Tag Archives: Coimbra

VITAMINs K2+D3 – VITAMIN DUO OF THE NEXT DECADE

update 16 May 2016.   to our health: neil.burman@gmail.com

HIGH TO MASSIVE DOSE VITAMIN D3 IMPORTANCE – TEN TIMES MORE THAN MAXIMUM SUNLIGHT CAN PROVIDE – IN REVERSING  COMMON VIT D DEFICIENCY/RESISTANCE FOUND IN ALL MAJOR DISEASE eg ALL  INFECTIONS, INSOMNIA, MULTIPLE SCLEROSIS MS,  Myasthenia Gravis, SLE, RA, PARKINSON’S, DEPRESSION, VASCULAR DISEASE, CANCER, VITILLIGO, PSORIASIS,  PERIPHERAL NEUROPATHIES, MENTAL ILLNESS.

  introduction:     Cape Town is the world epicenter of epidemics (of poverty – malnutrition- HIV- HAART- TB –Diabetes, asthma-COPD,  and vitamin D  and iodine deficiency). And we  are seeing neuroarthropathy with a vengeance in our township clinics, where a majority of such diabesity or/and HIV patients  admit if questioned to chronic burning cramping legs  and sore muscles/joints if not also consequent insomnia, falls and leg ulcers.

Poor ill patients  seem to  accept it- neuroarthropathy-  as a way of life since it  usually has no visible signs (for anyone to see) till late– poor circulation, ulcers, falls,  arthritis- , and  malnourished diabesity patients  have bigger worries with uncontrolled diabetes and often uncontrolled hypertension despite even insulin; and the HIV+-Tuberculosis patients  have the multiple toxic burdens of antiretroviral and antituberculous therapy.

Because the burden of these diseases as well as stress from corruption and violence  here  is amongst the highest in a major city in the world, affecting especially the poorest and most illiterate labourers, state clinics rarely have budgets to cover the necessary vitamin and mineral supplements the poor  also need on their poverty fast food diet.

Our patients  accept that in return for life extension by designer antimicrobials and antidiabetic/ antihypertensives, all they will get for pain relief  is the combination of physiotherapy, and  designer synthetic palliative drugs- paracetamol, ibrufen /diclofenac, tramadol, amitryptiline, and if lucky some ung meth sal . These factory-synthesised drugs  give little relief,  and no improvement in prognosis since they do not address the proximate causes of the neuroarthropathy,  associated depression and  work incapacity (and later strokes, arthritis, dementia, ulcers, gangrene, chronic lung/heart/ liver/ kidney/visual disease)- respective causes including stress,  infective, drug-induced, tissue glycogenation, the misguided fast-food high carbohydrate-low fat diet  obesity; and manual labour/multiple trauma  wear and tear, and nutritional deficiency including much-needed marine and saturated fats, vitamins and minerals..

The pioneer  work discussed below in Pakistan(Salahuddin ea, Basit ea), Italy (Cipriani ea) and Brazil (Coimbra ea) in using respectively Vit D3 ~700 000iu loading dose and chronically up to 1000iu /kg/day ie average 70 000iu/day, up to 120000iu per day to reverse deadly acute and chronic disease,  is comparable in its simplicity safety and low cost to :

*Semmelweis’ revolutionary discovery  Vienna in the mid 19thC  of hand disinfection to decimate childbirth sepsis deaths; and

*Pauling’s landmark lifesaving escalation of Vit C dose to a gm  per kg per day for all severe disease; and

*the parallel discovery in UK and USA of the crucial role of not just the RDA preventative microdose but also the pharmacological anti-disease benefits of 10 to 100times bigger doses of all the vitamins B complex 1 to 12.

Cipriani ea 2010 seems to be the first report on Pubmed of deliberate oral dosing with  megadose     600 000iu vit D3 ie 10 000iu/kg, albeit only in health to assess bloodlevel response and safety. Since then, as we previously noted, 2 million unit single overdose in nonagenarians in Netherlands  has been shown to do no harm – ie about 40 000iu/kg. .

And as the Australians and others report below, there is no hint of vigorous vitamin or mineral  supplements being stigmatized as performance enhancing for eg sport –  despite vitamin D3 having the distinction of being truly an anabolic ie performance-enhancing (seco)steroid .

There is no point in giving vitamin D by injection (except in those in ICU on prolonged nil per mouth) since it is so well absorbed provided given with fat eg in fishoil/coconut/DMSO oil. And obviously the higher the dose given, the more important to avoid more than a traditional multisupplement pill a day  with low calcium and vitamin A retinol; combined with a low calcium diet (ie low dairy low peanut) ; and supplementing plenty fresh green produce [providing magnesia a few hundred mgs a day, and vitamin K2 perhaps 35mcg/d].

Dr  Mike Holick Prof of Medicine at Boston University interviewed by Dr Joe Mercola Dec 2015 details  the  rationale underpinning the (eg Coimbra) massive vit D3 dose regime for severe immune disease, “as opposed to  plenty of sensible sun exposure for general good health and lower deathrate from all diseases and infections.                 Most melanoma occurs on the least sunexposed skin, with lower melanoma and all other deaths with high sun exposure. Dark days promote melatonin and thus daytime sleepiness and depression- which bright light in the morning for an hour reverses, and elevates b-endorphan, which has many times the painkilling effect of morphines ie opioids, and antidepressants. Vitamin D deficiency more than doubles the risk of all diseases; even 2000iu vit D3 a day in the 1st yr of life in Finland halved the risk of type 1 diabetes– with loss of protection if vit D dose dropped to 400iu/day. Vitamin D/ sunlight reverse leukemic cells. But maximum sunlight exposure nearer the tropics still only elevates 25OHvit D level to a maximum of about 50ng/ml- whereas increasing evidence proves that it may take more than 10 times that bloodlevel to prevent and treat deadly diseases- depending on your genetic vitamin D receptors.

 Even 1000iu/d vit D with bld level about 30ng/ml halves risk of many cancers, with doubling benefit as 25OHvit D level is doubled serially  eg by 10 000iu/d or 50 000iu/d. The kidneys however limit production of the hypercalcemic 1,25vit D, thus avoiding hypercalcemia provided calcium intake is not supplemented by calcium pills, nuts. vit A  etc. The higher the vit D level above 30ng/ml (up to >? 500ng/ml), the more  of our 2000 enzyme systems are activated  to fight all disease without hypercalcemic risks. Hunter gatherers had levels twice as high as dressed housed people today, around 50ng/ml, with increasing anticancer and antiinfection/antiautoimmune benefit from vit D up to safe levels eg 100ng/ml and higher. .”

At Thisisms.com this is multiple sclerosis  March 2016 seems to be the latest from neurologist  Dr Cicero Coimbra  via grassroots health. He stresses that to cure degenerative/ autoimmune disease eg  MS, Parkinson’s, SLE, RA, vitiligo ie to overcome genetic Vit D resistance may require vit  D titration up to 1000iu/kg/d ie up to even 40000iu/d to 200000iu/d,
And 25OHvitD blood level to 1000ng  and even 4000ng / ml for a few years to produce cure, before reducing to maintenance vit D3  eg 100iu/kg/day ie ~ 50000iu/wk.
Hypercalcemia and thus calcinosis  is avoided provided PTH level is maintained in the low normal range, not suppressed. Optimal support includes low calcium and  high water diet and  Vit B2, magnes selenium zinc phosphor  supps.

      COST IMPLICATION:

The spectrum of vitamin D3 adult dose thus extends from the

traditional prevention RDA 10iu/kg/ ie~700iu/d against rickets (infants start with 1000iu/d or 25000iu ie ½ scoop/month of standardized vit D3  100iu/mg powder)

to  vigorous 100iu/kg/day (ie 50 000iu scoop /wk ) for common disease prevention/treatment (toddlers 2000iu/d/ ½ scoop/fortnight));

 to  massive  1000iu/kg/day eg 60 000iu/dy for severe autoimmune/immunodeficiency diseases – with mandatory monitoring of levels of calcium, creatinine, 25OHvitD3 and now PTH levels;

to mega 10 000iu/kg eg 650 000iu as a loading dose for eg TB or meningitis or severe trauma—which dose may maintain  25OHvit D3 blood levels in a “sufficiency” range above ~40ng/ml for a month or two, so obviously requires appropriate maintenance dosing.

