Vitamin K2 Effective For The Prevention & Treatment of Osteoporosis? A review of the literature
INTRODUCTION
Vitamin K is a group of structurally related compounds that have anti-hemorrhagic activity. Vitamin K is well known for its role in blood clotting yet few people realize its importance in maintaining healthy bones and heart.
DIFFERENT FORMS OF VITAMIN K
1. Vitamin K1 (phylloquinone) is the major form found in plants such as spinach, kale, mustard greens, dandelion greens, Swiss chard, etc. In humans, it is crucial for proper blood clotting and in certain cases can be used topically on the skin to help diminish effects of bruising.
2. Vitamin K2 (menaquinone) is synthesized by colonic bacteria from vitamin K1 and it is also present in some foods. It consists of a group of lesser known compounds which help prevent the accumulation of calcium deposits in arteries by directing the calcium to the teeth and bones. Vitamin K2 is therefore essential for cardiovascular health as well as for bone and teeth health. It also has antioxidant properties and as such protects against the harmful effects of free radicals.
The different compounds are classified according to the number of isoprenyl units on the side chain1 ex.
MK-4, also known as menaquinone-4 (MK-4), is vitamin K2 with 4 isoprenyl units (1)
MK-7, also known as menaquinone-7 (MK-7), is vitamin K2 with 7 isoprenyl unit (1)
3. Vitamin K3 (ménadione) is a synthetic compound that is converted to MK-4 in vivo (1)
ABSORPTION AND DIGESTION OF VITAMIN K
Vitamin K1, mostly found in green leafy vegetables (15) is considered the major dietary form of vitamin K. It represents about 80% of the total amount of vitamin K in the human diet but only 10% of the vitamin K absorbed by the body due to its low bioavailability (31). Vitamin K1 also has a relatively short half-life and is gone from the body three to four hours after ingestion.
Vitamin K2 is found in animal products: organ meats, dairy & eggs and in fermented food (ex. cheese, yogurt, and natto). It is also found in the colon where it is synthesized by the intestinal microflora (15).
Vitamin K2 has a much higher bioavailability equal to about 80% (31) and a longer half-life. After being taken up by the liver it is redistributed to bone and vasculature.
After digestion, vitamin K is emulsified by bile salts and taken up by the enterocytes of the intestinal epithelium. Following intestinal absorption, all vitamin K forms are incorporated into TAG-rich lipoproteins and transported to several target tissues but primarily to the liver (8).
Being a fat soluble vitamin, the absorption of vitamin K is dependent on the presence of bile and absorbable fat in the intestinal tract and its excretion is mainly in the feces.
ROLES AND FUNCTIONS OF VITAMIN K IN HUMAN HEALTH
Hemostasis and Blood Coagulation: vitamin K is required to make prothrombin which is then converted to thrombin, the molecule which converts fibrinogen to the fibrin that creates the blood clot (1, 2, 3, 6)
Heart Health: vitamin K decreases calcification of blood vessels and protects against atherosclerosis (1, 2, 3, 7)
Bone Health: vitamin K is involved in the synthesis of osteocalcin for bone building, stimulating new bone growth and decreasing calcium loss (1,2,3,6, 28)
Preventing and/or treating muscle cramps (16)
Preventing nausea and vomiting of pregnancy (2)
IMPLICATIONS OF VITAMIN K DEFICIENCY (1, 2)
Major bleeding episodes and hemorrhagic disease of the newborn (28)
May promote the development of osteoporosis (20, 24)
An increased risk of coronary artery calcification, atherosclerosis and ischemic heart disease (18, 20, 24, 25, 28)
An increased risk of developing cancer and cirrhosis (MK-4) (3)
An increased risk of myelodysplasia (MK-4) (3)
Increased breakdown of skin collagen and a decrease in the amount of collagen in skin (2)
Associated with a drop in vitamin C levels (2)
CAUSES OF VITAMIN K DEFICIENCY
Decrease in green leafy vegetable consumption (1, 10)
Coumarins like warfarin and other coagulation inhibitors, which inhibit the vitamin K cycle (20, 28)
Cholesterol lowering drugs (1, 10)
Antibiotic use, which kills potassium making bacteria in the gut (1, 10)
Synthetic estrogen use (1, 10)
Gallstones (1, 10)
Liver disease (1, 10)
Unhealthy intestinal tract (1, 10)
Excess intake of vitamins A and E (1, 10)
VITAMIN K2 AND OSTEOPOROSIS
Osteoporosis
Osteoporosis is a disease characterized by deterioration of bone tissue along with a decrease in bone mineral density (BMD), as measured by dual-energy x-ray absorptiometry (DXA). Large areas of the affected bones become porous and brittle resulting in weakened bone structure subject to break more easily even when subjected to minor stress, such as a fall or a blow (9).
