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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.

Vitamin K and Bone

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.  Bone fulfills a number of essential functions.  It acts as a scaffold for muscle and other organs, allowing locomotion.  Bone is also an important reservoir for several minerals including calcium, phosphate, and magnesium (Murshed 2018; Whyte 2017).  And bone cells are involved in the maintenance of the hematopoietic stem cells (Asada et al, 2017; Roodman, 2017).

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).

Bone formation and development are most intense during childhood and adolescence.  The higher the bone mass acquired before the age of 20-25, the better prognosis for good bone health later in life as bone mass declines through adulthood.  By the age of 18 or 19, approximately 90% of peak bone mass is attained, without about 25% being acquired during the 2 year period surrounding peak height velocity of building bone mass (Bailey, 1997; Cashman, 2007).  Because of this, children have high needs for K vitamins (Koziol-Kozakowska & Maresz, 2022). 

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; Wein & Kronenberg, 2018).  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.  Bone remodeling is tightly linked to energy metabolism (Misra & Klibanski, 2011), and bone has come to be regarded as a bona fide endocrine organ. (Guntur & Rose, 2012; Mera et al, 2018).

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. Vitamin K2 possesses a rare capacity to stimulate bone formation while simultaneously suppressing bone resorption.  The studies by Yamaguchi (et al, 2011) suggest that vitamin K2 promotes bone formation and suppresses bone resorption by antagonizing basal and cytokine-induced activation of NF-κB. 

A detailed lab study of the effect of K1 and K2 on osteoblastic cells was recently conducted.  K1, MK4 and MK7 were administered at different concentrations, respectively for 3 days to an osteoblastic cell line.  The results indicated that all vitamin K species significantly increased cell proliferation, osteocalcin synthesis, phosphatase activity and calcium deposition in a dose-dependent manner.  MK4 and MK7 had more potent effects on calcium deposition that K1.  Warfarin only partly reduced the effects of MK4 and MK7, but abolished the induction activity of K1 on calcification, suggesting that K1 and K2 may have different mechanisms in stimulating osteoblast mineralization.  Also mRNA expression of osteoprotegerin and NF-kB, a transcription factor, was dramatically increased by K1 (62%), MK4 (247%) and MK7 (329%).  The results provide compelling evidence that K1 and K2 both promote bone health, likely through different pathways (Wu et al, 2019).

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.  

For a time, it was believed that supplementing with calcium would strengthen bones, however recent evidence suggests that calcium supplements increase the risk of cardiovascular disease (Reid, et al, 2011).   Thus, any potential benefit from a reduction in fracture risk may be canceled by the increase in cardiovascular risk, kidney stones, etc (Fusaro et al, 2012).

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; Palermo et al, 2017).  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 (Cosso & Falchetti, 2017).  These proteins include bone-Gla protein (BGP), matrix-Gla protein (MGP), protein S, Gla-rich protein (GRP) also known as UCMA, periostin, and periostin-like factor PLF (Price, et al., 1976: Luo et al, 1997; Rani, et al.  2009:  Price, et al.  1983;  Maillard, et al.  1992; Surmann-Schmitt et al, 2008; Coutu, et al, 2009; Bordolai et al, 2019). 

Periosteum is the tissue located at the outer surface of bone and is an essential player in the bone repair process, containing skeletal stem cells with high regenerative potential.  Periostin is a key matrix component of the periosteum (the surface of bone), and plays important roles through all stages of bone repair (Zhu et al, 2009; Cobo et al, 2016; Varughese et al, 2018; Duchamp de Legeneste et al, 2018; Duchamp de Lageneste & Colnot, 2019; Kudo, et al, 2919). Periostin levels are also associated with the incidence and progress of osteoarthritis in the knee (Rosseau, et al, 2015). 

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, and its level in the blood is closely related to bone building activity (Ducy et al, 1996).   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).

Osteocalcin was the first protein to be identified as bone specific.  It is synthesized by the bone-forming osteoblasts, and accumulates in the bone matrix bound to mineral (Hauschka et al, 1989). Osteocalcin is one of the most abundant matrix proteins found in bones and the only matrix protein synthesized exclusively there.  Serum osteocalcin is correlated with bone formation and osteoblast number and is used as a marker of bone formation. 

Additionally, vitamin K2 regulates bone metabolism through mechanisms not associated with OC activation (Bux & Szterk, 2021). MK-7 induces expression of alkaline phosphatase (ALP), Runx2 and Osterix in osteoblast precursor cells and also stimulates their differentiation into mineralizing osteoblasts. The opposite effect occurs in osteoclast precursor cells: vitamin K2 reduces cell differentiation, inhibiting osteoclasts, and bone resorption. The mechanism of this action is related to inhibition of cytokine-induced nuclear factor-kappa B (NF-κB) activation (Yamaguchi & Weitzman, 2011; Uchiyama et al, 2007). Moreover, vitamin K2, through the activation of pregnane X receptor (PXR or steroid and xenobiotic receptor SXR), regulates transcription of genes that encode extracellular matrix (ECM) proteins and therefore promotes collagen synthesis in osteoblasts (Azuma et al, 2014; Ichikawa et al, 2006).  

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.  For example, an increased diet of green leafy vegetables substantially increased blood levels of activated or carboxylated osteocalcin, which suggested increased entry of osteocalcin into the bone matrix, improvement of bone quality and a lowered fracture risk (Sim et al, 2020).  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 (Fusaro et al, 2017).  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; Tsugawa et al, 2008; Tanaka et al, 2011; Jaghsi, et al 2018; Moore et al, 2020).  Blood levels of uncarboxylated osteocalcin predicted future fractures in elderly people (Seibel et al, 1997; Vergnaud et al, 1997; Luukinen et al, 2000).   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).  Osteoarthritis is a chronic disabling joint disease that also increases in prevalence with age.  There can also be deterioration of cartilage, join space narrowing and other changes (Malemud, 2015).  There are no known therapies that can alter its progression or prevent its occurrence (Boer et al, 2021).  Vitamin K may represent a modifiable risk factor.  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).  Post-menopausal women with osteoporosis, taking bisphosphonates, and with a fracture had a significantly lower blood level of vitamin K1, compared to those without fractures.  The data showed a 50% reduction in fracture risk per micrograms/litre increase in serum levels of K1 (Moore et al, 2020).

When a woman goes through menopause, a sharp drop of estrogen levels can lead to more osteoclastogenesis, which can lead to an increase in bone resorption, the breakdown of bone metabolism balance and eventually osteoporosis (Ming et al, 2022).  Women with post-menopausal osteoporosis have more circulating activated T cells compared to healthy post-menopausal and pre-menopausal women (Adeel et al, 2013; D'Amelio et al, 2008).  T-cells are known to play a critical role in promoting bone loss in postmenopausal osteoporosis (Zhang et al, 2011).  Research has established that vitamin K2 can indeed suppress T-cell proliferation as part of its protective effect on bone health (Myneni et al, 2018).

Studies of people with osteoarthritis (of the bone) showed lower levels of carboxylated matrix Gla protein in the tissues with arthritis, then 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) (Silaghi et al, 2011; 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), and a positive regulator of bone formation (Zhang et al, 2019).  A recent study established that MGP plays an essential role in osteoclast differentiation and function.  When carboxylated and activated MGP was available, osteoclast development and bone loss was suppressed.  When MGP was depleted and not carboxylated bone resorption increased.  They authors concluded that taking vitamin K and having activated MGP could be a therapeutic target for low-bone-mass disorders (Zhang et al, 2019). 

