Alternative Medicine Review Volume 14, Number 3 2009

Vitamin K2 K2 (Menatetrenone/MK4)

'CH2CH = C - (CH2CH2CH = C ) 3 -

IntroductionVitamin K is a fot-soluble vitamin essential for the functioning of several proteins involved in blood clotting.'

Discovered in 1929 by Danish scientist Henrik Dam, the vitamin received the letter"K" because the initial discoverieswere reported in a German journal in which the substance was designated as"Koagulationsvitamin." Research duringthe last 30 years has resulted in greater appreciation for vitamin K. For instance, although vitamin K is usually identi-fied as a critical factor in blood coagulation, recent research reveals it is a cofactor in bone metabolism.^ " Inhibition ofcancerous cell growth in vivo and in vitro by vitamin K has also been observed.'^ ' Furthermore, recent findings suggestit may be an important cofactor in the treatment and prevention of atherosclerosis and calcified arterial plaque.'^'^" Tbeprimary dietary source of vitamin K is generally green leaiy vegetables. Consequently, high vitamin K intake may serveas a marker for a healthy diet rich in vegetables.''^

BiochemistryVitamin K2 is part of a family of structurally similar fat-soluble, 2-mctbyl-l,4-naphthoquinones that include

phylloquinone (Kl), menaquinones (K2), atid menadione (K3). l l ie members of tbe vitamin K family possess anidentical naphthoquinone skeleton with various side chains that distinguish them. Tlie best-known member oí thevitamin K family is phylloquinone, also known as phytonadione or menaphthone. so named because of its intimaterelationship with photosynthesis in plant leaves. Phylloquinone is found in many higher plants as well as algae, withthe highest concentrations found in green leafy vegetables. *'

Menaquinones also occur naturally, but are not produced by plants; ratber, they are produced by a vast array ofbacteria. Menaquinones were originally isolated from putrefied fisbmeal as a product of microbial synthesis.^' Recentstudies have discovered menaquinones can actually be produced by animals and probably humans from the conver-sion of other forms of vitamin K.- " The most common form of vitamin K in animals is menaquinone-4 (MK-4),produced by intestinal bacteria from exogenous naphthoquinones and transformed endogenously in our own cells. ''

PharmacokineticsVitamin Kl is absorbed from the gastrointestinal tract in the presence of bile salts and pancreatic Iipase. Once

absorbed, vitamin K accumulates in the liver, spleen, and lungs, but significant amounts are not stored in the body forlong periods.

Tlie action of vitamin Kl , wben administered parenterally, is generally detectable within 1-2 hours, and hem-orrhage is usually controlled within 3-8 hours. A normal prothrombin level may often be obtained in 12-14 hours.^^

The pharmacokinetics of supplemental vitamin K2 is not yet clearly understood, although its clinical efficacy

is evident.

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Mechanisms of ActionVitamin K ¡s a cofactor in a number of bio-

chemical pathways. Tliose most commonly associatedwith vitamin K are the vitamin K-dependent carboxyl-ation reactions. In these reactions the reduced form ofvitamin K (hydroquinone) de-protonates glutamate viathe ganinia-glutamyl carboxylase enzyme. Tlie epoxideformed is recycled via vitamin K epoxide reductase andquinone reductase, and glutamic acid-containing pro-teins, such as coagulation factors II (prothrombin), VII,IX, and X, protein C, and protein S, are carboxylated.Compared to the other vitamin K analogues, vitaminK2 has the most potent gamma-carboxylation activity. ^

Vitamin K fijnctions in the post-translationalmodification of a number of vitamin K-dependentproteins such as osteocalcin, a bone protein contain-ing gamma-carboxyglutamic acid, discovered in 1975."Gamma-carboxylation oí the glutamic acid in osteocal-cin is vitamin K dependent and involves the conversionof glutamic acid residues (Glu) to gamma-carboxyglu-tamic acid residues (Gla). A number of calcium-bind-ing proteins, such as calblndin and osteocalcin, containgamma-carboxyglutamate. Tliese proteins are involvedwith calcium uptake and bone mineralization, Osteo-calcin is synthesized in osteoblasts.'** Because osteocal-cin that is not carboxylated cannot bind to hydroxyapa-tlte, serum levels oí osteocalcin are a good biochemicalmnrkcr ot the metabolic turnover of bone. '*

