Sun_Arc_SUn Exposure North America Cancer incidence

Stop Vitamin D, Are You Joking ?

Sun_Arc_SUn Exposure North America Cancer incidenceDon’t Take Vitamin D Says New Study by Jeffrey Dach MD

A study proclaiming Vitamin D is useless and you should just stop taking it was published in Lancet this week and “went viral”. The news story was picked up and amplified by the media Here it is:

“The take-away message is that there is little justification currently for prescribing vitamin D to prevent heart attack, stroke, cancer, or fractures in otherwise-healthy people living in the community,” says lead study author Dr. Mark Bolland, a researcher at the University of Auckland, New Zealand.

Randomized Controlled Trials vs Other types of Studies

A common gimmick used by Drug Company sponsored studies is to claim that only RCT (randomized trials) are to be included as “evidence”. The Bolland report selected forty RCT studies to conclude Vitamin D is useless.  Dr Bolland conveniently excluded all the other basic science and observational studies. There are thousands of observational studies that show health benefits for Vitamin D. A search for Vitamin D in Google Scholar yields 2.2 million published articles. Mark Bolland has excluded 99.9% of the available information on vitamin D to arrive at his conclusion that Vitamin D has no health benefits.

Michael Holick MD

Dr. Michael F Holick, a vitamin D expert and author of the Vitamin D Solution book, says this is just “silly”. He points out that many of the studies in Bolland’s Lancet paper used does of vitamin D that were too low to be effective.

Dr Mark Bolland is a New Zealand professor and expert on Vitamin D, Calcium and bone density. He has published many previous papers. One of his previous papers reported that women who take calcium tablets have an increase in cardiovascular risk, and heart attacks.(55)  Apparently the calcium can be deposited in the arterial walls causes atherosclerotic vascular disease and increased calcium score. I have written about this previously.  

Vitamin K2 Prevents Arterial Calcification

Vitamin K2 is a useful supplement for women taking Vitamin D and Calcium Tablets to prevent osteoporosis..(71-78)  Vitamin K2 acts to prevent soft tissue and arterial calcifications from the calcium tablets, and instead directs the calcium into the bones.  Low vitamin K status is associated with increased vascular calcification as measured on coronary calcium CAT score in healthy women and in hemodialysis patients.  Patients on coumadin, which block vitamin K, have increased vascular calcification and increased coronary calcium scores. A good quality combination Bone Supplementwill typically include vitamin K2, along with the calcium and vitamin D3. (71-78)

Avoid Vitamin D in Sarcoidosis

Another of Dr. Bolland’s previous papers(53) dealt with the deleterious effects of Vitamin D in patients with Sarcoidiosis, a form of lung disease in which non-caseating granulomas in the lung tissue manufacture excessive amounts of vitamin D resulting in hypercalcemia (high serum calcium), which if severe, may cause renal failure.(57-65)


What Are The Health Benefits of Vitamin D ?

What if I told you I discovered a new drug that could reduce the number of cancer deaths in the US by 43,000 annually, reduce colon cancer by 50%, and breast and ovarian cancer by 30%. Would you be impressed?

What if I then told you this same drug could safely prevent or alleviate the following medical conditions:(5a)

Cardiovascular disease,
Type One Diabetes,
Insulin resistance,
Autoimmune Diseases,
Migraine Headache,
Polycystic Ovary Disease (PCOS),
Musculoskeletal and bone pain,
Rheumatoid Arthritis,
Inflammatory Bowel Disease (Crohn’s),
chronic lymphocytic leukemia (CLL)(15, 15a)

Improve calcium absorption and
Reduce hip fractures.(5a)

All of these health benefits can be obtained with Vitamin D3, an inexpensive vitamin, also obtained with sun exposure.

Vitamin D Deficiency in Florida, Surely You must Be Joking:

Everyone in Florida gets plenty of Vitamin D from sun exposure. This would be true except that as Floridians, we are all told to avoid the sun to prevent solar skin damage (brown wrinkling) and to avoid skin cancer.

So the question remains, do we get enough Vitamin D from sun exposure? To answer this question, we actually measured blood Vitamin D levels, and we were surprised to discover that the majority showed Vitamin D deficiency (less than 20 ng/ml), or insufficiency (less than 40 ng/ml).

What if you are not fortunate to live in sunny Florida and you live up north above the Mason Dixon Line, in Boston, New York, Chicago, Canada or Scandinavia? Northern latitudes have an even more serious vitamin D deficiency because of the lack of UV sunlight during the winter months. The angle of the sun through the atmosphere closes off the UltraViolet Light from reaching the earth.

An Epidemic of Vitamin D Deficiency

Vitamin D deficiency has been reported in 57% of 290 medical inpatients in Massachusetts, 93% of 150 patients with overt musculoskeletal pain in Minnesota, 48% of patients with Multiple Sclerosis, 50% of patients with lupus and fibromyalgia, 42% of healthy adolescents, 40% of African American Women, and 62 % of the morbidly obese, 83% of 360 patients with low back pain in Saudi Arabia, 73% of Austrian patients with Ankylosing Spondylitis, 58% of Japanese girls with Graves’s Disease, 40% of Chinese adolescent girls, 40-70% of all Finnish medical patients. (5a)

Vitamin D Toxicity

Vitamin D excess and toxicity requires daily dosage in excess of 40,000 units over a period of months, so 5,000 units a day is safe and far below the level needed to develop vitamin D toxicity. Remember Vitamin D is a fat soluble vitamin, so toxicity is possible with massive doses over long periods of time. Vitamin D toxicity causes elevated calcium levels. That’s why Vitamin D supplementation should done only under your physician’s supervision with monitoring of serum 25-Hydroxy Vitamin D levels.

Space Satellite Maps Maps of UV Sunlight

Sun_Arc_SUn Exposure North America Cancer incidenceAbove Image:Cancer mortality rates and multiple sclerosis prevalence rates for U.S. states compared to UVB doses for July 1992 (3)

Space Satellite Maps Maps of UV Sunlight exposure correlate with incidence of Cancer and Multiple Sclerosis (above image). If you take NASA space satellite photos of North America and color code the UV sunlight exposure as Dr. Grant has done (above image)(3), you will see a pattern remarkably similar to the incidence of cancer and multiple sclerosis. This is thought to be due to differences in Vitamin D levels. The farther north with less sun exposure and lower Vitamin D levels, there is an increased incidence of cancer and multiple sclerosis.

Diseases Caused By, or Associated With Vitamin D Deficiency:

Cardiovascular disease,
Depression, Epilepsy,
Type One Diabetes,
Insulin resistance,
Autoimmune Diseases,
Migraine Headache,
PolyCystic Ovary Disease (PCOS),
Musculoskeletal and bone pain,
Psoriasis, and
Chronic lymphocytic leukemia (CLL)(15).