Imported vitamin D3 100cwt concentrate powder (100iu/mg) per kg from an importing pharmacist costs about R500/kg ie R0.50/100 000iu- far lower than the cost of the highrisk plant xenocalciferol vitamin D2. Thus to the State (excluding packaging and dispensing cost) , the wholesale cost of vit D3 is about R0.15 per 50 000iu per week for maintenance dose; or for 50 000iu/day R10( US $0.6)/month ie retail abt R60pm ie US$5  for megadose therapy; compared to the quoted retail US$20/month in Brazil. .

     THE NEUROPATHY OF DIABETES, DRUGS/TOXINS, POST-VIRAL,TRAUMA,  SPONDYLOSIS, DEMENTIA:

PERIPHERAL NEUROPATHY:  Already in 2006 Oh-Park ,Sheehan .ea,  Lancet. Albert Einstein College of Medicine, New York wrote about AIDS-ARV neuropathy Charcot neuroarthropathy in the era of HAART.

Young, Dancho ea Tucson, Arizona, wrote 2012,   ” Charcot arthropathy is a devastating joint condition that affects persons with neuropathy. With HIV/AIDS treatments prolonging the lives of these persons, it is likely that long-term sequelae of the disease will become more evident in the near future. Patients with this disease frequently develop peripheral neuropathy. A high index of suspicion must be raised in any patient with peripheral neuropathy of any cause and a red, hot, swollen, painful foot for Charcot neuroarthropathy to give these patients proper treatment to help prevent the devastating effects of Charcot neuropathy with its potential consequences including foot ulceration and amputation. We know only too well the same applies to diabesity, as it did in the days of heavy smoking.”
In 2013 Zubair ea in India showed that diabetics with foot ulcers had vitamin D levels 1/4 of that of matched diabetics without foot ulcers; and “factors which predict the risk of developing ulcer independent of 25(OH)D status were A1c (>6.9%) [OR 4.3), neuropathy [OR 6.9retinopathy [OR 3.3;  nephropathy [OR 3.1) and smoking [OR 4.5]. It is not clear whether the suppression of delayed wound healing seen during 25(OH)D deficiency is a secondary effect or is a direct action of vitamin D on certain components of the immune system.”  

Tiwari, Singh, Swain  ea at Hindu Universities Uttar Pradesh,India have shown elegantly in                          

    *2012 Tiwari ea   Vascular calcification in diabetic foot and its association with calcium homeostasis.      Vascular calcification (VC), long thought to result from passive degeneration, involves a complex process of biomineralization, frequently observed in diabetes and an indicator of diabetic peripheral vascular disease.. ..In  74 patients with diabetic foot ulcer,   Vascular calcification was present in 42% of patients. Significant difference in vitamin D, HbA1C, and eGFR  levels was observed in VC +ve compared to VC -ve.  Severe vitamin D deficiency was more common in VC +ve (51%) compared to in VC -ve (18%). Sub-group analysis showed that the risk of VC was significantly higher (RR = 2.4, P < 0.05) in patients with vitamin D < 10 ng/ml compared to others. .and        

     * Br J Nutr. 2013. Tiwari  ea  Prevalence and severity of vitamin D deficiency in patients with diabetic foot infection.   In Diabetic Patients with and without  infection (n289), 25(OH)D (nmol/l) was significantly lower (16) v. 20ng/ml  P < 0·001) in cases than in controls. Risk of severe vitamin D deficiency (25(OH)D < 10ng/ml) was significantly higher in cases than in controls (OR 4·0, P < 0·0001). Age, duration of diabetes and HbA1c were significantly higher in cases than in controls and therefore adjusted to nullify the effect of these variables, if any, on study outcome. The study concluded that vitamin D deficiency was more prevalent and severe in patients with diabetic foot infection. ;  and the need for vitamin D supplementation in such patients for a better clinical outcome

*.in  Br J Nutr.. 2014 Tiwari ea  show Vitamin D deficiency is associated with inflammatory cytokine concentrations in patients with diabetic foot infection  . Vitamin D is a potent immunomodulator and  a common deficiency  in different population groups including patients with diabetic foot infection.   in 112 diabetic foot infection cases and 109 diabetic controls , cases had significantly higher concentrations of IL-6 (P≤ 0.001), IL-1β and TNF-α (P≤ 0.006) than controls. Risk of severe vitamin D deficiency (25(OH)D <10ng/ml) was significantly higher in cases than in controls (OR 4·0, P < 0·0001). A significant negative correlation was also observed between 25-hydroxyvitamin D concentration and circulating concentrations of IL-1β (r -0.323; P≤ 0.001) and  IL-6 but not between 25-hydroxyvitamin D and TNF-α and IFN-γ concentrations.

 

This year  2016     Wukich , Sadoskas  ea. University of Pittsburgh & Georgetown USA  in Diabetes Metab Res Rev.  show that (Charcot) neuroarthropathy (CN) of the ankle and hindfoot  is challenging to treat surgically or nonsurgically. Deformities associated with ankle/hindfoot CN are often multiplanar, resulting in  malalignment; and  shortening of the limb often occurs from collapse of the distal tibia, and ankle, with  significant alterations in the biomechanics of the foot. eg predisposing the patient to lateral foot ulceration. Collapse of the talus, secondary to avascular necrosis or neuropathic fracture, further accentuates these deformities and contributes to a limb-length inequality   CONCLUSION:  Surgical reconstruction of ankle and hindfoot CN is associated with a high rate of infectious and noninfectious complications. Preoperative measures that can improve outcomes include assessment of vascular status, optimization of glycemic control, correction of vitamin D deficiency and cessation of tobacco use. 

Now 2016 Basit A,  Malik RA5 ea in  Universities Karachi Pakistan & Manchester UK ,  show that A single intramuscular dose of 600000IU vitamin D in  143 participants with predominantly type 2 diabetes, aged ~ 52.3years, with high Douleur Neuropathique 4 (DN4) score  by  20weeks gave significant increase in 25(OH)D (from 31.7 to 46.2±10.2ng/mL, p<0.0001) and  significant  reduction (p<0.0001)  in positive symptoms on the DN4 , and total pain score (p<0.0001, The Basit – Malik Pakistan-Manchester paper showing great efficacy of 600 000iu vit D3 load dose in peripheral neuropathy diabetics matches the huge 40% improvement benefit of similar loading and monthly vit D3 dose against severe PTB shown by Salahuddin ea in Pakistan in 2013 http://www.ncbi.nlm.nih.gov/pubmed/23331510 that we have previously analyzed in this column

ie  apart from smoking; the very low vitamin D levels common in most but especially ill people  associate   with about 5 fold  risks of uncontrolled diabetes, infections,  retinopathy , progressive leg ulcers, peripheral neuropathy  and arthritis- Charcot arthroneuropathy- -and thus  gangrene and amputation; and vigorous safe (supraphysiological) vit D boost reverses the risks. .

 

And a reminder that a 2015 study in Cape town from Coussens ea Universities in W Cape and Penn State confirm what we see daily in practice, that vitamin D deficiency is endemic  in our population

 

while as we have pointed out repeatedly, the State here continues to dispense the inferior vitamin D2 (as the fraudulently labeled “strong calciferol”, not disclosing that it is ergocalciferol  D2) despite this plant xenohormone vit D2 having been rejected by world authorities in favour of the much cheaper and effective  human D3 cholecalciferol.