Unlike blood coagulation proteins, which needmuch lower levels of vitamin K for complete gamma-carboxylation, higher levels of vitamin K are essentialfor the total gamma-carboxylation of osteocalcin.'*'Dietary intake of vitamin K in 219 healthy adults eat-ing an average U.S. diet was found to be insuflicientior gamma-carboxylation of osreocalcin, while normalprothrombin time was maintained." An elevated levelof serum glutamic acid under-carboxylated osteocalcinis indicative of vitamin K deficiency and is associatedwith reduced hip bone mineral density (BMD) and in-creased iracture risk in healthy elderly women.^' Ratswith hypoprothrombinemia were given vitamin K3 orK2 orally (0.1 mg/kg) and absorption and concentra-tion in the liver were compared, l l ie most potent formwas found to be vitamin K2."

Vitamin K2, in the form of menaquinone-4,is the most biologically active form oí vitamin K, up-regulating rhe gene expression oí bone markers. MK-4has been clinically used in the treatment of osteoporosisin Japan, where extensive research in this field has beentaking place. Tills research confirms that MK-4 is con-verted from dietary vitamin Kl and then accumulatesin various tissues at high concentrations, although thepathway by which MK-4 is converted remains unclear."

Deficiency States and SymptomsDeficiency of vitamin K is associated with im-

paired blood clotting, demonstrated by such symptomsas easy bruising, frequent nosebleeds, bleeding gums,heavy menstrual periods, and presence oí blood in theurine and/or stool. Vitamin K deficiency may be dem-onstrated through laboratory measurement of bloodclotting time. Individuals at greatest risk íor vitamin Kdeficiency include those caking vitamin K antagonistanticoagulant drugs, those with significant liver impair-ment, and those who suflvr from fat malabsorptionconditions.^'''*' Vitamin K deficiency in a newborn isserious, as it tnay result in a bleeding disorder calledvitamin K deficiency bleeding (VKDB). VKDB is life-threatening, but it can be easily prevented by adminis-tering an Injection of vitamin K to newborns, a practicerecommended by the American Academy of Pediatricsand a number of similar international organizations.*"

Clinical IndicationsOsteoporosis

Several human trials have found vitamin K2effective In the treatment of osteoporosis.-''•'"*" In arandomized, open-label study, 241 osteoporotic womenwere given either 45 mg/day vitamin K2 and 150 mgelemental calcium (treatment group; n=120) or 150mg elemental calcium (control group; n-121). Aftertwo years, vitamin K2 was shown to maintain lumbarBMD. Patients receiving vitamin K2 also experiencedsignificantly lower fracture Incidence (10% versus 30%,in the treatment and control groups, respectively).'" Ina double-blind, placebo-controlled, 24-week study, 80patients with osteoporosis received either 90 mg/dayvitamin K2 or placebo. Second meracarpal BMD wasincreased by 2.20 ± 2.48 percent compared to placebo,which decreased by 7.31 ± 3.65 percent.'^

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Vitamin K2 in Osteoporosis of PostmenopausalWomen

The incidence of osteoporosis is high in post-menopausal women. A number of trials have demon-strated vitamin K2 induces significant reductions inbone loss in postmenopausal osteoporotic women. Ina controlled clinical trial, 172 osteoporotic/osteopenicwomen (BMD < 0.98 g/cm^) were randomly assignedto receive vitamin K2 (45 mg/day), 1-alpha-hydroxy-cholecalciferol vitamin D3 (a synthetic analog of ac-tive vitamin D3) 1 meg/day, both, or placebo for 24months. Combination therapy resulted in a significant4.92 ± 7.89 percent increase in BMD, while vitamin K2alone resulted in only a 0.135 ± 5.44 percent increase inBMD - higher, but not statistically significantly higher,than baseline values. However, at 18- and 24-monthevaluations, BMD was significantly higher in the vita-min K2 group compared to the control group. In thisstudy a combination of vitamins K2 and D3 provedmore protective than either supplement alone.^^

A longitudinal study of 17 postmenopausalwomen given vitamin K2 (43 mg/day) for one yearfound vitamin tC2 suppressed the decrease in spinalBMD, with a slight increase (0.23 ± 0.47%) comparedro the control group of 19 postmenopausal women whoexperienced a decrease (-2.87 ± 0.51%) in BMD.''^

Ninety-two postmenopausal women, ages55-81, were randomly assigned to one of four groups:vitamin K2 (45 mg/day), 1-alpha-hydroxyvitamin D3(0.75 meg/day), a combination of vitamins K and D(same dosage as above), or calcium lactate (2 g/day).The vitamin-K and -D groups experienced significantincreases in BMD compared to the calcium group overa two-year period, while the combined treatment wassynergistic, significantly increasing lumbar BMD by1.35

Vitamin K2 and BisphosphonatesA number ot bisphosphonates (e.g., etidronate,

alendronate, and risedronate) are used in the treatmentof osteoporosis. These drugs, although generally consid-ered to be more effective than vitamin K2 in increasingBMD, seem to work synergistic;illy with it.

