Vitamin K and bone health

doi:10.1016/S0899-9007(01)00709-2

Nutrition

Volume 17, Issue 10, October 2001, Pages 880-887

https://doi.org/10.1016/S0899-9007(01)00709-2 Get rights and content

Abstract

In the past decade it has become evident that vitamin K has a significant role to play in human health that is beyond its well-established function in blood clotting. There is a consistent line of evidence in human epidemiologic and intervention studies that clearly demonstrates that vitamin K can improve bone health. The human intervention studies have demonstrated that vitamin K can not only increase bone mineral density in osteoporotic people but also actually reduce fracture rates. Further, there is evidence in human intervention studies that vitamins K and D, a classic in bone metabolism, works synergistically on bone density. Most of these studies employed vitamin K₂ at rather high doses, a fact that has been criticized as a shortcoming of these studies. However, there is emerging evidence in human intervention studies that vitamin K₁ at a much lower dose may also benefit bone health, in particular when coadministered with vitamin D. Several mechanisms are suggested by which vitamin K can modulate bone metabolism. Besides the γ-carboxylation of osteocalcin, a protein believed to be involved in bone mineralization, there is increasing evidence that vitamin K also positively affects calcium balance, a key mineral in bone metabolism. The Institute of Medicine recently has increased the dietary reference intakes of vitamin K to 90 μg/d for females and 120 μg/d for males, which is an increase of approximately 50% from previous recommendations.

Section snippets

Dedication

When I met Larry for the first time, he was “officially” already retired. I say “officially” because he never did really retire from science. I got to know Larry as a person who loved to talk science. Actually, I was the person to succeed him in the Human Nutrition Group at the Roche Office in Nutley, New Jersey, which to me was a great honor and even more of a challenge. Although retired, Larry continued to come to our offices quite often. Actually, he was one of those wonderful people who

Dietary sources of vitamin K

Naturally occurring K vitamins can be classified into two groups: K₁ (phylloquinone), the major form occurring in plants, and K₂, which is synthesized by bacteria. Vitamin K₂ is a family of compounds called menaquinones (based on the number of the repeating prenyl units of the side chain, this number is given as a suffix, i.e., menaquinone-n). Natural sources of vitamin K₁ are green leafy vegetables.15 Dairy products such as cheese are a major source of vitamin K₂ (Table I). It is noteworthy

Mechanisms

Vitamin K is required for the biological activity of several coagulation factors such as factors II, VII, and IX and proteins C and S.19 This is considered the classic metabolic role of vitamin K. More precisely, vitamin K functions as a cofactor for the vitamin K–dependent carboxylase, a microsomal enzyme that facilitates the posttranslational conversion of glutamyl to γ-carboxyglutamyl residues.20, 21, 22, 23

In addition to the hepatic tissue, in which the synthesis of clotting factors occurs,

Vitamin K status and bone health

There is a wealth of epidemiologic studies investigating the association of vitamin K status and various markers of bone health including clinical endpoints such as BMD and fracture rate Table II, Table III. Consistently, these epidemiologic studies have suggested a beneficial effect of vitamin K on bone health, as discussed below in more detail.

The first report linking vitamin K serum levels to the risk of osteoporotic fractures (Table II) appeared in 1985, when Hart et al.41 demonstrated

Intervention studies

Several research groups have conducted intervention studies investigating the effect of vitamin K intake in nutritional and pharmacological dosages in relation to changes in serum levels of osteocalcin and/or bone density or fracture rates Table IV, Table V.

