Learn how Vitamin D is essential for good health
Watch a 5 minute video "Does Less Sun Mean more Disease?"
Browse for other Health Problems and D in left column or here
see also Supplementing and More in the menu at the top of every page
If you have a disease associated with low Vit D take Vit D
Raising your Vit D levels will substantially prevent other low-Vit D health problems
Often your specific health problem will also be treated
Metal | Migraine | No Migraine | Ratio | |
+Zinc | 0.24 ug | 5.77 ug | 24X LESS if increase |
https://www.foundmyfitness.com/topics/zinc
1 Background
2 Dietary sources
3 Recommended dietary allowances for zinc
4 Zinc deficiency
4.1Populations at risk for zinc deficiency
5 Measurement of zinc status
6 Zinc transport and absorption
7 Zinc homeostasis and bioavailability
7.1Zinc and nutrient interactions
8 Zinc and DNA damage
9 Zinc and immune function
10 Zinc and age-related immune dysregulation
11 Zinc and pneumonia
12 Zinc and the common cold
13 Zinc and sepsis
13.1Zinc and nutritional immunity
13.2Zinc supplementation for the treatment of sepsis
14 Zinc and HIV
15 Zinc and the treatment of acne
16 Zinc and its role in childhood development, disease, and death
17 Zinc and the brain
17.1Zinc and Alzheimer’s disease
17.2Zinc and brain injury
17.3Zinc and depression
18 Zinc and age-related macular degeneration
19 Zinc and metabolic regulation
19.1Zinc and diabetes mellitus
19.2Zinc and lipoprotein metabolism
20 Zinc safety
20.1Zinc supplementation and copper deficiency
20.2Zinc supplementation and drug interactions
21 Zinc supplementation
213 references
Selfhacked 2) Diarrhea; 3) Wilson’s disease; 4) Acrodermatitis Enteropathica; 5) Heart Disease; 6) Insulin Resistance and Diabetes; 7) Skin Health: Acne, Warts, Skin Damage; 8) Depression; 9) Appetite and Anorexia Nervosa; 10) Immunity & Infections; 11) Common Cold; 12) ADHD; 13) Eyesight; 14) Cognition; 15) Allergy and Asthma; 16) Wound Healing; 17) Bone Health; 18) Hair Loss; 19) Kidney Disease, Hemodialysis; 20) Pregnancy Outcomes; 21) Stunted Growth; 22) Women’s Health; 23) Liver Protection; 24) Hearing Disorders; 25) Oral Health; 26) Body Odor
Note: Taking Zinc acetate every 2 hours with vitamin C stops most colds
Proc Nutr Soc. 2000 Nov;59(4):541-52.
Rink L1, Gabriel P.
1Institute of Immunology and Transfusion Medicine, University of Lübeck School of Medicine, Ratzeburger Allee 160, D-23538 Lübeck, Germany. rink at immu.mu-luebeck.de
Zn is an essential trace element for all organisms. In human subjects body growth and development is strictly dependent on Zn. The nervous, reproductive and immune systems are particularly influenced by Zn deficiency, as well as by increased levels of Zn. The relationship between Zn and the immune system is complex, since there are four different types of influence associated with Zn.
Here we summarize all four types of influence on the immune function. Nutritional aspects of Zn, the physiology of Zn, the influence of Zn on enzymes and cellular functions, direct effects of Zn on leucocytes at the cellular and molecular level, Zn-altered function of immunostimulants and the therapeutic use of Zn will be discussed in detail.
PMID: 11115789
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https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/
has the following Zinc AI and RDA
Age | Male | Female | Pregnancy | Lactation |
0–6 months | 2 mg* | 2 mg* | ||
7–12 months | 3 mg | 3 mg | ||
1–3 years | 3 mg | 3 mg | ||
4–8 years | 5 mg | 5 mg | ||
9–13 years | 8 mg | 8 mg | ||
14–18 years | 11 mg | 9 mg | 12 mg | 13 mg |
19+ years | 11 mg | 8 mg | 11 mg | 12 mg |
* Adequate Intake (AI)
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Science Daily reporting on a 2014 study
Behavioral impairments in animal models for zinc deficiency - Jan 2015
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Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage
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WHO as of 2018
Good Zinc Overview - Dr. Jockers 2018
How To Test for Zinc
There are several ways to test zinc levels. One that I am a fan of due to its simplicity and cost-effectiveness is the zinc sulfate taste test. All you do purchase a bottle of zinc sulfate liquid (this a good one), place a capful in your mouth, and observe the sensations in your mouth.
Below are the possible outcomes and indications:
Do You Have A Copper and Zinc Imbalance? Dr. Jockers
Nice article has the following charts and many references
2013 with free PDF
Zinc administered within 24 hours of onset of symptoms reduces the duration of common cold symptoms in healthy people but some caution is needed due to the heterogeneity of the data. As the zinc lozenges formulation has been widely studied and there is a significant reduction in the duration of cold at a dose of ≥ 75 mg/day, for those considering using zinc it would be best to use it at this dose throughout the cold. Regarding prophylactic zinc supplementation, currently no firm recommendation can be made because of insufficient data. When using zinc lozenges (not as syrup or tablets) the likely benefit has to be balanced against side effects, notably a bad taste and nausea.
Diabetes Metab Syndr , 13 (3), 1773-1777 May-Jun 2019, DOI: 10.1016/j.dsx.2019.03.020
An Assessment of the Risk Factors for Vitamin D Deficiency Using a Decision Tree Model
Kayhan Gonoodi 1, Maryam Tayefi 2, Maryam Saberi-Karimian 3, Alireza Amirabadi Zadeh 4, Susan Darroudi 3, Seyed Kazem Farahmand 5, Zahra Abasalti 6, Alireza Moslem 7, Mohsen Nematy 1, Gordon A Ferns 8, Saeid Eslami 9, Majid Ghayour Mobarhan 10
Background and objectives: Vitamin D (25-hydroxyvitamin D or 25OHD) has a key role in the pathogenesis of several chronic disorders. Vitamin D deficiency is a common global public health problem. We aimed to evaluate the risk factors associated with vitamin D deficiency using a decision tree algorithm.
Methods: A total of 988 adolescent girls, aged 12-18 years old, were recruited to the study. Demographic characteristics, serum biochemical factors, all blood count parameters and trace elements such as Zinc, Copper, Calcium and SOD were measured. Serum levels of vitamin D below 20 ng/ml were considered to be deficiency. 70% of these girls (618 cases) were randomly allocated to a training dataset for the constructing of the decision-tree. The remaining 30% (285 cases) were used as the testing dataset to evaluate the performance of decision-tree.
In this model, 14 input variables were included: age, academic attainment of their father, waist circumference, waist to hip ratio, zinc, copper, calcium, SOD, FBG, HDL-C, RBC, MCV, MCHC, HCT. The validation of the model was assessed by constructing a receiver operating characteristic (ROC) curve.
Results: The results showed that serum Zn concentration was the most important associated risk factor for vitamin D deficiency. The sensitivity, specificity, accuracy and the area under the ROC curve (AUC) values were 79.3%, 64%, 77.8% and 0.72 respectively using the testing dataset.
Conclusions: The results suggest that the serum levels of Zn is an important associated risk factor for identifying subjects with vitamin D deficiency among Iranian adolescent girls.
]]>Osteoporosis and low bone mineral density affect millions of Americans. The majority of adults in North America have insufficient intake of vitamin D and calcium along with inadequate exercise. Physicians are aware that vitamin D, calcium and exercise are essential for maintenance of bone health. Physicians are less likely to be aware that dietary insufficiencies of magnesium, silicon, Vitamin K, and boron are also widely prevalent, and each of these essential nutrients is an important contributor to bone health. In addition, specific nutritional factors may improve calcium metabolism and bone formation. It is the authors' opinion that nutritional supplements should attempt to provide ample, but not excessive, amounts of factors that are frequently insufficient in the typical American diet.In contrast to dietary insufficiencies, several nutrients that support bone health are readily available in the average American diet. These include zinc, manganese, and copper which may have adverse effects at higher levels of intake. Some multivitamins and bone support products provide additional quantities of nutrients that may be unnecessary or potentially harmful.The purpose of this paper is to identify specific nutritional components of bone health, the effects on bone, the level of availability in the average American diet, and the implications of supplementation for each nutritional component. A summary of recommended dietary supplementation is included.
PMID: 22523525
Table 1. Common Nutrients for Bone Health
Nutrient | Recommended Dietary Allowance | Median Intake | Authors' Preferred Supplementation |
---|---|---|---|
Vitamin D | 600-800 IU | 150-300 IU | 400-1000 IU |
Calcium | 1000-1200 mg | 735 mg | 500 mg |
Magnesium | 320-420 mg | 243 mg | 250-350 mg |
Silicon | 140 mg for bone health | 21 mg | 20-40 mg |
Vitamin K | 90-120 µgm | 70-80 µgm | 50-150 µgm |
Boron | 13 mg for bone health | 1 mg | 1-3 mg |
Vitamin C | 75-90 mg | 103 mg | 50-100 mg |
Copper | 0.9 mg | 1.1 mg | None |
Zinc | 8-11 mg | 9.6 mg | None unless vegetarian or elderly |
Manganese | 1.8-2.3 mg | 2.8 mg | None |
Ref: [26-30]
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Bone - Health category starts with the following
Approximately ten million Americans over the age of fifty have osteoporosis and another 34 million have low bone mass [1]. After the age of 50 years, a woman’s risk of dying from a hip fracture is equal to her lifetime risk of dying from breast cancer [2, 3]. Almost one out of five patients with a hip fracture dies within six months and one out of four dies within a year [3, 4]. Many of these deaths are related to the immobility and increased metabolic demands caused by the fracture. Even though survival rates have improved in the first few weeks after a hip fracture, the one-year death rates have not improved over the last 40 years [4]. When patients survive more than a year, they are at increased risk for fracture of the opposite hip with subsequent morbidity and mortality. The limited mobility, and increased metabolic demand required to heal the injured hip contribute to weakening of the opposite hip. In the year following a hip fracture the loss of bone mineral density in the opposite hip is five times greater than expected bone loss in women who do not have a hip fracture [5]. Also, a younger age at time of the first fracture increases the risk of a second fracture [3].