The current recommendation for Vitamin D deficiency in those people who must avoid the sun is 5,000 IU of Vitamin D per day which costs 5 cents a day.

VitamineD3Vitamin D is not really a Vitamin, it is a Hormone.

Left Image vitamin D3  notice similarity to hormone steroid ring structure.Courtesy Wikimedia

Like all other steroidal hormones, vitamin D is made from a cholesterol precursor, converted in the skin by sunlight. Like all other hormones, Vitamin D enters the nucleus of the cell and binds to the DNA where it gives a message to the DNA to manufacture proteins.

Vitamin D And Multiple Sclerosis.(4,19,20)

A review by Dr. Brown reported that Vitamin D supplementation prevented the development and progression of experimental autoimmune encephalitis, an animal model of MS, in mice. A large, prospective, cohort study found that vitamin D supplementation was associated with a 40% reduction in the risk of developing MS. Four small, noncontrolled studies suggested that vitamin D supplementation may decrease exacerbation of MS symptoms.  MRI studies of multiple sclerosis lesions show improvement during summer months and worsening during winter months suggesting a Vitamin D link. (19,20)

Vitamin D and Cancer

A four-year clinical trial, involving 1,200 women found those taking the vitamin had about a 60-per-cent reduction in cancer incidence, compared with those who didn’t take it, a drop so large — twice the impact on cancer attributed to smoking — it almost looks like a typographical error. The study was done by professor of medicine Robert Heaney of Creighton University in Nebraska and was published in June 2007. (37)

Vitamin D and Total Mortality

A 2007 meta-analysis review by Dr. Philippe Autier reviewed 18 studies showed a reduction in all cause mortality of about 10% in people supplementing with commonly used doses of Vitamin D.(39)

Vitamin D Supplementation for Adults

The RDA in America is only 400 IU per day, yet current research suggests that our daily Vitamin D requirement is closer to 4,000 to 5,000 IU. Twenty minutes of Sun exposure will give us ten to twenty thousand IU of Vitamin D. Adult Supplementation with Carlson’s Cod Liver Oil can provide Vitamin D along with Vitamin A. However, for an intake of 5,000 IU vitamin D per day, inexpensive Vitamin D3 capsules are widely available for about 5 cents a day. We provide these as a convenience to our office patients. Vitamin D Testing at the Lab Optimal serum 25-hydroxyvitamin D values are 45-75 ng/ml. Below 40 ng/ml is called Vitamin D insufficiency, and below 20 ng/ml is deficiency.


Our health care system is in crisis. We are spending billions on expensive procedures like coronary artery bypass and organ transplantation, yet measurements of health are lower than other countries that spend less. In terms of getting more bang for your health care buck, Vitamin D testing and supplementation for the population is one solution which is guaranteed to improve overall health of the population at a ridiculously low cost. The cost saving in reduced cancer rates, and lower osteoporotic fracture rates would be enormous, and we would all enjoy improved health. My goal as a physician in our community is to improve the health of of our community, and Vitamin D testing and supplementation is one way to achieve that goal with no adverse side effects and enormous cost savings.

Click Here to Buy Vitamin D3.

Click Here to Buy Vitamin K

Click Here to Buy Bone Supplement

Articles with Related Interest:

Vitamin D for Multiple Sclerosis

Vitamin D Prevents Flu

Breast Cancer and Vitamin D

Link to this article:

Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie, Florida 33316


Reinhold Vieth PhD

(1) Pharmacology_Vitamin_D_Fortification_Vieth
Chapter 61. The Pharmacology of Vitamin D, Including Fortification Strategies Reinhold Vieth Dept Laboratory


Power Point Presentation: Prospects for Vitamin D Nutrition. Vitamin D and Human Evolution Clinical relevance of higher vitamin D intakes, Toxicology of Vitamin D Reinhold Vieth, Pathology and Laboratory Medicine, Mount Sinai Hospital, and Laboratory Medicine and Pathobiology, University of Toronto Calgary AB, Oct 13 2005.

Vitamin D and MS Dr Vieth

You Tube Video By Dr Vieth on Vitamin D

(2) Valuable Insights Into the Importance of Vitamin D and Sun on, Interview with William B. Grant, Ph.D.

(3) Satellite Maps, Cancer mortality rates and multiple sclerosis prevalence rates for U.S. states compared to UVB doses for July, William B. Grant, Ph.D.

Image:Cancer mortality rates and multiple sclerosis prevalence rates for U.S. states compared to UVB doses for July 1992

(4) Vitamin D Supplementation in the Fight Against Multiple Sclerosis, Ashton F. Embry, Ph.D. 2004, Journal of Orthomolecular Medicine, v.19, p. 27-38.

Use of Vitamin D in Clinical Practice John Cannell Alternative Medicine Review 2008

THE CLINICAL IMPORTANCE OF VITAMIN D (CHOLECALCIFEROL): A PARADIGM SHIFT WITH IMPLICATIONS FOR ALL HEALTHCARE PROVIDERS lex Vasquez, DC, ND, Gilbert Manso, MD, John Cannell, MD ALTERNATIVE THERAPIES, sept/oct 2004, VOL. 10, NO. 5 33 Vitamin D Council, John Cannell MD Web Site: Understanding Cholecalciferol Vitamin D

(6) Listing of the best Vitamin D articles on the internet posted by John Cannell Vitamin D Council.

Cancer Defeated: Vitamin D Pill For All. Economical Pill Would Cut Cancer Rates In Half. Bill Sardi Knowledge of Health Blog

Just One Pill Away, by Bill Sardi, review of Vitamin D on Lew Rockwell.

(9) Medical News Today. Healthcare Professionals Ignore Vitamin D Deficiency Epidemic by John Cannell MD

(10) Beware of prescription Vitamin D supplements, info from Mercola

(11) Vitamin D Lowers inlfammation by John Cannell MD on

(12) Linus Paulng Institute on Vitamin D

(13) Linus Pauling Institute Vit D References with Links.

(15) Vitamin D3 — Essential for Health June 15, 2004 by Chaya Venkat
The Flip Side of Sun Avoidance — Vitamin D Insufficiency

Blood. 2003 Apr 1;101(7):2454-60. Epub 2002 Nov 21.
The vitamin D3 analog EB1089 induces apoptosis via a p53-independent mechanism involving p38 MAP kinase activation and suppression of ERK activity in B-cell chronic lymphocytic leukemia cells in vitro. Pepper C, Thomas A, Hoy T, Milligan D, Bentley P, Fegan C. Department of Haematology, Llandough Hospital, Penarth, Vale of Glamorgan, United Kingdom.
EB1089, a novel vitamin D3 analog, has been shown to have cytotoxic and antiproliferative properties in a variety of malignant cells. However, its potential as a treatment for B-cell chronic lymphocytic leukemia (B-CLL) has not been evaluated. EB1089 induced apoptosis in all of the 102 B-CLL samples tested The B-CLL cells in the study were shown to highly express vitamin D receptor, but an additional receptor-independent mechanism of cell killing cannot be ruled out at this stage. These findings show that EB1089 is a potent apoptosis-inducing agent in B-CLL cells and may be useful in the treatment of B-CLL patients, particularly those with p53 mutations or drug-resistant disease.