Sokoll et al.64 provided nine young adult subjects diets containing approximately 420 μg/d of vitamin K and found that this dietary intervention significantly reduced the concentration of circulating ucOC. This effect of vitamin K on ucOC

Safety

Vitamin K has a very wide safety range. No adverse effects or hazards associated with the ingestion of natural sources of vitamin K have been reported.19 In fact, the human clinical intervention studies cited above impressively demonstrate the wide safety range of this nutrient. It is noteworthy, that in a double-blind, placebo-controlled, human study, even a daily dose of 90 mg of vitamin K₂ given for 2 y did not cause any relevant adverse effects.81 The recommendations for the daily dietary

Conclusions

Osteoporosis is a multifactorial chronic disease that may become even more prevalent and more of a public health problem in the decades to come.3, 4 Recent research has indicated that a number of macro- and micronutrients are involved in the development of bone health.8, 9, 10, 11, 12, 13, 14

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Osteoporosis and the effect of dysregulation of the transsulfuration pathway via taurine on intracellular calcium homeostasis, vitamin D absorption and vitamin K absorption
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In this article we connect the dysregulation of the transsulfuration pathway to bone dysregulations and propose a novel treatment for osteoporosis. Current treatments for osteoporosis are very frequently inadequate. In osteoporosis, the risk of fractures increases with increased homocysteine (Hcy).
Here, we conduct a review on the relationship between osteoporosis and the dysregulation of the transsulfuration pathway.
we show that the transsulfuration pathway metabolizes Hcy to L-cysteine. Increased Hcy levels point to the transsulfuration pathway being dysregulated. With the transsulfuration pathway dysregulated, there will be decreased levels of L-cysteine and decreased levels of taurine, which is synthesized from L-cysteine. Taurine levels are decreased in patients with osteoporosis. Taurine regulates intracellular calcium homeostasis. Taurine, also, when conjugated with bile acids assists with absorption of fats and fat-soluble vitamins such as vitamin D and vitamin K. Dysregulated calcium homeostasis, decreased calcium absorption and decreased absorption of vitamin D and vitamin K due to low levels of taurine negatively affect bone mineral density (BMD) leading to osteoporosis and fractures.
In this article, we propose that a combination of taurine, calcium, vitamin D and vitamin K, could increase BMD reducing number of years spent in disability and reducing deaths due to fractures in patients with osteoporosis.
Calcium prescription by Indian orthopaedic surgeons: A survey and a review of literature
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Citation Excerpt :
Vitamin K, specifically vitamin K2 (as it does not require activation in the liver) plays an important role in the activation of Matrix GLA Protein (MGP) which is a central calcification inhibitor, produced by vascular smooth muscle cells. MGP prevents the accumulation of excess calcium in the vascular lumen.26 Vitamin K is also considered to reduce the fracture rate and increase bone density.
Orthopaedic surgeons prefer calcium supplement for various pathologies like fracture, osteoporosis, chronic musculoskeletal pain, yet there is no proper evidence to support the benefits of taking them regularly. The average requirement for calcium is around 500–1000 mg/day for a healthy adult, this amount of calcium is not achieved by diet, especially in developing countries like India. Despite this, the serum calcium level remains unaltered, due to the well-controlled absorption and excretion of calcium by the human body. As there is no clarity over the dose, duration and the prefered calcium salts, we constructed a survey to find the preferred dose, duration, the preferred calcium salts among orthopaedic surgeons, and to give an in-depth review of literature about dose, duration, timing, preferred calcium salt and various other calcium-related queries.
The survey included 15 pre-structured questionnaires; these questions were formatted and validated by senior surgeons and other specialists after a through a review of calcium-related literature. These questionnaires were used in a pilot study conducted within the department and were later modified and separated into 7 sections. Data were collected by both online survey (google forms) and direct interviews.
128 Orthopedic surgeons responded. The total number of response obtained was 2355. Unanswered questions were 152. From the survey, it was found that most orthopaedic surgeons prefer to prescribe calcium routinely (55.46%). The commonly used calcium salt was calcium carbonate (47.65%), followed by citrate (32.8%). 42.18% were not aware of the efficiency of prescribing calcium in divided doses. Most responded that calcium is not to be given for patients with renal stones, but literature shows that calcium prescribed reduces the recurrence of commonest kidney stones, calcium oxalate stones.
Genetic Variation in VKORC1 and Risk for Osteoporosis
2021, Archives of Medical Research
Citation Excerpt :
The promoter of the osteocalcin gene contains a vitamin K-responsive element stimulates the transcription of osteocalcin directly (7). Vitamin K deficiency results in inadequate carboxylation of osteocalcin and leads to high serum levels of undercarboxylated (Glu) osteocalcin with low biologic activity (8). Evidence suggests that vitamin K1 deficiency is associated with decreased BMD (9,10) and that high-dose vitamin K supplementation prevents fractures in at-risk patients (11).