Healthy nutritional habits combined with exercise should be encouraged to maintain bone health [1]. However, dietary supplementation with calcium and vitamin D is recommended for postmenopausal women to decrease the risk of fracture [6]. Additional management for osteopenia or osteoporosis may include medications, lifestyle changes, home safety modifications, hip protectors, and fall prevention. The purpose of this review is to identify several essential nutrients for bone health and compare the recommended intake to the dietary intake from the average North American diet. The role of exercise will also be identified as an important and frequently insufficient factor for bone health.
There is increasing recognition that insufficient exercise, poor vitamin D levels and low dietary calcium are common in modern society. Approximately 70% of children in the USA are insufficient or deficient in Vitamin D [7]. Similar prevalence of vitamin D insufficiency has been reported in adults. Dietary sources of vitamin D include oily fish such as salmon and swordfish, with lesser amounts in tuna and other fish. It is difficult to consume sufficient amounts of vitamin D from dietary sources alone. The average adult American diet only contains 150-300 IU of Vitamin D per day [8]. Recommended dietary allowance of Vitamin D for adults is 600-800 IU per day, but higher levels may be optimal [9, 10]. A 2005 meta-analysis published in the Journal of the American Medical Association reported that supplements in the range of 700-800 IU/day decreased the risk of fractures, but doses of 400 IU/day were not as effective [11]. The Endocrine society recommends 1500-2000 IU of daily vitamin D, and current research suggests that supplemental vitamin D is associated with decreases in mortality [9, 10, 12, 13]. Therefore, supplementation with 400 IU to 1,000 IU of vitamin D per day is reasonable for the majority of healthy Americans.
Calcium intake is also low for most age groups in the United States. The principal dietary source of calcium is milk and milk products although lesser sources include salmon, almonds, and leafy green vegetables such as spinach, kale, and turnip greens. The recommended dietary allowance of calcium is 1,200 mg/day but the majority of women older than forty consume less than 600 mg/day in the United States [14]. The average dietary calcium intake is below the recommended amount for 60-70% of teenage girls and for 70% of post-menopausal women [15]. Low calcium intake correlates with increased risk of hip fracture, but increasing intake above 750 mg/day does not correlate with progressively lower risks of hip fracture [16-18]. There may be additional health benefits from slightly higher levels of calcium intake, so an appropriate supplementary dose is 400-800 mg/day in order to achieve 1,2000 mg/day as recommended by the National Institutes of Health [14, 19]. Very high levels of calcium supplementation have been associated with increased risks of kidney stones and myocardial infarction [19, 20]. Therefore, calcium supplementation should achieve the recommended dietary allowance without providing excessive amounts.
Modest exercise is also essential for general health and for bone health. Approximately 40% of adults do not participate in leisure time physical activity [21]. A 2005 report from the Centers for Disease Control and Prevention noted that two thirds of high school students were below national standards for moderate physical activity [22]. Just 15 minutes of modest exercise a day can significantly prolong life and decrease the risk of cancer and other diseases [23]. Only 20 minutes of modest impact activity, resistance training, or vibration therapy three times a week can improve bone mineral density [2, 24]. Exercise also decreases the risk of falls by improving muscle tone, balance and coordination [25]. Therefore, modest exercise should also be recommended as part of a bone health program.
What is less known to practicing physicians is that several other vitamins and minerals are associated with improved bone strength independent of vitamin D and calcium. As stated by Munger, et al., “The preoccupation to date with calcium has resulted in less emphasis on the role of other nutrients in bone quality and osteoporosis [16].” Examples of common insufficiencies in addition to Vitamin D and calcium are magnesium, silicon, vitamin K, and boron. (Table ?11) [26-30]
Table 1.
Common Nutrients for Bone Health
Magnesium is increasingly recognized as an important contributor to bone health [31-33]. A study of women with osteoporosis in Israel reported significantly increased bone mineral density with 250 mg/day of magnesium supplement when compared to a control group who did not take magnesium supplements [34]. Dietary sources of magnesium include almonds, cashews and peanuts. Other sources include raisin bran cereal, potato skins, brown rice, kidney beans, black-eyed peas and lentils. Eight ounces of milk has approximately 25 mg of magnesium. The recommended dietary allowance for optimum health is 320-420 mg [35]. However, more than half of the US population consumes less than 245 mg per day [28]. Thus modest supplementation with 250 mg/day of magnesium is reasonable to support bone health, and for other aspects of general health [32].
Silicon is another important contributor to bone health [36-38]. Silicon is an essential nutrient and silicon deficiency is associated with poor skeletal development [37, 39]. Carlisle performed electron probe microanalyses of various regions of bone and determined that silicon is twenty-five times more concentrated in immature osteoid than in mature bone [40]. Carlisle concluded that silicon plays a role in the initiation of the mineralization process. It is also known that silicon is used in micro-pressure transducers and in the computer electronics industry because of silicon’s unique piezoresistive properties as a semi-conductor element [41]. The relationship between silicon and bone mineralization is poorly understood, but negative piezoelectric forces are generated and stimulate bone formation when collagen matrix is subjected to compression [42, 43]. Epidemiological studies report that dietary silicon intake of more than 40 mg/day correlates with increased bone mineral density, but the average dietary intake of silicon is 20-30 mg/day [29, 44]. Dietary sources of silicon include whole grains and cereals, carrots and green beans [45]. Some types of mineral water also contain silicon in the form of orthosilicic acid [46]. Beer is a rich source of silicon because of the processing of barley and hops [47]. Men consume more silicon them women and this is primarily due to differences in beer consumption [45]. Post-menopausal women rarely achieve 40 mg of silicon per day and average approximately 18 mg per day [29, 48]. Also, post-menopausal women may not absorb silicon as well as younger women. Thus, silicon supplementation with approximately 20-30 mg/day may benefit bone health for the majority of Americans who do not consume beer on a regular basis.
Vitamin K is another lesser known nutrient that is important for bone health. Vitamin K has several different forms, but vitamin K1 and K2 are the naturally occurring forms [49]. The name for this vitamin comes from the German word “Koagulationsvitamin” because it is essential for coagulation of blood. Excessive vitamin K does not increase the risk of blood clots, but those taking warfarin (Coumadin®) for anti-coagulation should avoid supplemental vitamin K because warfarin is a vitamin K antagonist [28, 49]. Insufficient vitamin K is associated with under-carboxylation of osteocalcin, osteopenia and increased fracture risk, while vitamin K supplementation reduces bone turnover and improves bone strength [28, 49]. Useful dietary sources of vitamin K include kale, collard greens, fresh spinach, Brussels sprouts, iceberg lettuce, and prunes. The optimum daily intake of vitamin K has been established as 90 µgm (micrograms) per day for women and 120 µgm per day for men. However, larger amounts may be needed for complete carboxylation of osteocalcin [28]. According to the Third National Health and Nutrition Examination Survey, approximately half of the men and women in the United States consume less than the recommended amount of vitamin K, and one quarter of the population consumes less than 60 µgm per day [28] In a study of hip fracture risk, women who consumed more than 109 µgm of vitamin K per day had an decreased risk of hip fracture compared to women with lower levels of vitamin K intake [50]. Vitamin K2 has been administered in pharmacological doses for osteoporosis treatment in Japan with doses ranging from 15 mg/day to 135 mg/day (over 1,000 times the recommended daily allowance) [51]. Doses of 45 mg/day have decreased fracture rates 37% which is similar to fracture decreases following treatment with bisphosphonates. However, lower fracture rates from vitamin K supplementation are not accompanied by increased bone mineral density [51, 52]. This suggests that vitamin K improves bone properties that increase bone strength without increasing mineral content. Vitamin K has no toxicity except for those using warfarin, so supplementation with100 µgm/day would to achieve slightly more than the recommended daily allowance and may have beneficial effects on bone structure.
Boron is increasingly recognized as an element that has several health benefits including bone health [53-55]. Boron is a semi-conductor with the atomic number of 5. The precise mechanism of action of boron for bone health is unknown, but boron stabilizes and extends the half-life of vitamin D and estrogen [28, 53, 54]. Approximately half the population in the United States consumes less than 1 mg of Boron per day [28]. Supplementation with 3 mg. of boron per day for post-menopausal women has demonstrated improved calcium and magnesium retention by the kidneys [56]. Increased bone strength has also been demonstrated in pigs fed a diet supplemented with boron [57]. Prunes are a rich source of boron with approximately 3-4 mg of boron for every three ounce serving of prunes [30]. A study of postmenopausal women reported that a 3-ounce serving of prunes daily for a period of one year improved bone mineral density but dried apples did not [58]. The Recommended Daily Allowance of boron has not been established, but no toxicity has not been identified and excess boron is rapidly excreted in the urine [28]. Thus, it is reasonable to supplement the diet with 1-3 mg of boron although this dietary need may also be met by increased consumption of foods such as prunes, raisins, dried apricots, or avocados.
