Research Notes: Vitamin K (Phylloquinone and Menaquinones)

From Treatment of Mitochondrial Cytopathies (Medscape Pediatrics)

In vitro studies show that in the presence of complex I inhibitors, vitamin K₃ (menadione) stimulates oxygen utilization in mitochondria, resulting in an increase of NADH oxidation.[62] One group of investigators utilized 31P nuclear magnetic resonance to assess the response to treatment with menadione (40 to 80 mg per day) and ascorbate (4 g per day) of a 19-year-old patient with mitochondrial myopathy associated with complex III deficiency. This treatment approach resulted in both clinical and metabolic improvement that persisted at 1-year follow-up. She was no longer wheelchair-bound though overall her weakness remained unchanged. The clinical improvements were supported by 31P NMR data, which revealed an increase in phosphocreatine concentration at rest and postexercise. A doubling of the initial dose of K₃ improved the phosphorous NMR spectra even further without apparent side effects. Symptoms deteriorated with withdrawal of treatment with recovery of function once reinstated.[63,64]

Toscano et al[65] treated a 16-year-old girl with ataxia, myoclonus, lactic acidosis, and complex III deficiency with vitamins K₃ (40 mg per day) and C (4 g per day). There was no significant change in lactic acidosis but there was mild improvement of her ataxia. After 5 months of therapy, the brain 31P-MRS indices were restored to normal. Skeletal muscle evaluation, though, revealed only slight improvement of mitochondrial bioenergetics.

One larger trial in which patients were treated with 60 mg per day of menadione and 2 g per day of vitamin C (in addition to multiple other supplements) did not substantiate the therapeutic benefit seen by these other investigators.[33]

K₃ is known to cause hemolytic anemia, hyperbilirubinemia, and kernicterus and is therefore contraindicated for neonates, pregnant females, or those being treated with coumadin. It is also difficult to find, and K₁, the common form of vitamin K, may have no benefit. As a practical alternative, CoQ10 may provide the same benefit.

Osteoporos Int. 2007 Jul.
Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women.
Knapen MH, Schurgers LJ, Vermeer C.
CARIM, University of Maastricht, Maastricht, The Netherlands.
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SUMMARY: Vitamin K mediates the synthesis of proteins regulating bone metabolism. We have tested whether high vitamin K(2) intake promotes bone mineral density and bone strength. Results showed that K(2) improved BMC and femoral neck width, but not DXA-BMD. Hence high vitamin K(2) intake may contribute to preventing postmenopausal bone loss. INTRODUCTION: Vitamin K is involved in the synthesis of several proteins in bone. The importance of K vitamins for optimal bone health has been suggested by population-based studies, but intervention studies with DXA-BMD as a clinical endpoint have shown contradicting results. Unlike BMC, DXA-BMD does not take into account the geometry (size, thickness) of bone, which has an independent contribution to bone strength and fracture risk. Here we have tested whether BMC and femoral neck width are affected by high vitamin K intake. METHODS: A randomized clinical intervention study among 325 postmenopausal women receiving either placebo or 45 mg/day of vitamin K(2) (MK-4, menatetrenone) during three years. BMC and hip geometry were assessed by DXA. Bone strength indices were calculated from DXA-BMD, femoral neck width (FNW) and hip axis length (HAL). RESULTS: K(2) did not affect the DXA-BMD, but BMC and the FNW had increased relative to placebo. In the K(2)-treated group hip bone strength remained unchanged during the 3-year intervention period, whereas in the placebo group bone strength decreased significantly. CONCLUSIONS: Vitamin K(2) helps maintaining bone strength at the site of the femoral neck in postmenopausal women by improving BMC and FNW, whereas it has little effect on DXA-BMD.

Eur J Pediatr. 2007 Mar 1.
Incidence of late vitamin K deficiency bleeding in newborns in the Netherlands in 2005: evaluation of the current guideline.
Ijland MM, Pereira RR, Cornelissen EA.
Department of Paediatrics 833, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500, HB, Nijmegen, The Netherlands.

Vitamin K prophylaxis is recommended to prevent the hazard of haemorrhage caused by vitamin K deficiency in newborns. The present Dutch guideline recommends 1 mg of vitamin K(1) orally at birth, followed by a daily dose of 25 mug of vitamin K(1) from 1 to 13 weeks of age for breastfed infants. Since the introduction of this prophylaxis, the incidence of vitamin K deficiency bleeding (VKDB) has decreased; however, late VKDB is still reported. From 1 January to 31 December 2005, a nationwide active surveillance was performed by the Netherlands Paediatric Surveillance Unit (NSCK) to study the current incidence and aetiology of late VKDB in infants. Six cases could be validated as late VKDB: all were breastfed, one fatal idiopathic intracranial haemorrhage at the age of 5 weeks and five bleedings secondary to an underlying cholestatic liver disease between the age of 3 and 7 weeks. The total incidence of late VKDB and idiopathic late VKDB was calculated to be 3.2 (95% CI: 1.2-6.9) and 0.5 (95% CI: 0-2.9) per 100,000 live births, respectively. With the current Dutch guideline, idiopathic late VKDB is rare but late VKDB secondary to cholestasis still occurs in breastfed infants. Doubling the daily dose of vitamin K(1) to 50 mug, as is comparable to formula-feeding, may possibly prevent VKDB in this group. Further research, however, is needed to prove this hypothesis.