Osteoporosis affects an estimated 75 million people in Europe, the US and Japan (19). Responsible for at least 1.5 million fractures of the hip, vertebra (back or neck), or wrist in Americans aged 50 and older each year, it incurs billions of dollars in treatment costs (4). Osteoporosis can result in debilitating acute and chronic pain, further disability and loss of independence in the elderly and can lead to early mortality (5).
Western cultures and diets (Europe, Canada, and USA) eat a high protein, high dairy, high phosphorus acidifying diet which causes large amounts of calcium to be removed from bone tissue to try to preserve an alkaline cellular environment (25).
Pharmacological therapies include bisphosphonates (ex. Alendronate, Raloxifene and Risedronate) which
are antiresorptive medications that improve BMD (5). However, new evidence suggests that treatment with bisphosphonate medications for longer than 7 years may increase fracture risk (5). It has also associated been associated with a growing list of concerns including heartburn, esophageal irritation, ulcers and esophageal cancer (9). For these reasons there is currently an increased interest in non-pharmacological prevention and treatment options for this condition.
Relationship between Vitamin K2 and Osteoporosis
The effect of magnesium and vitamin D3 on calcium metabolism is well known and researched, however the importance of vitamin K in regulating healthy calcium function and distribution in the body has only recently been recognized (13).
Several studies support the hypothesis that vitamin K plays a pivotal role in bone tissue homeostasis because it acts as a cofactor of ϒ-carboxylase, the enzyme which converts glutamic acid (Glu) residue to a ϒ-carboxyglutamic acid (Gla) residue in osteocalcin molecules (OC) and Protein S (6, 14). It also appears to enhance the accumulation of osteocalcin in the extracellular matrix of osteoblasts, in vitro (6).
Growing evidence from recent studies suggests that vitamin K is a good option for preventing osteoporosis (7) and the incidence of vertebral fractures in postmenopausal women as well as in patients with steroid-induced osteoporosis (6).
Three k-dependent proteins, synthesized by osteoblasts have been isolated in bone (8):
Protein S, an anticoagulant protein
Matrix GLA Protein (MGP), found to prevent soft tissue and cartilage calcification due to its glutamate (Gla) residues and their inhibitory effect on calcium precipitation and crystallisation (20). It was also found to support normal bone growth in animal studies
Osteocalcin(OC), higher concentrations of OC indicate low vitamin K status and is associated with lower BMD and higher hip fracture risk (8)
THERAPEUTIC APPLICATIONS
A study conducted on rats, experimentally induced with osteoporosis, compared the effects of a single treatment with vitamin K2 versus a combined treatment with vitamin K2 and vitamin D3 or a combined treatment with vitamin K2 and Bisphosphonates demonstrated the following results (14):
Single treatment with vitamin K2: vitamin K is involved in the regulation of bone metabolism and in maintaining the trabecular architecture of bone in ovariectomized rats (14).
Combined treatment with vitamin K2 and vitamin D3: this combination was found to be useful in preventing loss of bone mass at the level of proximal tibia metaphysis and in increasing bone strength of the femoral diaphysis in ovariectomized rats (14).
Combined treatment with vitamin K2 and Bisphosphonates: this combination was found to have a preventive effect on the deterioration of the three-dimensional architecture of trabecular bone and an improvement in bone strength more effective than bisphosphonates alone (14) .
Poor vitamin K status results in increased levels of uncarboxylated, inactive osteocalcin. Significantly lower levels of vitamin K1 and k2 are found in the serum obtained from elderly patients within a few hours after a hip fracture (11). Research suggests that daily supplementation with 80 mcg is necessary to reach a premenopausal carboxylated osteocalcin/total osteocalcin ratio (11).
According to Vermeer and Hamulyak’s observations, on thousands of subjects, complete carboxylation of circulating osteocalcin is extremely rare in those not supplemented with vitamin K. This finding implies that protection against cardiovascular calcification is probably suboptimal in most of the population and can be improved by simple dietary measures, i.e. increasing our vitamin K intake (21).