These lesser known insufficiencies of magnesium, silicon, vitamin K, and boron are rarely explained to physicians although the more common insufficiencies of calcium, vitamin D and exercise are increasingly recognized as contributors to bone health. In addition to these essential nutrients, vitamin C, inositol and L-arginine have beneficial effects on bone health. These three nutrients have been correlated with increased bone mineral density and improved bone strength when provided in physiological amounts [59-64]. The actions of these three factors are to improve various aspects of the bone formation and remodeling as well as calcium absorption and retention. Vitamin C is essential for the formation of collagen and for fracture healing [65]. The evidence for supplemental vitamin C in the management of osteoporosis is weak, but increased bone mineral density has been noted in postmenopausal women taking vitamin C supplements [63, 66]. Inositol is a carbohydrate compound found in cantaloupe, grapefruit, oranges, and prunes [67]. It is also found in the form of phytate in whole grains. Experimental studies using radioactive calcium have reported increased calcium uptake in bone in response to supplementation with myo-inositol [68]. Low phytate consumption has also been associated with osteoporosis in an epidemiological study [64]. L-arginine is a semi-essential amino acid and serves as a substrate for production of nitric oxide (NO) that improves endothelial function, reduces vascular resistance, promotes angiogenesis, and influences numerous metabolic processes [69, 70]. Experimental studies have determined that nitric oxide is released in response to mechanical stress on bone, and that blocking the release of nitric oxide interferes with fracture healing [71, 72]. Dietary arginine is available in dairy products, poultry, seafood, and meat in addition to nuts and oatmeal. There is some evidence that supplemental l-arginine influences vascular relaxation and should not be used as a supplement following myocardial infarction, especially in patients older than 60 years at time of infarct [73, 74]. Studies where arginine, inositol, and silicon were taken together demonstrated increased bone mineral density and increased bone strength [61, 62, 75]. Mega-doses of these three supplements have been used without adverse effects as anti-oxidants (vitamin C), or to enhance sports performance (L-Arginine), or to improve psychiatric disorders (Inositol). However, mega-doses may not be required to influence bone health. Supplementing the diet with physiological amounts of these three nutrients may support bone health.
Some essential nutrients for bone health are readily available in the typical American diet. These include zinc, manganese, and copper. These nutrients are usually consumed in amounts that meet or exceed the recommended dietary allowance, so they should not need supplementation unless a disease state is present. Regardless of wide availability, these metals are frequently added to dietary supplements. It should be noted that high levels of supplementation with zinc, manganese and copper may have deleterious effects.
The Recommended Daily Allowance of zinc for men is 11 mg/day and for women is 8 mg/day. The average intake from dietary sources is 14 mg/day for men and 9 mg/day for women [28]. Therefore, supplementation is unnecessary for the typical American diet. Zinc is found in a wide variety of foods including red meat, lamb, shell fish, seeds, nuts, dairy products, poultry, and beans. Vegetarians and older individuals may have insufficient zinc intake. After the age of 60 years approximately 35-45% of Americans have inadequate dietary zinc intake unless they are receiving some dietary supplementation [43]. Several popular multi-vitamins provide more than 15-30 mg of zinc as a nutritional supplement even though the tolerable upper level recommended by the National Institutes of Health is 40 mg/day [76]. Long-term supplementation with more than 20 mg per day may be harmful unless the person is a vegetarian or malnourished [28, 77].
Manganese intake is also sufficient in the average American diet. The Recommended Daily Allowance is 1.8 mg/day for women and 2.3 mg/day for men. Typical non-vegetarian Western diets provide 3mg to7 mg of manganese per day [28]. Dietary sources of manganese include cereals, nuts, pineapples, beans, mollusks (clams, oysters, mussels), dark chocolate, cinnamon, and tea. Excessive intake of manganese is associated with cognitive disorders in adults and children [78, 79]. When intake of iron and manganese are increased through supplementation, the risk of Parkinson’s disease is doubled [80]. Consuming more than 11 mg/day may have harmful effects according to the National Institutes of Health [28]. In spite of this information, some daily multi-vitamins provide 2-4 mg of additional manganese.
The Recommended Daily Allowance of copper is 0.9 mg/day. However, dietary copper is available in a wide variety of foods including meats, seafood, nuts, grains, and cocoa products. The average American consumes 1.1-1.4 mg of copper per day and dietary copper insufficiency is rare in North America [28]. The National Academy of Sciences recommends that daily copper intake should be less than 10 mg/day [28].
Strontium is another nutritional supplement that should be questioned as a bone health product. Strontium is not an essential nutrient and it displaces calcium in bone [81]. Strontium has gained attention for bone mineralization in part because it increases bone density as measured by x-ray tests and DXA Scan [82, 83]. However, this effect is partly caused by the strontium itself because strontium is a heavier element than calcium. Strontium is considered an alkaline earth metal with an atomic weight of 87.63. That makes it much heavier than calcium and it replaces natural calcium in bone. This gives the DXA scan a denser appearance because strontium absorbs the x-rays [83]. The x-ray absorbing properties of strontium gave rise to its use in early color television tubes so that x-rays would be absorbed by the strontium and prevent irradiation of viewers [84]. Strontium ranelate in doses of 2 gm/day have been used for the treatment of osteoporosis in several countries, but the United States Food and Drug Administration has not approved the use of strontium ranelate in the United States [85, 86]. Oral intake of 2 gm/day of strontium ranelate have improved bone strength and reduced fracture rates in women with osteoporosis, but there are reports of increased risks of venous blood clots and memory loss [82, 87]. Strontium also accumulates in the body and remains there long term [82]. Therefore, strontium may need more evaluation before it becomes a routine treatment of osteoporosis.
Nutritional needs for bone health can be met with proper food choices. (Table ?22) However, supplementation of the average American diet is recommended for vitamin D, calcium, magnesium, silicon, vitamin K, and boron. Regular exercise is also important for bone health. Modest amounts of zinc supplementation may be appropriate for vegetarians and for older individuals. However, routine supplementation with zinc, manganese, copper and other metals is generally unnecessary, and excessive supplementation may be harmful. Supplementation with strontium should also be questioned until long-term risks and benefits are better understood.
Table 2
Nutrient and Dietary Sources
ACKNOWLEDGEMENTS
The authors thank Kenneth J. Koval, M.D., and George J. Haidukewych, M.D. for their review and comments prior to publication.
CONFLICT OF INTEREST
The authors are shareholders in the Institute for Better Bone Health, LLC, a nutritional supplement company.
T1
T2
F3_
Journal of Bone and Mineral Research DOI: 10.1002/jbm4.10417
Andrea Giustina,1 ® Roger Bouillon,2© Neil Binkley,3© Christopher Sempos,4 Robert A Adler,5 Jens Bollerslev,6 Bess Dawson-Hughes,7© Peter R Ebeling,8® David Feldman,9 Annemieke Heijboer,10 Glenville Jones,11 Christopher S Kovacs,12 Marise Lazaretti-Castro,13 Paul Lips,14 Claudio Marcocci,15 Salvatore Minisola,16© Nicola Napoli,17,18® Rene Rizzoli,19 Robert Scragg,20 John H White,21 Anna Maria Formenti,1 and John P Bilezikian22©
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The Third International Conference on Controversies in Vitamin D was held in Gubbio, Italy, September 10-13, 2019. The conference was held as a follow-up to previous meetings held in 2017 and 2018to address topics of controversy in vitamin D research. The specific topics were selected by the steering committee ofthe conferenceand based upon areas that remain controversial from the preceding conferences. Other topics were selected anew that reflect specific topics that have surfaced since the last international conference. Consensus was achieved after formal presentations and open discussions among experts. As will be detailed in this article, consensus was achieved with regard to the following: the importance and prevalence of nutritional rickets, amounts of vitamin D that are typically generated by sun exposure, worldwide prevalence of vitamin D deficiency, the importance of circulating concentrations of 25OHD as the best index of vitamin D stores, definitions and thresholds of vitamin D deficiency, and efficacy of vitamin Danalogues in th etreatment of psoriasis. Areas of uncertainly and controversy include the following:
With specific regard to the latter area, the proceedings of the conference led to recommendations for areas in need of further investigation through appropriately designed intervention trials.
Received in original form June 6, 2020; revised form August 18, 2020; accepted September 20, 2020. Accepted manuscript online September 29, 2020. Address correspondence to: John P Bilezikian, MD, Department of Medicine, Endocrinology Division, College of Physicians and Surgeons, 630 W 168th Street, PH 8-105G, New York, NY. E-mail: jpb2 at cumc.columbia.edu
Following meetings held in 2017⑴ and 2018,⑵ the Third International Conference on Controversies in Vitamin D was held in Gubbio, Italy, September 10-13, 2019. The aim of the conference was to convene leading worldwide experts in vitamin D research to address ongoing controversies and current topics of debate in vitamin D research. Following formal presentations on specific topics, discussions among experts were used to help resolve lingering issues and to clarify areas of uncertainty. Several core issues from the previous conference in 2018 were revisited, such as assays to determine serum 25OHD concentration, which remains a critical and controversial issue for defining vitamin D status. Definitions of vitamin D nutritional status were also revisited. New areas were discussed, including the epidemiology of vitamin D in developing countries and 25OHD threshold values and how they should be defined in the context of health and disease in different stages of human development. Therapeutic roles of vitamin D and findings from recent randomized clinical trials were also discussed for cancer, cardiovascular disease, and diabetes mellitus (DM). It was evident that results from recent trials are inconclusive because of questionable design, the treatment regimen adopted, or the baseline vitamin D status of the study subjects. Here we also identify issues concerning vitamin D in both skeletal and nonskeletal diseases where consensus is becoming established or is still lacking.
Nutritional rickets, caused by a simple vitamin D or calcium deficiency or both, still affects a significant number of infants and children worldwide.(3) Vitamin D-deficiency rickets is cured by vitamin D administration.(3) There is consensus that infants and most children require approximately 400 IU (or 600 IU for older children) of vitamin D per day to prevent rickets because direct exposure to sunlight is often avoided and not recommended for the very young.(4) However, such a supplementation policy is either not or not fully implemented in many countries.