(16) Vieth, Reinhold. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. American Journal of Clinical Nutrition, Vol. 69, No. 5, 842-856, May 1999

(17) Vieth, Reinhold, Vitamin D and Reduced Risk of Breast Cancer: A Population-Based Case-Control Study. Cancer Epidemiology Biomarkers & Prevention 16, 422-429, March 1, 2007.

(18) Veith R, Chan P-C R, MacFarlane G D. “Efficacy and safety of vitamin D3 intake exceeding the lowest adverse effect level.” Am J Clin Nutr 2001; 71: 288-294

(19) Munger, Levin,. Hollis, PhD Howard, Ascherio, Serum 25-Hydroxyvitamin D Levels and Risk of Multiple Sclerosis JAMA. 2006;296:2832-2838 Epidemiological and experimental evidence suggests that high levels of vitamin D, a potent immunomodulator, may decrease the risk of multiple sclerosis.

(20) Brown, Sherrill J, The Role of Vitamin D in Multiple Sclerosis , DRUG INFORMATION ROUNDS, The Annals of Pharmacotherapy: Vol. 40, No. 6, pp. 1158-1161. DOI 10.1345/aph.1G513

(21) Michael F Holick, Editorial: Too little vitamin D in premenopausal women: why should we care? Am J Clin Nutr 2002;76:3–4.

(22) Michael F Holick, Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis American Journal of Clinical Nutrition, Vol. 79, No. 3, 362-371, March 2004

(23) Holick , Michael F VITAMIN D AND HEALTH IN THE 21ST CENTURY: BONE AND BEYOND, Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease American Journal of Clinical Nutrition, Vol. 80, No. 6, 1678S-1688S, December 2004. Excellent full text article review.


Vitamin D Analogs in Cancer Prevention and Therapy By Jorg Reichrath, M. Friedrich,Chapter by Michael Holick Vitamin D in Book Online:

(25) 1,25-Dihydroxycholecalciferol Prevents and Ameliorates Symptoms of Experimental Murine Inflammatory Bowel Disease. Journal of Nutrition. 2000;130:2648-2652. Margherita T. Cantorna, Carey Munsick, Candace Bemiss and Brett D. Mahon

(26) Holick, Michael F, The Influence of Vitamin D on Bone Health Across the Life Cycle, The Vitamin D Epidemic and its Health Consequences J. Nutr. 135:2739S-2748S, November 2005

(27) The Miracle of Vitamin D by By Krispin Sullivan, CN on Weston Price Web Site.

(28) Webcasts : Contemporary Diagnosis and Treatment of Vitamin D-Related Disorders, American Society for Bone and Mineral Disorders.

(29) Garland CF, Comstock GW, et al. “Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study,” Lancet 1989; 2(8,673: 1,176-1,178

(30) Regulation of renin expression and blood pressure by vitamin D3 Curt D. Sigmund, J Clin Invest. 2002 July 15; 110(2): 155–156.

(31) Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001; 358(9,292): 1,500-1,5003. Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM.

(32) The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int J Clin Pract 2003; 57(4): 258-61. Borissova AM, Tankova T, Kirilov G, Dakovska L, Kovacheva R.

(33) Pfeifer M et al. “Effects of a short-term vitamin D3 and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women.” J Clin Endocrinol Metab 2001; 86: 1,633-1,637

(34) Lind L et al. “Reduction of blood pressure during long-term treatment with active vitamin D (alphacalcidol) is dependent on plasma renin activity and calcium status. A double-blind, placebo-controlled study.” Am J Hypertens 1989; 2: 20-25

(35) Lind L et al. “Vitamin D is related to blood pressure and other cardiovascular risk factors in middle-aged men.” Am J Hypertens 1995; 2: 20-25

(36) Embry AF, Snowdon LR, Vieth R.Ann Neurol. 2000 Aug;48(2):271-2. Vitamin D and seasonal fluctuations of gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis.

(36A) RTGAM.20070428.wxvitamin28/BNStory/specialScienceandHealth/home Vitamin D casts cancer prevention in new light by MARTIN MITTELSTAEDT, From Saturday’s Globe and Mail, April 28, 2007

(37) Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial American Journal of Clinical Nutrition, Vol. 85, No. 6, 1586-1591, June 2007 Joan M Lappe, Dianne Travers-Gustafson, K Michael Davies, Robert R Recker and Robert P Heaney.

(38) Wikipedia Vitamin D Page with Links

(39) Vitamin D Supplementation and Total Mortality A Meta-analysis of Randomized Controlled Trials Philippe Autier, MD; Sara Gandini, PhD Arch Intern Med. 2007;167:1730-1737. Conclusions Intake of ordinary doses of vitamin D supplements seems to be associated with decreases in total mortality rates.

(40) Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. American Journal of Clinical Nutrition, Vol. 85, No. 6, 1586-1591, June 2007 Joan M Lappe, Dianne Travers-Gustafson, K Michael Davies, Robert R Recker and Robert P Heaney.


Additional references

41) The Lancet Diabetes & Endocrinology, Early Online Publication, 24 January 2014. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Dr Mark Bolland, Bone and Joint Research Group, Department of Medicine, University of Auckland, 85 Park Road, Grafton, Private Bag 92019, Auckland, New Zealand Vitamin D insufficiency is associated with many disorders, leading to calls for widespread supplementation. Some investigators suggest that more clinical trials to test the effect of vitamin D on disorders are needed. Methods We did a trial sequential meta-analysis of existing randomised controlled trials of vitamin D supplements, with or without calcium, to investigate the possible effect of future trials on current knowledge. We estimated the effects of vitamin D supplementation on myocardial infarction or ischaemic heart disease, stroke or cerebrovascular disease, cancer, total fracture, hip fracture, and mortality in trial sequential analyses using a risk reduction threshold of 5% for mortality and 15% for other endpoints. Findings The effect estimate for vitamin D supplementation with or without calcium for myocardial infarction or ischaemic heart disease (nine trials, 48 647 patients), stroke or cerebrovascular disease (eight trials 46 431 patients), cancer (seven trials, 48 167 patients), and total fracture (22 trials, 76 497 patients) lay within the futility boundary, indicating that vitamin D supplementation does not alter the relative risk of any of these endpoints by 15% or more. Vitamin D supplementation alone did not reduce hip fracture by 15% or more (12 trials, 27 834 patients). Vitamin D co-administered with calcium reduced hip fracture in institutionalised individuals (two trials, 3853 patients) but did not alter the relative risk of hip fracture by 15% or more in community-dwelling individuals (seven trials, 46 237 patients). There is uncertainty as to whether vitamin D with or without calcium reduces the risk of death (38 trials, 81 173). Interpretation Our findings suggest that vitamin D supplementation with or without calcium does not reduce skeletal or non-skeletal outcomes in unselected community-dwelling individuals by more than 15%. Future trials with similar designs are unlikely to alter these conclusions. Funding health Research Council of New Zealand.


