350 replies to this topic

[tunt01]

Thanks for the analysis. One thing that stands out is that the body converts all of these forms to MK4, and to me the simplest solution is to use that form. I'm inclined to get a bottle of the Thorne drops at 1mg/drop and dose from there.

this is also what i ordered. i was using the pill form from carlson's (what michael rae takes), but want to try the liquid for the sake of it. i bought some pastured butter (high MK-4) and im going to try just droplets of the thorne product on the butter (a la weston price).

Erm, IIRC MK-ns directly act in gamma-carboxylation without any need for conversion (and unsurprisingly long chain Mk-ns are superior in those vitro assays). This study is only relevant to the putative, unique benefits of MK-4, I guess. But one thing is for sure and will not change anytime soon: in vitro evidence tells us nothing about in vivo results. Why are people still swayed by in vitro speculation? And why again this false dichotomy? "Take Mk-4 OR long chain menaquinones" Let's get all the vitamers that are naturally found in our diet, how about that?

there is a difference between MK-4 and MK-7. it's not just gamma carboxylation.

there is no false dichotomy, i don't really know what you mean. supplementing w/ MK-4 and eating a bit of edam cheese for longer chain MK as an insurance policy, doesn't seem that out of whack to me. after all, you are advocating a vegetarian diet. wouldn't that be a good approach for a vegetarian diet? i personally don't like dairy that much and avoid milk.

[kismet]

You were advocating the cheese as an "insurance policy", but other members continue to prefer isolated MK-4 based on such wacky evidence like the one just posted; of course actual human studies are supportive of K1 and MK-7 for longevity related outcomes (but do not exclude a role for Mk-4, hence low level Mk-4 supplementation might be regarded as insurance policy).

[tunt01]

You were advocating the cheese as an "insurance policy", but other members continue to prefer isolated MK-4 based on such wacky evidence like the one just posted; of course actual human studies are supportive of K1 and MK-7 for longevity related outcomes (but do not exclude a role for Mk-4, hence low level Mk-4 supplementation might be regarded as insurance policy).

AFAIK, the preference for mk-4 that myself, michael rae, and everyone else on planet earth prefers is based on human studies, not "wacky evidence". maybe supplementing MK-4 is an insurance policy, if you are consistently consuming chicken. but i'm closer to a vegan+fish diet (low dairy, low meat). so in my case, MK-4 is required. and given that most data seems to indicate MK-4 does everything MK-7 and other forms do... are longer chains necessary? i don't know, but a little bit of cheese as an insurance policy is probably fine.

whether or not the MK-7/8/9/10 will convert in vivo, who knows. getting a bit of both, with focus on mk-4 seems ideal to me.

[kismet]

To reiterate my main points:

AFAIK, the preference for mk-4 that myself, michael rae, and everyone else on planet earth prefers is based on human studies, not "wacky evidence".

Please do not involve any appeals to authority, because a. authority does not matter over evidence and b. you are wrong as the "authorities" tend to disagree and have differing opinions themselves and do not genuinely favour MK-4 over all the other vit K vitamers. The non-exclusive use of MK-4 among CRONies can be largely attributed to its potential, unique benefits on bone. It's not like K1 or long-chain vitamers are ignored and not used.
EDIT: as much as dislike to argue based on authority. There "could" be a reason why MK-4 is always studied at mega- and not dietary-doses and why on clinicaltrials.gov you can only find MK-7/k1 studies that are of relevance to LE (CVD, cancer)

maybe supplementing MK-4 is an insurance policy, if you are consistently consuming chicken. but i'm closer to a vegan+fish diet (low dairy, low meat). so in my case, MK-4 is required. and given that most data seems to indicate MK-4 does everything MK-7 and other forms do... are longer chains necessary? i don't know, but a little bit of cheese as an insurance policy is probably fine.

whether or not the MK-7/8/9/10 will convert in vivo, who knows. getting a bit of both, with focus on mk-4 seems ideal to me.

I don't want to discourage your opinion, but I would again like to emphasise that the evidence from randomised controlled trials (as of now) only supports phylloquinone for LE related outcomes (CVD /-surrogates, cancer in some cases); key examples being:

Vitamin K supplementation and progression of coronary artery calcium in older men and women. Shea et al.

Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study. Braam et al. 

Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): a randomized controlled trial. Cheung et al. (I did not manage to more than skim this pretty "famous" paper yet)

And the epidemiology almost always looks at a mix of K2 vitamers, perhaps even favouring long-chain vitamers in a few cases (CVD /-surrogates, cancer):

They all show pretty much the same; Rotterdam study, cross-sectional/prospective analyses of EPIC. To quote the most recent analysis from EPIC-Heidelberg, hot off the presses:
"Both MK-4 and the sum of MK-5 to MK-9 were significantly inversely  associated with total cancer mortality when modeled separately (data not 
shown)."
Dietary vitamin K intake in relation to cancer incidence and mortality: results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg). Nimptsch et al.

In the Rotterdam cohort long-chain menaquinones were more abundant and even based solely on this fact are more likely to drive the association (but see also below):


Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. Geleijnse et al.

In this study (though, it suffers from a small sample size and cross-sectional design) long-chain vitamers were solely responsbile for beneficial associations:
A high menaquinone intake reduces the incidence of coronary heart disease. Gast et al.

etc, etc.