 

 

       And now 2016 Cadegiani , Brasilia, Brazil another  landmark massive-vit D dose report ;  Remission of Severe Myasthenia Gravis After Massive-Dose Vitamin D Treatment.Vitamin D has been shown to be related to autoimmune diseases, such as multiple sclerosis and psoriasis. Correlations have been reported between vitamin D levels and prevalence and severity of other autoimmune disorders, and also between vitamin D therapy and disease improvement and remission. This reports a patient with severe and refractory myasthenia gravis (MG) who followed a massive-dose treatment (80,000 to 120,000 IU/day) promoted by a medical center in Brazil  (Coimbra ea) and she had her first complete remission after this type of treatment  for at least 18 months (ie at least 50 million iu) with increased vitamin D serum levels (400 to 700 ng/mL) and major fall in her AChR antibodies – but acute relapse when vit D was inadvertently stopped and her vit D level halved; with again recovery when megadose vit D was resumed  CONCLUSIONS: This case may reinforce the reported correlation between vitamin D level and disease severity and introduces a possible new use for vitamin D as a potential target for treating autoimmune diseases. We recommend large, double-blind, placebo-controlled, randomized studies using high-dose vitamin D treatment for refractory autoimmune diseases to reliably assess this pharmacotherapy target for these diseases

 

     The above case concurs with previous reported massive dose daily vitamin D3: Finamor , Coimbra ea , Universities of Brazil  2013 A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis. Autoimmunity has been associated with vitamin D deficiency and resistance, with gene polymorphisms related to vitamin D metabolism frequently described. High doses of vitamin D3 may conceivably compensate for inherited resistance to its biological effects. Nine patients with psoriasis and 16 patients with vitiligo received vitamin D3 35,000 IU once daily for six months ie ~7million iu  in association with a low-calcium diet (avoiding dairy products and calcium-enriched foods like oat, rice or soya “milk”) and hydration (minimum 2.5 L daily).. After treatment 25(OH)D3 levels significantly increased (from ~15 to 106-132ng/mL. PTH and 25(OH)D3 serum concentrations correlated inversely. The PASI score significantly improved in all nine patients with psoriasis. Fourteen of 16 patients with vitiligo had 25-75% repigmentation. Serum urea, creatinine and calcium (total and ionized) did not change and urinary calcium excretion increased within the normal range. High-dose vitamin D3 therapy may be effective and safe for vitiligo and psoriasis patients.

 

 

     neurologist Prof Dr Cicero Coimbra from Univ Sao Paulo  presents their results since 2002 in over 4000 pts ( 1000 patients each with multiple sclerosis and Parkinson’s diseases), who have been well controlled without other therapies,  provided the dose is high enough- 10 000iu/d up to about 1000iu/kg/d eg >70 000iu/d for the obese, on a low calcium ie low dairy/peanuts diet, high fluid intake and high exercise, to normalize blood calcium,  and titrate  PTH level to  the low normal range. Dr Cicero Coimbra discusses  high dose vitamin D toxicity: https://www.youtube.com/watch?v=Vxwk-YPrx7o&feature=youtu.be. PTH level should not be completely suppressed. In their clinic ( of 7 doctors)  for Autoimmune chronic diseases incl MS, RA, SLE, psoriasis, vitiligo, type 1 diabetes ,  they have treated over 4500 pts on this high quality vit D3 high fluid  low calcium diet  protocol, with only 14 cases of reversible vitamin D toxicosis (hypercalcemia) so far detected ie 0.3%. Babies of mothers thus treated in pregnancy  have high psychomotor development. (Vitamin C supplement should not be concurrently excessive to avoid oxalosis). They define success as being disease-free or non-progressive old fixed disabilities- 95% reach full cure. There vit D3 therapy  costs only ~US $20/mo, to optimize the immune system against both infections and autoimmune disease let alone cancer. Optimal dose of vit D3 replacement becomes at least 10 000iu/day for adults especially with autoimmune diseases  due to common vitamin D resistance. Ideally testing baseline blood and urine at baseline and after a few months on at least 10 000iu/d.

 

 

     In Effect of a single oral dose of 600,000 IU of cholecalciferol on serum calciotropic hormones in young subjects with vitamin D deficiency:. 2010. Cipriani ,Minisola ea .University of Rome  Italy tested    48 young subjects with vitamin D deficiency with a single oral dose of 600,000 IU of cholecalciferol. The 25(OH)D level was ~15.8ng/ml at baseline and became ~77ng/ml at 3 d (P < 0.001) and ~62 ng/ml at 30 d (P < 0.001). The trends were maintained in a subgroup followed up to 90 d (P < 0.001). Mean serum Ca and P significantly increased compared to baseline, whereas serum Mg decreased at 3 d. CONCLUSIONS: A single oral dose of 600,000 IU of cholecalciferol rapidly enhances 25(OH)D and reduces PTH in young people with vitamin D deficiency.

 

       Looking at some new alarmist myth refs about vit D3 overdose :

Moderate  ie physiological increase in just vitamin D levels and intake  (from average diet and sunshine and a traditional supplement) within the average population bloodlevel range understandably has modest  benefit- reversing at least rickets-  in an  indoor living clothed population, even  1st world middleaged:  from Wisconsin Univ, Karen Hansen ea’s recent RCT – JAMA 2015- Treatment of Vitamin D Insufficiency in Postmenopausal Women confirmed this, showing little practical benefit shortterm (ie over 12mo) between placebo, and supplemented vit D3  5600iu/wk and 25000 iu a week, (~3600iu/d);  the highest dose perhaps doubling the baseline 20ng/ml  25OH vit D level. ie into the low “adequate” range average around 40ng/ml.

Be aware again that  the same university’s group published in 2014   An Evaluation of High-Dose Vitamin D 2  for Rheumatoid Arthritis Karen Hansen ea that vit D2 ~100 00iu/month  for a year actually worsens patients and lowers vit D3 levels  , so there is no longer excuse for using vitamin D2 supplement when it blocks D3 receptors and lowers blood vit D3.

The inferiority of vit D2 was confirmed in eg    Clinical Trial of Vitamin D2 vs D3 Supplementation in Critically Ill Pediatric Burn Patients.  Gottschlich, Kagan U Cincinnati Ohio 201550  patients  aged 1 to 18yrs with burns  were enrolled. All participants received multivitamin supplementation ,  plus , 100 IU/kg D2, D3, or placebo daily  RESULTS: There were no significant differences in serum vitamin D levels between groups, but >10% of patients had low 25OHD  at discharge, and %deficiency worsened by the 1-year follow up for the placebo (75%), D2 (56%), and D3 (25%) groups. There were no statistical differences in clinical outcomes between treatment groups, although vitamin D supplementation demonstrated clinically relevant decreases in exogenous insulin requirements, sepsis, and scar formationThe high incidence of low serum 25OHvit D levels 1 year following serious thermal injury indicates prolonged compromise. Continued treatment with vitamin D3 beyond the acute phase postburn is recommended to counteract the trajectory of abnormal serum levels and associated morbidity. 

The perception seems to be that up to 40 000iu vit D3 a day, a bld level below abt 150-350ng/ml  is safe, ie unsafe above that. The evidence for such ceiling ie  higher dose harm in fact is lacking since as we have previously discussed here,  healthy people have taken up to 150 000iu a day for decades without evidence of harm…  provided they took adequate fluids, and did not take supplements of calcium, or also take high  vitamin A which notoriously causes acute hypercalcemic toxicity, or have rising calcium levels . .

But note that vit K2 improves absorption of vit D3 CHOLECALCIFEROL , and vit K2 and magnesia improve benefit of vit D3,while protecting against overdose effects ie calcification, stones  and confusion.  Problem in many  toxicity reports is that they used either vit D2 ergocalcif (WHICH BLOCKS THE NEEDED D3) , or used accidental massive overdose (millions of units vit D ) daily for months- or massive INJECTIONS) or combined vit D WITH CALCIUM REPLACEMENT AND/ OR EXCESSIVE VITAMIN  A  – which combinations are  dangerous;  we need magnesium (not calcium  or high vitamin A supplements).

    Vitamin D3: What’s the Latest? recent 2015 reviews from  Univ California and CommonHealth contrast the Instit Medicine IOM (Big-Pharma-sponsored)  conservative target of  vit D3 800 to max 4000iu/d with much evidence that safe optimal D3 dose may be up to 10 000 to 50 000iu/d, and up to  1 000 000iu as an acute eg antiinfection  loading dose; with risk of toxicity only if blood level exceeds 150-500ng/ml. the evidence-based IOM recommendation of optimal blood level 20-40ng/ml, up to 2000iu a day promoted by conservatives like Prof JoAnn Manson, contrasts with the more proactive view of eg Prof Michael Hollick and the Vitamin D Council promoting double that dose as supplements, safely up to 10 000iu/day.