Pediatr Res. 2007 Mar.
Pronounced elevation of undercarboxylated osteocalcin in healthy children.
van Summeren M, Braam L, Noirt F, Kuis W, Vermeer C.
Department of Pediatric Immunology, University Medical Centre Utrecht, 3584 EA Utrecht, The Netherlands.

The vitamin K-dependent protein osteocalcin is thought to play an important role in bone metabolism. Osteocalcin contains glutamic acid (Gla) residues, which have a high affinity for calcium. Vitamin K acts as an indispensable cofactor for the formation of these residues. Inadequate dietary vitamin K intake results in the synthesis of undercarboxylated (i.e. inactive) osteocalcin (ucOC). In adults, low vitamin K status of bone is associated with low bone density and increased risk of osteoporotic fractures. Little is known about vitamin K status and bone health in children. We used a cross-sectional study design to compare the vitamin K status of bone in healthy children (n = 86) with that of adults (n = 30). In children, a marked elevation of the ratio of ucOC/carboxylated osteocalcin (cOC), indicative of a poor vitamin K status, was observed. This difference persisted after adjusting for age, gender, puberty, height, weight. Furthermore, a marked correlation between the bone markers for bone metabolism and ucOC and cOC was found in the children's group. These findings suggest a pronounced low vitamin K status of bone during growth. The question remains, however, whether children would benefit from higher vitamin K intake, for instance, by improved bone health or stronger bones.

Comment: Given that vitamin K is mainly found in green vegetables and that these days most children's diets are woefully deficient in such veggies, it doesn't strike me as surprising that ucOC levels were found to be high in children in this study.

Yonsei Med J. 2006 Apr 30.
Effects of vitamin K2 on the development of osteopenia in rats as the models of osteoporosis.
Iwamoto J, Takeda T, Sato Y.
Department of Sports Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
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Vitamin K2 is widely used for the treatment of osteoporosis in Japan. To understand the effects of vitamin K2 on bone mass and bone metabolism, we reviewed its effects on the development of osteopenia in rats, which characterizes models of osteoporosis. Vitamin K2 was found to attenuate the increase in bone resorption and/or maintain bone formation, reduce bone loss, protect against the loss of trabecular bone mass and its connectivity, and prevent the decrease in strength of the long bone in ovariectomized rats. However, combined treatment of bisphosphonates and vitamin K2 had an additive effect in preventing the deterioration of the trabecular bone architecture in ovariectomized rats, while the combined treatment of raloxifene and vitamin K2 improved the bone strength of the femoral neck. The use of vitamin K2 alone suppressed the increase in trabecular bone turnover and endocortical bone resorption, which attenuated the development of cancellous and cortical osteopenia in orchidectomized rats. In addition, vitamin K2 inhibited the decrease in bone formation in prednisolone-treated rats, thereby preventing cancellous and cortical osteopenia. In sciatic neurectomized rats, vitamin K2 suppressed endocortical bone resorption and stimulated bone formation, delaying the reduction of the trabecular thickness and retarding the development of cortical osteopenia. Vitamin K2 also prevented the acceleration of bone resorption and the reduction in bone formation in tail-suspended rats, which counteracted cancellous bone loss. Concomitant use of vitamin K2 with a bisphosphonate ameliorated the suppression of bone formation and more effectively prevented cancellous bone loss in tail-suspended rats. Vitamin K2 stimulated renal calcium reabsorption, retarded the increase in serum parathyroid hormone levels, and attenuated cortical bone loss primarily by suppressing bone resorption in calcium-deficient rats while maintaining the strength of the long bone in rats with magnesium deficiency. These findings suggest that vitamin K2 may not only stimulate bone formation, but may also suppress bone resorption. Thus, vitamin K2 could regulate bone metabolism in rats, which represented the various models of osteoporosis. However, the effects of vitamin K2 on bone mass and bone metabolism seem to be modest.

J Mol Cell Cardiol. 2005 Jul.
Effects of menadione and its derivative on cultured cardiomyocytes with mitochondrial disorders.
Shneyvays V, Leshem D, Shmist Y, Zinman T, Shainberg A.
Gonda (Goldschmied) Medical Diagnostic Research Center, Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.

