Vitamin K and Bone Health in Adult Humans
Introduction
Vitamin K is the generic name for a family of related compounds with similar γ-carboxylation activity. Vitamin K was discovered in 1929 by the Danish scientist Henrik Dam. Three compounds of vitamin K are known: Phylloquinone, or vitamin K1, which is found mainly in green plants. Menaquinone, or vitamin K2, which is a bacterial by-product and, therefore, mainly found in fermented products or in food from animal origin. Menaquinone comprises a family of molecules with an isoprenoid side chain of varying length from 1 to 14 repeats. When the isoprenoid side chain length is 0, it is called menadione, or vitamin K3, which is a synthetic compound found only in supplements (Fig. 16.1).
For decades, it was believed that the sole function of vitamin K was in the coagulation cascade, but a number of other vitamin K-dependent proteins have been discovered. So far, it has amounted to at least 14 different vitamin K-dependent proteins. These comprise four procoagulants (factors VII, IX, X, and prothrombin) and three anticoagulant proteins (protein C, protein S, and protein Z), which are synthesized primarily in the liver. In addition, there are two proteins of bone and extracellular matrix [osteocalcin (OC) and matrix Gla protein], growth arrest-specific protein 6 (Gas6), which participate in a number of different processes (Berkner and Runge, 2004), as well as four membrane proteins with functions that have not yet been defined, the transmembrane Gla family, PRGP1, PRGP2, TMG3, and TMG4 (Kulman 1997, Kulman 2001). In addition to blood and bone, vitamin K-dependent proteins occur in dentin, renal stones, atherosclerotic plaques, semen, lung surfactant, neural tissue, and urine (Berkner and Runge, 2004). In all known cases, the Gla residues function as ligands for Ca2+ and are crucial for the biological activity of the proteins.
While γ-carboxylation of glutamic acid residues in vitamin K-dependent proteins is shared by vitamins K1 and K2, some vitamin K2-specific, γ-carboxylation-unrelated functions have also been demonstrated. Menaquinone was recently shown to be a ligand for the steroid xenobiotic receptor (SXR) and thereby inducer of the mRNA synthesis for osteoblast biomarkers such as alkali phosphatase, osteoprotegerin, osteopontin, and matrix Gla protein (Tabb et al., 2003).
Gla is biosynthesized as a posttranslational modification which is catalyzed by γ-glutamyl carboxylase, a resident enzyme of the endoplasmic reticulum. The polypeptide that is precursor for the modification comprises a single chain with an N-terminal signal peptide that is cleaved off prior to the synthesis of Gla. Binding of the substrate to the carboxylase is mediated by an adjacent propeptide of 18–28 amino acids. This binding activates the enzyme to γ-carboxylate the glutamyl residues located nearby (Berkner and Runge, 2004).
Three vitamin K-dependent proteins have been identified in bones (Maillard 1992, Price 1985, Price 1976). The most abundant noncollagenous protein of bone, OC, is vitamin K dependent. It has also been called bone γ-carboxyglutamic acid (Gla) protein (BGP). It is a small Ca2+-binding protein that contains three Gla residues and it is indigenous to the organic matrix of bone, dentin, and possibly other mineralized tissues (Hauschka et al., 1989). Matrix Gla protein is another Gla-containing protein associated with bone and cartilage. It contains five Gla residues and exhibits some peptide sequence homology to OC (Hauschka et al., 1989). The Gla residues are Ca-binding groups, which are essential for the biological activity of the proteins; consequently, undercarboxylated proteins have low affinity for Ca and low biological activity (Vermeer et al., 1998). The exact role of these proteins is not fully understood, but it is believed that OC is involved in regulation of the osteoblast and the growth of hydroxyapatite crystals (Iwamoto et al., 2004), while matrix Gla protein is involved in bone formation and mineralization and as an inhibitor of calcification of arteries (Proudfoot and Shanahan, 2006). OC is synthesized by the osteoblast by a synthesis induced by 1,25(OH)2D3 (Hauschka et al., 1989).