I do not want to go over the mechanistic, animal and in vitro data, but there is evidence to suggest that long-chain vitamers are (sometimes considerably) more effective at gamma-carboxylation (still the accepted main mechanism of action of vitamin K derivatives) than either short-chain vitamers and/or K1. In the case of K1 there is very strong evidence for the superiority of MK-7 and we should keep in mind that it was K1 showing the outstanding results in RCTs while MK-7 studies are ongoing (unfortunately no MK-4 studies to my knowledge, hence there will be no conclusive, esp. no head to head, evidence for a long time).

Still no credible evidence shows that MK-4 is superior other than for HCC and osteoporsis (!) Indeed, MK-4 may be similarly effective as MK-7, but I think doubts are justified that it isn't so mcg per mcg and that one would need unnatural, non-dietary mega-doses of MK-4. But if you go with mega-doses e.g. used to treat osteoporosis, you completely break with the "paleo ideology" and the idea of replicating the epidemiology and human biology anyway. If you take low MK-4 doses you could be taking an ineffective dose and I would strongly recommend to add (consume) either MK-7 or high dose K1. Hence I think that either and especially a vitamin K mix is a good "insurance policy".

There is all the reason in the world to favour K1 and MK-7 if osteoporosis is not a concern to you.

Edited by kismet, 28 April 2010 - 03:37 PM.

[imhotep]

I have been taking 200mcg of MK-7from the Vitamin Shoppe with 10001u of D3 jell caps. I was looking for a cheaper way to up my dosage. Has anyone found a bulk source? I found this company online.

http://www.falconti....MK4.htm#contact

Has anyone else gone this route. It looks like you could blend mk-7 with mk-4 and cover your bases.

[mikeinnaples]

I have been taking 200mcg of MK-7from the Vitamin Shoppe with 10001u of D3 jell caps. I was looking for a cheaper way to up my dosage. Has anyone found a bulk source? I found this company online.

http://www.falconti....MK4.htm#contact

Has anyone else gone this route. It looks like you could blend mk-7 with mk-4 and cover your bases.

Personally, I am still trying to sort this all out so I am taking this @ 5x/week atm as an insurance policy. (This is the LEF K product)

mk-7 100mcg
mk-4 1000mcg
K-1 1000mcg

[nameless]

It's been a while since I looked up MK-4 data, but what is the average amount consumed via diet (for populations studied)?

I think Rotterdam MK-4 amounts were pretty low, somewhere around 35-40mcg?

If so, wouldn't 1 gram of MK-4, such as in the LEF K product, be way overboard if viewing it as an 'insurance policy'? I'm not saying it's a bad thing to take, just that wouldn't gram+ amounts be way out of line in relation to dietary data for MK-4?

[mikeinnaples]

It's been a while since I looked up MK-4 data, but what is the average amount consumed via diet (for populations studied)?

I think Rotterdam MK-4 amounts were pretty low, somewhere around 35-40mcg?

If so, wouldn't 1 gram of MK-4, such as in the LEF K product, be way overboard if viewing it as an 'insurance policy'? I'm not saying it's a bad thing to take, just that wouldn't gram+ amounts be way out of line in relation to dietary data for MK-4?

1000 mcg = 1 mg ...not 1 gram. You are off x1000

[nameless]

It's been a while since I looked up MK-4 data, but what is the average amount consumed via diet (for populations studied)?

I think Rotterdam MK-4 amounts were pretty low, somewhere around 35-40mcg?

If so, wouldn't 1 gram of MK-4, such as in the LEF K product, be way overboard if viewing it as an 'insurance policy'? I'm not saying it's a bad thing to take, just that wouldn't gram+ amounts be way out of line in relation to dietary data for MK-4?

1000 mcg = 1 mg ...not 1 gram. You are off x1000

Yep, I meant mg, sorry about that.

But the question still remains, didn't the Rotterdam data support mcg doses? Just wondering if 1 mg would be considered 'insurance' or way more than is supported by dietary data?

[Jay]

I have a question about the interraction between K and D that I was wondering if anybody could shed some light on. This recent study found that K2 (mk-7) increases parathyroid hormone levels, suggesting a greater need for vitamin D. On some level that makes sense as K2 should help get calcium out of the blood, which would trigger a parathyroid response to get calcium back in the blood, which would use up some vitamin D through conversion of calcidiol to calcitriol in the kidneys.

However, if, as many people suspect, high serum calcidiol levels prevent cancer (through conversion to calcitriol in tissue), might K2 thwart some of vitamin D's anti-cancer benefit by lowering serum cacidiol? But, that's not what is being found... K1 + 800IU D3 resulted in 75% reduction in cancer. There have also been some epidmiological results recently (from the EPIC study) showing that K2 protects against cancer. I wonder what's going on? It reminds me of Cannell's hypothesis regarding vitamin A -- that vitamin A is protective against cancer in vitamin D deficient people but actually thwarts D's greater benefit in vitmain D sufficient people. I wonder if vitamin K works the same way...Of course, if K actually prevents as much cancer as does D (about 77% according to Lappe's study), it doens't much matter...

Edited by Jay, 28 April 2010 - 07:44 PM.

[Blue]

It should be noted we have no idea what the Ks are doing, if anything, in most tissues. For example the highest concentration of K1 and mk4 is in the pancreas, not in the liver (clotting) or bones. Some epidemiologic studies suggest a protective role against diabetes and related variables but how is completely unclear. So all attempts to make theoretical speculations are very problematic.

Edited by Blue, 28 April 2010 - 07:56 PM.

[Jay]

It should be noted we have no idea what the Ks are doing, if anything in most tissues. For example the highest concentration of K1 and mk4 is in the pancreas, not in the liver (clotting) or bones. Some epidemiologic studies suggest a protective role against diabetes and related variables but how is completely unclear. So all attempts to make theoretical speculations are very problematic.