Mitochondrial disorder is characteristic of many myocardial injuries such as endotoxemia, shock, acidosis, ischemia/reperfusion, and others. The goal of possible therapy is to increase ATP production. Derivatives of vitamins K may be a potent electron carrier between various mitochondrial electron-donating and electron-accepting enzyme complexes. We aimed to test the possibility that menadione or its water-soluble derivative AK-135, the newly synthesized analogues of vitamin K1 - N-derivatives of 2-methyl-3-aminomethyl 1.4-naphthoquinone, would reduce cardiomyocyte damage after hypoxia or mitochondrial respiratory chain inhibition in culture. Menadione, and more effectively, AK-135, restored the electron flow in defective respiratory chain (hypoxia or rotenone) systems. As was shown in this study, 3 microM of AK-135 restored ATP production after blockade of electron flow through mitochondrial complex I with 5 microM rotenone up to 13.18+/-1.56 vs. 3.21+/-1.12 nmol/mg protein in cells treated with rotenone only. In cultures pretreated with 4 microM dicumarol (DT-diaphorase inhibitor), the protective effect of AK-135 and menadione was abolished completely (1.67+/-1.43 and 2.97+/-0.57 nmol/mg protein, respectively). Inhibition of mitochondrial oxidative phosphorylation caused an increase in intracellular Ca(2+) levels. Here we have demonstrated restoration of calcium oscillations and cardiomyocyte contractility by menadione and its derivative after blockade of NADH: ubiquinone oxidoreductase with rotenone, and decrease of Ca(2+) overloading during hypoxia.

Eur J Nutr. 2004 Dec.
Beyond deficiency: potential benefits of increased intakes of vitamin K for bone and vascular health.
Vermeer C, Shearer MJ, Zittermann A, Bolton-Smith C, Szulc P, Hodges S, Walter P, Rambeck W, Stöcklin E, Weber P.
Dept. of Biochemistry, University of Maastricht, P. O. Box 616, 6200 MD Maastricht, The Netherlands.

Vitamin K is well known for its role in the synthesis of a number of blood coagulation factors. During recent years vitamin K-dependent proteins were discovered to be of vital importance for bone and vascular health. Recommendations for dietary vitamin K intake have been made on the basis of the hepatic requirements for the synthesis of blood coagulation factors. Accumulating evidence suggests that the requirements for other functions than blood coagulation may be higher. This paper is the result of a closed workshop (Paris, November 2002) in which a number of European vitamin K experts reviewed the available data and formulated their standpoint with respect to recommended dietary vitamin K intake and the use of vitamin K-containing supplements.

Neuroreport. 2004 Oct 5.
Menadione reduces rotenone-induced cell death in cerebellar granule neurons.
Isaev NK, Stelmashook EV, Ruscher K, Andreeva NA, Zorov DB.
Department of Bioenergetics, AN Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia.

Oxidative stress has been implicated in neuronal death caused by cerebral ischemia or some neurologic disorders. Chemical hypoxia (term defining the simulation by using respiratory inhibitors) chosen as in vitro ischemic model, was induced in primary cultures of rat cerebellar granule neurons by inhibitors of mitochondrial electron transport such as rotenone or paraquat (complex I), 3-nitropropionic acid (3-NPA, complex II), antimycin A (complex III), or sodium azide (complex IV). All compounds caused neuronal death determined by trypan blue staining and MTT-test. On the other hand, neurotoxicity of rotenone and paraquat but not of 3-NPA, antimycin or azide was significantly abolished by menadione (vitamin K3, 2-methyl-1,4-naphthoquinone). This neuroprotective effect of menadione was associated with a decrease of rotenone-induced free radical production.

Am J Clin Nutr. 2004 Oct.
Vitamin K, bone turnover, and bone mass in girls.
Kalkwarf HJ, Khoury JC, Bean J, Elliot JG.
Children's Hospital Medical Center, Cincinnati, USA.
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BACKGROUND: Vitamin K has been suggested to have a role in bone metabolism, and low vitamin K intake has been related to low bone density and increased risk of osteoporotic fracture. OBJECTIVE: The objective of this study was to determine whether phylloquinone (vitamin K(1)) intake and biochemical indicators of vitamin K status are related to bone mineral content (BMC) and markers of bone formation and bone resorption in girls. DESIGN: Vitamin K status [plasma phylloquinone concentration and percentage of undercarboxylated osteocalcin (%ucOC)] was measured at baseline in a study of 245 healthy girls aged 3-16 y. Cross-linked N-telopeptide of type 1 collagen (NTx) breakdown, osteocalcin, and bone-specific alkaline phosphatase were measured to reflect bone resorption and formation. BMC of the total body, lumbar spine, and hip and dietary phylloquinone intake were measured annually for 4 y. RESULTS: Phylloquinone intake (median: 45 microg/d) was not consistently associated with bone turnover markers or BMC. Better vitamin K status (high plasma phylloquinone and low %ucOC) was associated with lower bone resorption and formation. Plasma phylloquinone was inversely associated with NTx and osteocalcin concentrations (P < 0.05), and %ucOC was positively associated with NTx and bone-specific alkaline phosphatase concentrations (P < 0.05). Indicators of vitamin K status were not consistently associated with current BMC or gain in BMC over the 4-y study period. CONCLUSIONS: Better vitamin K status was associated with decreased bone turnover in healthy girls consuming a typical US diet. Randomized phylloquinone supplementation trials are needed to further understand the potential benefits of phylloquinone on bone acquisition in growing children.