 

   SO  I continue to take vit D3 ~70 000iu/wk ie ~10 000iu/d,  with vit K2 supp ~700mcg a wk ie 100mcg/dy and a balanced multisupplement incl. magnesia in addition to a multisupplement A-Z, and fish oil and Lugols iodine 15% 2 drops a day; with if I do get a “flu” attack during bad weather, prompt abolition by a few antibiotic doses of topup Lugols iodine 15% a few tsp (ie ~1000mgs iodine),  and vitamin D3 eg 300 000iu, and vitamin C a few tsp orally and by sniffing. .

The problem with many adverse effect reports of vit D3 overdose eg the Dominican Republic Soladek  2011 report Lowe ea below, and Prof Heaney’s response,  is that they failed to even consider the massive associated  overdose of the far more hypercalcemic vitamin A let alone calcium supp reported by most  patients. It becomes apparent that NO calcium supplement should be encouraged on a prudent diet; but instead supplements of  Vit D3, magnesia, vits K2 and C, CoQ10, and fish oil ; in addition to a balanced (A to Z) RDA-based multisupplement for seniors  like eg Solal’s,  Vital’s Multitime, Centrum etc.. with a low calcium diet if massive dose vitamin D3 is indicated as in autoimmune diseases (Coimbra ea).

Ndb

APPENDIX: RECENT REFS:
VITAMIN D ANABOLIC STEROID ABUSE IN SPORT?

the Australian Govt  Supplement Overview   has an intriguing report on vit D in sports, with no hint of vit D supplement being a steroid abuse. .http://www.ausport.gov.au/data/assets/pdf_file/0003/594174/CORP_33413_SSF_Vitamin_D_FS.pdf        Vitamin D is classified as a fat soluble vitamin which acts functionally as a steroid hormones. There are 2 different isoforms of Vitamin D: D3 (cholecalciferol) which is the important isomer formed in human   skin and D2 (ergocalciferol) which is the plant-derived ie xeno-equivalent. D2 was the first isoform to be characterised   and was first used in Vitamin D supplements and for food fortification. D3 is now considered preferable. D3 is   biologically inert until converted in the liver to 25(OH)D and to 1,25(OH)D in the kidney.  Vitamin D plays an important role in calcium and phosphorous homeostasis (bone health),but more so in  gene expression and cell growth. The recent recognition of Vitamin D receptors in most body tissues indicates a role for Vitamin D in  many aspects of health and function. Vitamin D is now known to be important for optimal muscle function.

         The principal source of circulating vitamin D comes from exposure to ultraviolet B (UVB) radiation from sunlight.   In 2010, the Institute of Medicine issued new Dietary Reference Intakes for Vitamin D, assuming no sunlight exposure: this included a Recommended Dietary Intake of 600 IU/d and an Upper Level intake of 4000 IU/d  (www.iom.edu/vitamind). BUT no evidence has ever been published to support this ceiling intake.

Whereas Vitamin D deficiency can lead to several health issues including increased risk of bone injuries, chronic musculoskeletal pain and viral respiratory tract infections. There is also emerging evidence that supplementing Vitamin D in athletes with sub-optimal Vitamin D levels may   have beneficial effects on athletic performance in particular strength, power, reaction time and balance.

         There is no universally accepted definition of vitamin D deficiency however, the following definitions based on  serum levels of 25(OH) Vitamin D are often cited:

Vitamin D deficiency: serum levels < 20 ng/ml (50 nmol/L);  Vit D insufficiency: serum levels < 30 ng/ml

Vit  D sufficiency: serum levels > 30 ng/ml    Ideal Vit D range*: 30-50ng/ml 

Toxicity: > 150ng/ml, when combined with raised serum calcium

(*Higher status may be preferred for athletes to allow a greater safety margin and to optimize performance;   some agencies working with elite athletes often set their own thresholds for desired Vitamin D concentrations)

Ie they quote no evidence for the 25OH vit D ceiling of 50ng/ml.

 

Confirmed in

  Owens DJ1, Close GL ea .  UK Universities  . 2015..A systems-based investigation into vitamin D and skeletal muscle repair, regeneration, and hypertrophy. Skeletal muscle is a direct target for  vitamin D. Observational studies suggest that low 25[OH]D correlates with functional recovery of skeletal muscle following eccentric contractions in humans and crush injury in rats. However, a definitive association is yet to be established. To address this gap in knowledge in relation to damage repair, a randomised, placebo-controlled trial was performed in 20 males with insufficient concentrations of serum 25(OH)D (~18ng/ml). Prior to and following 6 wk of supplemental vitamin D3 (4,000 IU/day) or placebo (50 mg of cellulose), participants performed 20 × 10 damaging eccentric contractions of the knee extensors.  Supplemental vitamin D3 increased serum 25(OH)D and improved recovery of peak torque at 48 h and 7 days postexercise. Together, these preliminary data are the first to characterize a role for vitamin D in human skeletal muscle regeneration and suggest that maintaining serum 25(OH)D may be beneficial for enhancing reparative processes and potentially for facilitating subsequent hypertrophy.

 

2016 Is there an optimal vitamin D status for immunity in athletes and military personnel?  He CS1, Gleeson M ea .Vitamin D is mainly obtained through sunlight ultraviolet-B (UVB) exposure of the skin, with a small amount typically coming from the diet.It is now clear that vitamin D has important roles beyond its well-known effects on calcium and bone homeostasis. Immune cells express the vitamin D receptor, including antigen presenting cells, T cells and B cells, and these cells are all capable of synthesizing the biologically active vitamin D metabolite, 1, 25 hydroxy vitamin D.There has been growing interest in the benefits of supplementing vitamin D as studies report vitamin D insufficiency (circulating 25(OH)D < 50 nmol/L) in more than half of all athletes and military personnel tested during the winter, when skin sunlight UVB is negligible. The overwhelming evidence supports avoiding vitamin D deficiency (25(OH)D< 30 nmol/L)to maintain immunity and prevent upper respiratory illness (URI) in athletes and military personnel.Recent evidence supports an optimal circulating 25(OH)D of 75 nmol/L to prevent URI and enhance innate immunity and mucosal immunity and bring about anti-inflammatory actions through the induction of regulatory T cells and the inhibition of pro-inflammatory cytokine production. We provide practical recommendations for how vitamin D sufficiency can be achieved in most individuals by safe sunlight exposure in the summer and daily 1, 000 IU vitamin D3 supplementation in the winter.

 

Sarris J1, Ng CH1. Ea, Universities  of Melbourne, & Deakin, Australia;  &  Harvard Boston; 2016  show in   Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. http://www.ncbi.nlm.nih.gov/pubmed/27113121  Adjunctive  standardized pharmaceutical-grade nutrients, known as nutraceuticals, has the potential to modulate several  neurochemical pathways implicated in depression. A systematic search up to 2015 for clinical trials using adjunctive nutrients for depression    RESULTS: Primarily positive results were found for studies testing S-adenosylmethionine (SAMe), methylfolate, omega-3 (primarily EPA or ethyl-EPA), and vitamin D,.  Mixed results were found for zinc, folic acid, vitamin C, and tryptophan. . No major adverse effects were noted in the studies  adjunctive omega-3 versus placebo revealed a significant and moderate to strong effect in favor of omega-3. CONCLUSIONS: Current evidence supports adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants to reduce depressive symptoms.