Agreed. But, in the meantime, we have to make decisions about supplementation. It may inform some people's decision to know that 180 mcg of mk-7 raises parathyroid levels and, presumably, lowers vitamin D levels.

[Blue]

It should be noted we have no idea what the Ks are doing, if anything in most tissues. For example the highest concentration of K1 and mk4 is in the pancreas, not in the liver (clotting) or bones. Some epidemiologic studies suggest a protective role against diabetes and related variables but how is completely unclear. So all attempts to make theoretical speculations are very problematic.

Agreed. But, in the meantime, we have to make decisions about supplementation. It may inform some people's decision to know that 180 mcg of mk-7 raises parathyroid levels and, presumably, lowers vitamin D levels.

PTH increases the conversion of calcifediol to calcitriol. That is, the active D vitamin form. Not sure how accurate conventional calcifediol measurements are regarding vitamin D needs in such a situation... One wonders if a very high dose D and K together can create too HIGH calcitriol values... But then we have ECKO trial we found only very positive effects of very high K1 and moderate D intake.

Edited by Blue, 28 April 2010 - 08:20 PM.

[Jay]

PTH increases the conversion of calcifediol to calcitriol. That is, the active D vitamin form. Not sure how accurate conventional calcifediol measurements are regarding vitamin D needs in such a situation... One wonders if a very high dose D and K together can create too HIGH calcitriol values.

Calcidiol is another name for calcifediol, so we are saying the same thing. The way I understand it, PTH increases conversion to calcitriol in the kidneys. Any left over is used in the tissue to make calcitriol. This tissue calcitriol is what's likely responsible to the anti-cancer effects, if any, of vitamin D. Excess calcidiol is stored in fat. I don't think calcitriol can go too high in the kidneys since it's highly regulated by PTH.

But then we have ECKO trial we found only very positive effects of very high K1 and moderate D intake

Agreed. This is the study that confused me the most. If K1 + moderate D really prevents 75% of cancer, that's pretty damn amazing. By the way, D is instrumental in the conversion of K1 to K2, so the moderate D may have been the key in this K1 trial.

Edited by Jay, 28 April 2010 - 08:26 PM.

[Blue]

PTH increases the conversion of calcifediol to calcitriol. That is, the active D vitamin form. Not sure how accurate conventional calcifediol measurements are regarding vitamin D needs in such a situation... One wonders if a very high dose D and K together can create too HIGH calcitriol values.

Calcidiol is another name for calcifediol, so we are saying the same thing. The way I understand it, PTH increases conversion to calcitriol in the kidneys. Any left over is used in the tissue to make calcitriol. This tissue calcitriol is what's likely responsible to the anti-cancer effects, if any, of vitamin D. Excess calcidiol is stored in fat. I don't think calcitriol can go too high in the kidneys since it's highly regulated by PTH.

But then we have ECKO trial we found only very positive effects of very high K1 and moderate D intake

Agreed. This is the study that confused me the most. If K1 + moderate D really prevents 75% of cancer, that's pretty damn amazing. By the way, D is instrumental in the conversion of K1 to K2, so the moderate D may have been the key in this K1 trial.

Do you have a source for that calcitriol is produced outside the kidney and without being affected by PTH? Even if it is produced in the kidney it may travel by blood to the rest of the body
.
D + K did not only greatly reduces fractures and cancer but also in general severe disease of various kinds if you look in the body of the paper. Although the study was small for studying cancer and other effects beside the bone variables.

"SAEs occurred in 9.1% (40/440) of participants: 6.9% (15/217) in the vitamin K group and 11.2% (25/223) in the placebo group. These included hospitalizations for pneumonia, heart failure, gastrointestinal bleeding, elective and nonelective surgeries, cancer, and death. Cancer incidence was lower in the vitamin K group than in the placebo group (three versus 12, p = 0.02; HR = 0.25, 95% CI 0.07 to 0.89) (Figure 4B). Higher mean serum vitamin K levels over the duration of the study correlated with lower cancer incidence (p < 0.05) (Figure 4C). Because half of the cases were breast cancers (one in the vitamin K group and six in the placebo group), we calculated the Gail breast cancer risk score [21] from baseline data and found that there was no difference between the vitamin K and the placebo groups (1.70% versus 1.71% risk of having invasive breast cancer in the next 5 y). There were five deaths during the study and follow-up period: one woman on vitamin K (passenger in a car accident) and four women on placebo (three who died of cancers, and one who died in her sleep from arrhythmogenic right ventricular cardiomyopathy). There was no difference in health-related quality of life between groups."

[Jay]

Do you have a source for that calcitriol is produced outside the kidney and without being affected by PTH? Even if it is produced in the kidney it may travel by blood to the rest of the body

Take a look at this.

Edited by Jay, 28 April 2010 - 09:56 PM.

[Blue]

Do you have a source for that calcitriol is produced outside the kidney and without being affected by PTH? Even if it is produced in the kidney it may travel by blood to the rest of the body

Take a look at this.

"At this point the data do not clearly demonstrate an essential role for CYP27b1 expression in any tissue outside the kidney, but several examples pointing in this direction are provided."

Even if it has an important role outside it kidney, and that this is more important for certain things than the circulating calcitriol which do is mainly produced in the kidneys as per this review, any evidence that tissue conversion is a PTH independent effect? Otherwise the result will be the same.