Vitamin D supplements won’t protect against disease in healthy adults, review says . By Ryan Jaslow CBS News January 24, 2014, 3: 31 PM “The take-away message is that there is little justification currently for prescribing vitamin D to prevent heart attack, stroke, cancer, or fractures in otherwise-healthy people living in the community,” lead study author Dr. Mark Bolland, a researcher at the University of Auckland, New Zealand. Researchers reviewed 40 scientifically rigorous studies that looked at whether taking vitamin D in supplement form would bring health benefits. The studies were called randomized controlled trials, which are considered the “gold standard” in research “The scientific term for it is ‘silly,'” ays Michael Holick, a professor of medicine at Boston University, told the paper. “There’s nothing new here.” Holick, who has written books promoting vitamin D use, says the analysis is flawed by the fact that most previous studies have used vitamin D doses that were too low, often 200 to 400 international units (IU) a day. Holick says there’s reason to believe higher doses, such as the 2,000 IU a day now being tested in one large U.S. trial, are needed to produce benefits.

43) Review of vitamin D studies finds little health benefit Kim Painter, Special for USA TODAY 6:30 p.m. EST January 23, 2014 Experts differ on whether it’s worthwhile to keep studying the popular vitamin supplement.

44) Vitamin D Supplements Don’t Help Your Health: Review Except in people with a vitamin deficiency, supplements may cause harm, doctor says. By Robert Preidt HealthDay Reporter Vitamin D supplements are taken by nearly half of American adults, according to the researchers. The review authors analyzed the findings of 40 studies and determined that taking vitamin D supplements does not reduce the risk of heart attack, stroke, cancer or bone fractures in the general population by more than 15 percent.

45) Vitamin D Study Suggests Use May Not Be Beneficial In Healthy Adults

46) Vitamin D Supplements Do Not Improve Health by Jean-Paul Gauthier on January 24, 2014.

47) Researchers Find No Significant Health Benefits From Vitamin D Supplements January 25, 2014

48) Vitamin D supplements may be unnecessary, study finds Very few foods have vitamin D, but the best sources are fatty fish. National Monitor, Rina Shah | January 24, 2014

49) Vitamin D supplements not very effective in preventing or curing diseases and illnesses, new study claims By Maryanne Moll, Tech Times | January 25, 8:54 AM

50) Vitamin D Role in Reducing Risk of Hip Fractures May Be Limited By Makiko Kitamura Jan 23, 2014

51) Top News in Endocrinology: Vitamin D Benefit Questioned Published: Jan 24, 2014 | Updated: Jan 24, 2014 By Kristina Fiore, Staff Writer, MedPage Today —————————



52) Importance of Vitamin D for Fibromyalgia & Chronic Fatigue Syndrome. By Adrienne DellwoJanuary 23, 2014


Sarcoidosis Articles by Bolland

53) BMJ Open. 2013 Oct 23;3(10)Randomised controlled trial of vitamin D supplementation in sarcoidosis. Bolland MJ, Wilsher ML, Grey A, Horne AM, Fenwick S, Gamble GD, Reid IR. The role vitamin D intake/production plays in sarcoidosis-associated hypercalcaemia is uncertain. However, authoritative reviews have recommended avoiding sunlight exposure and vitamin D supplements, which might lead to adverse skeletal outcomes from vitamin D insufficiency. We investigated the effects of vitamin D supplementation on surrogate measures of skeletal health in patients with sarcoidosis and vitamin D insufficiency. DESIGN:Randomised, placebo-controlled trial. SETTING:Clinical research centre. PARTICIPANTS:27 normocalcaemic patients with sarcoidosis and 25-hydroxyvitamin D (25OHD) <50 nmol/L. INTERVENTION:50 000 IU weekly cholecalciferol for 4 weeks, then 50 000 IU monthly for 11 months or placebo. PRIMARY AND SECONDARY OUTCOME MEASURES:The primary endpoint was the change in serum calcium over 12 months, and secondary endpoints included measurements of calcitropic hormones, bone turnover markers and bone mineral density (BMD). RESULTS:The mean age of participants was 57 years and 70% were women. The mean (SD) screening 25OHD was 35 (12) and 38 (9) nmol/L in the treatment and control groups, respectively. Vitamin D supplementation increased 25OHD to 94 nmol/L after 4 weeks, 84 nmol/L at 6 months and 78 nmol/L at 12 months, while levels remained stable in the control group. 1,25-Dihydroxy vitamin D levels were significantly different between the groups at 4 weeks, but not at 6 or 12 months. There were no between-groups differences in albumin-adjusted serum calcium, 24 h urine calcium, markers of bone turnover, parathyroid hormone or BMD over the trial. One participant developed significant hypercalcaemia after 6 weeks (total cholecalciferol dose 250 000 IU). CONCLUSIONS:In patients with sarcoidosis and 25OHD <50 nmol/L, vitamin D supplements did not alter average serum calcium or urine calcium, but had no benefit on surrogate markers of skeletal health and caused one case of significant hypercalcaemia.