Many human trials have found vitamin K2 effective in the treatment of osteoporosis. In one randomized open-label study, 241 osteoporotic women were given either both 45 mg/day vitamin K2 and 150 mg elemental Ca (treatment group n = 120) or 150 mg elemental Ca (control group n = 121). After two years, the vitamin K2 group was shown to maintain lumbar BMD and experience significantly lower fracture incidence versus the control group (27).
A three year trial of postmenopausal women between 50 and 60 years assessed vitamin K supplementation (in combination with vitamin D3 and calcium). Results showed that vitamin K supplementation delays postmenopausal bone loss and improves BMD compared to placebo; researches stated that these effects continued over decades and stipulated that lifelong supplementation could postpone fractures by up to 10 years (13). Another randomized clinical intervention study among 325 postmenopausal women receiving either placebo or 45 mg/day vitamin K2 (MK-4) during 3 years concluded that vitamin K2 helps maintain bone strength at the site of the femoral neck in postmenopausal women (29). According to Yamaguchi et al., MK-7 isolated from natto has stimulatory effects on calcification in femoral tissues obtained from normal young rats in vitro (11).
Another study conducted on 19 patients during 3 months evaluated the safety, tolerability and therapeutic activity of 100 mcg/day of vitamin K2 (MK-7), found this dose to be well tolerated and safe with a therapeutic relief of muscle cramps (16).
Finally, studies conducted on postmenopausal subjects with mild osteoporosis indicate that combined treatment with vitamin K2 and vitamin D3 may increase bone formation as well as bone resorption better than the mild anti-resorptive effect of vitamin D3 alone and shows the greatest effect on lumbar MBD or the incidence of vertebral fractures (17).
EVIDENCE FOR SAFETY OF VITAMIN K SUPPLEMENTATION
Vitamin K2 (menaquinone) is more effective in activating extra-hepatic proteins while vitamin K1 (phylloquinone) plays the major role in the blood-clotting process. The majority of vitamin K research has focused on vitamin K112 and present recommendations for vitamin K are exclusively based on phylloquinone’s function in coagulation (8). Furthermore, most of the data available today regarding menaquinone intakes are based on studies mainly performed in Japan and Europe where the normal diet includes menaquinone-rich foods (8).
It is postulated that excessive vitamin K intake may result in increased thrombosis risk due to excessive coagulation. However, there is no documented case of toxicity for phylloquinone or menaquinones (8). Furthermore, vitamin K-dependent proteins have a limited number of Glu residues capable of ϒ-carboxylation per molecule, beyond which there can be no further ϒ-carboxylation or excessive coagulation. Trials on rats showed that thrombosis risk is not increased at doses up to 250 mg/kg of MK-4 (8). Trials on humans showed that thrombosis risk is not increased at doses up to 360 mcg/d for 6 weeks of MK-7 (8).
According to a recent study, the incidence of hip fractures in Japanese women seemed to be strongly influenced by their vitamin K2 intake (22), and since 1995 high doses of vitamin K2 supplements have become approved as a treatment for osteoporosis in Japan (22).
Research supports that the use of both naturally occurring forms of vitamin K (K1 and K2) for the treatment of osteoporosis (9), maintaining lumbar bone mineral density and preventing osteoporotic fractures in patients with osteoporosis is both safe and relevant.
Optimum Daily Intake of vitamin K (ODI)
Vitamin K2 can be synthesized by colonic bacteria and can also be found in the following dietary sources: chicken, egg yolk, dairy products, cow liver, and natto (23). According to the Natural Medicine Journal OF 2009 optimal vitamin K daily supplementation is:
Men 120 mcg/day (10, 19)
Women 90mcg/day (10, 19)
CONCLUSION
Osteoporotic fractures have multifactorial origins; among these BMD is the most reliable predictor (26). Numerous studies have demonstrated that vitamin K2 treatment accelerates carboxylation of OC and improves trabecular BMD protecting against osteoporosis and bone fractures (26). Furthermore, these studies reveal a positive effect of MK-4 and MK-7 on BMD and the incidence of fractures in postmenopausal women with osteoporosis (11, 30).
Recent epidemiological studies suggest that most apparently healthy adults may be subclinically deficient in vitamin K2 (18, 25) resulting in an increase of uncarboxylated inactive K2-dependent proteins to about 10-40% (15). These findings support the rationale for postmenopausal supplementation with vitamin K2 to prevent osteoporosis.
Therefore a comprehensive guideline for optimizing bone health appears to be needed for preventing and treating osteoporosis rather than simply getting enough dietary calcium and magnesium or relying exclusively on pharmacological options including bisphosphonates which appear to be associated with various undesirable side effects.
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