[Jay]

Even if it has an important role outside it kidney, and that this is more important for certain things than the circulating calcitriol which do is mainly produced in the kidneys as per this review, any evidence that tissue conversion is a PTH independent effect? Otherwise the result will be the same.

That I can't find. But, look at figure 1 of this review (it seems to suggest as much).

[Blue]

Even if it has an important role outside it kidney, and that this is more important for certain things than the circulating calcitriol which do is mainly produced in the kidneys as per this review, any evidence that tissue conversion is a PTH independent effect? Otherwise the result will be the same.

That I can't find. But, look at figure 1 of this review (it seems to suggest as much).

The text itself says nothing regarding this. Maybe it is unknown.

[Stewill]

yeah those adverse effects look real serious.

human do not efficiently convert k1 to k2.
in korea and japan, 45mg a day (not mcg, mg) of k2 mk-4 is administered for osteoporosis and atherosclerosis (off label) patients.
in fact officially approved upper limit is 90mg mk-4 a day.

now i'll propose a challenge to you all.
take 45mg of either k1 or k2 mk-7 a day and see if you are still alive. (3x15mg will do)
chances are, you get hospitalised with ischemic stroke on the FIRST day.

Our body can tolerate megadose (45mg) of k2 mk-4 because it is almost immediately absorbed where it is needed, i.e. it is very bio-avaiable, but not k1 and k2 mk-7.
Go ahead try 45mg of k1 or k2 mk-7. if not, plz stop needless argument.

*
Blue is too afraid to try it. anyone else..?

As far as I am aware vitamin K does not make blood clot. Vitamin K activates proteins made by the body and these proteins produce clots in order to stop bleeding, it also activates proteins (C,S and Z) that the body makes to control the size of blood clots. So once all of these proteins are activated the amount of vitamin K you have is irrelevant with regard to blood clotting.
A concern I have about your statement is that I know of people who are scared of taking vitamin K (in whatever form) since they are worried about blood clots, so instead they are likely to suffer from the various diseases caused by lack of vitamin K.

Documented evidence provides vital guidance and so if you know any studies suggesting my understanding of blood clotting is wrong please post them.

[krillin]

Do you have a source for that calcitriol is produced outside the kidney and without being affected by PTH? Even if it is produced in the kidney it may travel by blood to the rest of the body

The best example is the unregulated overproduction of 1,25-OH D by macrophages in sarcoidosis, Lyme, etc. My second reference found that 45 mg MK-4 plus a piddly 1000 IU of D2 reduces PTH, so it looks pretty easy to satisfy the increased need for D. (I'm doing 90 mcg MK-7 every other day. I'm not going to take K1 until someone shows that it provides additional benefit to such a regimen.)

Med Sci Monit. 2007 Nov;13(11):CS133-136.
Hypercalcemia as a result of sarcoidosis with normal serum concentrations of vitamin D.

Falk S, Kratzsch J, Paschke R, Koch CA.

Division of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
Abstract

BACKGROUND: Hypercalcemia can occur in patients with granulomatous disorders such as sarcoidosis, and is commonly related to high serum 1,25-dihydroxyvitamin D (OHD) concentrations. CASE REPORT: We here report a 68-year-old man with a history of mild renal insufficiency who presented with hypercalcemia (serum calcium of 3.11 mmol) and normal 1,25-OHD levels (38 pg/ml, RIA/IDS, Boldon, UK, measuring both 1,25-OH D2 and D3). Imaging and laboratory investigations were suggestive of sarcoidosis. After hydration and prednisone therapy (40 mg/day) for 7 days, serum calcium dropped to 2.7 mmol and 1,25-OHD levels to 13.4 pg/ml. Six weeks after prednisone therapy, serum calcium was 2.41 mmol (normal) and 1,25-OHD 6.2 pg/ml (low). Computed tomography of the chest showed shrinkage of the right hilar mass. CONCLUSIONS: This case illustrates that hypercalcemia can occur in granuloma-forming disorders such as sarcoidosis in the setting of inappropriately normal (and not elevated) 1,25-OHD levels. Contributing factors may include dehydration, increased uptake of oral calcium and/or decreased calcium excretion, especially in mild renal insufficiency. Therapy of choice are hydration and glucocorticoid (prednisone) therapy. In this setting, prednisone may lead to a decline of activated mononuclear cells (in the lung and lymph nodes) that are able to produce extrarenal PTH-independent 1,25-OHD.

PMID: 17968303

Bone. 2005 Jan;36(1):61-8. Epub 2004 Nov 24.
Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer's disease.

Sato Y, Kanoko T, Satoh K, Iwamoto J.

Department of Neurology, Mitate Hospital, Tagawa 826-0041, Japan. y-sato@ktarn.or.jp
Abstract