BMJ. 2008 Feb 2;336(7638):262-6. Epub 2008 Jan 15. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. Bolland MJ, Barber PA, Doughty RN, Mason B, Horne A, Ames R, Gamble GD, Grey A, Reid IR. To determine the effect of calcium supplementation on myocardial infarction, stroke, and sudden death in healthy postmenopausal women. DESIGN:Randomised, placebo controlled trial. SETTING:Academic medical centre in an urban setting in New Zealand. PARTICIPANTS:1471 postmenopausal women (mean age 74): 732 were randomised to calcium supplementation and 739 to placebo. MAIN OUTCOME MEASURES: Adverse cardiovascular events over five years: death, sudden death, myocardial infarction, angina, other chest pain, stroke, transient ischaemic attack, and a composite end point of myocardial infarction, stroke, or sudden death. RESULTS: Myocardial infarction was more commonly reported in the calcium group than in the placebo group (45 events in 31 women v 19 events in 14 women, P=0.01). The composite end point of myocardial infarction, stroke, or sudden death was also more common in the calcium group (101 events in 69 women v 54 events in 42 women, P=0.008). After adjudication myocardial infarction remained more common in the calcium group (24 events in 21 women v 10 events in 10 women, relative risk 2.12, 95% confidence interval 1.01 to 4.47). For the composite end point 61 events were verified in 51 women in the calcium group and 36 events in 35 women in the placebo group (relative risk 1.47, 0.97 to 2.23). When unreported events were added from the national database of hospital admissions in New Zealand the relative risk of myocardial infarction was 1.49 (0.86 to 2.57) and that of the composite end point was 1.21 (0.84 to 1.74). The respective rate ratios were 1.67 (95% confidence intervals 0.98 to 2.87) and 1.43 (1.01 to 2.04); event rates: placebo 16.3/1000 person years, calcium 23.3/1000 person years. For stroke (including unreported events) the relative risk was 1.37 (0.83 to 2.28) and the rate ratio was 1.45 (0.88 to 2.49). CONCLUSION: Calcium supplementation in healthy postmenopausal women is associated with upward trends in cardiovascular event rates. This potentially detrimental effect should be balanced against the likely benefits of calcium on bone.

Vitamin D and Heart Attacks in Women

55) BMJ. 2011 Apr 19;342:d2040. doi: 10.1136/bmj.d2040. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women’s Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk. Reanalysis of WHI CaD Study limited access dataset and incorporation in meta-analysis with eight other studies. Data source WHI CaD Study, a seven year, randomised, placebo controlled trial of calcium and vitamin D (1g calcium and 400 IU vitamin D daily) in 36,282 community dwelling postmenopausal women. Main outcome measures Incidence of four cardiovascular events and their combinations (myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke) assessed with patient-level data and trial-level data. RESULTS: In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events. In the 16,718 women (46%) who were not taking personal calcium supplements at randomisation the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (P = 0.05 for clinical myocardial infarction or stroke, P = 0.04 for clinical myocardial infarction or revascularisation), whereas in the women taking personal calcium supplements cardiovascular risk did not alter with allocation to calcium and vitamin D. In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.21 (95% confidence interval 1.01 to 1.44), P = 0.04), stroke (1.20 (1.00 to 1.43), P = 0.05), and the composite of myocardial infarction or stroke (1.16 (1.02 to 1.32), P = 0.02). In meta-analyses of placebo controlled trials of calcium or calcium and vitamin D, complete trial-level data were available for 28,072 participants from eight trials of calcium supplements and the WHI CaD participants not taking personal calcium supplements. In total 1384 individuals had an incident myocardial infarction or stroke. Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), P = 0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), P = 0.009). CONCLUSIONS: Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.

56) Heart. 2012 Apr;98(8):609-14. doi: 10.1136/heartjnl-2011-301356. Epub 2012 Feb 28. Role of vitamin D deficiency in cardiovascular disease. Reid IR, Bolland MJ. Vitamin D is a fat-soluble secosteroid produced in the skin as a result of sunlight exposure, and its circulating levels are reduced in a wide variety of chronic illnesses and obesity. Observational studies clearly demonstrate a higher incidence of cardiovascular events in individuals with low circulating 25-hydroxyvitamin D [25(OH)D]. This relationship can potentially be explained by confounding, because individuals with low 25(OH)D are generally older, frailer, heavier, and have more comorbidities and higher estimated cardiovascular risk than individuals with higher 25(OH)D. The vitamin D receptor appears to be widely distributed, including in cardiovascular tissue, although this has recently been contested. Despite these epidemiological and laboratory findings, meta-analyses of clinical trials have not shown evidence of beneficial effects of vitamin D supplementation on cardiovascular endpoints. Trials are underway to assess these possibilities further. At present, there is insufficient evidence to support vitamin D supplementation for improving cardiovascular outcomes.

Sarcoidosis- Hypercalcemia from Vitamin D

57) Indian J Nephrol. 2013 Sep;23(5):375-7. doi: 10.4103/0971-4065.116325. Severe hypercalcemia unmasked by Vitamin D in a patient with sarcoidosis. Nayak-Rao S. Severe hypercalcemia is uncommon in clinical practice and is usually due to primary hperparathyroidism or malignancy. We present a patient who presented with severe hypercalcemia with renal failure; further evaluation of which revealed the diagnosis of sarcoidosis. This case is presented in view of the rarity of presentation of sarcoidosis with hypercalcemic crisis.

58) Eur J Emerg Med. 2005 Dec;12(6):320-1. A case of severe hypercalcemia with acute renal failure in sarcoidosis: a diagnostic challenge for the emergency department. Volpicelli G, Mussa A, Frascisco M. We present and discuss the case of a man admitted to our emergency room because of severe hypercalcemia and renal failure with maintained diuresis. We diagnosed a relapse of sarcoidosis, manifesting as hypercalcemia and renal failure, based on a history of lung sarcoidosis. This is a rare complication of sarcoidosis, due to granulomatous production of vitamin D. This mechanism may have been exacerbated by exposure of sunlight. The initial treatment of the patient was directed towards lowering the circulating calcium level through hyperhydration and forced diuresis, with secondary control of granulomatous activity using corticosteroid therapy. The patient was discharged after 7 days with normal levels of serum calcium, urinary calcium excretion and serum creatinine. Recognition of this rare cause of hypercalcemia is a challenge for the emergency physician.

59) Case Rep Med. 2010;2010:423659. doi: 10.1155/2010/423659. Epub 2010 Dec 16. Severe hypercalcemia and acute renal failure: an unusual presentation of sarcoidosis. Karnchanasorn R, Sarikonda M, Aldasouqi S, Gossain VV. Although hypercalcemia is a known metabolic complication of sarcoidosis, it is rarely a presenting manifestation. Long-standing hypercalcemia and hypercalciuria can cause nephrocalcinosis and chronic renal failure. Acute renal failure, although described, is also a rare presentation of patients with sarcoidosis. We describe two patients with sarcoidosis, who presented with severe hypercalcemia and worsening renal function. Parathyroid hormone levels were appropriately suppressed. This led to an extensive search for the cause of hypercalcemia. Finally, after a lymph node biopsy in both cases, a diagnosis of sarcoidosis was established, hypercalcemia resolved, and renal function improved in both cases after administration of prednisone.