Mol Genet Metab. 2004 Apr.
Cofactor treatment improves ATP synthetic capacity in patients with oxidative phosphorylation disorders.
Marriage BJ, Clandinin MT, Macdonald IM, Glerum DM.
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

Marked progress has been made over the past 15 years in defining the specific biochemical defects and underlying molecular mechanisms of oxidative phosphorylation disorders, but limited information is currently available on the development and evaluation of effective treatment approaches. Metabolic therapies that have been reported to produce a positive effect include coenzyme Q(10) (ubiquinone), other antioxidants such as ascorbic acid and vitamin E, riboflavin, thiamine, niacin, vitamin K (phylloquinone and menadione), and carnitine. The goal of these therapies is to increase mitochondrial ATP production, and to slow or arrest the progression of clinical symptoms. In the present study, we demonstrate for the first time that there is a significant increase in ATP synthetic capacity in lymphocytes from patients undergoing cofactor treatment. We also examined in vitro cofactor supplementation in control lymphocytes in order to determine the effect of the individual components of the cofactor treatment on ATP synthesis. A dose-dependent increase in ATP synthesis with CoQ(10) incubation was demonstrated, which supports the proposal that CoQ(10) may have a beneficial effect in the treatment of oxidative phosphorylation (OXPHOS) disorders.

Curr Pharm Des. 2004.
Effects of vitamin K2 on osteoporosis.
Iwamoto J, Takeda T, Sato Y.
Department of Sports Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.

Vitamin K2 is a cofactor of gamma-carboxylase, which converts the glutamic acid (Glu) residue in osteocalcin molecules to gamma-carboxyglutamic acid (Gla), and is, therefore, essential for gamma-carboxylation of osteocalcin. Available evidence suggests that vitamin K2 also enhances osteocalcin accumulation in the extracellular matrix of osteoblasts in vitro. Osteocalcin-knockout mice develop hyperostosis, suggesting that the Gla-containing osteocalcin promotes normal bone mineralization. Although the precise role of osteocalcin in bone mineralization remains obscure, it probably regulates the growth of hydroxyapatite crystals. Furthermore, vitamin K2 also inhibits the expression of the osteoclast differentiation factor (ODF)/RANK ligand, tartrate-resistant acid phosphatase activity, and mononuclear cell formation, and induces osteoclast apoptosis in vitro. There is some evidence indicating that vitamin K2 prevents bone resorption in ovariectomized rats, retards the increase in bone turnover in orchidectomized rats, ameliorates the increase in bone resorption and decrease in bone formation in sciatic neurectomized rats, and prevents the decrease in bone formation in glucocorticoid-treated rats. These findings suggest that vitamin K2 may not only stimulate bone formation but also suppress bone resorption in vivo. Clinically, vitamin K2 sustains the lumbar bone mineral density (BMD) and prevents osteoporotic fractures in patients with age-related osteoporosis, prevents vertebral fractures in patients with glucocorticoid-induced osteoporosis, increases the metacarpal BMD in the paralytic upper extremities of patients with cerebrovascular disease, and sustains the lumbar BMD in patients with liver-dysfunction-induced osteoporosis. Vitamin K deficiency, as indicated by an increased circulating level of undercarboxylated osteocalcin, may contribute to osteoporotic fractures. Even though the effect of vitamin K2 on the BMD is quite modest, this vitamin may have the potential to regulate bone metabolism and play a role in reducing the risk of osteoporotic fractures. No randomized well-controlled prospective studies conducted on a sufficiently large number of patients have been reported yet, therefore, further studies are needed to confirm the efficacy of vitamin K2 in the treatment of osteoporosis.

Eur J Pediatr. 2003 Dec.
Prevention of vitamin K deficiency bleeding with oral mixed micellar phylloquinone: results of a 6-year surveillance in Switzerland.
Schubiger G, Berger TM, Weber R, Bänziger O, Laubscher B; Swiss Paediatric Surveillance Unit.
Department of Paediatrics, Children's Hospital of Lucerne, 6000, Lucerne 16, Switzerland.