A high incidence of fractures, particularly of the hip, represents an important problem in patients with Alzheimer's disease (AD), who are prone to falls and may have osteoporosis. We previously showed deficiency of vitamins D and K1 causes reduced bone mineral density (BMD) in female AD patients. The present study was undertaken to address the possibility that treatment with vitamin K2 (menatetrenone; MK-4) may maintain BMD and reduce the incidence of nonvertebral fractures in elderly female patients with AD. In a random and prospective study of AD patients, 100 patients received 45 mg menatetrenone, 1000 IU ergocalciferol and 600 mg calcium daily for 2 years, and the remaining 100 (untreated group) did not. At baseline, patients of both groups showed vitamin D and K1 deficiencies. They also had high serum levels of parathyroid hormone (PTH) and Glu osteocalcin (OC) and low serum ionized calcium, indicating that vitamin D deficiency stimulates compensatory PTH secretion. During the 2-year study period, BMD in the second metacarpals increased by 2.3% in the treated group and decreased by 5.2% in the untreated group (P < 0.0001). Serum levels of vitamin K2 and 25-hydroxyvitamin D increased by 284.9% and 147.9%, respectively, in the treated group. Correspondingly, a significant decrease in Glu OC and PTH were observed, in association with an increased calcium levels, in the treated group. Twenty-two patients in the untreated group sustained nonvertebral fractures (15 with hip fractures, two fractures each at the distal forearm and the proximal femur, each one fracture at the proximal humerus, ribs, and pelvis), and three fractures (2 with hip fractures, one fracture at the proximal femur) occurred among the treated patients (P = 0.0003; odds ratio = 7.5). Treatment with MK-4 and vitamin D2 with calcium supplements increases the BMD in elderly female patients with AD and leads to the prevention of nonvertebral fractures.

PMID: 15664003

[krillin]

Regarding the phase I-II relation to K1 in rodents it is unclear if that is important regarding actual diseases even if you a rodent.

"K1 supplementation increases BP induced tumor formation in mice." In humans fetuses are low in K1, which may be responsible for the fact that "epidemiologic studies indicate that children of mothers who smoke during pregnancy may not be at increased risk of cancer."

(I just love the phrase "BP induced tumor formation.")

[krillin]

Great. So far then we don't have any reports of softer skin and reduction of tartar buildup with the MK7 form.

Calcium flux into keratinocytes inhibits skin barrier maintenance, and so does nitric oxide. It is possible that the calcium mechanism involves activation of nNOS. Calcium channel blockers, NMDA antagonists, nNOS inhibitors (but not iNOS inhibitors), etc. have been shown to help the barrier. For details see these papers.

http://www3.intersci...42720/HTMLSTART

http://www.nature.co...l/5603411a.html

http://www.nature.co...l/5700742a.html

I believe that my stack of felodipine, gabapentin, clonidine, and rimantadine (for reducing symptoms of my TRPpathic sensitivity to microbial VOCs and dust) is responsible for my not ever needing hand lotion last winter. Never noticed anything like that from MK-7.

[Blue]

Regarding the phase I-II relation to K1 in rodents it is unclear if that is important regarding actual diseases even if you a rodent.

"K1 supplementation increases BP induced tumor formation in mice." In humans fetuses are low in K1, which may be responsible for the fact that "epidemiologic studies indicate that children of mothers who smoke during pregnancy may not be at increased risk of cancer."

(I just love the phrase "BP induced tumor formation.")

An intraperitoneal injection of benzo(a)pyrene in a strain of tumor prone laboratory mice is hardly a normal situation for rodents. Says very little regarding whether K1 has a positive or negative effects on tumors overall during a normal environment for rodents.

The last sentence is just wild speculation. Lots of other possible explanation such as obviously the protective effect of the the placenta-fetus barrier in general against toxins in smoke. Also, the claim in this old study that smoking in mothers does not affect cancer in their children is dubious:
http://www.heraldsun...6-1111118541757

Furthermore, the claim in the fifteen years old study that there is a "small total body pool of K1 in the adult, which is sufficient only to meet continuing needs" is also incorrect. See the study in this thread showing that in humans K1 level in several organs are higher than mk4 levels. Also, according to this logic mk7 must be extremely harmful since it hardly found in any organs at all except blood.

Another claimed advantage of mk7 is a longer half-life. Well, according to a new study the tissue half-life of K1 is very long. 215 h!
http://journals.camb...ine&aid=7631140

Most importantly, cell, rodent, and epidemiologic studies are much less important than actual controlled clinical trials. There is none for mk7 and only for osteoporosis and maybe liver cancer for mk4. For K1 we have the EKO trial:

""SAEs occurred in 9.1% (40/440) of participants: 6.9% (15/217) in the vitamin K group and 11.2% (25/223) in the placebo group. These included hospitalizations for pneumonia, heart failure, gastrointestinal bleeding, elective and nonelective surgeries, cancer, and death. Cancer incidence was lower in the vitamin K group than in the placebo group (three versus 12, p = 0.02; HR = 0.25, 95% CI 0.07 to 0.89) (Figure 4B). Higher mean serum vitamin K levels over the duration of the study correlated with lower cancer incidence (p < 0.05) (Figure 4C). Because half of the cases were breast cancers (one in the vitamin K group and six in the placebo group), we calculated the Gail breast cancer risk score [21] from baseline data and found that there was no difference between the vitamin K and the placebo groups (1.70% versus 1.71% risk of having invasive breast cancer in the next 5 y). There were five deaths during the study and follow-up period: one woman on vitamin K (passenger in a car accident) and four women on placebo (three who died of cancers, and one who died in her sleep from arrhythmogenic right ventricular cardiomyopathy). There was no difference in health-related quality of life between groups."
http://www.plosmedic...al.pmed.0050196

[krillin]

An intraperitoneal injection of benzo(a)pyrene in a strain of tumor prone laboratory mice is hardly a normal situation for rodents. Says very little regarding whether K1 has a positive or negative effects on tumors overall during a normal environment for rodents.

Furthermore, the claim in the fifteen years old study that there is a "small total body pool of K1 in the adult, which is sufficient only to meet continuing needs" is also incorrect. See the study in this thread showing that in humans K1 level in several organs are higher than mk4 levels. Also, according to this logic mk7 must be extremely harmful since it hardly found in any organs at all except blood.