60) South Med J. 2004 Jun;97(6):590-2. Renal failure and hypercalcemia as initial manifestations of extrapulmonary sarcoidosis.Ponce C, Gujral JS. Sarcoidosis is a granulomatous, multisystem disease. Rarely, sarcoidosis may present with both renal failure and hypercalcemia. A 27-year-old black man presented with severe abdominal pain and renal failure. A kidney biopsy demonstrated features of both interstitial nephritis and membranous glomerulopathy thought to be secondary to nonsteroidal anti-inflammatory drugs. His renal function and symptoms improved with short-term prednisone therapy. Discontinuation of steroids led to a recurrence of renal failure and severe hypercalcemia. On the basis of an elevated angiotensin-converting enzyme level of 160 U/L and anemia, a bone marrow biopsy was performed. Acid-fast bacillus-negative, noncaseating granulomas suggested the diagnosis of sarcoidosis. The patient recovered after restarting prednisone. Sarcoidosis may cause both interstitial and membranous nephritis from direct infiltration. Hypercalcemia results from increased calcium absorption secondary to 1,25-dihydroxyvitamin D production by sarcoid granulomas. Sarcoidosis must be considered in the differential diagnosis of renal failure in black patients. Serum calcium and angiotensin-converting enzyme levels may aid the diagnosis.

61) Ther Umsch. 2007 May;64(5):281-6. [Hypercalcemia in sarcoidosis–case report, prevalence, pathophysiology and therapeutic options].Ackermann D. Hypercalcemia is a highly prevalent complication of sarcoidosis. A medical history of a patient with sarcoidosis is shown as case report. Depending on the population studied about 2-63% of sarcoidosis patients show hypercalcemia. The major difference in the prevalence of hypercalcemia may be in part due to the undulating course of subacute sarcoidosis, so hypercalcemia may be missed when serum calcium is not frequently measured. Hypercalciuria appears to be twice as prevalent then hypercalcemia and should be looked for in every sarcoidosis patient. Hypercalcemia in sarcoidosis is due to the uncontrolled synthesis of 1,25-dihydroxyvitamin D3 by macrophages. 1,25-dihydroxyvitamin D3 leads to an increased absorption of calcium in the intestine and to an increased resorption of calcium in the bone. Immunoregulatory properties have been ascribed to 1,25-dihydroxyvitamin D3. It is an important inhibitor of interleukin-2 and of interferon-gamma-synthesis, two cytokines that are important in granuloma formation in sarcoidosis. It is thought that 1,25-dihydroxyvitamin D3 counterregulates uncontrolled granuloma formation. Treatment of hypercalcemia depends on the serum level of hypercalcemia and its persistence. Generally sarcoidotic patients should be advised to avoid sun exposition to reduce vitamin D3 synthesis in the skin, to omit fish oils that are rich of vitamin D and to produce more than two liters urine a day by adapting fluid intake. Although severe hypercalcemia seems to be rare, glucocorticosteroid treatment should be started if corrected total calcium level rises beyond 3 mmol/l. If hypercalcemia is symptomatic, treatment should be started even at lower levels. Glucocorticosteroids act by inhibition of the overly 1alpha-hydroxylase activity of macrophages. Alternatively, treatment with chloroquine or ketoconazole can be established. If isolated hypercalciuria without hypercalcemia is present with evidence for recurrent nephrolithiasis, patients can be treated with a thiazide diuretic.

62) Chest. 1996 Feb;109(2):535-9. Vitamin D, calcium, and sarcoidosis.Sharma OP. Hypercalcemia occurs in about 10% of the patients with sarcoidosis; hypercalciuria is about three times more frequent. These abnormalities of calcium metabolism are due to dysregulated production of 1,25-(OH)2-D3 (calcitriol) by activated macrophages trapped in pulmonary alveoli and granulomatous inflammation. Undetected hypercalcemia and hypercalciuria can cause nephrocalcinosis, renal stones, and renal failure. Corticosteroids cause prompt reversal of the metabolic defect. Chloroquine, hydroxychloroqune, and ketoconazole are the drugs that should be used if the patient fails to respond or develops dangerous side effects to corticosteroid therapy.

63) Rheumatology (2000) 39 (7): 707-713. Calcium metabolism in sarcoidosis and its clinical implications Most patients present with the management problem of asymptomatic low‐grade hypercalcaemia, the treatment of which aims to prevent long‐term renal and bone complications. It is accepted practice that all patients be advised to minimize their exposure to sunlight, avoid fish oils rich in vitamin D and maintain a fluid intake of >2 l per day [51, 56]. Although many centres advise avoiding dairy products and calcium‐containing antacids [51], it is not our practice to recommend a low‐calcium diet as there is little evidence that it affects calcium balance and it may increase the risk of nephrolithiasis. A moderate dose of prednisolone (15–25 mg/day) is an effective treatment for hypercalcaemia and, if there is an alternative indication for corticosteroids, is the logical first‐line therapy. Because corticosteroids may exacerbate hypercalcuria [57], it is our practice to repeat the 24‐h measurement of urinary calcium excretion soon after commencing therapy.


Semin Respir Crit Care Med. 2010 Aug;31(4):474-84. doi: 10.1055/s-0030-1262215. Epub 2010 Jul 27. Calcium and vitamin D in sarcoidosis: how to assess and manage. Burke RR, Rybicki BA, Rao DS. The synthesis of vitamin D is altered by the granulomatous inflammation of sarcoidosis leading to increased production of 1, 25-dihydroxyvitamin D. Mounting evidence suggests that vitamin D is an immunomodulating hormone that inhibits both antigen presentation by cells of the innate immune system, and the cytokine release and proliferation of Th1 cells. These and other extraskeletal health benefits have led to an increase in vitamin D assessment and pharmacological supplementation in the general population. This review highlights the altered synthesis and general immunomodulating properties of vitamin D with a special emphasis on known interactions with sarcoidosis. In addition, the assessment of vitamin D nutritional status, its pharmacological supplementation, and the management of bone health in patients with sarcoidosis are reviewed.


free full text. Drug Des Devel Ther. 2013 Apr 12;7:325-38. Current and emerging pharmacological treatments for sarcoidosis: a review.Beegle SH, Barba K, Gobunsuy R, Judson MA. Author information Division of Pulmonary and Critical Care Medicine, Albany Medical College, Albany, NY 12208, USA.

Vitamin D Supplements’ Benefits Panned In Review Of Studies
CBC 01/24/2014

67)  Dr. Michael F. Holick on Vitamin D

Michael Holick, a professor of medicine at Boston University and advocate of vitamin D, disagrees with Bolland’s findings, saying that the studies on which Bolland based his study gave participants too low doses of vitamin D, about 200 to 400 international units (IU) per day. Holick says he believes a higher dose, such as 2,000 IU currently being administered in a major U.S. trial, would yield benefit. The vitamin D promoter also points out that Bolland neglects to explain the connection between low vitamin D levels in persons with chronic diseases (such as MS and colon cancer) and living in areas with little sun exposure.