Ducy et al. (1996) showed that OC might be involved in limitations of bone formation without impairing bone resorption or mineralization. An animal study with knockout mice showed that knock out of the OC genes resulted in an increased bone formation without a concomitant increase in numbers or surface of osteoblasts. The numbers and surface of osteoclasts, however, were increased. When mutant and wild-type mice were ovariectomized, both developed an increase in bone-marrow area, which is a good indicator of osteoclast function. The mutant mice had, however, weaker bones than sham-operated mice, indicating that the mutant mice may develop a more severe osteoporosis than the wild-type mice after estrogen depletion. Furthermore, staining for mineralization showed no difference between wild-type and mutant mice (Ducy et al., 1996). Another study showed that besides acting as an inhibitor of the osteoblast function, OC is also required for stimulation of bone mineral maturation (Boskey et al., 1998). Knock out of the matrix Gla protein gene results in short stature, osteopenia, fractures, and accelerated calcification of arteries and cartilage (Luo et al., 1997). This suggests that carboxylation of MGP may be important in bone formation and mineralization.
In the mid-1970s, the first report on serious bone malformation in children born by mothers treated with vitamin K antagonists during the first trimester was published (Pettifor and Benson, 1975). Soon after, it was reported that patients who had sustained an acute hip fracture or suffered from a chronic spinal crush fracture had lower circulating phylloquinone in plasma compared with healthy controls (Hart et al., 1984). This was later confirmed by Hodges 1991, Hodges 1993, who showed that patients with osteoporotic fractures of hip and spine had markedly decreased circulating levels of phylloquinone, menaquinone-7, and menaquinone-8. The question remains whether the decreased level of circulating vitamin K is the cause or a consequence of the fracture. The findings, however, have led to increased research in this area, and many studies have indicated that vitamin K is important for optimal bone health.
Section snippets
Epidemiological studies
A number of epidemiological studies have shown a relationship between vitamin K intake and bone health. The two largest of these studies are the Framingham Heart Study and the Nurses Health Study (Booth 2000, Booth 2003a, Feskanich 1999). Both of these studies have indicated that vitamin K intake, measured by food frequency questionnaire, correlates with hip fracture risk and bone mineral density (BMD). In the Nurses' Health study comprising 72,327 women aged 38–63 years, it was shown that an
Differences between vitamins K1 and K2
It cannot be ruled out that there are differences in the effect of vitamins K1 and K2; therefore, more long-term studies are needed to ascertain that vitamin K1 does have an effect on fracture risk. Furthermore, studies are lacking that compare the effects of vitamins K1 and K2 in order to rule out that the different effects seen may be because of ethnic differences (Beavan 2004, Yan 2005).
Besides the obvious possibility that vitamins K1 and K2 differ with respect to their action on bone
Vitamin K Recommendations
It could be argued, and some researchers do argue, that the present dietary recommendations are too low to be sufficient for optimal bone health. The present adequate dietary intakes (AI) of vitamin K are 120 and 90 μg/day for men and women, respectively, and are based on the effects of vitamin K on the coagulation system (Institute of Medicine, 2001). Determination of the requirement of vitamin K is difficult, as it is almost impossible to induce vitamin K deficiency on a vitamin K free diet.
Anticoagulation Treatment And Risk Of Osteoporosis
While some researchers are pleading for recommendations of higher intakes of vitamin K, others are using the conflicting results from studies with patients undergoing treatment with oral anticoagulants to argue against increasing the recommendations. While the use of oral anticoagulants during the first trimester of pregnancy clearly has deleterious effects on fetal bone development (Pettifor and Benson, 1975), it is unclear whether treatment with anticoagulants increases the risk of
Interactions Between Vitamin K And Vitamin D
An alternative explanation for the lack of a clear connection between the use of oral antiocoagulants and fracture could also be as has been suggested by some researchers, that the relationship with hip fracture reflects a combination of both poor vitamin K status and poor vitamin D status (Booth 1999, Szulc 1993). In women with low BMD, the increase in %ucOC and BMD was larger when the vitamins were given in combination than when vitamin K was given alone (Schaafsma 2000, Ushiroyama 2002).
Discussion And Conclusion
Overall, there are strong indications for an association between vitamin K status and optimal bone health. However, as long as the exact role of vitamin K is not known, a relationship between vitamin K intake and fracture risk needs to be established in order to increase the recommended levels.
References (85)
- et al.
Assessment of vitamin K status in human subjects administered “minidose” warfarin
Am. J. Clin. Nutr.
(1996) - et al.
The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis
J. Thromb. Haemost.
(2004) - et al.
Vitamin K nutrition and osteoporosis
J. Nutr.
(1995) - et al.
Vitamin K supplementation reduces serum concentrations of under-{gamma}-carboxylated osteocalcin in healthy young and elderly adults
Am. J. Clin. Nutr.
(2000) - et al.
A high phylloquinone intake is required to achieve maximal osteocalcin y-carboxylation
Am. J. Clin. Nutr.