Another claimed advantage of mk7 is a longer half-life. Well, according to a new study the tissue half-life of K1 is very long. 215 h!

Most importantly, cell, rodent, and epidemiologic studies are much less important than actual controlled clinical trials. There is none for mk7 and only for osteoporosis and maybe liver cancer for mk4. For K1 we have the EKO trial:

Isothiocyanates protect against cancer by inhibiting phase I and inducing phase II (PMID: 8137323), the opposite of what K1 does. You're gambling that the magnitude of this effect from an unnatural megadose of K1 is insignificant. We have only two human studies on K1 megadoses (and they're both short: 3-4 years), so it would only make sense to take them if there were no identified risks. MK-7 is taken at levels obtained by unsupplemented populations and has no identified risks, so it is the optimal choice.

215 hours is only 9 days. That's a lower tissue half-life than a lot of B-vitamins. And the correct logic is: K1 has a potentially harmful effect -> makes sense that the body doesn't keep a large supply on board like it does with A and D; MK-7 is converted to MK-4 -> makes sense that it isn't found in organs in large amounts.

[Blue]

An intraperitoneal injection of benzo(a)pyrene in a strain of tumor prone laboratory mice is hardly a normal situation for rodents. Says very little regarding whether K1 has a positive or negative effects on tumors overall during a normal environment for rodents.

Furthermore, the claim in the fifteen years old study that there is a "small total body pool of K1 in the adult, which is sufficient only to meet continuing needs" is also incorrect. See the study in this thread showing that in humans K1 level in several organs are higher than mk4 levels. Also, according to this logic mk7 must be extremely harmful since it hardly found in any organs at all except blood.

Another claimed advantage of mk7 is a longer half-life. Well, according to a new study the tissue half-life of K1 is very long. 215 h!

Most importantly, cell, rodent, and epidemiologic studies are much less important than actual controlled clinical trials. There is none for mk7 and only for osteoporosis and maybe liver cancer for mk4. For K1 we have the EKO trial:

Isothiocyanates protect against cancer by inhibiting phase I and inducing phase II (PMID: 8137323), the opposite of what K1 does. You're gambling that the magnitude of this effect from an unnatural megadose of K1 is insignificant. We have only two human studies on K1 megadoses (and they're both short: 3-4 years), so it would only make sense to take them if there were no identified risks. MK-7 is taken at levels obtained by unsupplemented populations and has no identified risks, so it is the optimal choice.

215 hours is only 9 days. That's a lower tissue half-life than a lot of B-vitamins. And the correct logic is: K1 has a potentially harmful effect -> makes sense that the body doesn't keep a large supply on board like it does with A and D; MK-7 is converted to MK-4 -> makes sense that it isn't found in organs in large amounts.

A study of broccoli extract given to tumor prone rodents given megadoses of another toxic substance as evidence for that your first study of is correct? Well, that cruciferous vegetables prevents cancer in humans is not proven, that it is isothiocyanates and not something else which causes a possible prevention is also uncertain (they are also rich in, say, vitamin K1), and that a possible effect is caused by phase 1/phase 2 changes is very uncertain since isothiocyanates have many other effects.
http://lpi.oregonsta...micals/isothio/

3-4 years is not a lifetime study (but longer than almost all clinical trials of supplements), and the ECKO trial was not very large, but it is certainly better than the total absence of clinical studies for mk7 (or isothiocyanates). You are gambling on rodents studies on sick animals given megadoses of toxic substances are more important than human, double-blind, clinical trials. I think you place way to much confidence in dubious animal studies and narrow theoretical reasonings. The history is littered with exciting substances with plausible theories and nice lab animal evidence but shown to be ineffectual or harmful in humans when doing actual human, clinitcal trials (beta-carotene, vitamin c, vitamin e, folate, selenium, and so on).

Another problem with mk7 is lack of evodence for what is a good intake level. Yes, one could argue for an intake at the level in western epidemiological studies but that is much lower than in Japanese natto eaters and thus Japanese epidemiological studies. For k1 we have some evidence that at least 1 mg is required to saturate certain K dependent functions in blood which is why the ECKO trial used 5 mg. Equivalent dosage of mk7 is completely unknown. The effects seen in the ECKO trial was simply astounding, although certainly needed to be replicated in larger studies, so it an be argued that it is those not following the dose there that is taking a very risky gamble.
http://www.ajcn.org/.../full/76/5/1055
http://www.plosmedic...ed-0050196-b013

According to your tissue logic, why is there more k1 than mk4 (not to mention mk7) in many organs? Does this not mean that they are both more harmfult than k1?

Edited by Blue, 21 June 2010 - 10:32 AM.

[Jay]

I also think the K1 trial is pretty amaxing and have added K1 to my regimen based on it, albeit only a small amount. As I have stated earlier in this thread, I am guessing that conversion of K1 to K2 occurs more readily at optimal vitamin D levels. Also, to add to the points that Blue made above, inducing phase II detox is not the only plausible explanation for the observed anti-cancer effects of isothiocyanates. Sulforaphane, for example, is also a HDAC inhibitor and, thus, may effect epigenetic change, like reactivating silenced tumor suppresor genes.