The vitamin K epoxide reductase complex subunit 1 (VKORC1) plays an important role in bone development and bone metabolism by influencing the vitamin K cycle. The aim of this study was to investigate the association between VKORC1 gene polymorphisms and bone mineral density and the risk of osteoporosis.
We determined VKORC1 gene polymorphisms (rs9923231 and rs9934488) by using polymerase chain reaction-restriction and Sanger sequencing method in 606 postmenopausal women including 288 osteoporosis patients and 318 healthy controls.
No significant differences were observed in the rs9934488 polymorphisms between the osteoporosis group and controls. Subgroup analyses also indicated no positive result. VKORC1 rs9923231 polymorphism increased the risk of osteoporosis in the homozygous and allelic models. A significant correlation was observed in a subgroup of the elderly (age ≥55 years). Additionally, the genotypes of the rs9923231 polymorphism were significantly associated with low body mass index, and T-score, but not with age, serum calcium, or phosphorus.
In conclusion, VKORC1 rs9923231 polymorphism is a genetic contributor to osteoporosis risk and it should be confirmed in large well-designed studies.
Synergistic factors ensue high expediency in the synthesis of menaquinone [K<inf>2</inf>] analogue MK-6: Application to access an efficient one-pot protocol to MK-9
2020, Tetrahedron
Here we report a practical and efficient method for the synthesis of menaquinone vitamin (K₂) analog MK-6 in all trans forms through “1 + 5 convergent synthetic approach” of pentaprenyl chloride with monoprenyl menadione derivative. In the synergistic factors, less efficient leaving group/more efficient nucleophile (Cl) in the substrate makes it more prominent reaction by eliminating all S_n^2’ side reaction products. Further, the addition of acetic acid in the last step (desulfonation) of reaction sequence removes the limitations of the reactions in terms of cyclized side product (multiple reactions of pentaprenyl alcohol with Et₃B), byproduct (Et₃B, incendiary compound) formations and their interruption in the tricky purification processes. The utility of this method was further extended to find an efficient one-pot synthesis to MK-9 to the gram scale synthesis. This approach is economical and efficient and avoids the awkward chromatographic separation processes.
Combinatorial engineering for improved menaquinone-4 biosynthesis in Bacillus subtilis
2020, Enzyme and Microbial Technology
Menaquinone-4 (MK-4), one form of vitamin K, plays an important role in cardiovascular and bone health. Menaquinone-4 (MK-4) is a valuable vitamin K2 that is diﬃcult to synthesize organically, and now is mainly produced by microbial fermentation. Herein we significantly improved the synthesis efficiency of MK-4 by combinatorial pathway engineering in Bacillus subtilis 168, a model industrial strain widely used for production of nutraceuticals. The metabolic networks related to MK-4 synthesis include four modules, namely, MK-4 biosynthesis module, methylerythritol phosphate (MEP) module, mevalonate-dependent (MVA) isoprenoid module, and menaquinone module. Overexpression of menA, menG, and crtE genes from Synechocystis sp. PCC 6803 in MK-4 synthesis module with strong constitutive promoter P₄₃ resulted in 8.1 ± 0.2 mg/L of MK-4 (No MK-4 was detected in the wild-type B. subtilis 168). MK-4 titer was further increased by 3.8-fold to 31.53 ± 0.95 mg/L by knockout of hepT gene, which catalyzes the conversion of Farnesyl diphosphate to Heptaprenyl diphosphate. In addition, simultaneous overexpression of dxs, dxr, and ispD-ispF genes in MEP module with strong promoter P₄₃ increased the titer of MK-4 to 78.1 ± 1.6 mg/L. Moreover, expression of the heterogeneous MVA module genes (mvaK1, mvaK2, mvaD, mvaS, and mvaA) resulted in 90.1 ± 1.7 mg/L of MK-4. Finally, in order to further convert the enhanced carbon metabolism flux to MK-4, simultaneous overexpression of the genes crtE, menA, and menG in menaquinone pathway with strong promoter P₄₃ increased the titer of MK-4 to 120.1 ± 0.6 mg/L in shake flask and 145 ± 2.8 mg/L in a 3-L fed-batch bioreactor. Herein the engineered B. subtilis strain may be used for the industrial production of MK-4 in the future.
Reversed phase UPLC/APCI-MS determination of Vitamin K<inf>1</inf> and menaquinone-4 in human plasma: Application to a clinical study
2020, Journal of Pharmaceutical and Biomedical Analysis
A rapid and sensitive liquid chromatographic-tandem mass spectrometric method was developed and validated to simultaneously quantitate vitamin K₁ (PK) and vitamin K₂ (MK-4) concentrations in human plasma to evaluate nutritional interventions. Charcoal-stripped human plasma was used for standard and calibration preparation with vitamin E-d6 as the internal standard. Patient plasma samples were extracted using n-hexane and analytes separated using an ACE –PFP C18 column (50 × 2.1 mm, 3 μ) equipped with standard C₁₈ guard. The mobile phase consisted of 0.1 % formic acid in water and 0.1 % formic acid in methanol at a flow rate of 0.5 mL/min. Analyte quantification was achieved by using MS/MS with a positive atmospheric pressure chemical ionization in multiple reaction monitoring (MRM) mode. The lower limit of quantification was 0.01 ng/mL for both PK and MK-4. The assay was linear over the concentration range from 0.01–50 ng/mL for all analytes with a determination coefficient (r²) of 0.998 or better. The intra-and inter-day accuracy and precision were within the acceptable limits per FDA guidance. The validated method was successfully applied to a clinical study for quantification of PK and MK-4 in human plasma to assess nutritional status and dietary interventions in patients with neurodegenerative diseases. Baseline plasma concentrations of PK and MK-4 ranged from 0.23 to 1.81 ng/mL and 0.33–0.57 ng/mL, respectively.