(2002) - et al.
Dietary intake and adequacy of vitamin K1
J. Nutr.
(1998) - et al.
Food sources and dietary intakes of vitamin K-1 (phylloquinone) in the American diet: Data from the FDA Total Diet Study
J. Am. Diet. Assoc.
(1996) - et al.
Response of vitamin K status to different intakes and sources of phylloquinone-rich foods: Comparison of younger and older adults
Am. J. Clin. Nutr.
(1999) - 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) - et al.
Effects of a hydrogenated form of vitamin K on bone formation and resorption
Am. J. Clin. Nutr.
(2001)
Vitamin K intake and bone mineral density in women and men
Am. J. Clin. Nutr.
Dietary phylloquinone depletion and repletion in older women
J. Nutr.
Fourier transform infrared microspectroscopic analysis of bones of osteocalcin-deficient mice provides insight into the function of osteocalcin
Bone
Vitamin K intake and hip fractures in women: A prospective study
Am. J. Clin. Nutr.
Bioavailability of phylloquinone and menaquinones after oral and colorectal administration in vitamin K-deficient rats
Biochem. Pharmacol.
Determination of the urinary aglycone metabolites of vitamin K by HPLC with redox-mode electrochemical detection
J. lipid res.
Circulating vitamin K1 levels in fractured neck of femur
Lancet
Depressed levels of circulating menaquinones in patients with osteoporotic fractures of the spine and femoral neck
Bone
Effects of vitamin K2 (menatetrenone) on calcium balance in ovariectomized rats
Jap. J. Pharmacol.
Transport of vitamin K to bone in humans
J. Nutr.
Bone health of adult hemodialysis patients is related to vitamin K status
Kidney Int.
Dietary and nondietary determinants of vitamin K biochemical measures in men and women
J. Nutr.
Heparins, coumarin, and bone density
Lancet
Primary structure of bovine matrix Gla protein, a new vitamin K-dependent bone protein
J. Biol. Chem.
Vitamin K and maintenance of skeletal integrity in adults
Am. J. Med.
Phylloquinone transport and its influence on gamma-carboxyglutamate residues of osteocalcin in patients on maintenance hemodialysis
Am. J. Clin. Nutr.
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.
Comparison of biochemical indexes for assessing vitamin K nutritional status in an healthy adult population
Am. J. Clin. Nutr.
Vitamin K deficiency from dietary vitamin K restriction in humans
Am. J. Clin. Nutr.
Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture: A three year follow-up study
Bone
Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR
J. Biol. Chem.
Effect of continuous combined therapy with vitamin K(2) and vitamin D(3) on bone mineral density and coagulofibrinolysis function in postmenopausal women
Maturitas
Vitamin K: Lessons from the past
J. Thromb. Haemost.
Ethnic differences in osteocalcin [gamma]-carboxylation, plasma phylloquinone (vitamin K1) and apolipoprotein E genotype
Eur. J. Clin. Nutr.
Compilation of a provisional UK database for the phylloquinone (vitamin K1) content of foods
Br. J. Nutr.
Associations between vitamin K biochemical measures and bone mineral density in men and women
J. Clin. Endocrinol. Metab.
Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age
Calcif. Tissue Int.
Factors affecting bone loss in female endurance athletes: A two-year follow-up study
Am. J. Sports Med.
Effect of phylloquinone supplementation on biochemical markers of vitamin K status and bone turnover in postmenopausal women
Br. J. Nutr.
Changes in bone density after exposure to oral anticoagulants: A meta-analysis
Osteoporos. Int.
Apolipoprotein E polymorphism: A new genetic marker of hip fracture risk—the study of osteoporotic fractures
J. Bone Miner. Res.
Vitamin K and the prevention of fractures
Arch. Intern. Med.
Cited by (80)
Do Titanium Dioxide Particles Stimulate Macrophages to Release Proinflammatory Cytokines and Increase the Risk for Peri-implantitis?
2023, Journal of Oral and Maxillofacial SurgeryCitation Excerpt :Other random errors could lie in the planning and execution of the implantological procedure, the surgical technique, the quality of the implant system used, the prosthetic concept or the (dental) technical design.50 The presence of osteoporosis due to estrogen, vitamin D, vitamin K2 (MK7), or calcium could affect osseointegration and thus influence the results of the study as a random error.51-53 The stress factors may also be a stimulator for inflammatory processes and could therefore have led to random error.54
Determination of vitamin K composition of fermented food
2019, Food Chemistry