[krillin]

A study of broccoli extract given to tumor prone rodents given megadoses of another toxic substance as evidence for that your first study of is correct? Well, that cruciferous vegetables prevents cancer in humans is not proven, that it is isothiocyanates and not something else which causes a possible prevention is also uncertain (they are also rich in, say, vitamin K1), and that a possible effect is caused by phase 1/phase 2 changes is very uncertain since isothiocyanates have many other effects.
http://lpi.oregonsta...micals/isothio/

3-4 years is not a lifetime study (but longer than almost all clinical trials of supplements), and the ECKO trial was not very large, but it is certainly better than the total absence of clinical studies for mk7 (or isothiocyanates). You are gambling on rodents studies on sick animals given megadoses of toxic substances are more important than human, double-blind, clinical trials. I think you place way to much confidence in dubious animal studies and narrow theoretical reasonings. The history is littered with exciting substances with plausible theories and nice lab animal evidence but shown to be ineffectual or harmful in humans when doing actual human, clinitcal trials (beta-carotene, vitamin c, vitamin e, folate, selenium, and so on).

Another problem with mk7 is lack of evodence for what is a good intake level. Yes, one could argue for an intake at the level in western epidemiological studies but that is much lower than in Japanese natto eaters and thus Japanese epidemiological studies. For k1 we have some evidence that at least 1 mg is required to saturate certain K dependent functions in blood which is why the ECKO trial used 5 mg. Equivalent dosage of mk7 is completely unknown. The effects seen in the ECKO trial was simply astounding, although certainly needed to be replicated in larger studies, so it an be argued that it is those not following the dose there that is taking a very risky gamble.
http://www.ajcn.org/.../full/76/5/1055
http://www.plosmedic...ed-0050196-b013

According to your tissue logic, why is there more k1 than mk4 (not to mention mk7) in many organs? Does this not mean that they are both more harmfult than k1?

Here's how proper supplement risk management works. If it's something that no large population has been taking without a problem, then you must take even flimsily-supported risks seriously yet require a high burden of proof for benefits. (Be like the FDA is when it's considering approving a new drug.) Thus, you are incorrect to demand ironclad proof that increasing the phase I/II ratio is dangerous before taking the risk (based on voluminous evidence pointing in that direction) seriously. Rather, you should be demanding ironclad proof that increasing the ratio is not dangerous, before committing yourself to an unnatural megadose regimen.

ECKO was "simply astounding"? Give me a break. Look at that huge CI: the HR could be as high as a ho-hum 0.89. The authors warn us that the study wasn't powered to examine cancer. You sound like an LEF stooge when you say that I'm arguably taking a huge risk by taking the authors' advice to hold off on taking K1 until better data are available.

Note how much time elapsed between the first few positive megadose MK-4 trials and the point at which we started hearing about adverse effects. How can you be so sure that it'll be different with K1?

MK-7 dosing isn't as hard as you make it sound. The top quartile of long-chain K2 in Heidelberg (which benefited the most) was >29 mcg/day (PMID: 18400723). Young Japanese women get an average of 57 mcg/day MK-7 (PMID: 18202532). That's just a factor of 2 difference, and 90 mcg EOD splits the difference nicely. (Too nicely...) ECKO used 5 times as much as the theoretical rationale you give and was thus a near-total shot in the dark.

You're still not getting my logic. Note how I don't start with tissue levels and make conclusions from them. I take known effects and then see if tissue concentrations and half-lives are consistent with them. There are too many possible determinants of tissue concentrations to draw any conclusions from the fact that K1 predominates over MK4 in some organs. My decision to avoid K1 megadoses is based mainly on the effect on phase I and II detoxification, with menadione production from K megadosing as a lesser concern. The short half-life of K1 is no reason to avoid it. I take vitamin C, after all.

C and selenium supplements do have benefits. 750 mg/day C vs cataracts (PMID: 11815895), selenium vs cancer if blood levels don't get beyond ~150-175 ng/ml. (150 based on epidemiology, 175 based on the estimated maximum level that someone in the lowest tertile of the Clark study would have achieved.) I take 200 mcg 13 days per fortnight to achieve a blood level of 134.

[Jay]

Here's how proper supplement risk management works. If it's something that no large population has been taking without a problem, then you must take even flimsily-supported risks seriously yet require a high burden of proof for benefits. (Be like the FDA is when it's considering approving a new drug.) Thus, you are incorrect to demand ironclad proof that increasing the phase I/II ratio is dangerous before taking the risk (based on voluminous evidence pointing in that direction) seriously. Rather, you should be demanding ironclad proof that increasing the ratio is not dangerous, before committing yourself to an unnatural megadose regimen.

ECKO was "simply astounding"? Give me a break. Look at that huge CI: the HR could be as high as a ho-hum 0.89. The authors warn us that the study wasn't powered to examine cancer. You sound like an LEF stooge when you say that I'm arguably taking a huge risk by taking the authors' advice to hold off on taking K1 until better data are available.

Note how much time elapsed between the first few positive megadose MK-4 trials and the point at which we started hearing about adverse effects. How can you be so sure that it'll be different with K1?

MK-7 dosing isn't as hard as you make it sound. The top quartile of long-chain K2 in Heidelberg (which benefited the most) was >29 mcg/day (PMID: 18400723). Young Japanese women get an average of 57 mcg/day MK-7 (PMID: 18202532). That's just a factor of 2 difference, and 90 mcg EOD splits the difference nicely. (Too nicely...) ECKO used 5 times as much as the theoretical rationale you give and was thus a near-total shot in the dark.

You're still not getting my logic. Note how I don't start with tissue levels and make conclusions from them. I take known effects and then see if tissue concentrations and half-lives are consistent with them. There are too many possible determinants of tissue concentrations to draw any conclusions from the fact that K1 predominates over MK4 in some organs. My decision to avoid K1 megadoses is based mainly on the effect on phase I and II detoxification, with menadione production from K megadosing as a lesser concern. The short half-life of K1 is no reason to avoid it. I take vitamin C, after all.