Gla rich protein carries exceptionally higher number of Gla residues which contributes to its outstanding capacity of binding and modulating calcium (Surmann-Schmitt et al, 2008; Bordoloi et al, 2018).   Research has shown that GRP stimulates osteoblast differentiation and mineral nodule formation (Lee et al, 2015), and has a role in skeletal development. Only carboxylated GRP was found to inhibit calcification in arthritis like conditions (Cavaco et al, 2016).  GRP levels in synovial fluid were elevated in osteoarthritis patients and they positively correlated to disease stage (Okuyan et al, 2019).  When cats with experimental osteoarthritis were given knee joint injections of GRP, the cartilage degeneration was ameliorated (Okuyan et al, 2020).  The early findings suggest that GRP is a multifunctional VKDP that promotes osteoarthritis related bone response (Stock et al, 2017), controls ectopic calcification, promotes bone turnover, and is a potent protector of cartilage during osteoarthritis (Bugel, 2008; Rafael et al, 2014; Seuffert et al, 2018; Stock & Schett, 2021).   Only carboxylated GRP was found to inhibit calcification in arthritis like conditions (Cavaco et al, 2016), and due to the lack of effective treatment and prevention methods, fully carboxylated GRP by vitamin K supplementation is a convenient and inexpensive candidate for the treatment of osteoarthritis (Viegas et al, 2015; Xiao et al, 2021).

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. Research has shown that the required dietary vitamin K for bone is significantly higher in the elderly than those in younger people (Tsugawa et al, 2006).

A prevalence of vitamin K deficiency has been found to be higher in older patients with hip fractures, than without (Hao et al, 2017; Bultynck et al, 2020).  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).  Higher vitamin K intake was associated with decreased knee symptoms in people already diagnosed with knee osteoarthritis (Liao et al, 2022).

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).  Research shows that children are showing a poor vitamin K status, and markedly low levels of vitamin K in the bone during growth (van Summeran et al, 2007; van Summeran et al, 2008). And in children, inadequate vitamin K intake was correlated with negative bone parameters (Szmodis et al, 2019).  Hungarian researchers demonstrated that changes in bone mineral status among 10-12 year children, assessed by ultrasound, are correlated with the amount of intense physical activity as well as with optimal vitamin K intake (Szmodis et al, 2019).  Subclinical vitamin K and vitamin D deficiency is present in healthy children who incur low energy bone fractures (Karpiński et al, 2017; Popko et al, 2018).

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), and a reduced risk of hip fracture (Nakano et al, 2011; Torbergsen et al, 2015; Finnes et al, 2016).  The mechanism likely involves mutual enhancement and potentiation of each vitamin’s effects on osteocalcin.  Gigante (2021) demonstrated that vitamin D3 in association with MK7 was able to induce osteogenesis (bone growth).  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, or VKAs.  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 these consequences is brittle bones or osteoporosis, through the inhibition of bone cell differentiation (Booth and Mayer, 2000; Simon et al.  2002; Rezaieyazdi et al, 2009; Jeong et al, 2011). The use of warfarin has been associated with a 2-fold increased risk of osteoarthritis incidence and progression in members of the Rotterdam Study (Boer et al, 2021).  Long-term warfarin use in elderly subjects was linked to osteoporotic fractures and decreased bone density (Gage et al, 2006; Koos et al, 2005).

The decrease in carboxylated periostin is one of the main causes of bone density reduction (Verma et al, 2019). And this reduction in bone density can lead to an increase in bone fractures (Gage et al, 2006; Rousseau et al, 2014; Kim et al, 2015).

The 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). Non vitamin K antagonists are being explored for their effect on bone parameters (Rodriguez-Olleros et al, 2019).

As evidence of the negative consequences of warfarin treatment mounts, some researchers are recommending the use of vitamin K in conjunction with warfarin treatment (Stafford et al, 2007). When patients with unstable INRs were given a dose of 150 ug of vitamin K1 during a period of 6 months, the group had a more stable INR and was in the therapeutic range 87%  of the time, compared with 58% before a daily vitamin K supplement was prescribed (Sconce et al, 2007).

Bisphosphonates

Bisphonphonates are a widely prescribed medication for the treatment of osteoporosis.  They work by inhibiting bone resorption (Lyles et al, 2007). A low incidence of atypical femoral fractures (AFFs) have emerged as a potential complication of long term BP treatment (Schilcher et al, 2011), like due to an over-suppression of bone turnover (Kwek et al, 2008). In addition, the reduced bone turnover rate may lead to delayed bone healing at the fracture site in patients with osteoporosis (Park-Wyllie et al, 2011).  A case report describes a patient who had been on bisphosphonates for more than 10 years, and developed an AFF of the left femur.  He took MK4, 15 mg, three times a day.  Within four months he reported reduced pain and x rays showed fracture healing (Wang et al, 2021).

 

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.  Research of the vitamin K intake in Japanese adolescents indicated that the dietary requirement to meet the needs of bone health was approximately 500 ug/ per day (Tsugawa et al, 2012).

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 study of Scottish women showed a significant association between intake of vitamin K1 and bone mineral density and markers of bone resorption, where low levels of K1 were associated with significantly higher levels of resorption and bone loss (MacDonald et al, 2008).   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).  

Natto, a delicacy of fermented soybeans, is the richest dietary source of MK7 (Walther et al, 2013).  A large cohort study of female participants in the Japanese Population-based Osteoporosis (JPOS) Cohort study, were followed for an average of 15.2 years.  They were older than 45 years of age and in menopause.  The results showed that a higher natto intake was associated with a reduced risk of osteoporotic fractures, independent of classical risk factors (Kojima et al, 2019).

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).  In fact it was only after 3 years of supplementation that the benefits of MK7 positively affected bone health (Knapen et al, 2015).  This also suggests that short-term studies do not allow for long-term changes to emerge.

A group of Greek postmenopausal women were randomly assigned to one of three intervention groups, or a control group.  One group received a dairy product enriched with calcium, a second group received a dairy product with calcium, vitamin D3 and K1, and a third group received the dairy product enriched with either calcium, vitamin D3 and MK7.  They found that total Bone Mineral Density significantly increased in all three intervention groups and these changes were significantly higher compared to the control group.  Furthermore, the groups which received K1 and MK7 had significant increases well beyond the other two groups (Mochonis et al, 2011).  A follow up publication indicated that the two groups who received K1 and MK7 also showed the most improvement in measures of bone metabolism and bone mass markers (Kenellakis et al, 2012).

A meta-analysis of vitamin K2 found that it prevented fractures in postmenopausal women with osteoporosis (Huang et al, 2015). 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).  A 2 year study conducted in postmenopausal women affected by osteopenia showed that women receiving MK7 and vitamin D3 showed an increased BMD at 6 months (Ushiroyama et al, 2002).

Elderly Japanese men with habitual intake of natto, which is high in MK-7, were found have significantly higher BMD at the hip and the femoral neck (Fujita et al, 2012). 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.  An analysis of research over the years shows that supplementation of vitamin K improves the skeletal system condition by decreasing bone loss and by protecting against fractures (Hao et al, 2017).  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).  Koshihara (et al, 2003) showed that both MK4 and K1 stimulate osteoblastogenesis (bone cell growth) in bone marrow cells and regulate osteoclastogenesis.  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).  When 45 mg of MK4 along with calcium carbonate were given for 48 weeks, the postmenopausal women showed a significant improvement in lumbar BMD (Purwosunu et al, 2006).  Doses of 45 mg of MK-4 led to a significant increase in femoral neck width at 3 years (Knapen et al, 2012).

A recent review highlighted the challenges of comparing all the research (Mott et al, 2019).  And a different review found that the research supports a clinically significant effect on clinical and vertebral fractures, and that vitamin K2 displayed a major role in bone formation, and that long term use with high dose intake was most beneficial (Ahmad et al, 2022).

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 improved lumbar BMD when compared with placebo (Su, et al 2019; Zhou et al, 2022).  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).  One study compared groups of postmenopausal patients with osteoporosis.  One group received calcium asparate daily while the other group received 45 mg of MK4 daily for six months.  They found significant improvements in the MK4 group for bone turnover markers and on the secretion and activation of osteocalcin (Shiraki & Itabashi, 2009).  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 2 year study followed a cohort of 200 people, average age 67 years, who consumed a traditionally healthy Mediterranean diet rich in vitamin K.  Analysis of bone healthy using QUS assessment (Qualitative UltraSound) revealed significant correlations between higher K1 intake and superior bone quality properties, lower losses of bone mineral density, and smaller increases in the porosity and elasticity attributed to aging.  The authors noted “Since the participants in this analysis already ate a healthy diet rich in K1, even more beneficial effects may be seen in populations with a lower intake of vitamin K or poor nutrition (Bullo et al, 2011).  A meta-analysis of the efficacy of MK4 showed it was effective in the prevention and treatment of postmenopausal osteoporosis and that it improves the lumbar spine bone mineral density, and that it is likely due to the activation of osteocalcin which promotes bone mineralization and increases bone strength (Ming et al, 2022). 