Review of vitamin D studies finds little health benefit Jan. 24, 2014
The new review focuses only on randomized trials, in which people were assigned to take vitamin D or placebos and then followed to see if their health differed as a result. It did not include observational studies, in which researchers simply asked people about vitamin D intake or measured levels in their blood and then looked at their health differences.  Those observational studies have found a link between low vitamin D levels and diseases ranging from cancer to heart disease and diabetes.

The Vitamin D Debate, There’s been a lot of controversy lately about vitamin D recommendations. If you’re confused about how much you should be taking, you’re not alone.

71)   Protecting Bone and Arterial Health with Vitamin k2 By William Davis, MD LE Magazine March 2008

Maturitas. 2014 Feb;77(2):137-41.008. Circulating uncarboxylated matrix Gla protein, a marker of vitamin K status, as a risk factor of cardiovascular disease . Heuvel EG1, van Schoor NM2, Lips P3, Magdeleyns EJ4, Deeg DJ5, Vermeer C6, den Heijer M7.

Vitamin K plays a pivotal role in the synthesis of Matrix Gla protein (MGP), a calcification inhibitor in vascular tissue. Vascular calcification has become an important predictor of cardiovascular disease. The aim of the current study was to examine the potential association of circulating desphospho-carboxylated and -uncarboxylated MGP (dp-cMGP and dp-ucMGP), reflecting vitamin K status, with the incidence of cardiovascular events and disease (CVD) in older individuals.
STUDY DESIGN:  The study was conducted in 577 community-dwelling older men and women of the Longitudinal Aging Study Amsterdam (LASA), aged >55 year, who were free of cardiovascular disease at baseline. Multivariate Cox proportional hazards models were used to analyze the data.  MAIN OUTCOME MEASURES: Incidence of CVD.
RESULTS:  After a mean follow-up of 5.6±1.2 year, we identified 40 incident cases of CVD. After adjustment for classical confounders and vitamin D status, we observed a more than 2-fold significantly higher risk of CVD for the highest tertile of dp-ucMGP with a HR of 2.69 (95% CI, 1.09-6.62) as compared with the lowest tertile. Plasma dp-cMGP was not associated with the risk of CVD.
CONCLUSIONS:  Vitamin K insufficiency, as assessed by high plasma dp-ucMGP concentrations is associated with an increased risk for cardiovascular disease independent of classical risk factors and vitamin D status.73)
J Nutr Biochem. 2013 Apr;24(4):624-8. doi: 10.1016/j.jnutbio.2012.02.012. Epub 2012 Jul 20.
Circulating matrix Gla protein is associated with coronary artery calcification and vitamin K status in healthy women.
Dalmeijer GW, van der Schouw YT, Vermeer C, Magdeleyns EJ, Schurgers LJ, Beulens JW.Matrix Gla protein (MGP) is a vitamin K-dependent protein and an inhibitor of vascular calcification. Vitamin K is required for the carboxylation of MGP and can thereby reduce calcification. Circulating MGP species with different conformations have been investigated as markers for coronary artery calcification (CAC). In high-risk populations, high total uncarboxylated MGP (t-ucMGP) was associated with decreased CAC, while high non-phosphorylated uncarboxylated MGP (dp-ucMGP) was associated with a poor vitamin K status. This cross-sectional study investigated the association of MGP species with CAC, vitamin K status among 200 healthy women. Circulating dp-ucMGP, t-ucMGP and, non-phosphorylated carboxylated MGP (dp-cMGP) levels were measured by ELISA techniques and Agatston score by multi-detector computed tomography. The ratio of uncarboxylated to carboxylated osteocalcin was used as proxy of vitamin K status. A borderline significant (P=.06) association between higher circulating dp-ucMGP levels and high CAC was observed (β=0.091, 95% CI-0.01; 0.19). In the entire study population, high t-ucMGP levels tended to be associated (P=.09) with lower CAC (β=-0.36, 95% CI:-0.78; 0.06). This association strengthened amongst women with CAC to a significant relation between high t-ucMGP levels and lower CAC (β=-0.55, 95% CI-1.01;-0.10). Dp-cMGP was not associated with CAC. Low vitamin K-status was associated with high dp-ucMGP concentrations (β=0.138, 95% CI 0.09; 0.19) but not with other MGP species.These results show that dp-ucMGP may serve as a biomarker of vitamin K status. Circulating dp-ucMGP and t-ucMGP may serve as markers for the extent of CAC, but these findings need to be confirmed.74)
Thromb Haemost. 2009 Feb;101(2):359-66.
Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients.
Cranenburg EC, Brandenburg VM, Vermeer C, Stenger M, Mühlenbruch G, Mahnken AH, Gladziwa U, Ketteler M, Schurgers LJ.
Matrix gamma-carboxyglutamate (Gla) protein (MGP) is a potent local inhibitor of cardiovascular calcification and accumulates at areas of calcification in its uncarboxylated form (ucMGP). We previously found significantly lower circulating ucMGP levels in patients with a high vascular calcification burden. Here we report on the potential of circulating ucMGP to serve as a biomarker for vascular calcification in haemodialysis (HD) patients. Circulating ucMGP levels were measured with an ELISA-based assay in 40 HD patients who underwent multi-slice computed tomography (MSCT) scanning to quantify the extent of coronary artery calcification (CAC). The mean ucMGP level in HD patients (193 +/- 65 nM) was significantly lower as compared to apparently healthy subjects of the same age (441 +/- 97 nM; p < 0.001) and patients with rheumatoid arthritis (RA) without CAC (560 +/- 140 nM; p < 0.001). Additionally, ucMGP levels correlated inversely with CAC scores (r = -0.41; p = 0.009), and this correlation persisted after adjustment for age, dialysis vintage and high-sensitivity C-reactive protein (hs-CRP). Since circulating ucMGP levels are significantly and inversely correlated with the extent of CAC in HD patients, ucMGP may become a tool for identifying HD patients with a high probability of cardiovascular calcification.75)
Eur J Clin Invest. 2010 Apr;40(4):344-9. Calcium scores and matrix Gla protein levels: association with vitamin K status.
Rennenberg RJ, de Leeuw PW, Kessels AG, Schurgers LJ, Vermeer C, van Engelshoven JM, Kemerink GJ, Kroon AA.Vascular calcification in humans is associated with an increased cardiovascular risk. Carboxylated matrix Gla protein (cMGP) inhibits vascular calcification. Vitamin K is an essential cofactor for the activation of uncarboxylated matrix Gla protein (ucMGP). It has been suggested that patients on long-term treatment with vitamin K antagonists develop aortic valve calcifications because of lower levels of circulating MGP. We therefore hypothesized that arterial calcification and a low vitamin K status are associated with ucMGP. To that aim, we measured arterial calcium scores, the osteocalcin ratio (OCR), as a proxy for vitamin K status, and ucMGP.
MATERIALS AND METHODS:  In 36 hypertensive patients, we determined the Agatston score with computer tomography scans of the abdominal aorta, carotid and coronary arteries. The total calcium score was calculated as the sum of the separate Z-scores.
RESULTS:  The total calcium Z-score was significantly correlated to age (r = 0.683, P < 0.001), smoking (r = 0.372, P = 0.026), total cholesterol (r = 0.353, P = 0.034), LDL cholesterol (r = 0.490, P = 0.003), triglycerides (r = 0.506, P = 0.002), fasting glucose (r = 0.454, P = 0.005), systolic blood pressure (r = 0.363, P = 0.029) and pulse pressure (r = 0.685, P < 0.001). In multivariate regression analyses, OCR and total calcium score were significantly associated with ucMGP.
CONCLUSIONS:  We found a positive association of total arterial calcium score and a high OCR (reflecting low vitamin K status) with ucMGP serum levels. This warrants further studies to explore the pathophysiological background of this phenomenon.76)
Adv Nutr. 2012 Mar 1;3(2):166-73. doi: 10.3945/an.111.001628.
The role of vitamin K in soft-tissue calcification.
Theuwissen E, Smit E, Vermeer C.