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Beyond deficiency: new roles for vitaminsVitamin K and bone health

Abstract

Section snippets

Dedication

Dietary sources of vitamin K

Mechanisms

Vitamin K status and bone health

Intervention studies

Safety

Conclusions

Am J Clin NutrBone

Am J Clin NutrBone

J Nutr

Mayo Clin Proc

J Nutr

J Nutr

Bone

Am J Clin Nutr

Lancet

Nutr Health

Biochem Pharmacol

Cytokine

Bone

Gynecol Obstet

Metabolism

Bone

Am J Clin Nutr

Am J Clin Nutr

Nutrition

Am J Med

Lancet

Am J Clin Nutr

Bone

Bone

J Orthop Sci

Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. WHO Technical Report Series 843

Clinical application of bone densitometry

How many women have osteoporosis now?

J Bone Miner Res

The worldwide problem of osteoporosisinsights afforded by epidemiology

Bone

The future of hip fractures in the United States

Clin Orthop

Epidemiology of osteoporosis

Nutrition in bone health revisitedA story beyond calcium

J Am Coll Nutr

Nutrition, and Osteoporosis

Bone healththe role of micronutrients

Br Med Bull

The role of vitamins in the prevention of osteoporosis—a brief status report

Int J Vitam Nutr Res

Nutrition, life style and quality of life

Scand J Rheumatol

Nutritional intake of vitamin K1 (phylloquinone) and K2 (menaquinone) in the Netherlands

J Nutr Environ Med

The importance of menaquinones in human nutrition

Annu Rev Nutr

The vitamin K-dependent proteinsan update

Nutr Rev

Beyond deficiency: new roles for vitamins
Vitamin K and bone health

Nutritional intake of vitamin K₁ (phylloquinone) and K₂ (menaquinone) in the Netherlands