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).   A later study found that MK7 given for 12 months preserved the trabecular bone structure in post menopausal women, while the control group had declining bone architecture (Rønn et al, 2016). A meta-analysis of vitamin K2 found that it prevented fractures in postmenopausal women with osteoporosis (Huang et al, 2015). 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).

Multiple pathways within bone are vitamin K dependent. The medication glucocorticoid has been widely used for the treatment of rheumatic, auto-immune and hematopoietic system diseases.  However, it is one of the most common causes of osteonecrosis of the femoral head, and the risk increases with higher doses and prolonged treatment. Patients treated with glucocorticoids and K2 did not show a decrease in bone density after 1 year, whereas the patients without K2 treatment had a significant decreased in bone density (Sasaki et al, 2005).  Glucocorticoids can harm endothelial cells and impair blood vessel functioning, as well as decreased the bone repair process.  Osteoporosis is considered a complication of chronic childhood illnesses cured with steroids (Ward, 2005, Aljebab et al, 2017).  A clinical study reported increased fracture risk in children who require more than forces of steroids, as its effects on born formation are more pronounced in a growing skeleton (Leonard, 2007). Japanese researchers found that vitamin K2 might be effective to prevent bone fracture in glucocorticoid-induced osteoporosis (Tanaka et al, 2007). 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.  The same research group showed that vitamin K2 was an effective antagonist for glucocorticoid induced osteonecrosis of the femoral head in rats, preventing the necrosis  and protecting the blood supply to the area (Zhang et al, 2016).  Additionally, the K2 increased bone marrow stem cell proliferation, which would lead to an increase in mature osteoblasts or bone building cells.

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 rheumatoid 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.

70 patients with rheumatoid arthritis were given 45 milligrams daily of MK4 for three months.  Disease markers of C-reactive protein (CRP), matrix metalloproteinease-3 (MMP-3), and the Disease Activity Score (DAS) were evaluated.  The patients who received MK4 had significantly reduced disease activity, as measured by CRP, MMP-3 and DAS.  Additionally, they showed lower doses and less need for prednisolone (steroid) treatment (Ebina et al, 2013).

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).

In a lab study of the differentiation of pluripotent stem cells into osteoblasts, MK7 was found to increase the expression of osteogenic markers, and improved osteoblast phenotypes.  When the stem cells were supplemented with M7, the expression of osteogenic markers increased, meaning a variety of bone growth markers improved.  The stem cells that did not receive MK7 did not show the improved bone markers (Akbulut et al, 2021).

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 (Amizuka et al, 2008).
 

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.

This study measured the serum levels of K1, MK7 and Mk8 in a group of 51 women within a few hours after a hip fracture.  Patients with hip fracture had a marked reduction in all three types of vitamin K, and a large number had undetectable levels.  The data suggested that patients with hip fracture have a vitamin K deficiency.


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. 

Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, et al.  Increased bone formation in osteocalcin-deficient mice.  Nature.  1996 Aug;382:448-452.

The molecular determinants of osteoblast activity are unknown.  This study investigated the role of osteocalcin, the most abundant osteoblast-specific non-collagenous protein.  They generated osteocalcin-deficient mice and showed that the absence of osteocalcin leads to an increase in bone formation without impairing bone resorption.

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. 

Baily DA.  The Saskatchewan paediatric bone mineral accrual study:  bone mineral acquisition during the growing years.  Int J Sports Med.  1997;18:191-94.


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. 

Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, et al.  Spontaneous calcification of arteries and cartilage in mice lacking matrix Gla protein.  Nature.  197 Mar;386(6):78-81.

Physiological calcification occurs in bone when the soft extracellular matrix is converted into a rigid material capable of sustaining mechanical force: Matrix Gla protein is identified as the first inhibitor of calcification of arteries and cartilage.  Matrix Gla protein binds minerals and mineral ions through gamma carboxylated glutamic acid residues, meaning sufficient vitamin K was present.


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. 

Seibel MJ, Robins SP, Bilezikian JP.  Serum undercarboxylated osteocalcin and the risk of hip fracture.  J Clin Endocrinol Metab.  1997;18:717-718.


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).


Nakamura YS, Hakeda Y, Takakura N, Kameda T, Hamaguchi I, Miyamoto T, et al.  Tyro 3 receptor tyrosine kinase and its ligand, Gas6, stimulate the function of osteoclasts.  Stem Cells.  1998;16:229-238.

 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.  2nd 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 MTGagnon DRCupples 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. 

Ushiroyama T, Ikeda A, Ueki M.  Effect of continuous combined therapy with vitamin K(2) and vitamin D(3) on bone mineral density and coagulofibrinolysis function in postmenopausal women.  Maturitas.  2002;41:211-21.


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 FHamulyák KGerichhausen 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.

Koshihara Y, Hoshi K, Okawara R, Ishibashi H, Yamamoto S.  Vitamin K stimulates osteoblastogenesi sand inhibits osteoclastogenesis in human bone marrow cell culture.  J Endocrinol.  2003;176(3):339-48.

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. 

Miki T, Nakatsuka K, Naka H, Kitatani K, Saito S, Masaki H, et al.  Vitamin K(2) (menaquinone-4) reduces serum undercarboxylated osteocalcin level as early as 2 weeks in elderly women with established osteoporosis.  J Bone Miner Metab.  2003;21:161-5.

Twenty elderly osteoporotic women with vertebral fracture(s) were randomly allocated to two groups; women in the MK(4) group received calcium with menaquinone 4 (MK(4)) at a dose of 45 mg/day for 2 weeks, and women in the control group received calcium alone for the same period. Serum intact osteocalcin (OC) and undercarboxylated osteocalcin (uc-OC) levels were measured at baseline and on the 7th and 14th days following the start of the treatment. There were no differences in the baseline data including age, weight, phylloquinone, menaquinone 4, menaquinone 7, OC, and uc-OC levels between the MK(4) group and the control group. Administration of MK(4) significantly raised the MK(4) level and reduced serum uc-OC levels.  No significant changes in these levels were observed in the control group. Serum OC levels were stable during the period in both groups. In this randomized prospective study, the MK(4) group shows a reduction in the serum uc-OC level within 2 weeks without any significant change in OC, suggesting that the uc-OC is changed to carboxylated OC. This early effect of MK(4) on bone metabolism may be estimated by the measurement of serum uc-OC in elderly osteoporotic women with vertebral fractures.


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. 

Koos R, Mahnken Ah, Mullenbruch G, et al.  Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography.  Am J Cardiol.  2005;96:747-749.

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.

Ward LM, Osteoporosis due to Glucocorticoid use in children with chronic illness.  Horm Res Paediatr.  2005;64;209-21.


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. 

Purwosunu Y,Muharram, Rachman, IA, Reksoprodjo S, Sekizawa A.  Vitamin K2 treatment for postmenopausal osteoporosis in Indonesia.  J Obstet Gynaecol Res.  2006 Apr;32(2):230-234. 

A double-blind, randomized, placebo-controlled study of 63 postmenopausal women with osteoporosis were given 45 mg of mk4 and 1500 mg calcium carbonate per day.  The control received just the calcium carbonate per day for 48 weeks.  The group who received the MK4 showed a significantly higher change in lumbar bone mineral density and a significant decrease in undercarboxylated OC levels.


Rejnmark, L, Vertergaard P, Charles P,
Hermann APBrot CEiken 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. 

Sasaki N, Kusano E, Takahashi H, et al.  Vitamin K2 inhibits glucocorticoid-induced bone loss partly by preventing the reduction of osteoprotegerin (OPG).  J Bone Miner Metab. 2006;23:41-47.

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. 