Although countries in Asia and the Middle East are most often affected by nutritional vitamin D deficiency, African and some Asian countries also encounter rickets caused by calcium defciency.(3) For newborns 0 to 6 and infants 6 to 12 months of age, adequate calcium intake is 200 and 260 mg/day, respectively, whereas for children over 12 months of age, a dietary calcium intake of <300 mg/day increases the risk of rickets independent of serum 25OHD levels.(5) For children over 12 months of age, classification of dietary calcium intake can be defined as: sufficiency = >500 mg/day; insufficiency = 300 to 500 mg/day, and deficiency = <300 mg/day.(6)
The pathogenesis of calcium deficiency rickets is probably more complex than previously thought. However, we do know that reduced calcium intake increases PTH secretion, which in turn increases FGF-23. Increases in both PTH and in FGF-23 lead to an increase in urinary phosphate excretion. This pathophysiological sequence leads to reduced serum phosphate, which, along with PTH, increases the 1,25-dihydroxyvitamin D [1,25 (OH)D] level. Elevated 1,25(OH)D upregulates a number of genes causing an increase in pyrophosphate, a known inhibitor of bone mineralization, along with osteopontin and small integrin- binding ligand N-linked glycoproteins (SIBLINGS; Fig. 1).(7-10) These abnormalities, along with low calcium and low phosphate levels, are primarily responsible for the osteomalacia characteristic of calcium deficiency. Although this pathophysiological sequence has been demonstrated in animals, it is likely that humans are affected in the same way.
Currently, there is still a high incidence of rickets, mainly based on clinical signs, in different countries around the world (Table 1).(11) Based on the widespread global prevalence of rickets, a task force should be established to deal with this problem. Such a task force comprised of representatives from societies such as the International Society of Endocrinology, the International Federation of Musculoskeletal Research Societies, the Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology, as well as representatives from the vitamin D conference should prepare and present a plan to the WHO to eradicate rickets before 2030.(3)
UVB light (wavelength of approximately 280 to 310 nm) opens the B ring of 7-dehydrocholesterol, the last step in the de novo synthesis of cholesterol, and generates previtamin D, which undergoes thermally induced isomerization into vitamin D3 before being transferred into the circulation by binding to the serum vitamin D binding protein (DBP).
Short periods of exposure to sunlight are beneficial for vitamin D production, whereas prolonged UVB exposure leads to sunburn and DNA damage.(12) Larger doses result in more intense peak reactions in a roughly linear fashion, with the actual slope of the lines defined by individual variability, which in turn is probably accounted for, at least in part, by genetic determinants. As UV doses increase, simple tanning is replaced by more advanced degrees of sunburn. In contrast, vitamin D formation is instantaneous and increases linearly in a time-dependent fashion from very small to very large UV exposures. The dose response for dermal photosynthesis of vitamin D increases linearly at small UV doses, but differs strikingly from the other dose-response curves in reaching a plateau well below the threshold dose for erythema; Fig. 2). (13,14) Thus, short UVB exposure times increase vitamin D photosynthesis. However, many other variables can influence vitamin D dermal photosynthesis such as age, skin color, sunscreen use, latitude, time of day, and season. As a result, there is no consensus on what constitutes safe and effective exposure to sunlight for the general pop- ulation.(6) Moreover, given the above-noted individual differences, attempting blanket guidance seems ill-advised.
Table 1. Prevalence of Rickets Worldwide
Although cutaneous vitamin D3 synthesis occurs rapidly in the presence of adequate solar UVB because of human behavior— indoor work, sun avoidance, etc.—vitamin D deficiency is wide- spread.(15) Using a definition of <20 ng/mL (<50 nmol/L),(16) as many as one third of the world7s population is deficient, with a percentage as high as 40% in Europe (Table 2). Severe vitamin D deficiency, defined as <30 nmol/L (or <12 ng/mL), is seen in approximately 7% of the population worldwide, with considerable variation observed between different countries and populations. Nevertheless, severe vitamin D deficiency occurs in high- risk populations worldwide.(17) High-risk groups for vitamin D deficiency include those who lack effective exposure to sunlight. This could be because ofavariety of climatologic, cultural, or religious reasons, as well to skin pigmentation. Vitamin D deficiency was long considered rare in Africa, but a systematic analysis of African countries revealed that severe vitamin D deficiency is present in18%ofall African subjects, with clusters having ahigh prevalence of deficiency widely dispersed based upon cultural/ behavioral practices.08-26)
The circulating 25OHD concentration is widely accepted as the best marker of an individual's vitamin D status, and has been used by numerous agencies in the establishment of vitamin D dietary requirements and for population surveillance of vitamin D deficiency or inadequacy.(27) However, circulating 25OHD has, at least historically, been felt to have little physiologic regulation, thus other measures could potentially be better indicators of vitamin D status. Notably, there is ongoing debate with regard to whether free 25OHD (unbound to carrier proteins) or the ratio of 24,25-dihydroxyvitamin D [24,25(OH)2D]:25OHD is a superior marker than total 25OHD.(28)
The ratio of 25(OH)D3:24,25(OH)2D3 has been developed as a diagnostic tool for idiopathic infantile hypercalcemia caused by mutations of CYP24A1.
Fig 2. Relationship between minimal erythema dose (MED) of UV exposure and level of DNA damage, suntan/tanning, and vitamin D synthesis.
Table 2. Vitamin D Deficiency Around the World
aHilger etal,201417 bSchleicher et al 201622
cCashman etal 201 723 dArabi etal 201024 eDurazo-Arvizu et al 201425 fZhang etal 201326
However, the ratio is also elevated in patients with vitamin D deficiency, who undergo dialysis for chronic kidney disease caused by downregulation of the CYP24A1 enzyme.(29,30) It is also possible in certain circumstances that the ratio of 1,25(0H)2D:250HD could be a useful markerforCYP27B1 activity.(31)
Importantly, vitamin D research data are plagued by variation in the quality of serum total 25OHD assay methods—which has compromised, and continues to compromise—the ability to distinguish among the different guidelines currently in use.(32) Similarly, uncertainty about the quality offree 25OHD measurement hinders its evaluation compared with serum total 25OHD. For 25OHD and 24,25(OH)D2, reference methods are available that are used to improve the standardization ofthese analytes. Standardization is encouraged by the Vitamin D Standardization
Program (VDSP) and by the Vitamin D External Quality Assurance Scheme (DEQAS). DEQAS, backed-up by CDC-standardized target values, has monitored the performance of 700 to 1000 laboratories assaying 25OHD quarterly for 30 years. Over the decades, it has documented problematic assays and kit manu- facturers.(33,34) DEQAS also promotes an accurate assay of 24,25 (OH)2D3 and 1,25(OH)2D by circulating serum samples.
Currently, the VDSP is coordinating an effort to harmonize direct free 25OHD measurement by the development of “trueness” controls (Personal Communication, Professor Chris T Sem- pos). Finally,the NIH Office of Dietary Supplements,as part ofthe VDSP, is sponsoring the development of a reference method for 1,25(OH)2D, which will help to standardize its measurement in vitamin D research and bring clarity to its role.(26) Such standardization efforts are essential to advance clarification of what truly constitutes vitamin D deficiency.
However, standardization is not the only analytical challenge in the measurement of vitamin D metabolites. Patient- or matrix-dependent deviations are a well-known confounder in many 25OHD immunoassays leading to inaccurate results, for example, in pregnant women or hemodialysis patients. In addition, differences in the affinity for, or release from DBP for 25(OH)D3 and 25(OH)D2 within immunoassays lead to important problems in the determination of the serum 25OHD concentration in subjects taking D2 supplements.(35) These problems cannot be solved by standardization initiatives, but are inherent in the specific immunoassays; it is therefore essential that these immunoassays should be improved as well. This is particularly important in regions where ergocalciferol is commonly used and for vegans who may choose to avoid cholecalciferol.
There is an ongoing debate regarding the definition ofvitamin D deficiency as noted by different recommendations from various expert groups.(4) However, there is consensus on two points: 25OHD levels below 12 ng/mL (30 nmol/L) are clearly deficient at all ages and levels above 30 ng/mL (75 nmol/L) are clearly sufficient. In contrast, there is disagreement on how to regard levels between 12 and 30 ng/mL (30 and 75 nmol/L). Some guidelines recommend a threshold value of 20 ng/mL (50 nmol/L),(36) whereas others aim for >30 ng/mL (> 75 nmol/L).(37) This discussion is based in large part on the lack of 25OHD assay standardization.(32)
These cut points have key implications for randomized clinical trials (RCTs). There are few clinical trials that enrolled clearly vitamin D-deficient subjects;one example is the workofChapuyand colleagues.(38,39) The importance of studying the effect(s) ofvita- min D supplementation only in deficient subjects cannot be overemphasized because vitamin D is a threshold nutrient,(40) which means that a physiological endpoint, such as calcium absorption, is enhanced in dose-response fashion up to the threshold value above which higher levels do not lead to a greater effect. If a clinical trial enrolls subjects whose 25OHD levels are above the threshold, randomizing subjects to receive additional vitamin D greatly reduces the likelihood of showing a benefit of supplementation. Recent well-publicized Rs published in major peer-reviewed journals illustrate this confounding point well.(41-44) One would not expect to see an effect of a threshold nutrient if both the control and the supplemented groups started at baseline with sufficient levels of 25OHD.(45)
The benefits of vitamin D analogues for the treatment of psoriasis are well-established.(46-48) A topical vitamin D analogue is a first-line choice in the management of psoriasis, either alone or in combination with topical corticosteroids.(49-54) Unlike corticosteroids, which can be associated with tachyphylaxis, topically administered vitamin D analogue treatment is effective longterm without side-effects in patients of all ages.(55-59)
The Institute of Medicine recommends 400-600-800 IU/day vitamin D supplementation if there is no exposure to sunlight for infants, children/adults, and elderly, respectively.(36) These recommendations are endorsed by guidelines formulated by Nordic and DACH (German-speaking) countries, Australia and New Zealand, the European Food Safety Agency, the European Calcified Tissue Society, and the International Osteoporosis Foundation.(61-65) The Endocrine Society recommends 600 IU/ day up to 2000 IU/day for so-called riskgroups.(37) UKguidelines (the Scientific Advisory Committee on Nutrition) recommend 400 IU/day for any age.(66) A few other organizations suggest much higher doses (4000 to 10,000 IU/day).(67) These recommendations are for individuals who do not have osteoporosis or other metabolic bone disease. Unfortunately, this point has not been appreciated by many organizations or practitioners. Errors can occur in two ways. First, subjects who are overly concerned about their skeletal health could conceivably take too much if recommendations by some bodies of up to 10,000 IU per day are followed. It is estimated, for example, that 3% of adults in the United States take a vitamin D supplement of >4000 IU/day.(68) Such amounts could potentially be deleterious as such doses may decrease rather than increase BMD or bone strength.(69) On the other hand, use of relatively low doses could be deleterious for those in whom requirements are higher (eg, malabsorption or obesity). It is clearly essential to define and reach consensus regarding what constitutes deficiency to allow resolution of existing differences in daily supplementation dose recommendations.