Raina AH1, Bhat FA1 ea ., India.. 2016 Association of Low Levels of Vitamin D with Chronic Stable Angina: A Prospective Case-Control Study.  http://www.ncbi.nlm.nih.gov/pubmed/27114971  Coronary artery disease (CAD) is a major cause of death and disability in developed countries. Chronic stable angina is the initial manifestation of CAD in approximately 50% of the patients. Recent evidence suggests that vitamin D is crucial for cardiovascular health. The prevalence of vitamin D deficiency in our region is 83%. METHODS: a prospective case-control study in  100 cases of chronic stable angina compared controls. Vitamin D deficiency was defined as <20 ng/mL, vitamin D insufficiency as 20-30 ng/mL and normal vitamin D level as 31-150 ng/mL.RESULTS: The prevalence of vitamin D deficiency among cases and controls was 75% and 10%, respectively. 13% had normal vitamin D levels (31-150 ng/mL). None had a toxic level of vitamin D. Among the controls, 10% were vitamin D-deficient, 57% had normal vitamin D levels. The mean vitamin level among cases and controls was 15.53 ng/mL and 40.95 ng/mL, respectively, statistically significant (P ≤ 0.0001). Among the cases, we found that an increasing age was inversely related to vitamin D levels (P = 0.027). Low levels may be an independent, potentially modifiable cardiovascular risk factor.

Jetty , Glueck   Kumar  ea . Jewish Hospital Cincinnati, Ohio, USA  2016  show 12mo Safety of 50,000-100,000 Units of Vitamin D3/Week in Hypercholesterolemic  Vitamin D-Deficient,   Patients with Reversible Statin Intolerance. : http://www.ncbi.nlm.nih.gov/pubmed/27114973   Such Vitamin D3 therapy (was safe and effective when given for 12 months to reverse statin intolerance in patients with vitamin D deficiency. Serum vitamin D rarely exceeded 100 ng/mL, never reached toxic levels, and there were no significant change in serum calcium or eGFR

https://riordanclinic.org/2013/10/vitamins-d3-and-k2-the-dynamic-duo/ As we explore the healing power of higher doses of vitamin D3 at the Riordan Clinic, we have found it prudent to partner the safety and effectiveness of this dynamic duo. For every 5,000–10,000 units of D3 being recommended and tested for, we are recommending 100 mcg of K2 mk7 to be sure and prevent the inappropriate calcification that higher doses of D3 alone could cause.

http://www.amazon.com/MIRACULOUS-RESULTS-EXTREMELY-SUNSHINE-EXPERIMENT-ebook/dp/B005FCKN2S#reader_B005FCKN2S     is a recent book by Jeff T Bowles .

 Newsletter: Gary Null and vitamin D toxicity    2010 by John Cannell, MD http://www.vitamindcouncil.org/newsletter/newsletter-gary-null-and-vitamin-d-toxicity/     “Warning: If you intend to take massive doses of vitamin D based on this newsletter, which I highly recommend you do not, read the entire newsletter. In addition, accurate determination of side effects of massive doses of vitamin D was not available in the early 1930s, nor was accurate determination of the true amount in each pill possible.    Is 2,000,000 IU/day of vitamin D toxic?   Ask Gary Null, alternative medicine guru and entrepreneur. He took his own supplement, Ultimate Power Meal, for a month and became extremely ill; one batch of Power Meal apparently contained 1,000 times more vitamin D than it should. That is, it contained 2,000,000 IU of vitamin D3 per serving instead of 2,000 IU per serving. Mr. Null became sicker and sicker as he gulped it down.

After suing his own supplier for permanent physical damage, Mr. Null then reported it took 3 months to get the extra vitamin D out of his system and that he is now alive and well. If Mr. Null took it for the full month that he claims, and if his Power Meal contained 2,000,000 IU per dose, Mr. Null consumed 60,000,000 IU in one month. Could he really be fine now with no lasting injuries?  In an attempt to answer that question, I went back to the 1930s and 40s.  Massive doses in the 1930s  The earliest references I could find to enormous doses of vitamin D were in the 1930s. In 1935, Drs. Dreyer and Reed, of the University of Illinois School of Medicine, published their observations on 700 patients treated with “massive” doses of vitamin D for up to two years.1  ….” read on..http://www.vitamindcouncil.org/newsletter/newsletter-gary-null-and-vitamin-d-toxicity/ http://www.livescience.com/50765-vitamin-d-supplements-toxicity.html

Vitamin D Overdose   Dr. Liji Thomas, MD  2016  http://www.news-medical.net/health/Vitamin-D-Overdose.aspx   vitamin D toxicity can occur from high intakes of supplements containing vitamin D, but not from dietary intake. Prolonged sun exposure also does not result in vitamin D toxicity because the previtamin D3 is degraded as the skin heats up, and also because of the formation of various other non-functional forms of vitamin D from the thermally activated compound.   Long term intakes of vitamin D above the upper limit recommended causes symptoms of toxicity. However, the intakes must be higher than about 40,000 IU/day, or the serum level of 25-hydroxy above 500-600 ng/mL, and the patient is usually also taking excessive amounts of calcium as well.

Dietary Supplement–Induced Vitamin D Intoxication  Klontz KC, Acheson DW.  To the Editor 2004:    Vitamin D intoxication that is associated with the consumption of dietary supplements is reported rarely. In 2004, the Food and Drug Administration (FDA) learned of the following case. A 58-year-old woman with diabetes mellitus and rheumatoid arthritis began taking a dietary supplement called Solutions IE Ageless Formula II on January 12, 2004. Fatigue, constipation, back pain, forgetfulness, nausea, and vomiting soon developed. On March 15, 2004, she was hospitalized because her speech was slurred, and a blood glucose reading taken at home was 30 mg per deciliter. On admission, her serum levels were as follows: calcium, more than 3.75 mmol per liter; 25-hydroxyvitamin D, 460ng/ml (normal range, 9-5);; parathyroid hormone, 12 ng per liter (normal range, 10 to 65); and creatinine, 265 μmol per liter.   The patient was treated with intravenous normal saline, furosemide, and pamidronate. On March 19, 2004, while still hospitalized, she was informed by the product distributor of an error in product formulation such that 188,640 IU of vitamin D3/d  had been added to the daily serving size of six capsules instead of the intended 400 IU. IE SHE HAD TAKEN ~12.2MILLION IU OF VIT D3 IN 2 MONTHS. At discharge on March 24, the patient’s serum levels were as follows: calcium, 2.60 mmol per liter; blood urea nitrogen, 10.0 mmol per liter; and creatinine, 221 μmol per liter. The patient died from a cause unknown to us on January 8, 2005.   Laboratory analysis of the product by the FDA, obtained from one of two lots reportedly overfortified with vitamin D3, revealed 186,906 IU of vitamin D3 in each serving size of six capsules, indicating that the patient had consumed roughly 90 times the recommended safe upper limit of 2000 IU per day. Long-term daily vitamin D consumption of more than 40,000 IU (1000 μg) is needed to cause hypercalcemia in healthy persons.2     In March 2004, the product distributor announced that during the previous month it had received three complaints from customers who had been hospitalized for hypercalcemia and vitamin D toxicity

2011 Vitamin D toxicity due to a commonly available “over the counter” remedy from the Dominican Republic. Lowe H1, Bilezikian JP. ea  Columbia Univ, NY.. http://press.endocrine.org/doi/10.1210/jc.2010-1999?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&   Hypercalcemia in ambulatory patients is occasionally caused by vitamin D toxicity. We report nine patients presenting to Columbia University Medical Center with hypercalcemia due to a supplement from the Dominican Republic containing massive amounts of vitamin D. All reported recently taking Soladek readily available in the Dominican Republic and in Upper Manhattan. serum calcium values before the ingestion of Soladek were not elevated  According to the manufacturer’s label, each 5-ml vial of Soladek contains vitamin D3 (600,000 IU), vitamin A (120,000 IU), and vitamin E (5 mg). Laboratory analysis by HPLC revealed that the supplement actually contained vitamin D(3) (864,000 IU) and vitamin A (predominantly retinyl palmitate 123,500 IU) per vial.IE 864000 IU VIT D /day FOR UNKNOWN DURATION. a similar case was reported earlier  http://www.thecamreport.com/2009/11/soladek-toxicity-in-a-60-year-old-woman/

Comments by Prof Robert P. Heany    Creighton University, Omaha, Nebraska  on Lowe et al:   Hypercalcemia in vitamin D intoxication JCEM   http://press.endocrine.org/e-letters/10.1210/jc.2010-1999        The report by Lowe et al. on vitamin D intoxication from an OTC supplement (1) is instructive and useful. I comment on the authors’  suggested mechanism of hypercalcemia in such cases. The authors propose that the elevated concentration of serum 25- hydroxy-vitamin D [25(OH)D] is the responsible agent, through loose binding to the vitamin D receptor. While my colleagues and I have shown that 25(OH)D can improve calcium absorption (2), I believe there is a simpler explanation for hypercalcemia in vitamin D intoxication, particularly as the reported values of 25(OH)D were not uniformly high in these nine cases. [In fact the patient with the highest serum calcium had actually the lowest value for 25(OH)D.] Instead, as Vieth suggested several years ago in a paper actually referenced by Lowe et al. (3), elevation of free circulating 1,25(OH)2D (calcitriol) is the most parsimonious explanation. This level is not commonly measured, and was not reported in the cases described by Lowe et al. Vieth has estimated the binding capacity of the D-binding protein (DBP) at approximately 4700 nmol/liter, and it is generally recognized that fewer than 5% of its binding sites are occupied at typical cholecalciferol inputs. However, in the face of huge cholecalciferol doses, as in the nine cases described here, it can easily be calculated that most or all of the binding sites on the DBP would be occupied by cholecalciferol itself as well as by 25(OH)D and 24,25(OH)2D, all of which are bound to the DBP more avidly than is calcitriol. Lowe et al. did not measure serum cholecalciferol, but it is virtually certain that its concentration would have been elevated, if for no other reason than that the capacity of the hepatic 25-hydroxylase is limited, and serum cholecalciferol concentration rises steeply for cholecalciferol inputs in excess of the saturation level of the 25-hydroxylase [which typically occurs at serum cholecalciferol levels of about 10 nmol/L and serum 25(OH)D of about 80 nmol/liter (4)].Even if all of the binding sites of the DBP were not continuously occupied by less polar metabolites, high occupancy would shift the equilibrium between the free and the bound calcitriol, so that free calcitriol concentration would likely have been substantially above normal values continuously. The authors speculate as to the origin of the elevated total calcitriol concentrations, given the down-regulation of the renal 1-á- hydroxylase in such cases. 

 

     2016.Deficient serum 25-hydroxyvitamin D is associated with an atherogenic lipid profile: The Very Large Database of Lipids (VLDL-3) study. Lupton JR1Michos  ea .  Cross-sectional studies have found an association between deficiencies in serum vitamin D, as measured by 25-hydroxyvitamin D (25[OH]D), and an atherogenic lipid profile. These studies have focused on a limited panel of lipid values including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG).OBJECTIVE: Our study examines the relationship between serum 25(OH)D and an extended lipid panel (Vertical Auto Profile) while controlling for age, gender, glycemic status, and kidney function.METHODS: We used the Very Large Database of Lipids, which includes US adults clinically referred for analysis of their lipid profile from 2009 to 2011. Our study focused on 20,360 subjects who had data for lipids, 25(OH)D, age, gender, hemoglobin A1c, insulin, creatinine, and blood urea nitrogen. Subjects were split into groups based on serum 25(OH)D: deficient (<20 ng/mL), intermediate (≥20-30 ng/mL), and optimal (≥30 ng/mL). The deficient group was compared to the optimal group using multivariable linear regression.RESULTS: In multivariable-adjusted linear regression, deficient serum 25(OH)D was associated with significantly lower serum HDL-C (-5.1%) and higher total cholesterol (+9.4%), non-HDL-C (+15.4%), directly measured LDL-C (+13.5%), intermediate-density lipoprotein cholesterol (+23.7%), very low-density lipoprotein cholesterol (+19.0%), remnant lipoprotein cholesterol (+18.4%), and TG (+26.4%) when compared with the optimal group.CONCLUSION:  Deficient serum 25(OH)D is associated with significantly lower HDL-C and higher directly measured LDL-C, intermediate-density lipoprotein cholesterol, very low-density lipoproteins cholesterol, remnant lipoprotein cholesterol, and TG

 

  1. Low-Level VitaminD Is strongly Associated with Atrial Fibrillation in Patients with Chronic Heart Failure.Belen E1, , Cetin M2ea. Atrial fibrillation (AF) freuently accompanies heart failure (HF), and causes exacerbation of symptoms and treatment failure in such patients. Vitamin D was recently suggested to be an important mediator of cardiovascular disease, including HF.OBJECTIVES: The aim of this study was to evaluate the relationship between vitamin D deficiency and AF in patients with chronic HF. METHODS: The study included 180 chronic HF patients that were divided into 2 groups based on having sinus rhythm [AF (-) group] or chronic AF [AF (+) group]. Vitamin D status was assessed via measurement of the serum 25-hydroxyvitamin D (25[OH]D) concentration.RESULTS: Mean age of the patients was 66 ± 8.7 years and 53.9% were male. There weren’t any significant differences in age, gender, body mass index, etiology or chronic HF stage between the 2 groups. The vitamin D level in the AF (+) group was significantly lower than in the AF (-) group (11.05 ng/mL vs. 20 ng/mL, p < 0.001) The left atrium to body surface area ratio (LA/BSA) was significantly higher in the AF (+) group (45.03 mm/m2 vs. 42.05 mm/m2, p < 0.01). Independent predictors (based on multiple regression) of AF were vitamin D level (OR = 0.854, 95% CI: 0.805-0.907, p < 0.001) and LA/BSA ratio (OR = 1.077, 95% CI: 1.003-1.156, p < 0.05). The optimal vitamin D cut-off value for the prediction of AF was 16.50 ng/mL, with a sensitivity of 76.0% and specificity of 65.5% (AUC = 0.75, 95% CI: 0.67-0.82).

 

Vitam Horm. 2016;100:255-71. doi: 10.1016/bs.vh.2015.10.001. Epub 2015 Nov 30. Molecular Approaches for Optimizing Vitamin D Supplementation.   Carlberg C1.Vitamin D can be synthesized endogenously within UV-B exposed human skin. However, avoidance of sufficient sun exposure via predominant indoor activities, textile coverage, dark skin at higher latitude, and seasonal variations makes the intake of vitamin D fortified food or direct vitamin D supplementation necessary. Vitamin D has via its biologically most active metabolite 1α,25-dihydroxyvitamin D and the transcription factor vitamin D receptor a direct effect on the epigenome and transcriptome of many human tissues and cell types. Different interpretation of results from observational studies with vitamin D led to some dispute in the field on the desired optimal vitamin D level and the recommended daily supplementation. This chapter will provide background on the epigenome- and transcriptome-wide functions of vitamin D and will outline how this insight may be used for determining of the optimal vitamin D status of human individuals. These reflections will lead to the concept of a personal vitamin D index that may be a better guideline for an optimized vitamin D supplementation than population-based recommendations.

 

  1. Comparative efficacy of vitamin D status in reducing the risk of bladder cancer: A systematic review and network meta-analysis.Zhao, , Huang J3. The optimal concentration of individual vitamin D intake for preventing bladder cancer has not, to our knowledge, been defined. To evaluate the comparative efficacy of different serum 25-hydroxyvitamin D concentrations in preventing bladder cancer, we conducted a systematic search of the literature published up to April 2015.METHODS: We applied a pairwise meta-analysis to estimate direct evidence from intervention-control studies and a network meta-analysis within a Bayesian framework to combine direct and indirect evidence. Moreover, a dose-response curve was utilized to predict the optimal median serum 25-hydroxyvitamin D concentration based on the odds ratio (OR) for each quintile concentration.: Seven studies of a total of 90757 participants, including 2509 bladder cancer patients, were included. Two prospective cohort studies with 57 591 participants and 494 bladder cancer patients, and five case-control studies with 33 166 participants and 2264 bladder cancer patients. From the network meta-analysis, we observed that sufficient serum 25-hydroxyvitamin D concentrations (>75 nmol/L) were superior to all other 25-hydroxyvitamin D concentrations in decreasing the risk of bladder cancer: OR = 0.68 and 95% credible interval (CrI) 0.52 to 0.87 compared with severely deficient concentrations (<25 nmol/L); OR = 0.65 and 95% CrI 0.49 to 0.86 compared with moderately deficient concentrations (25-37.5 nmol/L); OR = 0.61 and 95% CrI 0.47 to 0.80 compared with slightly deficient concentrations (37.5-50 nmol/L); and OR = 0.65 and 95% CrI 0.48 to 0.85 compared with insufficient concentrations (50-75 nmol/L). In addition, we noted a roughly inverse correlation between bladder cancer risk and 25-hydroxyvitamin D concentrations (R(2) = 0.98, P = 0.007).CONCLUSIONS:   Ensuring sufficient serum 25-hydroxyvitamin D concentrations might play an important role in decreasing the risk of bladder cancer. The serum 25-hydroxyvitamin D concentration ≥30ng/ml  was associated with a 60% lower risk of bladder cancer incidence.

the Ides of March 2016:  Where have we been the past 5 years in ignoring the crucial role of K2 supplement  with vit D3? against cancer, fractures, infections, vascular disease and diabetes , 

      like the crucial role of Lugols iodine + selenium, and magnesium (not calcium), coQ10, and animal, marine and coconut ie saturated fat oil- supplement  for all chronic disease prevention?

     Considering that our western processed food staple diet, and the diet of the poor majority everywhere,  is increasingly deficient especially in these nutrients,  with by profit-motivated industrial design  disease-promoting cholesterol-depletion, refined sugars, transfats, antibiotics, hormones,  and noxious at-any-dose elements from fluorine and aluminium upwards.

 

I see I was  promoting K2 in my emails 4 years ago,  and since 2009, on my Healthspanlife blog  ie in  my lectures  and thus in my healthspanlife blends .

     But  I indeed don’t seem to have published a review of K2 on my blog- till now!
– and there are so many refs out there since the first K2 mention on Pubmed in 1946,
and its first Pubmed  human supplement mention in 2002  Improvement with maternal supplement of vitamin K2  of vitamin K status of breastfeeding infants  (MK40).  Nishiguchi T, Terao T ea.   Semin Thromb Hemost. 2002 : 28533-8.

Unlike the Big Pharma-Disease-Industry- controlled denialists of conservative safe  natural phamacological vitamin therapy  like the   Linus Pauling Institute   and   Wikipedia                 https://en.wikipedia.org/wiki/Vitamin_K2,

the vitamin  K2 Polish scientist Dr Katarzyna Maresz PhD     2015 writes (see abstract below)  Proper Calcium Use: Vitamin K2 as a Promoter of Bone and Cardiovascular Health.  Maresz K1. International Science and Health Foundation Krakow, Poland    Inadequate calcium intake can lead to decreased bone mineral density, thus  increase the risk of bone fractures. Recent scientific evidence, however, suggests that elevated consumption of calcium supplements may raise the risk for heart disease and can be connected with accelerated deposit of calcium in blood-vessel walls and soft tissues. In contrast, vitamin K2 is associated with the inhibition of arterial calcification and arterial stiffening. Dosing of K2 was supported by a population-based study with 16 000 healthy women aged 49 to 70 years drawn from EPIC’s cohort population. After 8 years ,it showed that a high intake of natural vitamin K2 (ie, not synthetic K2, but not of vitamin K1) was associated with protection against cardiovascular events. For every 10 mcg of dietary vitamin K2 consumed (in the forms of menaquinone 7 (MK-7), menaquinone 8 (MK-8), and menaquinone 9 (MK-9), the risk of coronary heart disease was reduced by 9%. … The researchers found that a daily dose of 180 mcg was enough to improve bone mineral density, bone strength, and cardiovascular health. They also showed that achieving a clinically relevant improvement required at least 2 years of supplementation.
      While vit D3  cholecalciferol soltriol  was the multiprevention megavitamin   of the past decade, and CoQ10 the decade before that, catching up with the protean benefits of increasingly diet- deficient vitamins published (350 000 Pubmed citations) the past century, and of vitamin K since 1936, and K2 since 1946,
vit K2 is the most publicized ie advancing megavit of the current decade:
Adequate intake ie ~45 to ~150mcg/d is crucial with magnesium, boron etc to balance vigorous  vit D3 supplement,
for both bone, immune/cancer, and cardiovascular health.
Thus even just ~55mcg/d K2 supplement HALVES the risk of cardiovascular disease – very important in overweight/stressed/ aging people. 

BUT The authorities quoted have assessed safety and optimal longterm effective doses of vitamin K3 and vitamin D3 IN ISOLATION  for major prevention. However, we know that optimal nutrition is balanced nutrition, not one or two nutrient is superdose with an average fastfood mediocre diet. 

This finally convinces me to add vit K2 ~ 35 to 100mcg/day ie 200 to 700mcg/wk  to my own  vit D3 supplements. at a trivial bulk wholesale cost of  ~10mg/d 1% K2 ie ~R0.1/day or R14 – ( US$1)   bag  per 40 weeks of vit D3 @ 50 000iu vit D3 twice a month.

Like  Mercola 2010  http://articles.mercola.com/sites/articles/archive/2010/08/26/this-could-be-even-bigger-than-the-vitamin-d-discovery.aspx,             Byron Richards already in 2010 wrote a major review promoting K2 multipurpose: http://www.wellnessresources.com/health/articles/vitamin_k2_bones_cardiovascular_health_blood_sugar_control_cancer_prev/

As a recent BBC review   details,    “Vitamin K1 has a relatively short half-life and is rapidly cleared from the blood  by the liver within eight hours. In comparison vitamin K2 has a longer half-life of up to 72 hours, meaning it remains biologically active in the body for longer.   Vitamin K2 is also absorbed better by the body, and is linked to cardiovascular health. It directs calcium to the bones, and prevents it from being deposited where it shouldn’t be, for example arteries and organs, where it can cause harm.

The Kansas Riordan Clinic  promotes the Superhuman Duo  of D3+K:   they point out that ” Because an accurate LD50 for vit D in humans has never been determined (thank God!) most researchers use the LD50 for dogs as an estimate for humans, using a hypothetical human subject weighing  50kg, 110 pounds: in order to reach the LD50 dose, that subject would need to consume over 3,500 of the 50,000 IU D3 caps in a 24 hour period (146 capsules an hour,  total  175million iu) in order to have a 50% chance of dying. By conscientiously using vitamin K2 in conjunction with D3, this issue of “metastatic calcium” is thoroughly avoided.  Finally, like vitamin D3, strong evidence demonstrates vitamin K’s amazing ability to reduce cancer risk. For example, men taking vitamin K2 mk7 (a naturally occurring long acting form of K2) at 45 mcg a day can statistically reduce their risk of prostate cancer by 60%! That is just one of many cancer risks that are reduced significantly by regular K2 ingestion.      As we explore the healing power of higher doses of vitamin D3 at the Riordan Clinic, we have found it prudent to partner the safety and effectiveness of this dynamic duo. For every 5,000–10,000 units of D3 being recommended and tested for, we are recommending 100 mcg of K2 mk7 to be sure and prevent the inappropriate calcification that higher doses of D3 alone could cause.

            For the safety of vigorous dose of vitamin D3, the masses of D3  evidence we assembled by August 2015   is that 2million units as a single oral dose does no harm to nonagenarians, nor has over 100 000iu a day for 28 years ie over a billion  iu  in middle-aged women.  

 In 2015,    Like *Joe Leech                                          and             *Hogne Vik   ,                                                    *Angela Pifer nutritionist notes the essensiality of balancing vit D3 with K2  “Vitamin D3 should never be taken alone. Always take a combination Vitamin D3/ Vitamin K2 liquid emulsion, at night for best absorption. This is because vitamin D3 improves calcium absorption across the GI tract and vitamin K2 is the cofactor needed to transfer calcium into your bones, and not your arteries.   (Eur J Clin Nutr. 2016 Feb 24. doi: 10.1038/ejcn.2016.3. Steady-state vitamin K2 (menaquinone-7) plasma concentrations after intake of dairy products and soft gel capsules.   KnapenVermeer  ea . Maastricht University, Netherlands.   In a previous human intervention study, we observed an improved vitamin K status after 8 weeks of intake of a yogurt  fortified with vitamin K2 (as menaquinone-7, MK-7) and vitamins C and D3, magnesium and polyunsaturated fatty acids. It was hypothesized that the added nutrients contributed to this improvement. Here we report on a study in which we compared the fasting plasma concentrations of MK-7 from (a) yogurt enriched with MK-7, vitamins D3 and C, magnesium, n-3 poly unsaturated fatty acids (n-3 PUFA) and fish oil (yogurt Kplus), (b) yogurt fortified with MK-7 only (yogurt K) and (c) soft gel capsules containing only MK-7, For 42 days in healthy men and postmenopausal women between 45 and 65 years of age daily consumed either yogurt K, yogurt Kplus or capsules.  RESULTS: The increase in plasma MK-7 with the yogurt Kplus product was more pronounced than the increase in MK-7 with the capsules, reflecting vitamin K status improvement. No significant differences in fasting plasma concentrations of various biomarkers between the yogurts were found.   CONCLUSIONS: Dairy matrix and nutrient composition may affect MK-7 delivery and improvement of vitamin K status. Yogurt fortified with MK-7 is a suitable matrix to improve the nutritional status of the fat-soluble vitamins.)

Some recent of the other 5000 K2 refs on Pubmed, apart from the abundant reviews by Garry Gordon, Joe Mercola, Mike Howard, Jeff Dach, Townsend letter, ea  , are

Integr Med (Encinitas). 2015;14; 34-9.  Proper Calcium Use: Vitamin K2 as a Promoter of Bone and Cardiovascular Health.  Maresz K1. International Science and Health Foundation Krakow, Poland    Inadequate calcium intake can lead to decreased bone mineral density, thus  increase the risk of bone fractures. Supplemental calcium promotes bone mineral density and strength and can prevent osteoporosis. Recent scientific evidence, however, suggests that elevated consumption of calcium supplements may raise the risk for heart disease and can be connected with accelerated deposit of calcium in blood-vessel walls and soft tissues. In contrast, vitamin K2 is associated with the inhibition of arterial calcification and arterial stiffening. An adequate intake of vitamin K2 has been shown to lower the risk of vascular damage because it activates matrix GLA protein (MGP), which inhibits the deposits of calcium on the walls. Vitamin K, particularly as vitamin K2, is nearly nonexistent in junk food, with little being consumed even in a healthy Western diet. Vitamin K deficiency results in inadequate activation of MGP, which greatly impairs the process of calcium removal and increases the risk of calcification of the blood vessels. An increased intake of vitamin K2 could be a means of lowering calcium-associated health risks.    “  Calcium ConcernsIf at least 32 mcg/d of vitamin K2 is present in the diet, then the risks for blood-vessel calcification and heart problems are significantly lowered, the elasticity of the vessel wall is increased. Moreover, the beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women has been seen in clinical trials. If less vitamin K2 is present in the diet, then cardiovascular problems may arise. Dosing of K2 was supported by a population-based study with 16 000 healthy women aged 49 to 70 years drawn from EPIC’s cohort population. After 8 years ,it showed that a high intake of natural vitamin K2 (ie, not synthetic K2, but not of vitamin K1) was associated with protection against cardiovascular events. For every 10 mcg of dietary vitamin K2 consumed (in the forms of menaquinone 7 (MK-7), menaquinone 8 (MK-8), and menaquinone 9 (MK-9), the risk of coronary heart disease was reduced by 9%. A study on 564 postmenopausal women also revealed that intake of vitamin K2 was associated with decreased coronary calcification, whereas intake of vitamin K1 was not.  ”  A recent, double-blind, randomized clinical trial investigated the effects of supplemental MK-7, MenaQ7 (NattoPharma ASA, Hovik, Norway) for a 3-year period in a group of 244 postmenopausal Dutch women. The researchers found that a daily dose of 180 mcg was enough to improve bone mineral density, bone strength, and cardiovascular health. They also showed that achieving a clinically relevant improvement required at least 2 years of supplementation.It showed a significant improvement in cardiovascular health as measured by ultrasound and pulse-wave velocity, which are recognized as standard measurements for cardiovascular health. In that trial, carotid artery distensibility was significantly improved for a 3-year period as compared with that of a placebo group. Also, pulse-wave velocity showed a statistically significantly decrease after 3 years for the vitamin K2 (MK-7) group, but not for the placebo group, demonstrating an increase in the elasticity and reduction in age-related arterial stiffening.” 

*     Nutrients. 2015 Oct ;7;8905-15.  Menaquinone-7 Supplementation to Reduce Vascular Calcification in Patients with Coronary Artery Disease: Rationale and Study Protocol (VitaK-CAC Trial).Vossen, Kroon ea  Coronary artery calcification (CAC) develops early in the pathogenesis of atherosclerosis and is a strong and independent predictor of cardiovascular disease (CVD). Arterial calcification is caused by an imbalance in calcification regulatory mechanisms. An important inhibitor of calcification is vitamin K-dependent matrix Gla protein (MGP). Both preclinical and clinical studies have shown that inhibition of the vitamin K-cycle by vitamin K antagonists (VKA) results in elevated uncarboxylated MGP (ucMGP) and subsequently in extensive arterial calcification. This led us to hypothesize that vitamin K supplementation may slow down the progression of calcification. To test this, we designed the VitaK-CAC trial which analyses effects of menaquinone-7 (MK-7) supplementation on progression of CAC. The trial is a double-blind, randomized, placebo-controlled trial including patients with coronary artery disease (CAD). Patients with a baseline Agatston CAC-score between 50 and 400 will be randomized to an intervention-group (360 microgram MK-7) or a placebo group. Treatment duration will be 24 months.  We hypothesize that treatment with MK-7 will slow down or arrest the progression of CAC and that this trial may lead to a treatment option for vascular calcification and subsequent CVD.
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Ugeskr Laeger. 2015 Aug;177:V12140700. Vitamin K2 influences several diseases]. Hey H1, Brasen CL. Lillebælt, Kabbeltoft, In this paper we discuss the evidence of vitamin K2 deficiency which is a factor in several chronic diseases like diabetes, osteoporosis, cancer, inflammatory and cardiovascular diseases. This deficiency is very common in the mentioned diseases although it is rarely treated by clinicians. Randomized clinical trials have shown that patients witr can benefit from vitamin K2 supplement. Further studies are needed to ascertain the effect of vitamin K2 supplement in patients with diabetes and inflammatory bowel diseases.
*           Oman Med J. 2014;29;172-7. Vitamin k dependent proteins and the role of vitamin k2 in the modulation of vascular calcification: a review.  El Asmar, Arbid  ea, American University of Beirut, Lebanon. Vascular calcification, a cause of cardiovascular morbidity and mortality, is an actively regulated process involving vitamin K dependent proteins (VKDPs) among others. Vitamin K is an essential micronutrient, present in plants and animal fermented products that plays an important role as a cofactor for the post-translational γ-carboxylation of glutamic acid residues in a number of proteins. These VKDPs require carboxylation to become biologically active, and they have been identified as having an active role in vascular cell migration, angiogenesis and vascular calcification. calcification.
*             Dermatoendocrinol. 2015 Jan;6e968490. Vitamin K: an old vitamin in a new perspective.   Gröber U, Reichrath J, Holick MF, Kisters Essen, Germany.&  Boston, MA USA. The topic of “Vitamin K” is currently booming on the health products market. Current research increasingly indicates that the antihaemorrhagic vitamin has a considerable benefit in the prevention and treatment of bone and vascular disease. Vitamin K1 (phylloquinone) is more abundant in foods but less bioactive than the vitamin K2 menaquinones (especially MK-7, menaquinone-7). Vitamin K compounds undergo oxidation-reduction cycling within the endoplasmic reticulum membrane, donating electrons to activate specific proteins via enzymatic gamma-carboxylation of glutamate groups before being enzymatically reduced. Along with coagulation factors (II, VII, IX, X, and prothrombin), protein C and protein S, osteocalcin (OC), matrix Gla protein (MGP), periostin, Gas6, and other vitamin K-dependent (VKD) proteins support calcium homeostasis, inhibit vessel wall calcification, support endothelial integrity, facilitate bone mineralization, are involved in tissue renewal and cell growth control, and have numerous other effects.

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