Cashman KD.  Diet, nutrition and bone health.  J Nutr.  2007;137:2507-12.

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. 

Leonard MB, Glucocorticoid-induced osteoporosis in children:  impact of the underlying disease.  Pedatrics. 2007;119:S166-174.

Lyles KW, Colon-Emeric CS, magazine JS et al.  Zoledronic acid and clinical fractures and mortality after hip fracture.  NEJM.  2007;357:1799-1809.


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. 

Stafford DW, Roberts HR, Vermeer C.  Vitamin K supplementation during oral anticoagulation.  Concerns.  Blood.  2007;109:3607.

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

Tanaka I, Oshima H.  Vitamin K2 as a potential therapeutic agent for clucocorticoiod-induced osteoporosis.  Clin Calcium.  2007;17.


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. 

Uchiyama S, Yamaguchi M. Anabolic Effect of β-Cryptoxanthin in Osteoblastic MC3T3-E1 Cells Is Enhanced with 17β-Estradiol, Genistein, or Zinc Sulfate in Vitro: The Unique Effect with Zinc on Runx2 and A1(I) Collagen MRNA Expressions. Mol Cel Biochem. 2007;307:209–219.

van Summeran M, Braam L, Noirt F, Kuis W, Vermeer C.  Pronounced elevation of undercarboxylated osteocalcin in healthy children.  Pediatr Res.  2007;61:366-70.

Amizuka N, Li M, Kobayashi M, Hara K, Akahane S, Takeuchi K, et al.  Vitamin k2, a gamma-carboxylating factor of gla-proteins, normalizes the bone crystal nucleation impaired by Mg-insufficiency.  Histol Histopathol.  2008 Nov;23(11):1353-66.

Magnesium intake is correlated with bone mineral density, and a risk factor for bone frailty. Magnesium deficient rats develop bones that are fragile under mechanical loading, despite high BMD values, due to accelerated resorption and abnormal mineralization of collagen.  This study found that MK4 rescued the bone strength, in part by inhibiting accelerated bone resorption provoked by Mg insufficiency and by normalizing collagen mineralization.


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. 

Kwek EB, Goh SK, Koh JS et al.  An emerging pattern of subtrochanteric stress fractures:  a long-term complication of alendronate therapy?  Injury.  2008;39:224-31.

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.   

Macdonald HM, McGuigan FE, Lanham-New SA, Fraser WD, Ralston SH, Reid DM.  Vitamin K1 intake is associated with higher bone mineral density and reduced bone resorption in early postmenopausal Scottish women:  no evidence of gene-nutrient interaction with apolipoprotein E polymorphism.  Am J Clin Nutr.  2008 May;87(5):1513-20.

This study investigated the relation between dietary vitamin K1 intake, APOE polymorphisms, and markers of bone health in a cohort of Scottish women aged 49 –54 y in 1990 –1994 (baseline) and in 1997–2000 (visit 2). At visit 2, bone markers were measured, 3199 women completed a food-frequency questionnaire, and 2721 women were genotyped for APOE. They found that vitamin K1 intake was associated with markers of bone health, but no interaction was observed with APOE alleles on BMD or markers of bone turnover.

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.

Pizzorno L.  Vitamin K: beyond coagulation to uses in bone, vascular and anti-cancer metabolism.  IMCJ.  2008 Apr;7(2):24-30.

High levels of ucOC increase fracture risk, postmenopausal women with high ucOC have been found to have a 6-fold increased risk of hip fracture.

Surmann-Schmitt, C, Dietz U, Kireva T, Adam N, Park J, Tagariello A, et al.  Ucma, a novel secreted cartilage-specific protein with implications in osteogenesis.  J Biol Chem.  2008;283:7082-7093.

Tsugawa N, Shiraki M, Suhara Y, Kamao M, Ozaki R, Tanaka K, et al.  Low plasma phylloquinone concentration is associated with high incidence of vertebral fracture in Japanese women.  J Bone Min Metab.  2008;26:79-85.

The results of a three year study showed that subjects with low plasma vitamin K concentrations had significantly higher susceptibility for vertebral fractures, independent of their bone mineral density, compared to a high vitamin K1 group.

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. 

Rezaieyazdi Z, Falsoleiman H, Khajehdaluee M, Saghafi M, Mokhtari-Amirmajdi H, et al.  Reduced bone density in patients on long-term warfarin.  Int J Rheum Dis.  2009;12:130-135.

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. 

 
Shiraki M, Itabashi A.  Short-term menatetrenone therapy increases gamma-carboxylation of osteocalcin with a moderate increase of bone turnover in postmenopausal osteoporosis:  a randomized prospective study.  J Bone Miner Metab.  2009;27:333-340.

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 CThe 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.

Zhu S, Barbe MF, Liu C, Hadjiargyrou M, Popoff SN, Rani S, et al.  Periotin-like-factor in osteogenesis.  J Ce.. Physiol. 2009;218:584-592.

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.  

Bulló M, Estruch R, Salas-Salvadó J.  Dietary vitamin K intake is associated with bone quantitative ultrasound measurements but not with bone peripheral biochemical markers in elderly men and women.  Bone.  2011 Jun;48(6):1313-8.

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.

Falcone TD, Kim SSW, Cortazzo MH.  Vitamin K:  fractur eprevention and beyond.  PM&R.  2011;3:iss6S.

Increasing the dietary intake of vitamin K may have substantial utility in the prevention of disease. Based on a review of the literature, it appears advantageous to encourage patient sto eat a diet rich in vitamin K, and to convey the benefit of vitamin K supplementation.

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 warfarin 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.

Moschonis G, Kanellakis S, Papaionnou N, Schaafsma A, Manios Y.  Possible site-specific effect of an intervention combining nutrition and lifestyle counseling with consumption of fortified dairy products on bone mass:  the Postmenopausal Health Study II.  J Bone Miner Metab.  2011 Jul;29(4):501-6.

The aim of the present study was to examine whether a holistic approach combining nutrition and lifestyle counselling with the consumption of milk and yoghurt enriched with calcium, vitamin D(3) and phylloquinone (vitamin K(1)) or menaquinone (vitamin K(2)) would have any additional benefit on bone mineral density (BMD) indices measured at various skeletal sites using two different techniques, dual energy X-ray absorptiometry and quantitative ultrasonography (QUS). A sample of 115 postmenopausal women were randomized to three intervention groups, receiving daily via fortified milk and yoghurt and for 12 months, 800 mg calcium and 10 μg vitamin D(3), 800 mg calcium, 10 μg vitamin D(3) and 100 μg vitamin K(1), or 800 mg calcium, 10 μg vitamin D(3) and 100 μg vitamin K(2) and a control group. All three intervention groups attended biweekly nutrition and lifestyle counseling sessions. Total BMD significantly increased in all three intervention groups and these changes were significantly higher compared to the control group.  Furthermore, the significant increases observed for L2-L4 BMD in the groups who received vitamin K, were found to be significantly higher compared to the decrease observed in the CO (P = 0.001).

Nakano T, Tsugawa N, Kuwabara A, Kamao M, Tanaka K, Okano T.  High prevalence of hypovitaminosis D and K in patients with hip fracture.  Asia Pac J Clin Nutr.  2011;20:56-61.

Park-Wyllie LY, Mamdani MM, Jurrlink DN et al.  Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women.  JAMA. 2011;305:783-89.

Reid IR, Bolland MJ, Avenell A, Grey A.  Cardiovascular effects of calcium supplementation.  Osteoporos Int.  2011;22(6):1649-1658.

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.

Schilcher J, Michaelsson K, Aspenberg P.  Bisphosphonate use and atypical fractures of the femoral shaft.  NEJM.  2011;364:1728-37.

Silaghi CN, Fodor D, Cristea V, Craciun AM.  Synovial and serum levels of uncarboxylated matrix Gla-protein (ucMGP) in patients with arthritis.  Clin Chem Lab Med 2011;49:1-4.

Arthritis is defined by inflammation, cartilage and bone destruction/ formation and articular calcifications. Our objectives were to evaluate ucMGP levels in synovial fluid (SF) in arthritis patients and to investigate the relationship between local and circulating ucMGP and their association with age and inflammation.  Patients were divided into inflammatory and non-inflammatory groups.  They found that the inflammatory group had the lowest ucMGP serum levels and the highest levels of ucMGP in synovial fluid.  They concluded that the ucMGP (uncarboxylated matrix Gla protein) can serve as a join inflammatory marker in arthritis patients.


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.

Yamaguchi M, Weitzmann MN.  Vitamin K2 stimulates osteoblastogenesis and suppresses osteoclastogenesis by suppressing NF-xB activation.  Int J Mol Med.  2011 Jan;27(1):3-14.

Vitamin K has been associated with bone protective activities and are receiving intense interest as nutritional supplements for the prevention or amelioration of bone disease in humans.  This study looked at the mechanisms of vitamin K action on bone and found that vitamin K2 moderated the receptor activator NF-kB (RANK) ligand and activated the activation of osteoclast precursors.  NF-κB is a critical pathway for osteoclast development, function, and survival, meaning that vitamin K2 suppressed it, and ameliorated bone loss.


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. 

Fusaro M, Crepaldi G, Miozzo D, Gravellone L, Gallieni M.  Effects of vitamin K intake on gamma-carboxylated proteins, bone fractures, and vascular calcifications.  Osteoporosis Int.  2012;23:1637-1638.

Adequate levels of vitamin K2 in circulation could favor a better handling of serum calcium to maintain both bone and vessel health.

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.   

Guntur AR, Rosen CJ.  Bone as an endocrine organ.  Endocrine practice:official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.  2012;18:758-762.

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 Osteoporosis2012;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.

Tanaka S, Narusaw K, Onishi H, Miura M, Hijioka A, Kanazawa Y, et al.  Lower osteocalcin and osteopontin contents of the femoral head in hip fracture patients than osteoarthritis patients.  Osteoporos Int.  2011;22:587-597.

This study looked at risk factors for fractures related to bone quality. They found that low level sof osteopontin and osteocalcin in the bone promoted vulnerability to hip fractures.

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. 

Tsugawa N, Ueinishi K, Ishida H, Minekami T, Doi A, Koike S, et al.  A novel method based on curvature analysis for estimating the dietary vitamin K requirement in adolescents.  Clin Nutr.  2012;31:255-60.

This study established a novel method for estimating the vitamin K status in adolescents, using the serum concentration s of undercarboxylated osteocalcin, a sensitive biomarker of vitamin K status in the bone.  It was also compared to vitamin K concentrations required for good bone health and for normal blood coagulation.  They showed that bone metabolism requires significantly more vitamin K than blood coagulation.

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. 

Ebina K, Shi K, Hirao M, Kaneshiro S, Morimoto T, Koizumi K, et al.  Vitamin K2 administration is associated with decreased disease activity in patients with rheumatoid arthritis.  Mod Rheumatol.  2013;23:1001-1007.

RA patients were treated with a high dose of 45 mg of MK4 for three months.  Several markers of RA, such as CRP, MMP-3 and Disease Activity scores all were lowered, and they required less prednisolone (steroid) treatment.

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.

Walther B, Karl JP, Booth SL, Boyaval P.  Menaquinones, bacteria, and the food supply:  the relevance of dairy and fermented food products to vitamin K requirements.  Adv Nutr.  2013;4:463-73.

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.

Rousseau JC, Sornay-Rendu E, Bertholon C, chapuriat R, Garnero P.  Serum periostin is associated with fracture risk in postmenopausal women:  A 7-year prospective analysis of the OFELY study.  J Clin Endocrinol Metab.  2014;99:2533-2539.

In a cohort of 607 postmenopausal women from France that were followed up for 7 years, a positive correlation between serum periostin and fracture risk was observed.  Periostin was an independent predictive marker of fracture risk.

 

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.

 

Huang Z-B, Wan S-L, Lu Y-J, Ning L, Liu C, Fan S-W.  Does vitamin K2 play a role in the prevention and treatment of osteoporosis for postmenopausal women:  a meta-analysis of randomized controlled trials.  Osteoporos Int.  2015;26:1175-1186.

This meta-analysis supported the hypothesis that vitamin K2 plays a role in the maintenance and improvement of vertebral BMD and the prevention of fractures in postmenopausal woth with osteoporosis. 

Gigante A,  Brugè F, Cecconi S, Manzotti S, Littarru GP, Tiano L.  Vitamin MK-7 enhances vitamin D3-induced osteogenesis in hMSCs: modulation of key effectors in mineralization and vascularization.  J Tissue Eng Regen Med.  2015 Jun:9(6):691-701.

The aim of this work was to evaluate the effects of vitamin MK-7, alone or in association with vitamin D3, in differentiating human Mesenchymal stem cells (hMSCs) in vitro.In particular, primary endpoints of the study include gene and protein markers of osteoblast differentiation. Considering genes involved in bone formation and mineralization, our data show that vitamin MK-7 enhances vitamin D3 gene induction of osteocalcin (OC). These results stress the relevance of MK-7 and D3 co-supplementation in the bone-healing process as able to modulate the expression of genes involved in both mineralization and angiogenesis. 


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. 

Lee YJ, Park SY, Lee SJ, Boo YC, Choi JY, Kim JE.  Ucma, a direct transcriptional target of Runx2 and Osterix, promotes osteoblast differentiation and nodule formation.  Osteoarthr. Cartil.  2015;23:1421-1431.

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. 

Kim BJ, Rhee Y, Kim CH, Baek KH, Min YK, Kim DY, et al.  Plasma periostin associates significantly with non-vertebral but not vertebral fractures in post-menopausal women:  Clinical evidence for the different effects of periostin depending on the skeletal site.  Bone.  2015;81:435-441.

Rousseau JC, Sornay-Rendu E, Bertholon C, Garnero P, Chapurlat R.  Serum periostin is associated with prevalent knee osteoarthritis and disease incidence/progression in women:  the OFELY study.  Osteoarthritis Cartilage.  2015 Oct;23(10):1736-42.

We show for the first time that serum POSTN is associated with prevalence and the risk of development/progression of knee OA in women.

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.

Viegas CSB, Rafael M, Enriquez JL, Teixeira A, Vitorino R, Luis IM et al.  Gla-rich protein (GRP) acts as a calcification inhibitor in the human cardiovascular system.  Arteriorscler Thromb Vasc Biol.  2015;35:399-408.

Calcification related chronic inflammatory disease are multifactorial pathological processes, involving a complex interplay between inflammation and calcification events in a positive feed-back loop driving disease progression. Gla-rich protein is a vitamin K dependent protein shown to function as a calcification inhibitor in cardiovascular and articular tissues.  This study indicated that carboxylated GRP was an endogenous mediator of inflammatory responses, and a participant in the immune system.

Bonnet N, Garnero P, Ferrari S.  Periostin action in bone.  Mol Cell Endocrinol.  2016;432:75-82.

Preliminary clinical data suggest that serum periostin could become a useful biomarker for the investigation of metabolic bone diseases such as osteoporosis and joint inflammatory and non-inflammatory disorders.

Cavaco S, Viegas CS, Rafael MS, Ramos A, Magalhaes J,  Blanco FJ, et al.  Gla-rich protein is involved in the cross-talk between calcification and inflammation in osteoarthritis.  Cell Mol Life Sci.  CMLS 2016;73:1051-1065. 

Cobo T, Viloria CG, Solares L, Frontanil T, Gonzalez-Chamorro E, et al.  Role of periostin in adhesion and migration of bone remodeling cells.  PLoS One.  2016;11:e0147837.

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. 

Finnes TE, Lofthus CM, Meyer HE, Søgaard AJ, Tell GS, Apalset EM, et al.  A combination of low serum concentrations of vitamins K1 and D is associated with increased risk of hiop fractures in elderly Norwegians:  a NOREPOS study.  Osteo Int.  2016;27:1645-1652.  

This study showed that the combination of low concentrations of both vitamin D and K1  provides a significant risk factor for hip fractures.

Rønn SH, Harsløf T, Pedersen SB, Langdahl BL. Vitamin K2 (menaquinone-7) prevents age-related deterioration of trabecular bone microarchitecture at the tibia in postmenopausal women.  European J of Endocrin.  2016;175:541-549.

Clinical studies suggest that vitamin K2 protects against bone loss and fractures; however, its effect on bone quality has never been investigated. We investigated the effect of vitamin MK-7 on undercarboxylated osteocalcin (ucOC), and bone mass and quality.  They investigated the effect of MK-7 375 µg for 12 months on bone mineral density (BMD) measured by dual X-ray absorptiometry (DXA), bone microarchitecture measured by high-resolution peripheral quantitative computed tomography (HRpQCT) and biochemical bone turnover markers in 148 postmenopausal women with osteopenia. All of them were supplemented with calcium and vitamin D.  They found that changes in bone microarchitecture in the placebo group are consistent with the age-related deterioration of trabecular structure, with a loss of trabeculae and a greater mean thickness of the remaining trabeculae. This suggests that vitamin MK-7 preserves trabecular bone structure at the tibia.

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.

Glucocorticoid medication is one of the most common causes of atraumatic osteonecrosis of the femoral head and K2 has been shown to play a beneficial role in bone metabolism.  This study looked at whteher K2 could decrease the incidence of osteonecrosis.They found that K2 was an effective antagonist for glucocorticoid, contributing to the prevention of glucocorticoid induced necrosis in bones of rats.  

Aljebab F, Choonara I, Conroy S.  Systematic review of the toxicity of long course oral corticosteroids in children.  PLoS ONE.  2017;12:e0170259.

Asada N, Takeishi S, Frenette PS.  Complexity of bone marrow hematopoietic stem cell niche.  Int J Hematol.  2017 Jul;106(1):45-54.

Cosso R, Falchetti A.  Vitamin K and bone metabolism:  the myth and the truth.  Expert Review of Precision Medicine and Drug Development:  2017 May;70_57-71.

The existence and importance of vitamin K have been confirmed.  This review aims to explore the possible and hypothetical pathophysiological roles that VK molecules may have in bone health and metabolism, tracing a distinction between what has been assessed from what is still to be better defined.

Fusaro M, Mereu MC, Aghi A, Iervasi G, Gallieni M.  Vitamin K and bone.  Clin Cases Miner. Bone Metab.  2017;14, 200-206. See if have in bone folder

Vascular calcification is one of the strongest predictors of cardiovascular risk in chronic kidney disease patients.  New diagnostic/prognostic tools are required for early detection of calcification for treatment purposes.  GRP is a cardiovascular calcification inhibitor.  This study established correlations between levels of GRP in serum with CKD stage, in diabetic patients with CKD, with levels of GRP declining as kidney disease advanced, and correlating with markers of calcification. 

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. 

Hao G, Zhang B, Gu M, Chen C, Zhang Q, Zhang G, et al.  Vitamin K intake and the risk of fractures.  A meta-analysis.  Medicine.  2017;96:17(e6725).

In a meta-analysis of cohort or nested case-control studies they found that higher dietary vitamin K intake may moderately decrease the risk of fractures. 

Karpiński MP, Popko J, Maresa K, Badmaev V, Stohs SJ.  Roles of vitamins D and K, nutrition, and lifestyle in low-energy bone fractures in children and young adults.  J Am Coll Nutr.  2017;36:399-412.

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.

Palermo A, Tuccinardi D, D’Onofrio L, Watanabe M, Maggi D, Maurizi AR, et al.  Vitamin K and osteoporosis:  myth or reality.  Metabolism.  2017 May;70:57-71.

Aside from its established role in blood clotting, several studies now support a critical function of vitamin K in improving bone health. Vitamin K is in fact required for osteocalcin carboxylation that in turn regulates bone mineral accretion; it seems to promote the transition of osteoblasts to osteocytes and also limits the process of osteoclastogenesis. Several observational and interventional studies have examined the relationship between vitamin K and bone metabolism, but findings are conflicting and unclear. This systematic review aims to investigate the impact of vitamin K (plasma levels, dietary intake, and oral supplementation) on bone health with a particular interest in bone remodeling, mineral density and fragility fractures.

Roodman DGDG. Multiple myeloma and bone. Cold Spring Harb Perspect Med. 2017;10.1101/cshperspect.a031286. 


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.

Stock M, Menges S, Eitzinger N, Geßlein M, Botschner R, Wormser L, et al.  A dual role of upper zone of growth plate and cartilage matrix-associated protein in human and mouse osteoarthritic cartilage.  Arthritis Rheumatol.  2017;69:1233-1245.

This study looked at the role of UCMA in osteoarthritis-related cartilage and bone changes.  Our findings show that UCMA supports, on the one hand, the integrity of the articular cartilage by controlling aggrecanase activity, while on the other hand, it promotes osteoarthritis-related bone responses.

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.


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. 

Bordoloi J, Dihingia A, Kalita J, Manna P.  Implication of a novel vitamin K dependent protein GRP/Ucma in the pathophysiological conditions associated with vascular and soft tissue calcification, osteoarthritis, inflammation, and carcinoma.  Int J Biol Macromol.  2018 Jul;113:309-316.

Recent studies demonstrated a critical function of GRP in the regulation of different pathophysiological conditions associated with vascular and soft tissue calcification including cardiovascular diseases, osteoarthritis, inflammation, and skin and breast carcinomas. These findings established an important relationship between γ-carboxylation of GRP and calcification associated disease pathology suggesting a critical role of vitamin K in the pathophysiological features of various health disorders. This review for the first time summarizes all of the updated findings related to the functional activities of GRP in the pathogenesis of several diseases associated with vascular and soft tissue mineralization, osteoarthritis, inflammation, and carcinoma.

Duchamp de Legeneste O, Julien A, Abou-Khalil R, Frangi G, Carvalho C, Cagnard N, et al.  Perosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin.  Nat Commun.  2018;9:773.

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.

Myneni VD, Mezey E.  Immunomodulatory effect of vitamin K2:   implications for bone heatlh.  Oral Dis.  2018;24:67-71. 

Popko J, Karpinski M, Chojnowska S, Maresz K, Mileski KR, Badmaev V, et al.  Decreased levels of circulating carboxylated osteocalcin in children with low energy fractures:  a pilot study.  Nutrients.  2018;10:734.

The aim of the current study was to evaluate vitamin D and K status in children with low-energy fractures and in children without fractures.  The study group of 20 children (14 boys, 6 girls) aged 5 to 15 years old, with radiologically confirmed low-energy fractures was compared with the control group of 19 healthy children (9 boys, 10 girls), aged 7 to 17 years old, without fractures. There were no significant differences in the serum calcium, total vitamin D levels, and other measures of bone health between the two groups.  However, that a significant difference in the ratio of uncarboxylated osteocalcin to carboxylated osteocalcin (UCR).  The median UCR in the fracture group was 0.47 compared with a control group value of 0.245, making an increased risk of fractures by 78.3 times more likely in the group love in K status.  They concluded that vitamin K levels as measured by osteocalcin was positively and significantly correlated with lower rates of low-energy fracture incidence.

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.

Seuffert F, Weidner D, Baum W, Schett G, Stock M.  Upper zone of growth plate and cartilage matrix associated protein protects cartilage during inflammatory arthritis.  Arthritis Res Ther.  2018;20:88.

This study identifies the cartilage-derived protein Ucma as a protective factor for cartilage loss in the context of inflammatory arthritis. Ucma represents a cartilage-derived factor with regulatory functions and the potential to limit cartilage degradation during inflammatory arthritis. In conjunction with anti-inflammatory treatment, Ucma treatment could therefore allow a better protection of the articular cartilage in arthritis.

Varughese R, Semprini R, Munro C, Fingleton J, Holweg C, Weatherall M, et al.  Serum periostin levels following small bone fractures, long bone fractures and joint replacements.  An observational study.  Allergy Asthma Clin Immunol.  2018;14:30.

Wein MN, Kronenberg HM.  Regulation of bone remodeling by parathyroid hormone.  Cold Spring Herb Perspect Med.  2018 Aug;8(8):a031237.

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.

Duchamp de Lagenest O, Conot C.  Periostin in bone regeneration.  Adv Exp Med Biol.  2019;1132:49-61.

The matricellular protein Periostin has several roles through all stages of bone repair: in the early days of repair during the initial activation of stem cells within periosteum, in the active phase of cartilage and bone deposition in the facture callus, and in the final phase of bone bridging and reconstitution of the stem cell pool within periosteum.

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.

Kudo A.  Periostin in bone biology. Adv Exp Med Biol.  2019;1132:43-47.

Recent fndings have revealed that periostin is essential for bone repair.

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.  

Mera P, Ferron M, Mosialou I.  Regulation of energy metabolism by bone-derived hormones.  Cold Spring Harb Perspect Med.  2018;8:a031666.

Bone can act as an endocrine organ, and regulate energy metabolism through the secretion of bone-specific hormones, such as osteocalcin and lipocalin-2.  Osteocalcin stimulates the production and secretion of insulin by the pancreatic beta cells, but also favors adaptation to exercise by stimulating glucose and fatty acid utilization by the muscle.  Lipocal-2 activates appetite-suppressing signaling in the brain.

Mott A, Bradley T, Wright K, Cockayne ES, Shearer MJ, Adamson J, et al.  Effect of vitamin K on bone mineral density and fractures in adults:  an updated systematic review and meta-analysis of randomized controlled trials.  Osteo Intern.  2019;30:1543-1559.

Vitamin K may affect bone mineral density and fracture incidence. This systematic review highlighted the challenges of comparing clinical trials, given the different populations, and differing methods for reporting and diagnosing fractures and different measures of outcomes. 

Murshed M.  Mechanism of bone mineralization.  Cold Spring harb Perspect Med.  2018 Dec;8(12):a031229.

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. 

Okuyan HM, Terzi MY, Ozcan O, Kalaci A.  Association of UCMA levels in serum and synovial fluid with severeity of knee osteoarthritis.  Int J Rheum Dis.  2019;22:1884-1890.

Rodriguez-Olleros Rodriguez, Diaz Curie.  Vitamin K and Bone health:  a review on the effects of vitamin K deficiency and supplementation and the effect of non-vitamin K antagonist oral anticoagulants on different bone parameters.  Hindawi J Osteopor.  2019,2069176.

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, dietary intake 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. 

Verma D, Jumar R, Pereira RS, Karantanou C, Zanetti C, Minciacchi VR, et al.  Vitamin K antagonism impairs the bone marrow microenvironment and hematopoiesis. Blood.  2019;134:227-238.

This study shows that VKAs alter parameters of bone physiology and reduce functional bone stem cells 8-fold. We implicate impairment of the functional, secreted, vitamin K-dependent, γ-carboxylated form of periostin by macrophages.  These results demonstrate that VKA treatment impairs hemipoetic stem cell function possibly associating with increased MDS risk. MDS or Myelodysplastic syndromes are a group of cancers in which immature blood cells in the bone marrow do not mature or become healthy blood cells.

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.

Wu W-J, Gao H, Jim J-K, Ahn B-Y.  A comparatively study of menaquinone-7 isolated from Cheonggukjang with vitamin K1 and menaquinone-4 on osteoblastic cells differentiation and mineralization.  Food & Chem Toxic.  2019;131:110540.

In a lab study, K1, MK4 and MK7 were administered at different concentrations, respectively for 3 days to an osteoblastic cell line.  The results indicated that all vitamin K species significantly increased cell proliferation, osteocalcin synthesis, phosphatase activity and calcium deposition in a dose-dependent manner.  Mk4 and Mk7 had more potent effects on calcium deposition that K1.  Warfarin only partly reduced the effects of MK4 and MK7, but abolished the induction activity of K1 on calcification, suggesting that K1 and K2 may have different mechanisms in stimulating osteoblast mineralization.  Also, mRNA expression of osteoprotegerin and NF-kB, a transcription factor, was dramatically increased by K1 (62%), MK4 (247%) and MK7 (329%).  The results provide compelling evidence that K1 and K2 all promote bone health.

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.

Zhang J, Ma Z, Yan K, Wang Y, Wang Y, Wu X.  Matrix Gla protein promotes the bone formation by up-regulating Wnt/β-catenin signaling pathway.  Front Endocrinol.  2019 Dec;10:891.

This in vitro study looked at the role of MGP in bone metabolism.  They found that MGP promoted osteoblast proliferation, differentiation and mineralization and may be a mechanism to prevent osteoporosis, through a signaling pathway.  The data suggested an important role of MGP as a novel positive regulator of bone formation and the possible use of MGP as a therapeutic target in the management of osteoporosis. 

Zhang Y, Zhao L, Wang N, Li J, He F, Xu L, et al.  Unexpected role of Matrix Gla protein in osteoclasts:  Inhibiting osteoclast differentiation and bone resorption.  2019 June;39(12):300012-19.

Matrix Gla protein (MGP) is a protein responsible for inhibiting mineralization. MGP regulates the deposition of bone matrix. An important factor in maintaining bone mass is osteoclast-mediated bone resorption.  This study looked at the role of MGP in osteoclastogenesis, and bone resorption. They found that osteoclast differentiation and bone resorption are accelerated by MGP depletion while suppressed by MGP overexpression, meaning bone loss is accelerated when MGP is not activated, and bone loss is reduced when MGP is activated and available. These observations establish that MGP plays an essential role in osteoclast differentiation and function, and indicate the potential of MGP as a therapeutic target for low-bone-mass disorders.

Bultynck C, Munim N, Harrington D, Judd L, Ataklte F, Shah Z, et al.  Prevalence of vitamin K deficiency in older people with hip fracture.  Acta Clin Belg.  2020;75:136-140.

A high proportion of people who sustain a hip fracture are already malnourished, compounded by fasting for surgery which might further increase deficiency. This study explored the prevalence of vitamin K deficiency in hip fracture patients and the impact of a short period of fasting.  We found that the prevalence of vitamin K deficiency in hip fracture patients is high and increases further following a short period of fasting. It may be important to supplement with vitamin K supplements peri-operatively.

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.

Fusaro M, Cianciolo G, Brandi ML, Ferrari S. Nickolas TL, Tripepi G, Plebani M., Zaninotto M, Iervasi G, La Manna G, et al. Vitamin K and Osteoporosis. Nutrients2020;12:3625.

Kojima A, Ikehara S, Kamiya K, Kajita E, Sato Y, Kouda K, et al.  Natto intake is inversely associated with osteoporotic fracture risk in postmenopausal Japanese women.  J Nutr.  2020 Mar 1;150(3):599-605.

This study aimed to investigate whether habitual natto intake is associated with a risk of osteoporotic fractures. This prospective cohort study included 1417 postmenopausal Japanese women who were enrolled in the Japanese Population-Based Osteoporosis cohort study in 1996, 1999, 2002, and 2006 and were aged ≥45 y at baseline. The intake of natto, tofu, and other soybean products was surveyed with use of a FFQ at baseline. Fractures were ascertained in follow-up surveys conducted in 1999, 2002, 2006, and 2011/2012.   They found that a higher natto intake was associated with a reduced risk of osteoporotic fractures in Japanese postmenopausal women during a median follow up period of 15.2 years.  The association was independent of classical risk factors such as age, BMI, history, smoking, alcohol intake, or present of diabetes, etc.

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.

Moore AE, Kim E, Dulnoan D, Dolan AL, Voong K, Ahmad I, et al. Serum vitamin K 1 (phylloquinone) is associated with fracture risk and hip strength in post-menopausal osteoporosis:  A cross-sectional study.  Bone.  2020;141:115630.

This study found that serum vitamin K1 concentrations were significantly higher in the group with fewer fractures and negatively associated with fracture risk.  The results showed that women with fractures had a significantly lower serum vitamin K1, compared to those without fractures.  Their data suggested that a higher intake of vitamin K is needed to maximize its effects on the skeleton.

Okuyan HM, Terzi MY, Karaboga I, Dogan S, Kalaci A.  In vivo protective effects of upper zone of growth plate and cartilage matrix associated protein against cartilage degeneration in a monosodium iodoacetate induced osteoarthritis model.  Can J Physiol Pharmacol.  2020;98:763-770.

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.

Sim M, Lewis JR, Prince RL, Levinger I, Brennan-Speranza TC, Palmer C, et al.  The effects of vitamin K-rich green leafy vegetables on bone metabolism:  A 4-week randomised controlled trial in middle-aged and older individuals.  Bone Rep.  2020;12:100274.

This study looked at the increased consumption  of green leafy vegetables daily on bone metabolism over a four week period.  They found that short-term increases of about 200 grams per day  of green leafy vegetables containing about 164 ug/d of K1 results in a 31% and 14% reduction in serum ucOC and tOC, respectively, where it may improve the material property of bone and reduce fracture risk.

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.

Bus K, Szterk A, Relationship between structure and biological activity of various vitamin K forms.  Foods. 2021 Dec;10(2):3136.

Vitamin K is involved many biological processes, such as the regulation of blood coagulation, prevention of vascular calcification, bone metabolism and modulation of cell proliferation. Menaquinones (MK) and phylloquinone vary in biological activity, showing different bioavailability, half-life and transport mechanisms. Vitamin K1 and MK-4 remain present in the plasma for 8–24 h, whereas long-chain menaquinones can be detected up to 96 h after administration. Geometric structure is also an important factor that conditions their properties. Cis-phylloquinone shows nearly no biological activity. The effective dose to decrease uncarboxylated osteocalcin was six times lower for MK-7 than for MK-4. Similarly, MK-7 affected blood coagulation system at dose three to four times lower than vitamin K1. Both vitamin K1 and MK-7 inhibited the decline in bone mineral density. 

Stock M, Schett G.  Vitamin K-dependent proteins in skeletal development and disease.  Int J Mol Sci.  2021;22:9328.

At least 6 Vitamin K dependent proteins play important roles in skeletal biology and disease, including osteocalcin, matrix Gla protein, GRP, periostin, Protein S and Gas6.  The roles for these VKDPs are diverse but include the control of calcification and turnover of bone and cartilage.  This review focuses on the roles of osteocalcin, MGP, and GRP in skeletal development and disease.  These proteins represent promising targets for treatment.

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.

Akulut AC, Wasilewski GB, Rapp N, Forin F, Singer H, Czogalla-Nitsche K, et al.  Menaquinone-7 supplementation improves osteogenesis in pluripotent stem cell derived mesenchymal stem cells.  Front Cell Dev Biol.  2021;8:618760.

This study generated mature osteoblasts from stem cells, tracking the phenotype of cells under osteogenic conditions, as well as the effect of MK-7 being available.  The data showed that MK7 promoted osteoblast maturation  and a variety of positive bone markers, thereby increasing osteogenic differentiation.

Boer CG, Szilagyi I, Nguyen NL, Neogi T, Meulenbelt I, Ikram MA, et al.  Vitamin K antagonist anticoagulant usage is associated with increased incidence and progression of osteoarthritis.  Osteoarthritis. 2021 Mar;80:598-604.

VKAs affect the functioning of vitamin K dependent proteins such as matrix Gla protein.  This study looked at the effect of warfarin usage on the progression and incidence of osteoarthritis (OA), tracking participants in the Rotterdam Study.  They found that warfarin usage was associated with a 2-fold higher risk of osteoarthritis incidence and progression both for knees and hips.  The results pointed to the importance of vitamin K in the pathology of arthritis and the results may help with clinical prevention and treatment of OA.

Wang B, Tang J, Weng S, Chen L, Wu Z, Xie Z, Yang L.  Is vitamin k2 a treatment choice for atypical femoral fractures in patients with secondary osteoporosis?  J Int Med Res.  2021;49(4):1-7.

An atypical femoral fracture (AFF) is a rare complication associated with excessive inhibition of osteoclast expression during treatment of osteoporosis.  This is a single case study of a patient who had been treated with alendronate, a bisphosphonate, for more than 10 years and who developed an AFF.  With treatment of 15 mg of MK4, three times a day, it healed.    The case report indicates that vitamin K2 may be a potential direction for pharmacological treatment of AFFs in the future.

Xiao H, Chen J, Duan L, Li S.  Role of emerging vitamin K-dependent proteins:  growth arrest-specific protein 6, Gla-rich protein and periostin (Review).  Int J Mol Med.  2021;47:2.

This review summarizes three important emerging vitamin K dependent proteins: Gas6, GRP and periostin in terms of their function in physiological and pathological conditions.  Vitamin K is essential for their function, and thus may be a potential preventive and therapeutic agent for many diseases. They believe a high intake of vitamin K, especially vitamin K2, is beneficial for the cardiovascular system and bones. 

 Ahmad SS, Karim S, Ibrahim IM, Alkreathy HM, Alsieni M, Khan MA.  Effect of vitamin K on bone mineral density and fracture risk in adults:  systematic review and meta-analysis.  Biomedicines.  2022 May 1;10:1048.

This analysis explores the effect of VK deficiency and its supplementation on various bone parameters.  They concluded that vitamin K decreases general fracture risk, and it can be an option to counter bone loss disorders.  

Koziol-Kozakowska A, Maresz K.  The impact of vitamin K2 (menaquinones) in children's health and diseases:  a review of the literature.  Children.  2022;9:78.

Due to the transformation of food habits in developed countries over the last five decades, vitamin K and, specifically, vitamin K2 intakes among parents and their offspring have decreased significantly, resulting in serious health implication.  The therapeutics used in pediatric practice (antibiotics and glucocorticoids) are also to blame.  An ongoing clinical trial is intended to address whether vitamin K2 and D3 supplementation might positively impact the biological process of bone healing.  The lack of adverse effects of MK7 makes it the ideal choice for supplementation by pregnant and nursing women and children.

Liao Z, Chang J, Zhu Z, Han W, Meng T, Zhang S, et al.  Associations between dietary intake of vitamin K and changes in symptomatic and structural changes in patients with knee osteoarthritis.  Arthritis Care & Res.  2022 Jun;doi: 10.1002/acr.24964.

Patients with symptomatic knee OA were enrolled and followed for 2 years.  Baseline dietary vitamin K intake was calculated from a validated food frequency questionnaire.  Knee symptoms were assessed by the WOMAC Index of osteoarthritis.  They found an association of higher vitamin K intake with decreased knee symptoms over 24 in patients, suggesting that clinical trials examining the effect of vitamin K supplementation for knee OA were warranted.

Ming M-L, Ma Z-J, He Y-L, Sun H, Yang B, Ruan B-J.  Efficacy of vitamin K2 in the prevention and treatment of postmenopausal osteoporosis:  a systematic review and meta-analysis of randomized controlled trials.  Front Public Health.  2022;10:979649.

The results of this meta-analysis indicate that vitamin k2 supplementation has a positive effect on the maintenance and improvement of bone mineral density lumbar spine in postmenopausal women and it can also reduce the fracture incidence, serum uc-OC levels and the ration of uc-OC to t-OC.  They concluded that MK4 can indirectly promote bone mineralization and increase bone strength.

Zhou M, Han S, Zhang W, Wu D.  Efficacy and safety of vitamin K2 for postmenopausal women with osteoporosis at a long-term follow-up:  meta-analysis and systematic review.  J Bone and Miner Metab.  2022;40:763-772.

Vitamin K2 supplementation has been revealed to be effective in the prevention and treatment of osteoporosis in Japan, but further proof for the effectiveness of this practice is still needed. This review looked at whether vitamin k2 supplementation plays a role in maintaining bone mineral density and reducing the incidence of fractures in postmenopausal women with osteoporosis at long term follow-up. A systematic search of studies showed that vitamin k2 was associated with a significantly increased percentage change of lumbar BMD and forearm BMD, and decreases in inactive osteocalcin at long term followup.  They concluded that the research shows that vitamin K2 supplementation is beneficial and safe in the treatment of osteoporosis for postmenopausal women.

Written by RPT 1/2/13

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