In patients who have osteoporosis or other metabolic bone diseases, the discussion about vitamin D is different from that for the general population.(70) Clearly, greater emphasis is placed upon first ensuring that the 25OHD level is sufficiently above the threshold, whichever one is being followed, either 20 or 30 ng/mL (50 or 75 nmol/L). Furthermore, there is evidence that the response to antiosteoporosis drugs may be enhanced when vitamin D and calcium sufficiency are ensured.(71,72)
This consensus has recently been questioned by a meta-analysis conducted by Bolland and colleagues.(73) In their review, they stated: “Our findings suggest that vitamin D supplementation does not prevent fractures or falls or have clinically meaningful effects on bone mineral density.” They concluded their discussion with the following statement: “There is little justification to use vitamin D supplements to maintain or improve musculoskeletal health” and “This conclusion should be reflected in clinical guidelines. ”(73) First, other experts, who have taken issue with their statements, have questioned such conclusions. Lips, Bilezikian, and Bouillon(74) note that this meta-analysis excluded all studies that compared calcium plus vitamin D versus double placebo. Boonen and colleagues showed many years ago that it is necessary to administer both calcium and vitamin D in sufficient amounts to observe a reduction in fractures.(75) Weaver and colleagues, representing the National Osteoporosis Foundation, came to the same conclusion,(76) as did Yao and colleagues in a recent meta-analysis.(77) Second, over 60% of the studies were short-term, <1 year. It is unreasonable to expect a beneficial effect of antiosteoporotic nutrients on fracture risk over such a short period. Third, vitamin D-deficient individuals (25OHD <12 ng/mL or 30 nmol/L) represented a miniscule percentage oftheentire population studied: <2.1%. Fourth,the trial that constituted individuals at highest fracture risk (18%) was hampered by poor compliance (〜50。/。).(78) Another flaw in this metaanalysis was inclusion of studies that utilized high intermittent boluses ofvitamin D, which might increase fracture risk.(79) Moreover, the two main authors of this meta-analysis have independently published separate meta-analyses in which they conclude that combined vitamin D and calcium supplements can reduce the risks of hip and nonvertebral fractures in the elderly.(73,80) This earlier review was not mentioned or discussed in their latest meta-analysis. Other experts have reached similar conclusions.(74,81) Nevertheless, the debate is alive with contrary views still being expressed as recently as the 2019 meeting ofthe ASBMR.(82)
Studies led by Holickand colleagues have repeatedly stated that a full day of sun exposure can produce 10,000 to 25,000 IU of vitamin D.(83-85) To this point, in other studies it has been shown that the indigenous, very dark-skinned Masai people are said to make 10,000 or 20,000 IU per day. More recent studies have raised questions about the magnitude of the sun7s effect on dermal vitamin D production. Young Danish women exposed to intensive sun in the Canary Islands showed an increase in 25OHD that was equivalent to only 600 to 1000 IU/per day. A similar increase in serum 25OHD was induced by comparing total-body UVB exposure three times per week with an oral daily intake of only 800 IU of vitamin D.(86,87) Another study from the Canary Islands of young Danish women, exposed to 1 week of daily sunlight, showed that serum levels of 25OHD increased by only 20 nmol/L (8 ng/mL), equivalent to about 800 IU of oral vitamin D per day.(88) In yet another study from the Canary Islands, young Polish volunteers with near total body sun exposure achieved a change in 25OHD of 28 nmol/L or approximately 12 ng/mL equivalent to approximately 600 to 1200 IU (~15to30pg)o for al vitamin D per day.(89)Finally, exposure of 1000 cm2 on the back three times per week at half the minimal erythematous dose in nursing home residents increased median serum 25OHD in 3 months from 7.2 to 24 ng/mL (18 nmol/L to 60 nmol/L), equivalent to a supplement of 400 IU/day.(90) It is at this time unclear what full daily exposure to sun produces. Is it about 1000 IU or closer to 10,000 IU? An answer to that question may be helpful in the interpretation of the daily requirements of vitamin D in subjects with little exposure to sunlight.
Biochemical dogma states that vitamin D is hydroxylated in the liver to 25OHD by the constitutively active hydroxylase, CYP2R1. Although this enzyme is clearly the major converting enzyme, it is not the only way in which hydroxylation occurs.(91) Recent data have also called into question the constitutive nature ofthis reaction by evidence suggesting this enzyme is subject to several different control mechanisms. For example, in the fasting state, a significant reduction in the expression of CYP2R1 can be observed.(92) In a murine model of DM, a 50% reduction in mRNA and protein expression of CYP2R1 is demonstrable.(92) This study identified novel molecular mechanisms (involving PPARy coactivator a1 and estrogen-related receptor) for vitamin D deficiency in DM and showed a novel negative feedback mechanism that controls cross-talk between energy homeostasis and the vitamin D pathway. Activation of the glucocorticoid receptor (by dexamethasone or other corticosteroids) also supresses the activity of CYP2R1.Thus, rather than viewing the liveras a constitutive factory for the quantitative conversion of vitamin D to 25OHDvia an unregulated CYP2R1 enzyme, metabolic and hormonal mechanisms are operative. More research is clearly needed to understand better how the production of 25OHD is regulated in the liver.
The classical concept ofvitamin D toxicity was thought to be that level above which hypercalcemia was likely to occur. Serum 25OHD values in excess of 100 or 150 ng/mL (250 or 375 nmol/ L) may lead to hypercalcemia and, thus, these cut points became frames of reference for a number of authoritative bodies, such as the Institute of Medicine, the Endocrine Society, and reference laboratories/36,37,93)
Although it would seem reasonable to identify hypercalcemia as a threshold oftoxicity, other indices of toxicity, such as hyper- calciuria could occur at much lower levels.(94) In the study by Gal- lagherand colleagues, hypercalciuria occurred in 30%ofvitamin D-deficient individuals administered only 800 to 2000 IU per day for 1 year, whereas hypercalcemia occurred in 9%.
Further human studies conducted by Gallagher and colleagues and reanalyzed by Kaufmann and colleagues showed that doses up to 4000 IU/day for a year resulted in serum 25OHD <90 ng/mL.(29)
There was no relationship between the administered amount ofvitamin D and the level of urinary calcium excretion or hypercalcemia. Moreover, in half of these subjects, the hypercalciuria was transient. Adding further uncertainty to these data, however, was the observation that those receiving placebo experienced the same incidence of hypercalciuria. These data do not provide compelling support for the idea that such low-dose regimens may be harmful. In fact, most experts agree that doses up to 4000 IU are probably safe.(41,95) A more compelling discussion focuses upon fall risk associated with high doses of vitamin D.(69,96,97) Intermittent high boluses or administration of vitamin D to older individuals on a regular basis, associated with levels of 25OHD >45 ng/mL (>113 nmol/L), may lead to an increase risk of falls.(79) Further research is needed to further clarify whether such 25OHD levels do indeed increase falls risk.
Skeletal health has also been a focus of recent studies related to adverse effects of high vitamin D dosing. In the Calgary study performed on healthy volunteers without osteoporosis whose mean baseline 25OHD was approximately 31 to 32 ng/mL, treatment with vitamin D for 3 years at a dose of 4000 IU/day or 10,000 IU/day, compared with 400 IU/day, resulted in statistically significant reduction in radial volumetric BMD.(69) However, no significant differences in bone strength at either the radius or tibia were observed. Burt and colleagues concluded from this study that there was no benefit from doses of vitamin D at 4000 IU or higher as an adjunct to bone health.
In the setting of acute illness, levels of 25OHD may be low because of the acute reduction in circulating DBP.(98) Dilutional effects of acute fluid shifts in the intravascular space may also be a factor. Additionally, pre-existing vitamin D nutritional status is also a factor. This latter point leads to the suggestion that correction of poor vitamin D status may decrease morbidity and mortality. Christopher and colleagues suggest that very high doses of vitamin D may be needed to see a benefit in patients in the intensive care unit.(99) The higher doses may be needed because acutely ill patients may have secreted stress amounts of cortisol, which in turn could impair hepatic and renal hydroxylation ofvitamin d.(100,101)
There is a lack of consensus on the use of vitamin D during reproduction. On the one hand, maternal vitamin D requirements are not increased during pregnancy or lactation. The achieved 25OHD level is not affected by either reproductive state, and there is no evidence that women should maintain higher 25OHD levels when pregnant or breastfeeding as compared with the healthy nonpregnant ideal. On the other hand, poor maternal vitamin D status during pregnancy can affect fetal and neonatal health; so it certainly makes sense to ensure that maternal vitamin D status is optimized during pregnancy. This does not mean that women require “more” vitamin D when pregnant than when nonpregnant. During lactation maternal vitamin D status does not matter directly because little vitamin D gets into milk, and especially because RCTS have shown that across a range of low to high 25OHD levels, the calcium content of milk is independent of maternal vitamin D status. Breastfed babies need supplemental vitamin D, whereas formula-fed babies get their vitamin D in the supplemented formula.
Although variability exists among different studies, evidence from RCTs and systematic reviews suggests a benefit of vitamin D repletion with up to 2000 IU/day for preeclampsia and gestational DM,(102) as well as for neonatal outcomes.(103-107) It seems reasonable to recommend that normal vitamin D status should be ascertained in pregnancy.
The potential for a broad spectrum of cellular and organ activities under the influence of the vitamin D receptor
The vitamin D receptor (VDR) is present in virtually all cells and tissues. The 1a-hydroxylase, CYP27B1, is also found throughout the body and in many cell types.(108) It has been estimated that 3% to 10% of all genes in vertebrates, from zebrafish to mice to humans, are under the direct or indirect control of 1,25 (OH)2D3.(109) This evolutionary omnipresence suggests a fundamental role for vitamin D in the functioning of all organs. Experiments to delete this gene in a tissue-specific manner in mice have confirmed this expectation. A sampling of tissue-specific KO experiments shows that mammary glands are more prone to breast cancer,(110) cardiac muscle develops cardiac hypertrophy,(111) the liver becomes fatty (nonalcoholic fatty liver syndrome),(112,113) the prostate develops hyperplasia,(114) atherosclerosis is accelerated,(115) and mice become resistant to diet- induced obesity.(116) Conversely, overexpression of the VDR leads to obesity(117) in the mouse, but not in humans.(118) More work is needed to understand how these KO and overexpression models in mice relate to human pathophysiology.
Recent mortality data show an association between low 25OHD and increased risk of all-cause mortality.(119,120) These findings were also observed in a European consortium.(121) Several association analyses of overall mortality and cardiovascular mortality have shown a U-shaped curve with increases at both ends.(122) Ameta-analysis based on 75,000 patients from 38 supplementation trials also showed a small, but significant reduction in mortality (relative risk [RR], 0.94; 95% CI, 0.91-0.98).(123)
From Mendelian randomization studies examining the effects of vitamin D on autoimmune diseases, three independent findings show that decreased vitamin D levels (5% to 7% lower than normal levels) significantly increased the susceptibility to developing multiple sclerosis.(124-126) Finally,one Mendelian randomization study showed an association with type 1 diabetes mellitus (T1DM) risk.(127)
The data on cancer in mice are also of interest. 1,25(OH)2D3- deficient mice have a greater chance of developing cancer with increasing age,(128) and an increased rate of proliferation in intestinal and breast cells. Although VDR-null mice usually do not spontaneously develop more cancers, they are more likely to develop a range of malignancies, such as breast,(129) colon,(130)
and skin(131,132) cancer, when exposed to oncogenes, loss ofanti- oncogenes, or exposure to carcinogens or UVB light.(133,134) This is in line with the “cancer hypothesis,” where the risk of cancer development is associated with multiple events. Although these mice data appear to be compelling, Mendelian randomized studies in humans have not been supportive.(135)
Many cross-sectional, observational, and retrospective studies have associated low vitamin D status with many human diseases.(136-139) In the aggregate,these reports suggesta pervasive influence of vitamin D on the health of most human organ systems. Preclinical evidence for a role of vitamin D in immune system regulation is perhaps strongest as the VDR and CYP27B1 are expressed in cells of both the innate and adaptive arms ofthe immune system. Moreover, CYP27B1 expression in immune cells is regulated by a complex innate immune and cytokine network.(136-141) There is widespread clinical evidence in both pediatric and adult populations that maintenance of vitamin D sufficiency should lower the incidence of infections of viral or bacterial origin.(142) Accumulated evidence suggests that any role for vitamin D in autoimmune conditions would be preventive rather than therapeutic. One condition for which vitamin D supplementation may be of benefit is in the treatment of the inflammatory bowel condition Crohn disease, where metaanalyses of a series of small-scale trials suggest that supplementation reduces disease severity.(143,144) It would be important to conduct a large-scale RCTin patients with Crohn disease to solidify these findings. Large-scale RCTs are essential to determine whether the relationship between vitamin D deficiency and disease is causal or simply an association.
Another disorder to which vitamin D deficiency has been linked is DM. It has been shown that vitamin D prevents insulitis and the development of experimental DM by acting on the defective suppressor cellular function or by cytokine-expression modulation.These observations have been confirmed,in part, by clinical findings showing that supplementation with vitamin D during early childhood may decrease the risk of developing T1DM.(145,146) However, further studies have not shown any significant effect of calcitriol supplementation on insulin secretion, insulin sensitivity, or insulin requirement or improvement in bone turnover in patients with newly diagnosed T1DM.(147,148)
It is uncertain whether 25OHD levels in pregnancy or at birth reduce the risk of childhood T1DM. However, when the interaction with genetic variants is taken in consideration, higher 25OHD levels at birth predict a decreased risk of developing T1D or islet autoimmunity.(149,150) Both child or maternal VDR SNPs may lower VDR expression, and by consequence, inhibit T-cell proliferation, thus increasing the risk of autoimmunity.
The recent Vitamin D Assessment (VIDA), Vitamin D and Omega-3(VITAL), and Vitamin D and Type 2 Diabetes (D2d) trials represent examples of attempts to translate these observations into clinical relevance.(43,151,152)
The VIDA trial tested the effect of a monthly dose of 100,000 IU of vitamin D3 compared with a placebo over a mean period of 3.4 years on cardiovascular disease among 5110 subjects.053) There was no statistical difference between the two groups. In the VITAL trial, there were no significant differences between the vitamin D and placebo groups in any individual cardiovascular event, such as myocardial ischemia, or in the composite
cardiovascular end point.(145)
The much larger VITAL trial(151) of 25,871 men and women aged over 50 years tested the effects of 2000 IU/day of vitamin D3 over 5 years on cardiovascular events and cancer. There was no significant difference between the vitamin D and placebogroups on the risk of developing any invasive cancer or individually in breast, prostate, or colorectal cancer. However, among those with a BMI <25, there was a significant reduction in any invasive cancer. Excluding the first 2 years of the study, there was also a reduction in the incidence of death from cancer. The study by Lappe and colleagues is noteworthy in this context; they show that calcium and vitamin D appeared to have an effect to reduce new cancer risk, but statistical significance was not achieved.(154)
A subsequent meta-analysis by some of the invesitigators from the VITAL trial is noteworthy.(155) Whereas VITAL appreciated a “signal” of improved survival in the vitamin-D- supplemented group, the meta-analysis of VITAL and several additional studies found a highly significant benefit on survival in the vitamin-D-supplemented subjects, but again no benefit on risk of developing cancer. For total cancer incidence, 10 trials were included (6537 cases; 3 to 10 years of follow-up; 54-135 nmol/L of attained levels of circulating 25OHD in the intervention group). The summary for cancer risk remained null across the subgroups tested, including when attained 25OHD levels exceeded 100 nmol/L. For total cancer mortality, five trials were included (1591 deaths; 3 to 10 years of follow-up; 54 to 135 nmol/L of attained levels of circulating 25OHD in the intervention group). The summary RR was 0.87 (95% CI, 0.79-0.96; p = 0.005), which was largely attributable to interventions with daily dosing (as opposed to infrequent bolus dosing). Thus, this updated meta-analysis of RCTs showed that vitamin D supplementation significantly reduced total cancer mortality, but did not reduce total cancer incidence. In the Torfadottir study, the goal was to explore whether prediagnostic circulating levels of 25OHD among older individuals were associated with overall and cancer-specific survival after diagnosis.(156) They used data from the AGES- (Gene/Environment Susceptibility-) Reykjavik study on participants (n =4619) without cancer at entry, when blood samples were taken for 25OHD standardized measurements. The association with cancer risk and all-cause- and cancer-specific mortality was assessed among those later diagnosed with cancer, comparing four 25OHD categories, using 50 to 69.9 nmol/L (20-28 ng/mL) as the reference category. Cancer was diagnosed in 919 participants on average 8.3 years after initial sampling. No association was observed between the reference group and other 25OHD groups and total cancer incidence. Mean age at diagnosis was 80.9 (土 5.7) years. Of those diagnosed, 552 died during follow-up: 67% from cancer. Importantly, low prediagnostic levels of 25OHD <30 nmol/L (<12 ng/mL) were significantly associated with increased total mortality (hazard ratio [HR], 1.39; 95% CI, 1.03-1.88) and not significantly with cancer-specific mortality (HR, 1.33; 95% CI, 0.93-1.90). Among patients surviving more than 2 years after diagnosis, higher prediagnostic 25OHD levels (>70 nmol/L) were associated with lower risk of overall (HR, 0.68; 95% CI, 0.46-0.99) and cancer- specific mortality (HR, 0.47; 95% CI, 0.26-0.99). It appeared that among elderly cancer patients, low prediagnostic serum 25OHD levels (<30 nmol/L [<12 ng/mL]) were associated with increased overall mortality.
The D2d trial examined the effect of vitamin D3 at 4000 IU/day on the development of overt DM among 2423 men and women aged >30 years, who had risk factors for DM. There was no difference in the probability of developing DM over this period between the vitamin D and placebo groups. However, a post hoc analysis in participants with a baseline 25OHD <12 ng/mL (or < 30 nmol/L) showed a 62% reduction in DM in the vitamin D group.
Additionally, from the VIDA trial, central blood pressure was significantly reduced in patients taking vitamin D supplementation (-7.5 mmHg, p = 0.03),(157) and the number of patients taking NSAIDs was significantly reduced (RR, 0.87,p = 0.01).(158) Furthermore, giving vitamin D to the normal population and to the vitamin D-deficient population improves lung function,(159) in line with a meta-analysis,(160) as well as reducing age-related bone
loss.(161,162) In an individual participant data meta-analysis of 15 RCTs, daily or weekly supplementation in individuals with vitamin D deficiency, defined as a serum 25OHD level <10 ng/ mL, reduced risk of acute respiratory infection by 30% (odds ratio, 0.30; 95% CI, 0.17-0.53).(142)
Unfortunately, what VIDA, VITAL, and D2d studies share is that baseline 25OHD levels were not deficient in the majority of participants. Mean baseline levels from VIDA (24.2 ng/mL or 60.5 nmol/L), VITAL (30.8 ng/mL or 77.0 nmol/L), and D2d (28.2 ng/mL or 70.5 nmol/L) were all within the normal range as defined by the Institute of Medicine. Levels below 20 ng/mL (50 nmol/L) were seen in only 33% of the VIDA, 12.7% of the VITAL,and 20.7% ofthe D2d populations. One important conclusion from these studies is that they did not show that a vitamin D-deficient population would benefit by vitamin D repletion because the populations were already replete. As noted earlier, if subjects are already above the level for a threshold nutrient, giving more will not necessarily lead to beneficial effects. Therefore, it is not evidence-based to claim, based on these studies, that vitamin D has no effects on cancer, the cardiovascular system, or the development of DM. A clue to the importance of this statement is the post hoc analysis of the D2d study in which subjects who were frankly vitamin D deficient, namely with levels of 25OHD <12 ng/mL (30 nmol/L) at baseline, were at reduced risk of developing DM (HR, 0.38; 95%CI,0.18-0.80) if they were in the vitamin-D-supplemented group (Fig. 3). Other clues are noted above with regard to blood pressure and pulmonary infections in which vitamin D did appear to have beneficial effects.
Another methodological issue is the duration of the studies. One has to consider how long prior to the development of cancer or cardiovascular disease or DM must an intervention have to influence the development of overt disease. For example, the Torfadottir study had a mean duration of 8.3 years from no sign of cancer to the cancer diagnosis.(156) Is it likely that giving a vitamin D supplement for 5 years or less will alter the time course of cancer becoming apparent? Carcinogenesis is usually a slow process that proceeds undiagnosed in a stepwise fashion, perhaps for many years prior to the diagnosis. Thus, the finding that vitamin D supplementation can improve survival once the cancer is apparent, even if it does not reduce the risk of developing cancer over a 5-year period of intervention, is nevertheless a major factor demonstrating the benefit of maintaining adequate levels ofvitamin D.
Rigorous studies of vitamin D supplementation in subject cohorts deficient in vitamin D compared with adequate levels are needed to resolve the controversy surrounding potential/ purported nonskeletal effects of vitamin D. For endpoints like cancer and cardiovascular disease, studies need to be carried out for longer duration than 5 years to clearly demonstrate the presence or absence of a benefit on risk. The benefit on cancer survival seems to be solidly demonstrated.
In this review, we have highlighted areas of consensus and uncertainty with regard to vitamin D as a nutrient and regulator ofcellularaction. Although nutritional rickets is well-defined and highly prevalent worldwide, a concerted global effort is required to eradicate this eminently curable condition. A better understanding of the endogenous production of vitamin D and the regulation of its metabolism along with the development of universally useful assays with proper quality control remain worthy goals. Although animal data provide a useful backdrop to hypotheses arguing for nonskeletal effects of vitamin D, human studies both in terms of several meta-analyses, as well as recent RCTs, have not been designed to permit any definitive conclusions. We look forward to future well-designed studies that can clearly establish the extent to which vitamin D7s actions are pervasive and extend beyond the skeleton.
Disclosure
The coauthors of this article have no conflicts to declare with regard to its content.
Acknowledgments
This report summarizes the proceedings of the Third International Conference on Controversies in Vitamin D. It was held on September 10-13, 2019, Gubbio, Italy. The meeting was funded by an unrestricted grant provided by Abiogen Pharma, Pisa, Italy. Abiogen Pharma had no role in the selection of discussion topics, speakers/authors, preparation or review of this paper. The authors would like to acknowledge the support of Dr Colin Egan in the writing of the manuscript. We wish to acknowledge those who also participated in this meeting, but are not listed as coauthors: D Bikle, L Degli Esposti, G El-Haj Fuleihan, S Giannini, AR Martineau, M Hewison, UA Liberman, A Mithal, F Nannipieri, L Plum, A Pittas, S Sciacchitano, and J Virtanen.
Authors' roles: AG and JPB served as Program Coordinators of the Third International Conference on Controversies in Vitamin D. All authors researched data for the conference. AG and JPB wrote the manuscript, and all authors reviewed and/or edited the manuscript before submission.
Author contributions
Andrea Giustina and John P. Bilezikian: Conceptualization; data curation; methodology; supervision; writing-original draft; writing-review and editing. Roger Bouillon: Writing-review and editing. Neil Binkley: Writing-review and editing. Christopher Sempos: Writing-review and editing. Robert Adler: Writing-review and editing. Jens Bollerslev: Writing-review and editing. Bess Dawson-Hughes: Writing-review and editing. Peter Ebeling: Writing-review and editing. David Feldman: Writing-review and editing. Annemieke Heijboer: Writing- review and editing. Glenville Jones: Writing-review and editing. Christopher Kovacs: Writing-review and editing. Marise Lazaretti-Castro: Writing-review and editing. Paul Lips: Writing-review and editing. Claudio Marcocci: Writing-review and editing. Salvatore Minisola: Writing-review and editing. Nicola Napoli: Writing-review and editing. Rene Rizzoli: Writing-review and editing. Robert Scragg: Writing-review and editing. John White: Writing-review and editing. Anna Maria Formenti: Writing-review and editing.
Peer review
The peer review history for this article is available at https:// publons.com/publon/10.1002/jbm4.10417.
Note: Osteoporosis causes bones to become fragile and prone to fracture
Osteoarthritis is a disease where damage occurs to the joints at the end of the bones
but not TREAT Osteoporosis
Vitamin D, in combination with it’s co-factors of Calcium, Magnesium, Vitamin K2, etc. is able to increase Bone Mass Density, that is, increase the amount of bone in the body. A bone is made up of a large number of tiny bridges. One a bridge is broken, adding bone bone does not repair the bridge, it just thickens the bridge supports.
Osteppenia and Osteoporosis Orthobullets 2020
A few of their excellent tags. Ceased updating in Aug 2015
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Top 20 diseases related to Osteoporosis via genes ( most of which are associated with low vitamin d)
"Like a diet rich in calcium and vitamin D, exercise helps strengthen bones at any age"
__No mention was made of vitamin D supplements, Vitamin D co-factors, UV, Vitamin K, or Whole Body Vibration
Did have the following nice graphic however
Note: Vitamin D does even better than Fosamax at PREVENTION
Med Hypotheses. 2019 Oct 10;134:109427. doi: 10.1016/j.mehy.2019.109427
Xiong Z1, Wu J1, Liu Z1, Jing W2.
There have been increasing numbers of reports that anti-osteoporosis drugs cause osteonecrosis. A typical example is medication-related osteonecrosis of the jaws (MRONJ) which can cause massive necrosis and defects of the jaws. Thus, the dosage and effects of anti-osteoporosis drugs should be re-examined. Our hypothesis is that primary moderate osteoporosis itself is beneficial for bones and should not be excessively treated other than vitamin D, calcium supplementation and functional exercises. The self-repair and anti-infection abilities of bone depend on its organic tissues including stem cells, blood vessels, osteoclastic and osteogenic factors in bone, which jointly fight against invading pathogens and repair bone damage. Recent evidence supports age-related changes in mesenchymal stem cell including loss of self-renewal and increases in senescent cell numbers. Thus, the number of MSCs and vessels need to be increased to achieve functions similar to those in young people. This requires dissolving a portion of inorganic materials and providing extra space to hold more cells and blood vessels. In contrast, anti-osteoporosis drugs prevent bone destruction, and increase mineralization that occupies the space of organic materials, reduces bone immunity and self-repair. Moreover, long term use of anti-osteoporosis drugs also have negative effects on long bones and cartilages. Therefore, moderate age-related osteoporosis is natural in humans to protect bones. Excessive treatment of osteoporosis weakens immunity and self-repair.
CLICK HERE which includes
Dr. Colgan recommends the following supplements for Strong Bones (page 140)
400 mcg of Vitamin K daily in the form of menaquininone, MK4 or MK7,
2000 mg of calcium carbonate, (update: this is too much if you also take > 2000 IU of vitamin D)
1,000 mg of phosphorus,
800 msg of magnesium citrate,
350 mg of strontium citrate,
20 mg of zinc picolinate,
200 mg of silicon (Horsetail extract),
3 mg of boron,
25 mcg of Vitamin D3, (1000 IU)
VitaminD2 was the first to be discovered and, until 2011, was the only one that most doctors could prescribe
The D3 form has been known for many decades, but the medical profession has not yet adapted - after all, only 20,000 papers on D3 so far.
Several recent studies have shown that vitamin D2 actually reduces the levels of D3 in the blood
AND, worse still, D2 actually INCREASES a health problem, instead of reducing it, the way vitamin D3 does
Hint: if you can buy it, it is Vitamin D3. Vitamin D2 is only available by prescription
Note: some multivitamins and milk/food fortifications still use D2, sut in such low quantities that it can be ignored.
The 2006 study can be read at Vitamin D2 should not be used as a Vitamin supplement for any mammal – Oct 2006
TREATMENT WITH 50000 IU VITAMIN D 2 EVERY OTHER WEEK AND EFFECT ON SERUM 25-HYDROXYVITAMIN D2. .
No such attachment on this page
Assessing the impact of a mushroom-derived food ingredient on vitamin D levels in healthy volunteers
1000 IU D2 daily from irradiated Mushrooms for 12 weeks
No such attachment on this page
here are some images of D2 to stay away from
Changes in circulating 25-hydroxyvitamin d according to vitamin D binding protein genotypes after vitamin D3 or D2 supplementation April 2013
Yet again: D2 reduces the levels of D3 in the blood. Also, D2 does not turn on genes.
Vitamin D2 Supplementation Amplifies Eccentric Exercise-Induced Muscle Damage in NASCAR Pit Crew Athletes: Jan 2014
Vitamin D2 made muscle damage WORSE. 3,800 IU D2 from Portobello mushroom powder
Vitamin D Council post on this item
short url for the page = http://is.gd/vitd3d2
]]>Notional Graph of Expert Opinions of levels with Vitamin D MONOTHERAPY
Note: Monotherapy just increases vitamin D levels, and rarely adjusts the cofactor intake (Ca, Mg, Vitamin K2, Omega-3, etc)
The U-shaped relationship comes only from prospective studies with long follow-up times.