In 1995, a new form of vitamin K prophylaxis with two oral doses of 2 mg mixed micellar phylloquinone (Konakion MM) on the 1st and 4th day of life was introduced in Switzerland. It was hoped that this new galenic preparation of phylloquinone would protect infants with insufficient or absent bile acid excretion from late vitamin K deficiency bleeding (VKDB). Subsequently, the occurrence of VKDB was monitored prospectively between July 1, 1995 and June 30, 2001 with the help of the Swiss Paediatric Surveillance Unit (SPSU). Over a period of 6 years (475,000 deliveries), there were no cases of early (<24 h of age), one case of classical (2-7 days of life), and 18 cases of late (1-12 weeks) VKDB fulfilling standard case definitions. In 13/18 patients with late VKDB there was pre-existing liver disease and in 4/18 patients, parents had refused prophylaxis. The incidence of late VKDB for infants with completed Konakion MM prophylaxis was 2.31/100,000 (95% CI: 1.16-4.14) and for the entire population 3.79/100,000 (95% CI: 2.24-5.98). There was only one case of late VKDB after complete prophylaxis in an infant without underlying liver disease. Conclusion: two oral doses of 2 mg of a mixed micellar vitamin K preparation failed to abolish VKDB. The recommendations for vitamin K prophylaxis in Switzerland have therefore been changed to include a third dose at 4 weeks of age. Starting on January 1, 2004, the incidence of vitamin K deficiency bleeding will again be monitored prospectively by the Swiss Paediatric Surveillance Unit.

Proc Nutr Soc. 2003 Nov.
Vitamin K and bone health.
Bügel S.
Department of Human Nutrition, The Royal Veterinary and Agricultural University, Rolighedsvej 30, 1958 Frederiksberg C, Denmark.

Vitamin K, originally recognised as a factor required for normal blood coagulation, is now receiving more attention in relation to its role in bone metabolism. Vitamin K is a coenzyme for glutamate carboxylase, which mediates the conversion of glutamate to gamma-carboxyglutamate (Gla). Gla residues attract Ca2+ and incorporate these ions into the hydroxyapatite crystals. There are at least three Gla proteins associated with bone tissue, of which osteocalcin is the most abundant and best known. Osteocalcin is the major non-collagenous protein incorporated in bone matrix during bone formation. However, approximately 30% of the newly-produced osteocalcin stays in the circulation where it may be used as an indicator of bone formation. Vitamin K deficiency results in an increase in undercarboxylated osteocalcin, a protein with low biological activity. Several studies have demonstrated that low dietary vitamin K intake is associated with low bone mineral density or increased fractures. Additionally, vitamin K supplementation has been shown to reduce undercarboxylated osteocalcin and improve the bone turnover profile. Some studies have indicated that high levels of undercarboxylated osteocalcin (as a result of low vitamin K intake?) are associated with low bone mineral density and increased hip fracture. The current dietary recommendation for vitamin K is 1 microg/kg body weight per d, based on saturation of the coagulation system. The daily dietary vitamin K intake is estimated to be in the range 124-375 microg/d in a European population. Thus, a deficiency based on the hepatic coagulation system would be unusual, but recent data suggest that the requirement in relation to bone health might be higher.

Semin Thromb Hemost. 2003 Aug.
New aspects of vitamin K prophylaxis.
Sutor AH.
Section of Pediatric Hematology, Universitäts-Kinderklinik Freiburg, Freiburg, Germany.

Vitamin K-deficiency bleeding (VKDB) is rare, unpredictable, and life-threatening. Warning signs such as minimal bleeds, evidence of cholestasis, and failure to thrive often are present but overlooked. Therefore VK prophylaxis is necessary, at least for breastfed infants. Most effective is the intramuscular application, which unfortunately has real disadvantages (trauma, poor acceptance by parents) and potential risks due to very high VK levels, since VK affects not only coagulation but all processes associated with carboxylation. Three oral doses of VK protect many babies (2-mg doses giving better protection than 1 mg) but the prevention of VKDB is not assured even with the mixed-micelle preparation. Use of small VK doses either daily or weekly seems to give effective prophylaxis without the adverse effects of intramuscular VK application. The risks of VKDB are minimized if prophylaxis recommendations are followed and if warning signs are recognized and promptly acted upon. The next goal is the search for methods of identifying early the few infants destined to bleed so that targeted prophylaxis can replace the current "prophylaxis for all."

J Am Diet Assoc. 2003 Aug.
Nutritional cofactor treatment in mitochondrial disorders.
Marriage B, Clandinin MT, Glerum DM.
Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.

Mitochondrial disorders are degenerative diseases characterized by a decrease in the ability of mitochondria to supply cellular energy requirements. Substantial progress has been made in defining the specific biochemical defects and underlying molecular mechanisms, but limited information is available about the development and evaluation of effective treatment approaches. The goal of nutritional cofactor therapy is to increase mitochondrial adenosine 5'-triphosphate production and slow or arrest the progression of clinical symptoms. Accumulation of toxic metabolites and reduction of electron transfer activity have prompted the use of antioxidants, electron transfer mediators (which bypass the defective site), and enzyme cofactors. Metabolic therapies that have been reported to produce a positive effect include Coenzyme Q(10) (ubiquinone); other antioxidants such as ascorbic acid, vitamin E, and lipoic acid; riboflavin; thiamin; niacin; vitamin K (phylloquinone and menadione); creatine; and carnitine. A literature review of the use of these supplements in mitochondrial disorders is presented.