A randomized, open-label study of 98 post-menopausal, osteoporotic women found significantlydecreased fracture rates in 23 subjects (2/23) taking

vitamin K2 (45 mg/day) and 25 subjects (2/25) tak-ing etidronate (200 mg/day for two weeks every threemonths), compared to 24 subjects (6/24) taking cal-cium lactate (2 g/day). Tlie fracture rate was decreasedfijrther in 26 subjects (1/26) taking a combination ofvitamin K2 and etidronate.'''

Tlie bisphosphonate, alendronate (Fosamax*),encourages cortical bone growth by inducing apopto-sis of osteoclasts. In a 2004 study, the influence of vi-tamin K2 on trabecular and cortical bone formationwas shown not to interfere with bisphosphonates andthe apoptosis of osteoclasts. The authors concluded thecombination of vitamin K2 and bisphosphonates couldproduce an additive effect in osteoporosis prevention."'

Vitamin K2 in Osteoporosis of Parkinson'sDisease

As a general population the eldeily are at highrisk for osteoporosis; Parkinson s disease, however,compounds the risk. Research of elderly populationshas found a high incidence of hip fractures and osteo-porosis in Parkinson's patients,"'""* in part related tovitamin D deficiency''^ and immobilization-^" The defi-ciency does not appear to be related to lack of 25-hy-droxyvitamin D3, but rather to suppression of 1,25-di-hydroxyvitamin D3 (the active form of vitamin D) byhigh serum calcium. The apphcation of vitamin K2 sig-nificantly increased 1,25-dihydroxyvitamin D3 and de-creased serum calcium.^" Vitamin K2 (45 mg/day for 12months) to 54 female osteoporotic Parkinson s patients65 years or older resulted in one hip fracture, comparedto 10 fractures (eight hip, one radius, one ankle) in 54matched, untreated, osteoporotic Parkinson's patients.Hip fractures were caused by falls and no significant dif-ferences were noted in number of falls between groups.The average bone loss in the untreated group was 4.3± 2.5 percent of BMD compared to 1.3 ± 0.4 percentin age-matched controls. Vitamin K2-treated patientsexperienced a 0.9 ± 1.2 percent gain in BMD. "

Vitamin K2 in Bone Loss from LeuprolideA moderate reduction in BMD is one of the

frequent side effects ofthe gonadotropin-releasing hor-mone antagonist leuprolide for endometriosis, leiomyo-mas, and prostate cancer. '' ^ Administration of vitaminK2 (45 mg/day; n=:28) or the combination of K2 and1,25-dihydroxyvitamin D3 (45 mg/day and 0.5 meg/

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day, respectively; n=28) resulted in partial prevention ofbone loss compared to the leuproHde-only group (n=:28)or the vitamin D-only group (n=26}. Bone loss after sixmonths as measured by lumbar spine BMD was 5.25percent in the leuprolide-only group, 4.13 percent in thevitamin D group, 3.72 percent in the vitamin K group,and 3.59 percent in the group taking vitamins K and D.^'

Vitamin K2 in Bone Loss from PrcdnisoloneUse oí glucocorticoids is the most common

cause of drug-induced secondary osteoporosis.^^ Ad-ministration of glucocorticoids for long periods of timecan lead to a decrease in bone mineral density.'''' Severalstudies iound vitamin K2 has a marked effect on theloss of BMD in prednisolone-treated patients. Sixtypatients with chronic glomcrulonephHtis were random-ized to tour groups: control, 1-alpha-hydroxyvitaminD3 (0.5 meg/day), vitamin K2 (45 mg/day), or vi-tamins K2 with D3. Patients concomitantly receivedprednisolone ar a daily dose of 0-7 mg/kg up to a maxi-mum of 40 mg for four weeks, then tapered to 25 mgdaily for another four weeks prior to assessment. Thecontrol group experienced a significant decrease fromba.seline in BMD over the eight-week study: -3.19 ±1.11 percent, compared to the vitamins D, K., andD+Kgroups that maintained baseline levels (0.28 ± 1.30,0.50 ± 1.17, and 0.44 ± 1.36 percent, respectively).**

In a prospective pilot study, 20 children beingtreated with prednisolone and vitamin D3 (0.03 meg/kg/day) were continued on D3 plus prednisolone orgiven that combination plus vitamin K2 (approximately2 mg/kg/day) for 12 weeks. Vitamins K2 and D3 com-bined had an additive effect, with a significant increasein lumbar BMD and osteocalcin compared to vitaminD3 alone/'

Similar results were obtained in a random-ized, prospective, controlled study of 20 patients withglomerulonephritis given 0.8 mg/kg/day prednisoloneup to a maximum of 40 mg/day for four weeks, then ta-pered to 20 mg/day over a six-week period. One groupreceived only prednisolone, while a second group alsoreceived vitamin K2 ( 15 mg three times daily). After 10weeks, a reduction in lumbar spine BMD (from 1.14± 0.12 g/cm^ to 1.10 ± 0.11 g/cm^) was noted in theprednisolone-only group. The vitamin K2 group dem-onstrated a somewhat slower rate of bone loss (from1.09 ± 0.09 g/cm- to 1.07 ± 0,07 g/cm')."

Vitamin K2 in the Treatment of Bone Loss inBiliary Cirrhosis

Patients with primary biliary cirrhosis expe-rience osteodystrophy and increased fracture rate andfar malabsorption that can result in deficiencies of vi-tamins D and K. Scrum levels of vitamin K have beenfound to be low in this population. In a randomized,controlled trial of 27 patients with primary biliary cir-rhosis, the treatment group (n= 14) received vitamin K2(45 mg/day) lor two years. Afrer one year the controlgroup (n=13) experienced a 3.5 ± 1.2 percent decreasein BMD, while the vitamin K2 group demonstrated a0.3 ± 2.3 percent increase in BMD. After two years,the control group demonstrated a 6.9 ±2.1 percent de-crease in BMD, compared to only a 0.8 ± 3.4 percentdecrease in the K2 group. BMD was significantly high-er in the vitamin K2 group during the cwo-year periodcompared to controls.'**

Vitamin K2 in the Treatment of Osteopenia ofStroke Patients and Skeletal Unloading

Victims of stroke are often immobilized, lead-ing to significant loss of BMD. The most pronouncedloss of bone occurs on the hémiplégie side comparedto the unaffected side. Tliis loss has been attributedto increased bone résorption, immobilization-inducedhypercalcemia, and hypovitaminosis D. ^ A random-ized, controlled rrial of 108 hémiplégie stroke victims(54 subjects treared with 45 mg vitamin K2 daily for12 months and 54 subjects serving as controls) foundvitamin K2 effective for preventing disuse bone loss.Second metacarpal BMD on the hémiplégie side in-creased an average of 4.3 percent with vitamin K2 anddecreased an average of 4.7 percent with no treatment.Hie unaffected side had a 0.9-percent decrease in sec-

ond metacarpal BMD with vitamin K2 treatment com-pared to 2.7-percent decrease with no treatment.''"

Cardiovascular HealthAnimal studies have demonstrated vitamin

K2, but not vitamin Kl , may inhibit the calcification ofarterial plaque. A 1996 study on male rats found high-dose vitamin K2 (100 mg/kg body weight daily) inhib-ited the increase in aortic or kidney calcium induced bymegadose synthetic vitamin D2.*'

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Similarly, a 1997 study was conducted onhypercholesterolemic rabbits placed on a 0.5-percentcholesterol diet. The study demonstrated that admin-istration of high-dose vitamin K2, 1-10 mg/kg bodyweight daily for 10 weeks, suppressed the progressionof atherosclerotic plaques in the aorta and pulmonaryarteries. Vitamin K2 was also observed to lower totalcholesterol, lipid peroxidacion, and factor X activity inplasma, and the ester cholesterol deposition in the aortacompared to the control group.**"

Human smdies also suggest that dietary vita-min K2 might reduce the risk of cardiovascular diseaseby reducing coronary calcification. A cross-sectionalstudy of 564 postmenopausal women investigated theassociation between intake of vitamin Kl and vitaminK2 with coronary calcification. Dietary intake of vita-mins Kl and K2 was determined using a food-frequen-cy questionnaire. Of the women sampled, 62 percent(n = 360) had coronary calcification. Although vitaminKl was not associated with any significant effect oncoronary calcification (RR=1.17; 95% confidence in-terval: 0.96-1.42; p(trend)=0.11), it was observed thatvitamin K2 intake was associated with the trend towarddecreased coronaiy calcification (RR-0.80; 95%-CI:0.65-0.98; p(trend)=0.03).'"

CancerBoth in vitro and in vivo studies have shown

that vitamin K2 exhibits anticancer effects. A number ofcancer cell lines have been screened (including liver, co-lon, leukemia, lung, stomach, lymphocyte, nasopharynx,breast, and oral epidermoid) for inhibition by vitaminK2. Vitamin K.2 was found to have an ID.^, value from0.8-2 mM, which, although lower than Kl, is still muchhigher than inhibitory levels of vitamin K3 (18-45 pM).^

Other in vitro studies have found lower concen-trations of menaquinones are effective anticancer agentsfor a number of cancer cell types. The HOS TE85 hu-man osteosarcoma cell line and the MC3T3-E1 mouseosteobla.stic cell line were cultured for three days in amedium containing various concentrations of MK-4.Tlie proliferation of HOS cells was suppressed by vita-min K2 in a dose-dependent manner up to 56 percentof control by 10'M of K2, and that of MC3T3-E1 cellswas suppressed to 84 percent of control by lO'^M of vi-tamin K2.*** MK-3 had an ID^^ of 112 ^M (112 x 10 ^M) for the human hepatoma cell line Hep3B.*''

Vitamin K2 induced growth inhibition via cellcycle arrest and apoptosis In a dose-dependent mannerfor glioma cells in both rat (C6) and human cell types(RBR17T, T98G).^^ Incubation with 3 iM of MK-4for 72 hours decreased cultured leukemic blast cellsfrom 27.6 percent to 17.7 pcixent. Increasing the con-centration of MK-4 to 10 |4.M decreased blast cell num-bers to 3.9 percent.^ Vitamin K2 was able to inducecell cycle arrest in the GOGl transition as well as induceapoptosis in a dose-dependent manner in glioma, hepa-toma, and leukemia cell lines. ''' "' '' Leukemia cell linesresistant to apoptosis still demonstrated induction ofdifferentiation.''**

Myeloblastic (MLl) and promyclocytic(HL60) cell lines cultured with 1 |iM of vitamin K2showed an 84-percent differentiation induction as mea-sured by nirrotetrazolium blue staining (NBT), whilevitamin Kl showed no differentiation effect. Otherdifferentiation-inducing agents such as retinoic acid, in-terferon-gamma, and camptothecin were found to havea synergistic effect when combined with vitamin K2.*''''''"Further studies with isolated leukemia cells (post-my-elodysplastic syndrome [MDS] and acute myclocyticleukemia) determined that vitamin K2 at 10 \iM wasable to selectively induce apoptosis in the leukemia cellsin 48 hours. " Three naturally occurring vitamin K2analogues, MK-3, MK-4, and MK-5, were tested withleukemic blast cells. One ofthe more potent vitamin K2analogues tested, MK-4, was found to induce apoptosisin 90 percent of leukemic blast cells. NormaJ bone mar-row cells were also tested with the same concentrationof the vitamin K2 analogues for 72 hours. The cyto-toxicity to leukemia cells was much more pronounced,while the vitamin K2 analogues had "almost no effect"on normal bone marrow cells.'''* Tlie selective cytocidaleffect of the three vitamin K2 analogues on immaturetransformed blasts was confirmed using a more sensi-tive antibody APO2.7 technique.'''

A number of case studies support tlie use of vi-tamin K2 as an anticancer agent. An 80-yeai--old womanwith MDS received an oral dose of 45 mg/day of vita-min K2. After 14 months of treatment her pancytope-nia improved and rransfiisions were no longer needed.''A 72-year-oId woman diagnosed with acute promyelo-cytic leukemia achieved remission when given all-trans-retinoic acid (60 mg/day), enocitabine (200 mg/day),and daunorubicin (40 mg/day) for one week. Relapse

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occurred eight months later at which time 20 mg/dayot vitamin K2 as MK-4 (route of dose unspecified burassumed to be oral) in conjunction with the previousprotocol resulted in the complete disappearance of pro-myelocytes after two months. Analysis of bone marrowconfirmed complete cytogenic remission." A 65-year-old man with MOS who had progressed to acute my-eloid leukemia (AML) was treated orally with 90 mg/day of MK-4. Within six weeks he experienced a .sig-iiihcant decrease in blast count from 34 to eight percentand increase in platelet count fi-om 31 x lOVL to 133 xlO'VL. At 10 months rhe dosage was reduced to 45 mg/day with an absence of side effects and continuing goodperformance without myeloablative therapy."^

These encouraging results from vitamin K2rherapy have led ro a multi-center pilot study in Japanof MDS and post-MDS acute myeloid leukemia (post-MDS AML treatment with vitamin K2 [MK-4])."- In11 independent institutes, 47 patients received treat-ment with MK-4. Of 47 patients, 15 had refi-actoryanemia; six had refractory anemia with excessive blast;11 had refractory anemia with excess of blast and intransformation; three had chronic myelomonocytic leu-kemia; and 12 had post-MDS AML. MK-4 was effec-tive in reducing blast cell numbers in bone marrow and/or peripheral blood in 71.4 percent (10/14) of those re-ceiving other medications concomitantly. PatienLs withrefractory anemia with excess of blasr in transforma-tion, and those with post-MDS AML who used oralvitamin K (MK-4) without other medications, demon-strated 44 percent (4/9) hematological improvement.MK-4 dosage ranged from 20-135 mg/day orally or 10-50 mg/day intravenously, with 83 percent receiving anoral dose of 45 mg/day."'

A Japanese trial enlisted 121 parients with he-patocellular carcinoma undergoing conventional ther-apy consisting of percutaneous tumor ablation and/ortranscatheter arterial enibolization. Patients were given45 mg/day oral vitamin K2, which resulted in a signifi-cant improvement in survival. Portal vein invasion af-ter 12 months was two percent in the treatment groupcompared to 23 percent in the control group. At twoyears, 23 percent in the treatment group, compared to47 percent in the control group, were found to have in-vasion into the portal

Drug-Nutrient InteractionsNutrient Interactions

Animal studies have demonstrated high-dosevitamin A can interfere with vitamin K absorption, al-though it is not known if this would affect humans inthe same manner.'^'''

Vitamin E at doses greater than 800 lU mayantagonize the effects of vitamin K, potentially increas-ing the risk of bleeding in individuals on anticoagula-tion medication or with low vitamin K intake.^" "** Onestudy in adults with normal coagulation status foundsupplementation with 1,000 IU vitamin E tor 12 weeksdecreased gamma-carboxylarion of prothrombin, avita-min K-dependent protein/'*

Drug InteractionsHigh dietary or supplemental vitamin K intake

may inhibit the anticoagulant effect of vitamin K an-tagonists (e.g., warfarin). Generally, it is recommendedthat individuals on these medications limit vitamin Kconsumption to amounts typically found in the aver-age diet (90-120 mcg).* " Pregnant women on warfarin,anticonvulsants, rifampin, or isoniazid place the new-born at increased risk ot vitamin K deficiency as thesemedications can interfere with fetal vitamin K synthe-sis.""' Extended use of broad spectrum antibiotics maydecrease vitamin K synthesis by intestinal bacteria. Useof cephalosporins and salicylates may adversely affectvitamin K recycling by inhibiting vitamin K epoxide re-ductase. Furthermore, absorption of vitamin K may bedecreased wich the use of drugs such as cholestyramine,colestipol, orlistat, and substances such as mineral oiland the fat substitute, olestra."

Side Effects and ToxicityFrom a large number of clinical rrials using

dosages in excess of 40 mg/day, rhere were no reports ofside effects associated with any type of hypercoagulablestate.^-'^-"" Both animal and clinical studies supportthe conclusion that vitamin K2 has no abnormal hemo-staric activity. In one study, vitamin K2 given ro rats ata dose of 250 mg/kg body weight per day for 10 daysresulted in no appreciable change in blood coagulationcharacteristics or platelet aggregation.*"'

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In a clinical study, 29 elderly, osteoporotic pa-tients were given vitamin K2 (15 mg three times daily,30 minutes post-meals) for 12 weeks and monitoredfor any change in hemostatic balance. After 12 weeks ofadministration, all hemostatic markers remained withinnormal range.''* In another study, examining the effectof vitamins K2 (45 mg/day) and D3 (1 meg/day) onBMD in postmenopausal women, hemostatic measureswere also examined. Increases in both coagulation andtibtinolysis were noted, but remained within normalrange and in balance, witli no adverse reactions ob-served.*^

DosageTliere are no established recommended daily

allowances (RDAs) for vitamin K2, although daily ad-equate intake values have been formed for vitamin Kl(Table 1).'^

A typical therapeutic oral dosage for vitaminK2 for osteoporosis is 45 mg/day. ^-'' ' ''° One study,however, suggested a dosage as low as 1.5 mg/day mayprovide benefit in maintaining healthy bones in alreadyhealthy postmenopausal women.**" Therapeutic oraldosages in cancer based on clinical studies range from20-135 mg/day; however, the most common dosageused has been 45

Warnings and ContraindicationsIt should be noted that the anticoagulant effect

of warfarin (Coumadin), functioning by its interfer-ence with the clotting effect of vitamin K, can be ofîsetwith as little as 1 mg of vitamin K.^' Therefore, use ofvitamin K is contraindicated in individuals on antico-agulant therapy.

References1. Brody T. Nutritional Biochemistry. 2nd ed. San Diego,

CA: Academic Press; 1999.2. Ranncls SR, Galhilicr KJ, Wallin R, R.innels DE.

Vitamin K-dependcnt carboxylation of pulmonarysiirfaccant-associated proteins. Proc Nati Acad Sei U SA 1987:84:5952-5956.

3. Shearer MJ. Role of vitamin K and Gla proteins inthe pathophysiology of osteoporosis and vascularcalcification. Curr Opin Clin Nutr Metab Care2000;3:433-438.

Table 1. Daily Adequate Intakes of Vitamin Kl

Life Stage (Age)

infants (0-6 mo)

Infants {642 mo)

Children (1-3 y)

Children (4-8 y)

Chiidren(9-13y)

Adoiescents (14-18 y, includingpregnant/nursing females)

Men (>19 y)

Women (>19 y, includingpregnant/nursing)

Daily AdequateIntake Vaiues

2,0 meg

2.5 meg

30 meg

55 meg

60 meg

75 meg

120 meg

90 meg

4. Suttie JW. Synthesis of vitamin K-dependent proteins.FASEBJ 1993:7:445-452.

5. Wu FY, Liao WC, Chang HM. Comparison ofantitumor activity of vitamins Kl, K2 and K3 onhuman tumor cells by two (MTT and SRB) cellviability assays. Life Sei 1993:52:1797-1804.

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9. Prasad KN, Edwards-Prasad J, Sakamoto A. VitaminK3 (mcnadione) inhibits the growth of mammaliantumor cells in culture. L|/i-Sei 1981 ;29:1387-1392.

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12. Ngo EO, Sun TP, Chang JY, er al. Menadionc-lnducedDNA damage in a human tumor cell line. BtochemPharmacol 1991:42:1961-1968.

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13. Wu FY. Chang NT. Chen WJ. Juan CC. VitaminK3-indiiced cell cycle ;irrest and apoptotic cell deathare accompanied by altered expression of c-fos andc-myc in nasopharyngeal carcinoma cells. Oncogene1993:8:2237-2244.

14. Su WC, Sun TP, Wu F Y. Ilie in I'lfro and in vivocycotoxicity of menadione (vitamin K3) against rattransplantahlc hepatoma induced hy 3'-methyl-4-dimethyl- aminoazohenzene. Gaoxion^ Yi Xue Ke Xue

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in rumor-hearing animals. Cancer Treat Rep1986;70:1433-1435.

16. W ing Z, Wang M, Finn F, Carr BI. Tlie growthinhibitory effects of viramins K and their actions ongene expression. Ht'patology 1995;22:876-882.

17. Geleijnse JM, Vermeer C. Grobbee DE, et al. Dietaryintake of mcnaquinone is associated with a reduced riskof coronary heart disease: the Rotterdam Study, J Nutr2004;134:3100-3105.

18. Beulens J W. Bots ML, Atsma F, et al. High dietarymenaquinone intake is associated with reducedcoronary calcification. Athcroidcroiis 2009;203:489-493.

19. Booth SL, Mayer J. Wirfarin use and fractLirc ri.sk.Nutr Rev 2000:58:20-22.

20. Tliomson RH. Naturally Occurring Quiñones. NewYork, NY: Academic Press; 1971.

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