E.  Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women.  Osteoporosis Int.  2013 Sep;24(3):2499-507.  

The prevalence of osteoporosis increases markedly with age.  This study investigated whether low-dose vitamin K2 supplements, menaquinone-7 (MK-7), would beneficially affect bone health.  MK7 was chosen because of its longer half life and greater potency.  Healthy postmenopausal women (n=244) received placebo or MK7 (180 ug) per day for three years.  The results showed that MK7 significantly improved the vitamin K status and decreased the age-related decline in Bone Mineral Content and Bone Mineral Density at the lumbar spine and femoral neck, but not at the total hip.  Bone strength was also favorably affected.  They concluded that postmenopausal women may benefit from taking supplements with MK7 to prevent age-related bone loss.  A key finding was that the rate of bone loss in both groups was comparable for the first year, and that it was only with continued supplementation for three years that the group taking MK7 showed significantly improved bone health.

Misra D, Booth SL, Tolstyka I, Felson DT, Nevitt MC, Lewis CE, et al.  Vitamin K deficiency is associated with incident knee osteoarthritis.  Am J Med.  2013 Mar;126(3):243-48.

Because of vitamin K's role in regulating skeletal mineralization, it has the potential to be an preventive option for osteoarthritis.  Subclinical vitamin K deficiency may affect the functioning of Gla proteins involved in the regulation of bone and cartilage mineralization.  This study found that vitamin K deficiency was associated with the development of both new-onset knee osteoarthritis and new cartilage lesions in knees free of osteoarthritis.  Taking vitamin K as a supplement may serve to prevent or delay knee osteoarthritis.

Allen MR, Burr DB. Bone Modeling and Remodeling. Basic and Applied Bone Biology Chapter. 2014;4:75–90. 

Azuma K, Ouchi Y, Inoue S.  Vitamin K:  novel molecular mechanisms of action and its roles in osteoporosis.  Geriatrics & Gerontology International.  2014 Jan;14(1):1-7.

Vitamin K has been shown to prevent bone fractures in clinical studies.  Epidemiological studies suggest that a lack of vitamin K is associated with osteoporosis and vitamin K is used as a drug to treat osteoporosis in several Asian countries.  Vitamin K can be considered as a "vitamin from the cradle to the grave".

Baucom K, Pizzorno L, Pizzorno J.  Osteoporosis:  The need for prevention and treatment.  J of Restor Med.  2014 Apr;3(1):2-29.

The seeds of osteoporosis are sown during adolescence, when the skeleton is most active in building bone mass.  Dietary intake of vitamin K and vitamin D, are critical during this life stage for optimal bone growth.  Supplementing with nutrients are risk factors that can be managed.

Iwamoto J.  Vitamin K2 therapy for postmenopausal osteoporosis.  Nutrients.  2014 May;6(5):1972-80.

Vitamin K may play an important role in preventing fractures in women with osteoporosis.  Osteocalcin (OC) is a vitamin K dependent protein centrally involved in bone health.  Without vitamin K to carboxylate OC, it lacks structural integrity, resulting in an increased risk for fractures.  Menatetrenone is the brand name of a synthetic vitamin K2 that is chemically identical to menaquinone 4.  It is approved as an anti-osteoporotic medicine by the Ministry of Health, Labour, and Welfare in Japan.  A previous study found that 45 mg was the minimum effective dose for improving bone mass in women with osteoporosis.  This dose is 150-180 times greater than the recommended daily intake of Vitamin K.  No toxic effects have been reported.  This study reviewed the results of randomized controlled trials in the literature, and found positive evidence for the effects of menatetrenone on fracture incidence.  

Jiang Y, Zhang ZL, Zhang ZL, Shu HM, Wu YY, Cheng Q, et al.  Menatetrenone versus alfacalcidol in the treatment of Chinese postmenopausal women with osteoporosis:  dummy, positive drug-controlled clinical trial.  Clin Interv Aging.  2014;9:121-127.

The conclusion from this study was the MK4 is an effective and safe choice in the treatment of post-menopausal osteoporosis in Chinese women.  