Acta Paediatr. 2003 Jul.
Weekly oral vitamin K prophylaxis in Denmark.
Hansen KN, Minousis M, Ebbesen F.
Department of Paediatrics, Viborg-Kjellerup Hospital, Denmark.

AIM: To evaluate oral vitamin K prophylaxis at birth by giving 2 mg phytomenadione, followed by weekly oral vitamin K prophylaxis; 1 mg was administered by the parents until 3 mo of age. METHODS: A total of 507850 live babies were born in Denmark during the study period, November 1992 to June 2000. Of these infants, 78% and 22% received oral and intra-muscular prophylaxis, respectively; i.e. about 396000 neonates received oral prophylaxis at birth. Weekly oral prophylaxis was recommended for all infants as long as they were mainly breastfed. A survey of possible cases of vitamin K deficiency bleeding (VKDB) was carried out by repeated questionnaires to all Danish paediatric departments and by checking the National Patient Register. RESULTS: No cases of VKDB were revealed, i.e. the incidence was 0-0.9:100000 (95% CI). The questionnaires were used to evaluate compliance with the regimen. Parents of 274 infants participated. A dose of vitamin K was regarded as having been given if the infant received a drop of vitamin K or was mostly formula-fed that week, and the prophylaxis was regarded as completed if the infant had received at least 9 doses. Compliance was good, with 94% of the infants completing the course of prophylaxis. CONCLUSION: Weekly oral vitamin K supplementation during the first 3 mo of life was an efficient prophylaxis against VKBD. Parental compliance with the regimen was good.

Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2003 Jun.
Vitamin K and osteoporosis. [Article in Chinese]
Luo LZ, Xu L.
Department of Scientific Research, PUMC Hospital, CAMS, PUMC, Beijing, China.

There is a closely relationship between vitamin K and osteoporosis. As a cofactor for carboxylase activity, vitamin K can facilitate the conversion of glutamyl to gamma-carboxyglutamyl residues and influence the synthesis and excretion of gamma-carboxylation of osteocalcin to increase the formation of bone. Vitamin K can also effectively inhibit the absorption of bone mass. Besides, there are increasing evidences that vitamin K can effect the synthesis and excretion of nephrocalcin and interlukin-1,6 that can regulate calcium balance and bone metabolism. Meanwhile, there is a consistent line of evidence in human epidemiologic and intervention studies that clearly demonstrate that vitamin K can not only increase bone mineral density in osteoporotic people, but also reduce fracture rates to improve bony health. However more researches are required before vitamin K is widely applied in prevention and treatment of osteoporosis. The American Medical Association recently has increased the dietary reference intakes of vitamin K to 90 mg/d for females and 120 mg/d for males.

Curr Opin Clin Nutr Metab Care. 2001 Nov.
Effects of vitamin K on calcium and bone metabolism.
Zittermann A.
Department of Nutrition Science, University of Bonn, Germany.

The K vitamins, a group of napthoquinones, are required for the carboxylation of a limited number of proteins including the bone matrix protein osteocalcin. Vitamin K1 (phylloquinone) and vitamin K2 (menaquinones), differ regarding food source (green vegetables and fermented products, respectively), bioavailability and intermediate metabolism. Epidemiological studies provide evidence for an association between a low vitamin K intake and an enhanced osteoporotic fracture risk. Doses of vitamin K1 up to 15 times the current recommended dietary allowance have successfully been used to reduce the percentage of undercarboxylated osteocalcin in the circulation. Studies demonstrating clear beneficial effects on bone health, however, are still lacking. In contrast, therapy with very high pharmacological doses of the vitamin K2 menatetrenone has impressively been used to prevent further bone mineral loss and fracture risk in osteoporotic patients.

Paediatr Drugs. 2001.
Vitamin K in neonates: how to administer, when and to whom.
Autret-Leca E, Jonville-Béra AP.
Department of Clinical Pharmacology, H pital Bretonneau, University François Rabelais, Tours, France.

Vitamin K-dependent factors are lower in neonates than in adults, and these anomalies are more prevalent in preterm neonates and in breast-fed infants. Vitamin K deficiency can account for vitamin K deficiency bleeding (VKDB) which occurs in 3 forms - early, classic and late. Vitamin K should be administered to all neonates at birth or immediately afterwards. However, the protocols for administration (route of administration, dosage, number of doses) remain a subject of discussion. Oral administration of a single dose of vitamin K protects against classical and early VKDB, but is less effective than intramuscular (IM) prophylaxis for the prevention of late VKDB. Although an increased risk of solid tumour, associated vitamin K administration, can be definitively excluded, a low potential risk of lymphoblastic leukaemia in childhood can not be ruled out. For formula-fed neonates without risk of haemorrhage, a 2 mg oral dose of vitamin K at birth, followed by a second 2 mg oral dose between day 2 and 7, is probably sufficient to prevent VKDB. For infants who are exclusively or nearly exclusively breast-fed, weekly oral administration of 2mg (or 25 microg/day) vitamin K after the initial 2 oral doses is justified at completion of breast-feeding. For neonates at high risk of haemorrhage (premature, neonatal disease, birth asphyxia, difficult delivery, any illness which will delay feeding, known hepatic disease, maternal drugs inhibiting vitamin K activity), the first dose must be administered by the IM or slow intravenous route. Doses should be repeated, particularly in premature infants, by a route of administration decided for each dose according to the clinical state of the infant. For infants of mothers treated with drugs inhibiting vitamin K activity, antenatal maternal prophylaxis (10 to 20 mg/day orally for 15 to 30 days before delivery) prevents early VKDB. After neonatal prophylaxis, as for infants at high risk of haemorrhage, doses need to be repeated at a rate and route of administration decided for each dose, according to the clotting factor profile specific for each infant.