Seventeen vitamin K-dependent proteins have been identified to date of which several are involved in regulating soft-tissue calcification. Osteocalcin, matrix Gla protein (MGP), and possibly Gla-rich protein are all inhibitors of soft-tissue calcification and need vitamin K-dependent carboxylation for activity. A common characteristic is their low molecular weight, and it has been postulated that their small size is essential for calcification inhibition within tissues. MGP is synthesized by vascular smooth muscle cells and is the most important inhibitor of arterial mineralization currently known. Remarkably, the extrahepatic Gla proteins mentioned are only partly carboxylated in the healthy adult population, suggesting vitamin K insufficiency. Because carboxylation of the most essential Gla proteins is localized in the liver and that of the less essential Gla proteins in the extrahepatic tissues, a transport system has evolved ensuring preferential distribution of dietary vitamin K to the liver when vitamin K is limiting. This is why the first signs of vitamin K insufficiency are seen as undercarboxylation of the extrahepatic Gla proteins. New conformation-specific assays for circulating uncarboxylated MGP were developed; an assay for desphospho-uncarboxylated matrix Gla protein and another assay for total uncarboxylated matrix Gla protein. Circulating desphospho-uncarboxylated matrix Gla protein was found to be predictive of cardiovascular risk and mortality, whereas circulating total uncarboxylated matrix Gla protein was associated with the extent of prevalent arterial calcification. Vitamin K intervention studies have shown that MGP carboxylation can be increased dose dependently, but thus far only 1 study with clinical endpoints has been completed. This study showed maintenance of vascular elasticity during a 3-y supplementation period, with a parallel 12% loss of elasticity in the placebo group. More studies, both in healthy subjects and in patients at risk of vascular calcification, are required before conclusions can be drawn.

Blood. 2010 Jun 17;115(24):5121-3. doi: 10.1182/blood-2010-01-264598. Epub 2010 Mar 30.
Chronic coumarin treatment is associated with increased extracoronary arterial calcification in humans.
Rennenberg RJ, van Varik BJ, Schurgers LJ, Hamulyak K, Ten Cate H, Leiner T, Vermeer C, de Leeuw PW, Kroon AA.

Vascular calcification is a marker of increased cardiovascular risk. Vitamin K-dependent matrix Gla protein (MGP) is important in inhibiting calcification. Because MGP activation is vitamin K dependent, we performed a cross-sectional study investigating the relationship between the use of vitamin K antagonists and extracoronary vascular calcification. From the Dutch thrombosis services we selected 19 patients younger than 55 years who had no other cardiovascular risk factors and who had used coumarins for more than 10 years, and compared these to 18 matched healthy controls. MGP was measured, and a plain x-ray of the thighs was taken to assess femoral arterial calcifications. The odds ratio for calcification in patients versus controls was 8.5 (95% confidence interval [CI] 2.01-35.95). Coumarin use and MGP were associated with calcification, even after adjusting for other risk factors. We conclude that long-term use of coumarins is associated with enhanced extracoronary vascular calcification, possibly through the inhibition of MGP carboxylation.

J Vasc Res. 2008;45(5):427-36.
The circulating inactive form of matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification.
Cranenburg EC, Vermeer C, Koos R, Boumans ML, Hackeng TM, Bouwman FG, Kwaijtaal M, Brandenburg VM, Ketteler M, Schurgers LJ.

Matrix gamma-carboxyglutamate (Gla) protein (MGP) is a vitamin K-dependent protein and a strong inhibitor of vascular calcification. Vitamin K deficiency leads to inactive uncarboxylated MGP (ucMGP), which accumulates at sites of arterial calcification. We hypothesized that as a result of ucMGP deposition around arterial calcification, the circulating fraction of ucMGP is decreased. Here we report on the development of an ucMGP assay and the potential diagnostic utility of monitoring serum ucMGP levels.

An ELISA-based assay was developed with which circulating ucMGP can be determined. Serum ucMGP levels were measured in healthy subjects (n = 165) and in four patient populations; patients who underwent angioplasty (n = 30), patients with aortic stenosis (n = 25), hemodialysis patients (n = 52), and calciphylaxis patients (n = 10). All four patient populations had significantly lower ucMGP levels. In angioplasty patients and in those with aortic stenosis, some overlap was observed with the control population. However, in the hemodialysis and calciphylaxis populations, virtually all subjects had ucMGP levels below the normal adult range.
CONCLUSION:  Serum ucMGP may be used as a biomarker to identify those at risk for developing vascular calcification. This assay may become an important tool in the diagnosis of cardiovascular calcification.

Link to this article:

Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie, Florida 33314

Disclaimer click here:

The reader is advised to discuss the comments on these pages with his/her personal physicians and to only act upon the advice of his/her personal physician. Also note that concerning an answer which appears as an electronically posted question, I am NOT creating a physician — patient relationship. Although identities will remain confidential as much as possible, as I can not control the media, I can not take responsibility for any breaches of confidentiality that may occur.

Link to this article:

Copyright (c) 2014 Jeffrey Dach MD All Rights Reserved. This article may be reproduced on the internet without permission, provided there is a link to this page and proper credit is given.

FAIR USE NOTICE: This site contains copyrighted material the use of which has not always been specifically authorized by the copyright owner. We are making such material available in our efforts to advance understanding of issues of significance. We believe this constitutes a ‘fair use’ of any such copyrighted material as provided for in section 107 of the US Copyright Law. In accordance with Title 17 U.S.C. Section 107, the material on this site is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes.



%d bloggers like this: