MK4 Research Summary Tables

More than 100 scientific studies support using MK4 for cancer support and bone health. This page summarizes the available MK4 in vitro and human cancer research. And more than 6,000 people with many conditions, including osteoporosis, liver cancer (hepatocellular carcinoma), liver failure, AML, MDS, Parkinson disease, Alzheimer disease, anorexia nervosa, liver cirrhosis, hepatitis C, primary biliary cirrhosis, diabetes mellitus, myelofibrosis and kidney failure on hemodialysis have taken MK4 for up to eight years without any serious side effects.

Watch the videos of a 59-year old woman and 70-year old man with AML who were both told they were going to die, but who started taking Osteo-K and they improved.

Clinical trials and case reports:

Basic (in vitro) research:

MK4 in People with MDS and AML

MK4 alone and with vitamin D has been extensively studied for its effects on promoting healthy cells in people with cancer. Clinical trials and case reports have been published detailing the potential benefits of MK4 in people with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) showing up to 56% response rate. With respect to MDS and AML, published studies have documented one hundred people with MDS and AML being administered MK4 for up to 38 months without any serious side effects.

Table 1. MDS and AML (watch a webinar reviewing this research)

Researchers

Indications

Design

Volunteers

MK4 Dose

Duration

Outcomes

Adverse Events

Akiyama and Miyazawa

MDS

Multicenter, open-labeled, single-arm, prospective phase II clinical trial

n = 38 (20 male, 18 female); median age 65 years

45 mg/day orally or MK4 + Vitamin D

16 weeks

13% in the MK4 group and 30% in the MK4 + Vitamin D group improved as defined by IWG-2000 criteria.

1 case of grade I nausea, 1 of grade I lower abdominal pain, and 1 of grade I skin rash

Miyazawa and Nishimaki

MDS and Post-MDS AML

Retrospective, questionnaire survey at 11 different institutions

n = 47 (30 male, 17 female); median age 66 years

20-135 mg /day orally, and 10-50 mg /day intravenously

Not stated.

MK4 alone: 44.4% (4/9) of RAEB-T and Post-MDS AML showed hematological improvement.

None

Takami and Asakura

MDS

Prospective, randomized trial

n = 18 (9 male, 9 female); mean age 72 years

45 mg/day orally

38 months

56% (5/9) in MK4 group improved as defined by IWG-2000 criteria

No signs of toxicity or progression to acute leukemia were observed.

Takami and Nakao MDS with refractive anemia (RA) Case report 80 year old woman 45 mg/day orally 14 months Woman's health improved and transfusions were no longer needed. When MK4 was stopped, her blood results worsened, but improved again when MK4 (45 mg/d) was restarted. Not reported

Yaguchi and Miyazawa

RAEB-T with myelofibrosis (MDS/AML)

Case report

65 year old male

90 mg/day orally, reduced to 45 mg/day orally after hematological response

10 months (6 weeks at 90 mg/day orally and the remainder at 45 mg/day orally

Peripheral blast cell count significantly decreased, platelet count normalized

None

 

Table 2. Acute Promyelocytic Leukemia

Study

Indication

Comorbidity

Design

Volunteers

MK4 Dose

Duration

Outcomes

Adverse Events

Fujita and Tomiyama

Acute promyelocytic leukemia refractive to conventional chemotherapy

 

Case report

n = 1 (woman); 72 years old with t(15;17) translocation

MK4 20 mg/day orally plus all trans retinoic acid

2 months

After 7 d promyelocytes disappeared from peripheral blood. Two months later, bone marrow aspiration revealed complete remission. In addition, genetic abnormalities (PML/RARa fusion transcript and t(15;17) translocation) disappeared.

Not reported

Table 3. Liver Cancer and Hepatitis C

Study

Indication

Comorbidity

Design

Volunteers

MK4 Dose

Duration

Outcomes

Adverse Events

Nouso and Uematsu

Hepatocellular carcinoma

Hepatitis C and diabetes mellitus

Case report

n = 1 (man); 85 years old who declined interventional therapies or angiography "because of the patient's advanced age and advanced stage of HCC"

MK4 45 mg/day orally

2 months

Blood markers (serum alpha-fetal protein, AFP) and des-gamma-carboxy-prothrombin (DCP) normalized after 3 months. Tumor decreased from 13.3 cm to 5.5 cm after 5 months. Ultrasound demonstrated the tumor regressed and the margin of the tumor became obscure. After 22 months after initiating MK4 there were no signs of recurrence observed and tumor markers remained within the normal limits.

Not reported

Yoshiji and Noguchi

Hepatocellular carcinoma

Liver cirrhosis, hepatitis C

Case report

n = 1 (woman); 66 years old

MK4 45 mg/day orally plus perindopril 4 mg/day orally

5 years

Blood markers--AFP and lectin-reactive alpha-fetal protein (AFP-L3) normalized after 1 year. After 15 months of treatment, the hepatic nodule disappeared. MK4 and ACE-I was continued, and neither AFP nor AFP-L3 levels increased again. This combination was continued, and no HCC developed.

None

Jancin

Hepatocellular carcinoma

 

Randomized, controlled

n = 121 who had received conventional therapy with percutaneous tumor ablation and/or transcatheter arterial embolization.

MK4 45 mg/day orally or no MK4

24 months

Rate of portal vein invasion at 12 months of follow-up was 2% in those taking MK4 and 23% in controls. At 2 years, portal vein invasion was present in 23% of the MK4 group and 47% of controls. Additionally, one-year survival in patients treated with MK4 was 76%, compared with 66% in controls. Two-year survival was 66% in the MK4 group and just 28% in controls.

Not reported

Yoshiji and Noguchi

Hepatocellular carcinoma

Hepatitis C

Phase I: Randomized, controlled

n = 60 (52 men, 32 women); mean age 50 years. All had undergone percutaneous radiofrequency ablation (RFA), considered "curative therapy"

Group A: no intervention control
Group B: MK4 45 mg/day orally plus perindopril 4 mg/day orally

48 months

 

None

Hepatitis C

Phase II: Randomized, controlled

n = 40; mean age 61 years

Group A: MK4 45 mg/day orally
Group B: perindopril 4 mg/day orally

36 months

Cumulative recurrence after four years was 36%, meaning 64% exhibited normal test results.

None

Mizuta and Ozaki

Hepatocellular carcinoma

Hepatitis C

Randomized, controlled

n = 61 (41 men, 20 women); mean age 64 years

MK4 45 mg/day orally or no MK4

36 months

Cumulative survival for volunteers who received MK4 were 100% at 12 months, 96.6% at 24 months, and 87.0% at 36 months; and the corresponding survival rates for patients in the control group were 96.4%, 80.9%, and 64.0%. After 3 years, 23% more people taking MK4 were alive compared to those not taking MK4.

None

Kakizaki and Sohara

Hepatocellular carcinoma

Hepatitis C

Randomized, controlled

n = 60 (35 men, 25 women); mean age 69 years who had undergone radiofrequency ablation

MK4 45 mg/day orally or no MK4

36 months

After 36 months, 38.8% of volunteers taking MK4 were "recurrence-free" compared to only 9% of those not taking MK4.

At 36 months, 77.5% of those taking MK4 were still alive versus 66.4% of those who did not take MK4.

None

Habu and Shiomi

Liver cirrhosis becoming liver cancer

Hepattis C

Randomized, controlled

n = 43 (all women); mean age 60 years

MK4 45 mg/day orally or no MK4

8 years

After 8 years only two volunteers taking MK4 developed liver cancer compared to nine volunteers in the group not taking MK4. The researchers concluded that MK4 decreased the chance of developing liver cancer in this study by 80%.

None

Table 4. MK4 Research in People with Osteoporosis and Other Conditions

Study

Indication

Comorbidity

Design

Volunteers

MK4 Dose

Duration

Outcomes

Adverse Events

Binkley and Harke

Osteoporosis

 

Double-blind, placebo-controlled study

n = 381 (all women); mean age 62.5 years

MK4 45 mg/day orally or phylloquinone 1 mg/day orally or placebo

12 months

Bone laboratory markets: Improved lab markers for bone health.

None

Knapen and Schurgers

Osteoporosis

 

Randomized, placebo-controlled

n = 325 (all women); mean age 66 years

45 mg/day orally or placebo

36 months

Bone density: Bone mineral content and bone strength improved in those those taking MK4.

Minor, and no different than placebo group

Inoue and Fujita

Osteoporosis

 

Open-labeled

n = 4,378 (all women); mean age 68 years

MK4 45 mg/day orally alone or with calcium (1.2 to 3 grams) orally per day

48 months

Fractures: Fractures were decreased in those taking MK4+calcium.

Minor and statistically lower incidence in MK4 monotherapy group

Sasaki and Kusano

Osteoporosis

Chronic glomerulonephritis
(Kidney disease)

Randomized, controlled

n = 20 (12 men, 8 women), mean age 40 years

MK4 15 mg/day orally plus glucocorticoids (prednisone) or glucocorticoids without MK4

12 months

Bone density: MK4 preserved bone mineral density (BMD) while those not taking MK4 lost BMD.

None

Yonemura and Fukasawa

Osteoporosis

Chronic glomerulonephritis
(Kidney disease)

Randomized, controlled

n = 60 (28 men, 32 women), mean age 32 years

Group A: control (glucocorticoids only)
Group B:MK4 (45 mg/day) orally plus glucocorticoids
Group C: vitamin D alone, plus glucocorticoids
Group D: MK4 (45 mg/day) plus vitamin D and glucocorticoids.

24 months

Bone density: Those taking just glucocorticoids lost BMD. Those taking just vitamin D or vitamin D plus MK4 had their bone density maintained. However, those taking just vitamin D also had an increase in serum calcium, while serum calcium did not increase in those taking vitamin D plus MK4.

None

Yonemura and Kimura

Osteoporosis

Chronic glomerulonephritis
(Kidney disease)

Randomized, controlled

n = 20 (14 men, 16 women), mean age 28 years

Group A: Prednisolone orally
Group B: MK4 (45 mg/day) orally plus prednisolone orally

10 weeks

Bone density: MK4 maintained bone density while those not taking MK4 lost bone density.

None

Inoue and Sugiyama

Osteoporosis

Juvenile rheumatoid arthritis, systemic lupus erythrematosus, dermatomyositis, muscular dystrophy, myasthenia gravis, autoimmune hepatitis, lymphoid interstitial pneumonia, IgA nephropathy, nephrotic syndrome, mebranoproliferative glomerulonephritis

Randomized, controlled

n = 18 (5 boys, 13 girls), ages 4 to 14 years

Group A: MK4 (2 mg/kg/day) plus glucocorticoid
Group B: MK4 (2 mg/kg/day) pluse Vitamin D (0.03 μg/kg/day) plus glucocorticoid

12 weeks

Bone density: MK4 maintained bone density while those not taking MK4 lost bone density.

None

Sato and Kanoko

Osteoporosis

Alzheimer's disease

Randomized, controlled

n = 200 (all women); mean age 78 years

MK4 45 mg/day orally, plus vitamin D 1000 IU/day orally and calcium 600 mg/day orally, or no MK4

24 months

Bone density: MK4 increased bone density. Those not taking MK4 lost bone density.

Fractures: In the group taking MK4 there were two hip fractures compared with fifteen hip fractures in those not taking MK4, an 87% reduction.

Three patients in the intervention group experienced gastrointestinal symptoms such as epigastric discomfort and nausea, but they subsided within a week without discontinuing MK4 or ergocalciferol. No patient in the intervention group experienced liver or renal dysfunction.

Iketani and Kiriike

Osteoporosis

Anorexia nervosa

Controlled

n = 39 (all women); mean age 22 years

MK4 45 mg/day orally or no MK4

10.8 months

Bone density: MK4 preserved bone density compared with those not receiving MK4

None

Shiomi and Nishiguchi

Osteoporosis

Cirrhosis of the liver and viral hepatitis

Randomized, controlled

n = 50 (all women); mean age 60 years

MK4 45 mg/day orally or no MK4

24 months

Bone density: MK4 preserved bone density compared with those not taking MK4

None

Ushiroyama and Ikeda

Osteoporosis

 

Randomized, controlled

n = 172 (all women); mean age 53 years

Group A: MK4 45 mg/day orally
Group B: vitamin D3 1 μg/day orally
Group C: MK4 plus vitamin D3
Group D: Control group

24 months

Bone density: MK4+Vitamin D increased bone density nearly 5% while those taking MK4 alone had a 0.14% increase in bone density.

None

Purwosunu and Muharram

Osteoporosis

 

Double-blind, randomized, placebo-controlled

n = 63 (all women); mean age 60 years

MK4 group: MK4 45 mg/day orally plus calcium carbonate 1500 mg/day orally
Control group: placebo plus calcium carbonate 1500 mg/day orally

48 weeks

Bone density: MK4 increased bone density 1.74%, while those not taking MK4 lost bone density.

Two minor gastrointestinal symptoms, which subsided after temporary cessation of therapy.

Nakashima and Yorioka

Hypopara-thyroidism

Chronic renal failure in patients on dialysis with underlying chronic glomerulonephritis, nephrosclerosis and diabetes
mellitus

Randomized, noncontrolled

n = 32 hemodialysis patients (19 men and 13 women) with low parathryoid hormone (PTH); mean age 58 years

MK4 45 mg/day orally

12 months

Bone laboratory markers: MK4 improved bone laboratory markers (eg, undercarboxylated osteocalcin)

None

Bunyaratavej and Penkitti

Osteoporosis

 

Randomized, controlled

n = 83 (all women)

MK4 group: MK4 45 mg/day orally plus calcium 800 mg/day orally
Control group: calcium 800 mg/day orally

12 months

Bone density: MK4 improved bone density compared to those taking calcium alone.

Two cases of mild skin rash that subsided upon discontinuation of MK4

Shiraki and Shiraki

Osteoporosis

 

Randomized, open-label, controlled trial

n = 241 (all women); mean age 67 years

Group A: MK4 45 mg/day orally plus calcium 150 mg/day orally
Group B: calcium 150 mg/day orally

24 months

Fractures: MK4 group experienced 60% fewer fractures compared with the calcium-only group, including, including a 54% decrease in vertebral fractures.

Bone density: MK4 maintained bone density compared to those not taking MK4.

Not reported

Iwamoto and Kosha

Osteoporosis

 

Randomized, controlled

n = 72 (all women)

Group A: no intervention control
Group B: conjugated equine estrogen 0.625 mg/day orally and medroxyprogesterone 2.5 mg/day orally
Group C: vitamin D3 1000 mg/day
Group D: MK4 45 mg/day

12 months

Bone density: MK4 increased bone density while bone density decreased in the control group.

Not reported

Iwamoto and Takeda

Osteoporosis

 

Randomized

n = 92 (all women); mean age 64 years

Group A: vitamin D3 0.75 μg/day orally
Group B: MK4 45 mg/day orally
Group C: MK4 plus vitamin D3
Group D: calcium lactate 2000 mg /day orally

24 months

Bone density: MK4 plus Vitamin D increased bone density compared to all other groups.

None

Sato and Honda

Osteoporosis

Hemiplegia following stroke

Randomized, controlled

n = 108 (65 men, 78 women); mean age 66 years

MK4 45 mg/day orally or no MK4

12 monthst

Bone density: MK4 increased bone density by 4.7% compared to a loss of 4.7% in the group not taking MK4

Fractures: There were no fractures in the MK4 group and one fracture in the group not taking MK4.

None

Sato and Honda

Osteoporosis

Parkinson's disease

Randomized, controlled

n = 120 (all women); mean age 71.9 years

MK4 45 mg/day orally or no MK4

12 months

Bone density: MK4 inreased bone density 0.9% while those who did not take MK4 had a loss of 4.3%

Fractures: There was one fracture in the MK4 group and ten fractures in people not taking MK4. The MK4 group experience 90% fewer hip fractures.

None

Nishiguchi and Shimoi

Osteoporosis

Primary biliary cirrhosis stages I-IV

Randomized, controlled

n = 30 (all women); mean age 55 years

MK4 45 mg/day orally or no MK4

24 months

Bone density: MK4 increased bone density by 0.3%, while those not taking MK4 lost 3.5%.

None

Somekawa and Chigughi

Osteoporosis

Estrogen-dependent diseases (eg, endometriosis and leiomyomas) being treated with leuprolide

Randomized, controlled

n = 110 (all women); mean age 46.2 years

Group A: leuprolide (Lupron, Eligard)
Group B: leuprolide plus MK4 45 mg/day orally
Group C: leuprolide plus vitamin D3 0.5 μg/day orally
Group D: leuprolide plus MK4 and vitamin D3

6 months

Bone density: MK4 slowed the bone loss from estrogen deprivation.

Not reported

Sugiyama and Tanaka

Osteoporosis

Arnold-Chiari deformity

Case report

n = 1 (girl); age 8 years

MK4 2 mg/kg/day and vitamin D3 0.05 μg/kg/day

15 months

Bone density: MK4 plus vitamin D increased bone density.

None

Nagasawa and Fujii

Hyperlipi-demia

Chronic renal failure in patients on peritoneal dialysis

 

n = 17 (8 men, 9 women); ages 36-70 years

MK4 45 mg/day orally

1 year

Total Cholesterol: MK4 significantly reduced total cholesterol.

Not reported

Ochiai and Nakashima

Hypopara-thyroidism

Chronic renal failure in patients on dialysis

Randomized, controlled

n = 33(18 men, 15 women) mean age 65 years

MK4 45 mg/day orally or no MK4

12 months

Bone remodeling: MK4 improved laboratory indicators of bone remodeling.

Not reported

 

In Vitro Data on MK4 in Cancer Cell Lines

Table 5. Leukemic Cell Lines

Study

Model

Cell line

Control

MK4 Dose

Duration

Outcomes

Yaguchi and Miyazawa

MDS and Post-MDS AML, CML, Promyelocytic leukemia

Leukemia cells freshly isolated from bone marrow or peripheral blood samples from 12 patients diagnosed with AML and MDS based on FAB criteria. Patients included four with AML (two M2 and two M3), two with CML in blastic crisis, three with MDS (one RAEB, one RAEB-T and on CMML), and three with post-MDS AML.

MDS92, an IL-3 dependent myeloid cell line established from a patient with MDS

 

NB4, a cell line established from a patient with promyelocytic leukemia, and MDS92, an IL-3-dependent myeloid cell line from a patient with MDS

10 μM

48 hours

Apoptosis observed in cells from all 12 patients.

IC50 ≈ 10 μM

Exposure selectively eliminated the leukemic cell populations

Nishimaki and Miyazawa

MDS in blastic transformation (MDS becoming AML)

Established from a 73-year-old female with MDS, RAEB-T, with chromosomal anomalies chromosomal anomaly including -4, 5q-, -7, 20q-

 

10 μM

72 hours

↓ BCL-2
↑ BAX
↑ Caspase-3

Miyazawa and Yaguchi

Leukemia

BCL-2 overexpressed HL-60 leukemic cell line by bcl-2 gene transfection (HL-60-bcl-2)

HL-60-neo cells

0.1 to 50 μM

72 hours

↑Apoptosis in HL-60-neo but not HL-60-bcl-2
↑Differentiation
↑G0/G1 arrest in HL-60-bcl-2 that were resistant to MK4-inducing apoptosis, and also HL-60-neo cells
↓ Cell growth at 5 µM in HL-60-bcl-2 cells
↑ p27KIP1 (a CDK inhibitor) in HL-60-neo cells
↑Monocytic differentiation in HL-60-neo cells evidenced by increased CD-14, CD-15 and CD16 antigen expression

IC50
6 µM for HL-60-neo cells
14 µM for HL-60-bcl-2 cells

10 mm

24 hours

↑Depolarization of the mitochondrial membrane potential in HL-60-neo cells

↑Caspase-3 in HL-60 neo but not HL-60-bcl-2

Tsujioka and Miura

Myeloma, Promyelocytic leukemia, Follicular lymphoma, T-cell acute leukemia, Adult T-cell lymphoma/leukemia, histiocytic leukemia, Burkitt's lymphoma

U266 and RPMI8226, KMM-1, KMS-11, KMS-12PE, KMS-12BM. KMS-20, KMS-24, KMS-26, KMS-27, KMS-28PE, KMS-34, SU-DHL-4, CEM, Molt4 and Jurkat, MT-1

 

0 to 30 μM

Up to 72 hours

↑Apoptosis
↑Mitochondrial apoptotic pathway
↑Caspase-3
↓ Bcl-XL/XS expression

Table 6. Liver Cancer (Hepatocellular Carcinoma, HCC)

Study Type Cell Line Control MK4 Dose Duration Outcomes
Ozaki and Zang

In vitro (test tube)

HepG2, Hep3B and Huh7 human HCC cell line No MK4 10-6 M, 10-5 M and 10-4 M 48 hours

↓HCC cell growth in a dose-dependent manner
↓DNA synthesis in HCC cells
↑ G1 cell cycle arrest
↓ Cyclin D1 expression at the mRNA and protein level
↑p21 and p27 expression
↓ −1745CD1Luc, −964CD1Luc, −964AP-1mutCD1Luc, and −66CD1Luc promoters
↓ NFκB expression and DNA binding

Otsuka and Kato In vitro HepG2 and PRF/PLC/5, murine embryonic fibroblasts (NIH3T3) and a human primary hepatocyte cell culture (ACBRI) No MK4 0 μM, 30 μM, 50 μM and 80 μM 5 days

↑protein kinase A (PKA)
↓cell growth
MK4 did not adversely effect "primary hepatocytes" (non-cancerous cells)
↓cancer cell invasion by increasing PKA activity
↑DNA transcription in 3.4% of 10,000 genes evaluated
↑AP-2–, USF-1–, and CREB-related transcriptional activities
↓RhoA activation
↓ DCC production

IC50= 45 μM

Otsuka and Kato Animal

Athymic nude mice inoculated subcutaneously with 1x107 PRF/PLC/5 cells, then tumors allowed to develop for two weeks.

Ethanol 20 mg/kg/d MK4 by mouth 6 weeks Four of the five ethanol-treated mice developed large visible tumors. While three of the four MK4-treated mice also developed visible tumors, the tumors were smaller than those in ethanol-treated mice. Also, body weight decreased less in the animals fed MK4.
Azuma and Urano In vitro

HepG2, HuH7 as HCC cell lines.

LS180, a colorectal cancer cell line, as a positive control
  10 μM 24 hours

↓ Steroid and xenobiotic receptor (SXR), also called pregnane X receptor (PXR)
↓Cell motility, an indicator of decreased potential of cancer cells to metastasize (spread to other parts of the body)

Ide and Zhang In vitro HepG2, HuH7, HLE   0, 10-6, 10-5 and 10-4 M 48 hours

↓ Matrix metalloproteinases (MMP) expression in a dose-dependent manner
↓ Protein kinase C (PKC) activity
↓ MMP gene promoter activity
↓ NFκB

MK4 activity was dose-dependent

 

Table 7. Cholangiocellular Carcinoma (CCC)

Study Type Cell Line Control MK4 Dose Duration Outcomes
Enomoto and Tsuchida

In vitro

Cholangiocellular carcinoma (CCC) cell lines TFK-1, MEC and HuCC-T1 HL-60 leukemic cells 0.1, 0.5, 1, 2, 5, 10, 20, 50 and 100 μM 96 hrs

Dose-dependent cell growth inhibition.
↓CCC cell growth
MK4 induced autophagy in CCC cells

IC50 = 7.3-10.7 for the three cell lines.

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