Eur J Pediatr. 1999 Jul.
Oral vitamin K1 prophylaxis for newborns with a new mixed-micellar preparation of phylloquinone: 3 years experience in Switzerland.
Schubiger G, Stocker C, Bänziger O, Laubscher B, Zimmermann H.
Department of Paediatrics, Kinderspital, Luzern, Switzerland.

In 1995, a new water-soluble mixed-micellar analogue of vitamin K1 (Konakion MM paediatric) was introduced in Switzerland to replace the formerly used fat-soluble Konakion drops for the prevention of vitamin K1-deficiency-bleeding (VKDB) in infants. According to the new guidelines, an oral dose of 2 mg is given after birth and again on the 4th day of life. We examined the compliance with these guidelines and the impact on the incidence of VKDB. To assess compliance, questionnaires were sent to all hospitals with delivery services 6 months after the introduction of the new guidelines. Using the database of the Swiss Paediatric Surveillance Unit (SPSU) which records rare paediatric diseases, we assessed the incidence of VKDB in Switzerland between July 1995 and June 1998. In addition, we determined the precise circumstances under which the episodes of VKDB occurred. More than 99% of infants received vitamin K1 prophylaxis. Since July 1995, 93% of newborns have received prophylaxis according to the new guidelines; the remaining infants were given fat-soluble Konakion drops or parenteral vitamin K1. Within 3 years, one case of classical and 12 cases of late-onset VKDB (11 confirmed, 1 probable) were reported to the SPSU. Of the 11 confirmed late-onset cases, 7 received the recommended prophylaxis, whereas 3 had not and 1 had been given fat-soluble Konakion drops. All confirmed cases of late-onset VKDB occurred in fully breast-fed infants and 8 of 11 had hepatobiliary disease. CONCLUSION: With the introduction of two oral doses of a mixed-micellar vitamin K1 preparation administered in the 1st week of life, the incidence of late vitamin K1-deficiency-bleeding has decreased from 7.2:100,000 between 1986-1987 to 2.8:100,000 between 1995 and 1998. This regimen may be suitable for prophylaxis of vitamin K1-deficiency-bleeding, however, it does not fully protect infants with cholestatic disease from late-onset bleeding. If oral prophylaxis is considered for these infants, vitamin K1 has to be administered repeatedly to all infants during the breast feeding period.

Eur J Pediatr. 1997 Feb.
Prevention of vitamin K deficiency bleeding: efficacy of different multiple oral dose schedules of vitamin K.
Cornelissen M, von Kries R, Loughnan P, Schubiger G.
Department of Paediatrics, University Hospital Nijmegen, The Netherlands.

There is consensus that late vitamin K deficiency bleeding (VKDB) should be prevented by vitamin K prophylaxis. One single dose of 1 mg vitamin K1 is effective if given i.m. or s.c., but not if given orally. Repeated oral doses might be as effective as the parenteral dose but the optimal dose regimen remains to be established. Different oral dose schedules are presently used in different countries. In Australia, Germany, The Netherlands and Switzerland active surveillance data on late VKDB were collected in a similar manner and failure rates compared. Identical case definitions were used. There were three basic strategies for oral and one for parenteral vitamin K prophylaxis for healthy newborns in the four countries: (1) daily supplementation of low dose vitamin K (25 micrograms) for breast-fed infants (The Netherlands); (2) 3 x 1 mg orally [Australia (January 1993-March 1994) and Germany (December 1992-December 1994)]; (3) 1 mg vitamin K i.m. (Australia since March 1994); and (4) 2 x 2 mg vitamin K (new mixed micellar preparation) (Switzerland). The respective failure rates per 100,000 live births (including cases given all recommended doses and those given incomplete prophylaxis) were for strategy: (1) 0.2 (0-1.3) in The Netherlands; (2) 2.3 (95% CI 1.6-3.4) in Germany and 2.5 (1.1-4.8) in Australia (oral prophylaxis); (3) Australia (i.m. prophylaxis) 0 (0-0.9); and (4) 3.6 (0.7-10.6) in Switzerland. The failure rates for complete prophylaxis only were: strategy (1) 0 (0-0.7) in The Netherlands; (2) 1.8 (1.1-2.8) in Germany and 1.5 (0.5-3.6) in Australia; (3) Australia (i.m.) 0 (0-0.9); and (4) 1.2 (0-6.5) in Switzerland. Conclusions: The Australian data confirm that three oral doses of 1 mg vitamin K are less effective than i.m. vitamin K prophylaxis. A daily low oral dose of 25 micrograms vitamin K1 following an initial oral dose of 1 mg after birth for exclusively breast-fed infants may be as effective as parenteral vitamin K prophylaxis. The effectiveness of the "mixed-micellar" preparation of vitamin K1 needs further study.