C and selenium supplements do have benefits. 750 mg/day C vs cataracts (PMID: 11815895), selenium vs cancer if blood levels don't get beyond ~150-175 ng/ml. (150 based on epidemiology, 175 based on the estimated maximum level that someone in the lowest tertile of the Clark study would have achieved.) I take 200 mcg 13 days per fortnight to achieve a blood level of 134.

Agreed that the ECKO trial does not alone support megadosing with K-1 (I take just 100mcgs of K1 a few times per week as part of a "bone-up" multi-mineral/vitamin). I can't find much on phase I/II ratio. Do you have any references/summary papers that will help me get acquainted with these concepts?

[Blue]

Here's how proper supplement risk management works. If it's something that no large population has been taking without a problem, then you must take even flimsily-supported risks seriously yet require a high burden of proof for benefits. (Be like the FDA is when it's considering approving a new drug.) Thus, you are incorrect to demand ironclad proof that increasing the phase I/II ratio is dangerous before taking the risk (based on voluminous evidence pointing in that direction) seriously. Rather, you should be demanding ironclad proof that increasing the ratio is not dangerous, before committing yourself to an unnatural megadose regimen.

ECKO was "simply astounding"? Give me a break. Look at that huge CI: the HR could be as high as a ho-hum 0.89. The authors warn us that the study wasn't powered to examine cancer. You sound like an LEF stooge when you say that I'm arguably taking a huge risk by taking the authors' advice to hold off on taking K1 until better data are available.

Note how much time elapsed between the first few positive megadose MK-4 trials and the point at which we started hearing about adverse effects. How can you be so sure that it'll be different with K1?

MK-7 dosing isn't as hard as you make it sound. The top quartile of long-chain K2 in Heidelberg (which benefited the most) was >29 mcg/day (PMID: 18400723). Young Japanese women get an average of 57 mcg/day MK-7 (PMID: 18202532). That's just a factor of 2 difference, and 90 mcg EOD splits the difference nicely. (Too nicely...) ECKO used 5 times as much as the theoretical rationale you give and was thus a near-total shot in the dark.

You're still not getting my logic. Note how I don't start with tissue levels and make conclusions from them. I take known effects and then see if tissue concentrations and half-lives are consistent with them. There are too many possible determinants of tissue concentrations to draw any conclusions from the fact that K1 predominates over MK4 in some organs. My decision to avoid K1 megadoses is based mainly on the effect on phase I and II detoxification, with menadione production from K megadosing as a lesser concern. The short half-life of K1 is no reason to avoid it. I take vitamin C, after all.

C and selenium supplements do have benefits. 750 mg/day C vs cataracts (PMID: 11815895), selenium vs cancer if blood levels don't get beyond ~150-175 ng/ml. (150 based on epidemiology, 175 based on the estimated maximum level that someone in the lowest tertile of the Clark study would have achieved.) I take 200 mcg 13 days per fortnight to achieve a blood level of 134.

Well, for one thing you have not shown any studies that K1 changes phase I/phase II in general. Only an old study finding that giving high doses of K1 and intraperitoneal benzo(a)pyrene was bad in a strain of tumor prone lab rodents. Why may be due any numer of factors not including phase I/phase II. You cite another study on chick embryo liver that found changes from K1 in certain phase I / phase II enzymes which does not ever prove that such changes take place in adult chickens or that such changes affect all or many phase I/phase II enzymes in the livers of chick embryos. No evidence that any of this applies to humans.

Adverse effects for mk4? As far as I know such bad effects were apparent even in the one and two year long Japanese 45 mg mk4 studies, such as increased risk for skin lesions. There were no adverse effects in the four year ECKO trial. On the contrary, regsrding the adverse effect you are afraid of, cancer, exactly the opposite was seen.

You comparison of the Western and Japansese intake is strange. Obivously you cannot compare the highest western quartile in the Heidelberg with the average intake in young Japense women. Obviously the highest Japanese quartile will be higher than the average value. Further, most likely the not unusual Japanese who eat natto regularly as part of the breakfast will have an mk7 intake monstrously larger than those who do not eat natto. Which makes it important to differentiate natto and not natto eaters in Japan.

Regarding the theoretical dosage of K1, a nonsignificant higher effect for 2 mg than 1 mg was seen in the earlier study. Higher amounts was not tested. This makes it not impossible that a higher amount than 2 mg would have achieved a significantly higher effect than 1 mg which was why 5 mg was choosen.

Anyway, it seems to me that your are making a classic human cognitive mistake. Which is to assume that best course of action is to do nothing when there are any conflicting data. Which is incorrect, no action is also an action. Lets weight the evidence: a chick embryo liver study and a cancer prone rodents given an intraperitoneal toxin study against a small four year double-blind human trial showing large, blood concentration dependent, reductions in cancer (p = 0.02; HR = 0.25, 95% CI 0.07 to 0.89) and general severe disease. The evidence weighs overwhelmingly in favor of K1. By the way, the same really applies to FDA approval or not. The FDA prefers to have overhelming evidence for no negative effects for political and judicial reasons. But for a patient dying of a disease, the rational course is not to wait and die by waiting many years for the FDA to cover its ass by superexpensive and very long safety studies, but to take a new drug immediately when the risk:reward ratio get largely favorable.

Edited by Blue, 22 June 2010 - 05:37 PM.