Koitaya N, Sekiguchi M, Tousen Y, Nishide Y, Morita A, Yamauchi J, et al.  Low-dose vitamin K1 (MK-4) supplementation for 12 months improves bone metabolism and prevents forearm bone loss in postmenopausal Japanese women.  J Bone Mineral Metab.  2014 Mar;32(2):142-50.  

Menaquinone-4 (MK4) at 45 mg/day has been used for the treatment of osteoporosis in Japan.  However, it is not known whether a lower dose of MK4 supplementation is beneficial for bone health in healthy postmenopausal women.  This study examined the long-term effects of 1.5 mg daily supplementation of MK4 on the various markers of bone turnover and bone mineral density (BMD).  After 6 and 12 months, the serum ucOC concentrations were significantly lower in the MK4 group than in the control group.  Also the control group showed a significant loss of BMD in the forearm after 12 months, while the MK4 group showed no loss.  The results suggest that low dose supplementation with MK4 for 6-12 months improved bone quality in postmenopausal Japanese women.

Levinger I, Scott D, Nicholson GC, Stuart AL, Duque G, McCorquodale T, et al.  Undercarboxylated osteocalcin, muscle strength and indices of bone health in older women.  Bone.  2014 Jul;64:8-12.

Muraki S, Akune T, En-yo Y, Yoshida M, Tanaka S, Kawaguchi H, et al.  Association of dietary intake with joint space narrowing and osteophytosis at the knee in Japanese men and women:  the ROAD study.  Mod Rheumatol.  2014 Mar:24(2):236-42.

The present study identified dietary nutrients associated with joint space narrowing and osteophytosos at the knee in a rural cohort of men and women.  The data revealed that low dietary intake of vitamins K, B, and C are associated with JSN and osteophytosis in women. 

Nakamura, E.; Aoki, M.; Watanabe, F.; Kamimura, A. Low-dose menaquinone-4 improves γ-carboxylation of osteocalcin in young males: A non-placebo-controlled dose–response study. Nutr J. 2014;13:85.

Rafael MS, Cavaco S, Viegas CS, Santos S, Ramos A, Willems BA, et al.  Insights into the association of Gla rich protein and osteoarthritis, novel splice variants and gamma-carboxylation status.  Mol.  Nutr.  Food Res.  2014;58:1636-46.

Abdel-Rahman MS, Alkady EA, Ahmed S.  Menaquinone-7 as a novel pharmacological therapy in the treatment of rhuematoid arthritis:  a clinical study.  Eur J Pharmacol.  2015 Aug 15;761:273-8.

Menaquinones (vitamin K2) reduce cell death in rhuematoid arthritis.  MK4 is a potential agent for treatment of rhuematoid arthritis.  As MK7 has greater bioavailability than MK4, this study clarified the therapeutic role of MK7 with arthritis.  84 patients were enrolled and either received 100 ug/day or not.  They found a marked decrease in RA clinical and biochemical  markers in the MK7 treated group, with improved disease activity.  MK7 represented a new promising agent for rheumatoid arthritis treatment.

Bing W., Feng L. Attenuate Synovial Fluid Uncarboxylated Matrix Gla-Protein (ucMGP) Concentrations Are Linked with Radiographic Progression in Knee Psteoarthritis. Adv. Clin. Exp. Med. 2015;24:1013–1017.

Inaba, N.; Sato, T.; Yamashita, T. Low-dose daily intake of vitamin K2 (Menaquinone-7) improves osteocalcin γ-carboxylation: A double-blind, randomized controlled trial. J. Nutr. Sci. Vitaminol. 2015, 61, 471–480. 

Malemud CJ.  Biologic basis of osteoarthritis:  State of the evidence.  Curr Opin Rhematol.  2015;27:289-94.

Knapen, M.H.J.; Braam, L.A.J.L.M.; Drummen, N.E.; Bekers, O.; Hoeks, A.P.G.; Vermeer, C. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomised clinical trial. Thromb. Haemost. 2015, 113, 1135–1144. 

Shea MK, Kritchevsky SB, Hsu F-C, Nevitt M, Booth SL, Kwoh CK, et al.  The association between vitamin K status and knee osteoarthritis features in older adults.  The Health, Aging and Body Composition Study.  Osteoarthritis Cartilage.  2015 Mar;23(3):370-8.

Vitamin K dependent proteins, including the mineralization inhibitor matrix Gla protein, are found in joint tissues including cartilage and bone.  This study looked at cross sectional and longitudinal association between vitamin K status and knee osteoarthritis structural features. The results showed that folks with very low plasma levels of vitamin K were more likely to have progression of cartilage and meniscus damage after three years.

Torbergsen AC, Watne LO, Wiler TB, Frihagen F, Sromsoe K, Bohmer T, et al.  Vitamin K1 and 24(OH)D are independently and synergistically associated with a risk for hip fracture in an elderly population:  a case control study.  Clin Nutr. 2015;34(1):101-6.

This study examined whether vitamin K1 and vitamin D were associated with an increased risk of hip fracture, and whether the synergistic effect of these two micronutrients is mediated through bone turnover markers.  They found that both vitamin K and D were independently associated with a risk of hip fracture. Vitamin K1 and D were lower in hip fracture patients compared with controls.  The odds for a hip fracture when vitamin K was low was three-fold increased when vitamin D was also low.

El-Brashy AEWS, El-Tanawy RM, Hassan WA, Shaban HM, Bhnasawy MM.  Potential role of vitamin K in radiological progression of early knee osteoarthritis patients.  Egypt Rhuematol.  2016;38:271-23.

Knee osteoarthritis patients have significantly decreased plasma levels of vitamin K, that was remarkably associated with radiological progression of early disease suggesting that vitamin K levels could be a useful marker to reflect OA severity and implies a possible role in the disease pathogenesis.

Volpe SL.  Vitamin K, osteoarthritis, and athletic performance.  ACSM’s Health & Fitness Journal.  2016;20(1):32-33.

Lower intakes of vitamin K are related to knee osteoarthritis, and may relate to high bone turnover in athletes.  Recommends more research on vitamin K supplementation in larger populations.

Zhang Y, Yin J, Ding H, Zhang C, Gao Y-S.  Vitamin K2 ameliorates damage of blood vessels by glucocorticoid:  a potential mechanism for its protective effects in glucocorticoid-inuced osteonecrosis of the femoral head in a rat model.  Int J Biol Sci.  2016;12(7):776-85.

An important mechanism of osteonecrosis of the femur head is from decreased blood vessel number and a reduced blood supply.  In this study, vitamin K2 significantly protected endothelial cells.

van Ballejooijen AJ, Pilz S, Tomaschitz A, Grubler MR, Verheyen N.  The synergistic interplay between vitamin sD and K for bone and cardiovascular health:  A narrative review.  Int J Endocrinol.  2017; 2017: 7454376.

Vitamins D and K are both fat-soluble vitamins and play a central role in calcium metabolism.  Vitamin D promotes the production of vitamin K-dependent proteins, which require vitamin K for carboxylation in order to function properly.  This review summarizes the evidence of the synergistic interplay between vitamins D and K on bone and cardiovascular health.

Guss JD, Horsfield MW, Fontenele F, Sandoval TN, Luna M, Apoorva F, et al.  Alterations to the gut microbiome impair bone strength and tissue material properties.  J Bone Miner Res.  2017 Jun;32(6):1343-1353.

Alterations in the gut microbiome have been associated with changes in bone mass and microstructure, but the effects of the microbiome on bone biomechanical properties are not known. Here we examined bone strength under two conditions of altered microbiota:  (1) an inbred mouse strain known to develop an altered gut microbiome due to deficits in the immune system (the Toll-like receptor 5-deficient mouse [TLR5KO]); and (2) disruption of the gut microbiota (ΔMicrobiota) through chronic treatment with selected antibiotics (ampicillin and neomycin). We conclude that alterations in the gut microbiota for extended periods during growth may lead to impaired whole-bone mechanical properties in ways that are not explained by bone geometry. 

Marles, R.J.; Roe, A.L.; Oketch-Rabah, H.A. US Pharmacopeial Convention safety evaluation of menaquinone-7, a form of vitamin K. Nutr. Rev. 2017, 75, 553–578. 

Myneni VD, Mezey E.  Regulation of bone remodeling by vitamin K2.  Oral Dis. 2017 Nov;23(8):1021-28.

All living tissues require essential nutrients such as amino acids, fatty acids, carbohydrates, minerals, vitamins, and water. The skeleton requires nutrients for development, maintaining bone mass and density. In recent years, there has been growing interest in promotion of bone health and inhibition of vascular calcification by vitamin K2. This vitamin regulates bone remodeling, an important process necessary to maintain adult bone. Bone remodeling involves removal of old or damaged bone by osteoclasts and its replacement by new bone formed by osteoblasts. The remodeling process is tightly regulated, when the balance between bone resorption and bone formation shifts to a net bone loss results in the development of osteoporosis in both men and women. In this review, we focus on our current understanding of the effects of vitamin K2 on bone cells and its role in prevention and treatment of osteoporosis.

Rsaouli-Ghahroudi AA, Akbari, S, Nqjafji-Alishah M, Bohloli M.  The effect of vitamin K2 on osteogenic differentiation of dental pulp stem cells:  An in vitro study.  Regeneration, Reconstruction & Restoration.  2017;2(1):26-29.

Dental pulp stem cells have a great capacity to differentiate and they can be a great cell source for bone engineering.  The vitamin K family, especially vitamin K2 (MK4) have been shown to have an osteoprotective role.  This study investigated the effect of various concentrations of MK4 on dental pulp stem cell differentiation.  Within fourteen days, the MK4 had a significant effect on differentiation.  They concluded that MK4 can improve the outcomes of cell-based bone tissue treatments. Research indicates that MK4 can help dental pulp stem cells differentiate into osteoblasts and may enhance bone regenerative capacity. 

Shea MK, Loeser RF, McAlindon TE, Houston DK, Kirtchevsky SB, Booth SL.  Sufficient vitamin K status combined with sufficient vitamin D status is associated with better lower extremity function:  a prospective analysis of two knee osteoarthritis cohorts.  Arthritis Care and Research.  2017 Oct 17.  Doi. 10.1002/acr.23451.

Vitamins K and D are important for the function of vitamin K-dependent proteins in joint tissue.  This study looked at the association of vitamin K and D sufficiency with lower-extremity function in the Health ABC study and in an independent cohort, the Osteoarthritis Initiative (OAI).  Extremity function was assessed using the short physical performance battery.  Participants with sufficient plasma vitamin K and D generally had better SPPB scores and faster gait speed.  They concluded that sufficient vitamin K status combined with sufficient vitamin D status was associated with better lower-extremity function in two knee OA cohorts.

Schwalfenberg GK. Vitamins K1 and K2: The emerging group of vitamins required for human health. Journal of Nutrition and Metabolism. 2017;2017:6.

Vitamin K supplementation may be useful for a number of chronic conditions that are afflicting North Americans as the population ages, and appears promising in the areas of diabetes, cancer, and osteoarthritis. Vitamin K2 may be a useful adjunct for the treatment of osteoporosis, rivaling bisphosphonate therapy without toxicity.

Villa JKD, Diaz MAN, Pizziolo VR, Martino HSD.  Effect of vitamin K in bone metabolism and vascular calcification:  A review of mechanisms and evidences.  Crit Rev in Food Sci Nutr.  2017;57(18):3959-3970.

Osteoporosis is a public health concern associated with an increased risk of bone fractures and vascular calcification.  Vitamin K presents unique benefits on these issues.  This study looked at vitamin K2 on bones and vessels.  The commonly used dosage of vitamin K2 in human studies is 45 mg/day and eating natural sources of vitamin K2, as well as taking supplements, can be an important strategy in benefiting bone and vascular health, especially for osteoporotic post-menopausal women.

Zhang Y, Weng S, Yin J, Ding H, Zhang C, Gao Y.  Vitamin K2 promotes mesenchymal stem cell differentiation by inhibiting miR-133a expression.  Mol Med Rep.  2017;15:2473-80.

Vitamin K2 has been demonstrated to promote the osteogenic differentiation of mesenchymal stem cells; however, the mechanisms underlying this effect remain unclear. The results of the present study demonstrated that miR-133a inhibited osteogenic differentiation and VKORC1 expression in hBMSCs, whereas VK2 inhibited miR-133a expression accompanied by the stimulation of osteogenesis and VKORC1 expression, indicating that miR-133a may participate in the regulation of bone metabolism by VK2.

Akbari S, Rasouli-Ghahroudi AA.  Vitamin K and bone metabolism:  A review of the latest evidence in preclinical studies.  BioMed Research Int.  2018 Jun;25:1-8.

Bone is a metabolically active tissue that renews itself throughout life.  Vitamin K is a multi-functional vitamin that plays a pivotal role in maintenance of bone strength and bone turnover, and protects bone metabolisms.  Based on the evidence, adding vitamin K as an adjunct may stimulate bone cells to differentiate into osteoblasts and to produce native bone, with promising results. 

 Jaghsi S, Hammoud T, Haddad S.  Relation between circulating vitamin K1 and osteoporosis in the lumbar spine in Syrian post-menopausal women.  Open Rheumatology Journal.  2018;12:1-9.

Azuma K, Inoue S.  Multiple modes of vitamin K actions in aging-related musculoskeletal disorders.  Int J Moi Si.  2019 Jun;20(11):2844.

Vitamin K status is associated with some aging-related diseases including osteoporosis, osteoarthritis, and sarcopenia.  Several clinical studies show that vitamin K may have a beneficial effect on muscle quality reflected by physical performance.  This article reviews those findings and calls for more research into the biological mechanisms whereby vitamin K contributes to human longevity and health.

Guss JD, Taylor E, Rouse Z, Roubert S, Higgins CH, Thomas CJ, et al.  The microbial metagenome and bone tissue composition in mince with microbiome-induced reductions in bone strength.  Bone.  2019 Oct;127:146-54.

Modifications to the microbiome have been implicated in disease processes and influence bone.  This study looked at mice that had been given oral antibiotics and its effects on the gut microbiome.    The results showed that the vitamin K content of the cecum, liver and kidneys were decreased by 32-66%, and the microbial genes that synthesized menaquinones were modified, compared to untreated mice.  They concluded that menaquinones regulate bone quality. 

Jeong Y, Kim J-W, You HJ, Park S-J, Lee J, Ju JI, et al.  Gut microbial composition and function are altered in patients with early rheumatoid arthritis.  J Clin Med.  2019 May;8(5):693.

This study found that genes related to the biosynthesis of menaquinoe were enriched in healthy subjects, while iron transport-related genes were enriched in early RA patients.  The differences in the gut microbial diversity, taxa and associated functions of the gut microbiota between healthy subjects and early RA patients highlight the involvement of the gut microbiome in early stages of RA, and the possible role of vitamin K.

Li W, Zhang S, Liu J, Liu Y, Liang Q.  Vitamin K2 stimulates MC3T3-E1 osteoblast differentiation and mineralization through autophagy induction.  Mol Med Rep.  2019 May;19(5):3676-84.

Vitamin K2 likely exerts its protective effects during osteoporosis by promoting osteoblast differentiation and mineralization. This study verified that vitamin K2 can induce autophagy during the differentiation and mineralization of osteoblasts.  The study also confirmed the association between autophagy and osteoblast differentiation and mineralization.  

Nollet L, Van Gils M, Verschuere S, Vanakker O.  The role of vitamin K and its related compound sin Mendelian and Acquired Ectopic Mineralization disorders.  Int J Mol Sci.  2019 Apr 30;29(9):2142.

In this review, we highlighted the importance of deficient γ-carboxylation of several vitamin K-dependent proteins, in particular the potent calcification inhibitor, MGP, which has greatly contributed to a better understanding of the precise molecular mechanisms leading to the abnormal deposition of calcium crystals in connective tissues.  Further basic and clinical research into this subject is warranted, as only limited data exist today due to the rarity of these orphan diseases. 

Rangel LBA, de Siqueira D, Soares OR, Santana HS, Miguel EC, da Cunha M, et al.  Vitamin K supplementation modulates bone metabolism and ultra-structure of ovariectomized mice.  Cell Physiol Biochem.  2018;51:356-374.

Osteoporosis is a bone metabolic disease that affects mostly post-menopausal women.  This study looked at the beneficial role of vitamin K on ovarectomized mice.  They found that the vitamin K led to beneficial effects on bone ultrastructure, by altering osteoblastic function and secretion of organic bone matrix.  Additionally there was also amelioration of microfractures.

Su S, He N, Men P, Song C, Zhai S.  The efficacy and safety of menatetrenone in the management of osteoporosis: a systematic review and meta-analysis of randomized controlled trials.  Osteoporos Int.  2019;30(1175-86).

In our systematic review and meta-analysis, we comprehensively evaluated MK4 (menatetrenone) in the management of osteoporosis. We found that menatetrenone decreased the ratio of undercarboxylated osteocalcin to osteocalcin (ucOC/OC) and improved lumbar BMD compared with placebo based on the 18 studies assessed. However, its benefit in fracture risk control was uncertain.

Szmodis M, Bosnyak E, Protzner A, Szots G, Trajer E, Toth M.  Relationship between physical activity, dietaryintake and bone parameters in 10-12 years old Hungarian boys and girls.  Cent Eur J Public Health.  2019 Mar;27(1):10-16.

Physical activity and adequate macro and micronutrient intake have a favorable influence on bone status.  10-12 year old Hungrian children were studied for their physical activity, dietary intake, anthropomorphic data and ultrasound bone characteristics.  They found that favorable bone measures depended on intense physical activity, adequate vitamin K intake and variables related to age.

van Boolegooijen AJ, Pilz S, Tomaschitz A, Grubler MR, Verheyen N.  The synergistic interplay between vitamins D and K for bone and cardiovascular health:  A narrative review.  Int J Endocrin.  2017;2017:7454376.

This review summarized the available evidence of the synergistic interplay between vitamins D and K on bone and cardiovascular health.  Animal and human studies suggest that optimal concentrations of both are beneficial, and are supported by genetic, molecular, cellular, and human studies.

Weng S-J, Yan D-Y, Gu L-J, Chen L, Zie Z-J, Wu Z-Y, et al.  Combined treatment with vitamin K2 and PTH enhanced bone formation in ovariectomized rats and increased differentiation of osteoblast in vitro.  Chem Biol Interact.  2019 Feb;300:101-10.

Osteoporosis is accompanied by insufficient osteogenic capacity.  This study investigated the effect of combined treatment with vitamin K2 and PTH on bone formation in osteoporotic rats.  The results showed that the combination of vitamin K2 and PTH increased differentiation of osteoblasts and had a synergistic effect on bone formation.

Yuanyang G, Runlin X, Bo X et al.  Effect of vitamin K2 on bone mineral density and serum cathepsin in female osteoporosis patients.  Tropical Journal of Pharmaceutical Research.  2019;18(1):181-5.

In this study, 210 osteoporosis patients in China were randomly divided into a vitamin K2 group, a strongtium renelate group, and a control group.  After six months, the results showed that vitamin K2 increased bone density, promoted bone growth and inhibited bone fracture and was more effective than strontium.  They concluded that vitamin K was a safe, effective and suitable drug for treatment of osteoporosis in the elderly.

Capozzi A, Scambia G, Migliaccio S, Lello S.  Role of vitamin K2 in bone metabolism:  A point of view and a short reappraisal of the literature.  Gynecol Endocrinol.  2020 Apr;36(4):285-88.

Vitamin K2 has been recognized as efficacious and safe in treatment of bone loss, and preserving bone quality/strength.  Low vitamin K2 is linked to bone loss and increased fracture risk in both sexes.

Chin K-Y.  The relationship between vitamin K and osteoarthritis:  A review of current evidence.  Nutrients.  2020;12:1208.

This review collates the evidence on the relationship between vitamin K status and osteoarthritis.  The literature generally agrees that a sufficient level of vitamin K is associated with a lower risk of arthritis and pathological join features.  They concluded that sufficient dietary intake seems to protect the elderly from arthritis.

Giri TK, Newton D, Chaudhary O, Deych E, Napoli N, Villareal R, et al.  Maximal dose-response of vitamin -K2 (menaquinone-4) on undercarboxylated osteocalcin in women with osteoporosis.  Int J Vitamin Nutr. Res.  2020 Jan;90(1-2):42-48.

High levels of undercarboxylated osteocalcin and bone fractures accompany low levels of vitamin K.  This study assessed the improvement in carboxylation of osteocalcin in response to escalating doses of MK supplementation.  Postmenopausal women who had suffered hip or vertebral fractures, were given three doses for three weeks, each.  They found that supplementation with with either 5 or 45 mg/day of MK4 increased the carboxylation of osteocalcin to levels found in healthy women.

Kuang X, Liu C, Guo X, Li K, Deng Q, Li D.  The combination effect of vitamin K and vitamin D on human bone quality:  A meta-analysis of randomized controlled trials.  Food & Function.  2020;4:

A comprehensive review of the research literature was conducted, and the results indicate that vitamin K combined with vitamin D significantly increased the bone mineral density of subjects and significantly decreased undercarboxylated osteocalcin.

Sato T, Inaba N, Yamashita T.  M-7 and its effects on bone quality and strength.  Nutrients.  2020;12:965.

In this review, we comprehensively discuss the various properties of MK-7.  The current recommended daily intake (RDI) of vitamin K in most countries has been established based on normal coagulation requirements. Vitamin K1 and menaquinone (MK)-4 has been shown to decrease osteocalcin (OC) γ-carboxylation at RDI levels. Among the several vitamin K homologs, only MK-7 (vitamin K2) can promote γ-carboxylation of extrahepatic VKDPs, OC, and the matrix Gla protein at a nutritional dose around RDI. MK-7 has higher efficacy due to its higher bioavailability and longer half-life than other vitamin K homologs. As vitamin K1, MK-4, and MK-7 have distinct bioactivities, their RDIs should be established based on their relative activities. MK-7 increases bone mineral density and promotes bone quality and strength. Collagen production, and thus, bone quality may be affected by MK-7 or MK-4 converted from MK-7. 

Shea MK, Kritchevsky SB, Loeser RF, Booth SL.  Vitamin K status and mobility limitation and disability in older adults:  The Health, Aging, and Body Composition Study.  J Gerontol A Biol Sci Med Sci.  2020 Mar 9:75(4):792-797.

This study looked at the association between vitamin K status and incident mobility disability.  They found that participants with low vitamin K2 levels were more likely to develop mobility limitation and disability. They concluded that vitamin K may be involved in the disablement process in older age.

Schröder M, Riksen EA, He J, Skallerud BH, Møller ME, Lian A-M, Syversen U, et al.  Vitamin K2 modulates vitamin D-induced mechanical properties of human 3d bone spheroids in vitro.  JBMR Plus.  2020 Sep; 4(9): e10394.

Cell‐based bone models enable us to investigate the effect of different agents on the mechanical strength of bone. Low dietary intake of both vitamin D and K is negatively associated with fracture risk.  Both vitamins D and K play important roles in bone health; however, their combined effects on mechanical properties of 3D bone spheroids have, to our knowledge, not been studied before. Therefore, we wanted to investigate the in vitro effects of vitamin D and K, alone and in combination on the biomechanical properties of 3D bone spheroids.  Mechanical testing revealed that 25(OH)D₃ induced a stiffer and vitamin MK‐4 a softer or more flexible osteosphere compared with control. Still, based on our results, it can be hypothesized that combined administration of K2 and 25(OH)D₃ could contribute to stronger bone also in vivo.  These effects may translate to increased fracture resistance in vivo.

Zhang Y, Liu Z, Duan L, Ji Y, Yang S, Zhang Y, et al.  Effect of low-dose vitamin K2 supplementation on bone mineral density in middle-aged and elderly Chinese:  A randomized controlled study.  Calcif Tissue Int.  2020 May;106(5):476-85.

The aim of this study was to explore a low and effective dose of VK2 for improving BMD, and to examine whether the co-supplementation of VK2, calcium and vitamin D₃ would bring greater effects. In this trial, a total of 311 community-dwelling men and postmenopausal women aged 50 and 75 years were randomly assigned to four groups, receiving placebo, 50 µg/day, 90 µg/day or co-supplementation with calcium (500 mg/day) and vitamin D₃ (10 µg/day) for 1 year. VK2 supplementation in dose of 90 µg/day performed a significant effect on reducing bone loss in postmenopausal women, but the combination with calcium and vitamin D₃ brought no additional effects.

Written by RPT 1/2/13

"In life, in any given situation, one can either be a winner, a loser, or a victim. If you keep your nose clean, work hard, work smart, and pay attention, you will win far more than you lose - - - but every now and then you will lose - - - no worries - - - but what is unacceptable is being a victim. I chose not be a victim.” - Pat

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