J Nutr. 1996 Apr.
Effects of vitamin K on bone mass and bone metabolism.
Vermeer C, Gijsbers BL, Crāciun AM, Groenen-van Dooren MM, Knapen MH.
Department of Biochemistry and Cardiovascular Research Institute Maastricht, University of Limburg, The Netherlands.
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Vitamin K is involved in blood coagulation and in bone metabolism via the carboxylation of glutamate residues in (hepatic) blood coagulation factors and (osteoblastic) bone proteins. The bioavailability of nutritional vitamin K depends on the type of food, the dietary fat content, the length of the aliphatic side chain in the K-vitamer and probably also the genetically determined polymorphism of apolipoprotein E. Although undercarboxylation of blood coagulation factors is very rare, undercarboxylated osteocalcin (bone Gla-protein) is frequently found in postmenopausal women. Supplementation of these women with extra vitamin K causes the markers for bone formation to increase. In parallel, a decrease of the markers for bone resorption is frequently seen. Insufficient data are available to conclude that the regular administration of vitamin K concentrates will reduce the loss of bone mass in white women at risk for developing postmenopausal osteoporosis.

Semin Thromb Hemost. 1995.
Vitamin K deficiency bleeding in infants and children.
Sutor AH.
Universitäts-Kinderklinik, Freiburg, Germany.

The historical term "hemorrhagic disease of the newborn," which is used as a synonym for vitamin K deficiency bleeding (VKDB) in infancy, preferably should be abandoned, since neonatal bleeding is often not due to vitamin K (VK) deficiency and VKDB may occur after the neonatal period. VKDB is a form of bleeding that is caused by reduced activity of VK-dependent coagulation factors (II, VII, IX, X), has normal or even increased activity of VK-independent coagulation factors, and responds to VK. Acarboxy proteins are present. In a bleeding infant a prolonged one-stage prothrombin time (a decreased Quick value, which means prothrombin time expressed as percent of normal) in association with a normal (or increased) fibrinogen level and platelet count is almost diagnostic of VKDB. The diagnosis is proven, if administration of VK is followed by a shortening of the prothrombin time (after only 30 minutes) or cessation of bleeding. Classification is by age of onset as early, classic, and late form of VKDB. Rare cases of VKDB occur also after week 15; therefore the upper age limit should be 6 months and not 3 months. In idiopathic VKDB the cause (ther than breast-feeding) is unknown. In secondary VKDB additional factors can be demonstrated, such as poor intake or absorption of VK and increased consumption of VK. Most often cholestasis is present. Postnatal VK provides effective protection from the classic and late form of VKDB. The classic form can be prevented equally well by a single oral dose of 1 mg VK after birth as by parenteral VK. Parenteral prophylaxis appears to be more effective in preventing the late form, especially in patients with hepatobiliary disease. The protection achieved by single oral prophylaxis can be improved by repeated oral administration. In addition to reducing the incidence of VKDB, VK prophylaxis also reduced the proportion of intracranial hemorrhages and increases the age at onset of bleeding, parenteral prophylaxis being more effective than single oral prophylaxis in this respect. Because of the potential risks (cancer?) associated with extremely high levels of VK (20,000-fold the normal value for healthy newborns) and the possibility of injection injury, parenteral VK has been questioned as the first choice of prophylaxis for normal neonates. These disadvantages do not apply to oral prophylaxis. The major disadvantage of oral prophylaxis, namely, its lesser reliability in terms of intake and absorption, could be largely overcome by repeated administration. Although VK prophylaxis seems to be necessary only for breast-fed infants, breast-feeding should be promoted. As VK is involved not only in coagulation but also in carboxylation with multiple effects, care should be taken to avoid any excessive deviation from the physiologic conditions, that prevail in the fully breast-fed healthy mature infant, with low VK levels in the postnatal period. Repeated (daily or weekly) oral doses of VK are closer to physiologic conditions than single parenteral bolus doses, which expose neonates to excessively high VK levels. The incidence of intracranial VKDB can be reduced if the grave significance of warning signs is recognized (icterus, failure to thrive, feeding problems, minor, bleeding, diseases with cholestasis) or if a simple test for acarboxy proteins (similar to the Guthrie test) would be applicable. Whether or not the more reliable absorption of the new mixed micellar preparation of VK could reduce the protective oral dose of VK prophylaxis has to be evaluated.