In my considered opinion, it is an artifact of the long follow-up time, not high latitude.
short URL = http://is.gd/Dlevels
Revue d'Épidémiologie et de Santé Publique. Volume 66, Supplement 5, July 2018, Page S271, https://doi.org/10.1016/j.respe.2018.05.092
T.Waldhoera, G.Endler, .Yang, G.Haidinger, O.Wagner, R.Marculescu
Analysis of 78,000 patients at one hospital - 20 years
Measured Vitamin D levels then looked at change in death rates 3 or more years later
If < 4 ng of Vitamin D
If > 36 ng of Vitamin D
Diabetes
Items in both Vitamin D Life categories of Diabetes and Mortality:
Introduction
Vitamin D deficiency, as reflected by low 25-hydroxyvitamin D blood levels (25D), is a prevalent correctable risk factor for death in most populations around the globe. The evidence ranges from numerous association studies and meta-analyses thereof, over Mendelian randomization studies, to randomized controlled trials (RCTs). However, most studies reported to date were performed in rather older populations and some of the largest association studies may have been confounded by increased vitamin D supplementation at old age, especially in women, and by the use of vitamin D2, which is fully measured by 25D immunoassays but biologically considerably less active. In addition, cause-specific mortalities and the impact of age on the 25D association with the risk of death have not been reported in detail, yet.
Methods
Data of all patients who had a 25D measurement at the Department of Laboratory Medicine, General Hospital of Vienna between 1991 and 2011 were retrieved and matched with the Austrian national register of deaths. First 3 years of mortality since 25D measurement were excluded in the analyses. Fine-Gray regression models adjusting for competing risks were used to estimate the survival time in dependence on 25D, adjusting for sex, age, year and month of blood draw. 25D was represented using a spline with 5 knots placed on the corresponding 1/6th quantiles. Age group (0– < 45, 45– < 60, 60– < 75, 75+ years) specific analyses were conducted owning to a strong interaction between 25D and age, where age was kept as a continuous variable to avoid remaining residual confounding. Using 50 nmol/L as the reference value, we estimated hazard-ratios of chosen serum vitamin D concentration levels (10 and 90 nmol/L). All analyses were conducted in SAS 9.4 (SAS Institute Inc., Cary, NC, US). The significance level was set to 1% in order to adjust for multiple testing.
Results
Data from 78,581 patients (mean age = 51.0 years, men 31.5%) were used for analyses. During 20 years (median = 10.5) of follow-up, 11877 deaths were observed.
Among these patients, 25D ≤ 10 nmol/L had 2-3 fold increased risk of death (
Whereas 25D ≥ 90 nmol/L has shown to be associated with up to 40% reduced all-cause mortality (
No associations were observed in the age group 75 years and older (10 nmol/L: HR = 1.1, 95% CI:[1.0, 1.2]; 90 nmol/L: HR = 1.0, 95% CI:[0.9, 1.0]). In terms of cause-specific mortality, we found only a relatively modest relationship for cancer and cardiovascular disease. The strongest association was found for other causes of death with the largest effect size for diabetes HR = 4.4, 95% CI:(3.1,6.3).
Conclusions
Our survival data from a large cohort, covering all age groups, from a population with minimal vitamin D supplementation at old age and negligible intake of vitamin D2, confirm a strong association of vitamin D deficiency (25D < 50 nmol/L) with increased mortality. This association is most pronounced in the younger and middle-aged groups and for causes of deaths other than cancer and cardiovascular disease. Some J-shaped curves were found only for the 25D association with cancer and cardiovascular mortality in certain age groups. Our findings strengthen the rationale for wide spread vitamin D supplementation to prevent premature mortality, emphasize the need for it early in life and mitigate concerns about a possible negative effect at higher 25D levels up to 150 nmol/L. RCTs in younger age groups are needed to confirm these findings.
Sue K. Park1-2-3, Cedric F. Garland4 cgarland at ucsd.edu, Edward D. Gorham4, Luke BuDoff4, Elizabeth Barrett-Connor4
1 Department of Preventive Medicine, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea,
2 Department of Biomedical Science, Seoul National University Graduate School, Jongno-gu, Seoul, Korea,
3 Cancer Research Institute, Seoul National University, Jongno-gu, Seoul, Korea,
4 Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, California, United States of America
Vitamin D appears to both prevent and treat diabetes
Number of articles in both categories of Diabetes and:
see also Overview Diabetes and vitamin D Overview Metabolic Syndrome and vitamin D
Autoimmune category listing hasT1 diabetes OR type1 diabetes in title 107 as of April 2018
prediabetes OR prediabetic 336 items as of Jan 2018
Search Vitamin D Life for Peripheral Neuropathy 238 items April 2018
No such attachment on this page
Background
It has been reported that higher plasma 25-hydroxyvitamin D is associated with lower risk of type 2 diabetes. However the results to date have been mixed and no adequate data based on a cohort are available for the high end of the normal range, above approximately 32 ng/ ml or 80 nmol/L.
Methods
We performed a cohort study of 903 adults who were known to be free of diabetes or prediabetes during a 1997-1999 visit to a NIH Lipid Research Centers clinic. Plasma 25(OH)D was measured at Visit 8 in 1977-1979. The mean age was 74 years. The visit also included fasting plasma glucose and oral glucose tolerance testing.
Follow-up continued through 2009.
Results
There were 47 cases of diabetes and 337 cases of pre-diabetes. Higher 25(OH)D concentrations (> 30 ng/ml) were associated with lower hazard ratios (HR) for diabetes: 30-39 ng/ ml or 75-98 nmol/L: HR = 0.31,95% CI = 0.14-0.70; for 40-49 ng/ml or 100-122 nmol/L:
HR = 0.29, CI = 0.12-0.68; for > 50 ng/ml or 125 nmol/L: HR = 0.19, CI = 0.06-0.56. All HRs are compared to < 30 ng/ml or 75 nmol/L. There was an inverse dose-response gradient between 25(OH)D concentration and risk of diabetes with a p for trend of 0.005. Each 10 ng/ mL or 25 nmol/L higher 25(OH)D concentration was associated with a HR of 0.64, CI = 0.48-0.86. 25(OH)D concentrations were more weakly inversely associated with pre-diabetes risk, and the trend was not significant.
Conclusion
Further research is needed on whether high 25(OH)D might prevent type 2 diabetes or transition of prediabetes to diabetes.
The public health impact of vitamin D deficiency has received attention due to the discovery of associations between low plasma concentrations of vitamin D metabolites and higher risk of several cancers, cardiovascular disease, bone fractures [1-3] and the metabolic syndrome [4]. Trends in energy intake and anthropometric characteristics have paralleled the increase in incidence of type 2 diabetes mellitus. It is unclear whether vitamin D deficiency might be contributing to increased risk [5].
If defining 25(OH)D levels < 32 ng/ml (< 80 nmol/L) as deficiency [6], 77% of U.S. adults were deficient. The prevalence of vitamin D deficiency by this criterion has doubled since 1980 in U.S. adults [6].
Several cohort studies have examined the association of circulating 25(OH)D concentrations with risk of diabetes. Of these, 12 found significantly higher incidence rates in individuals with lower circulating 25(OH)D concentrations [5, 7-16]. The association in one was limited to overweight subjects [16]; and the significant finding in another [14] was limited to women. One study found a benefit of 25(OH)D > 11 ng/ml compared to < 11 ng/ml, but no further benefit with higher concentrations [15]. Two studies reported a significant inverse association in men, but not women [17,18]. One study reported a favorable association that did not reach statistical significance [19]. A study by Schafer et al. reported a statistically significant inverse association between 25(OH)D and hazard ratio of diabetes after adjustment for age and clinic location, but that was weak and no longer statistically significant after adjustment for more factors that included BMI [20].
The association of plasma 25(OH)D deficiency with risk of diabetes also has been examined in four meta-analyses [11,13, 21,22], and all reported an inverse association of circulating 25 (OH)D with risk of diabetes.
The aim of this study was to examine whether lower concentrations of 25(OH)D or 1,25 (OH)2D were associated with higher incidence of diabetes and pre-diabetes in a prospective cohort study with an overall follow-up period of 12 years.
This cohort may have a lower than usual prevalence of vitamin D deficiency due to year- round sunshine and good weather in a sunny and clear area of southern California [23]. It may also be possible that the cohort has a lower than usual prevalence of vitamin D deficiency due to a higher standard of education and socioeconomic status and a high proportion of Caucasians. This cohort has the highest known published median 25(OH)D concentration, 42 ng/ ml or 105 nmol/L in men [24] and 39 ng/ml or 98 nmol/L in women [25] of any population that has reported data on diabetes incidence by 25(OH)D. No previous study of the association of 25(OH)D with diabetes has included a substantial population in the high range of > 30 ng/ ml or 75 nmol/L.
Participants
Participants were from the Rancho Bernardo Study, a population-based cohort of primarily older, middle-income, community-dwelling Caucasian adults living in a southern California suburb. They were subjects in a Lipid Research Clinics Prevalence Study consisting of a series of visits. This was part of an NIH study of lipid-lowering agents established in 1972 [26]. The individuals did not receive any medication, but rather served solely as an untreated comparison group. From 1997 to 1999,1,098 surviving community-dwelling participants attended a follow-up visit known as Visit 8. Of these, 1,080 received measurements of their plasma 25 (OH)D. Details of the inclusions are shown in the Supplementary Figure.
We followed the cases until diagnosis of pre-diabetes or diabetes and non-cases until their last test of 8-hour fasting plasma glucose (8-FPG) and oral glucose tolerance testing (OGTT). Of the total participants, 52 had a history of diabetes and were excluded at baseline. Of the remaining N = 1,028 participants, we first screened for diabetes using 8-FPG and excluded 60 participants with 8-FPG concentrations > 126 mg/dL or 7.0 mmol/L or had missing data on 8-FPG. We further excluded 65 with 2-hour OGTT > 200 mg/dL or 11.1 mmol/L.
Finally, a total of 903 participants were included in this study. Of these, 47 incident type 2 diabetes and 337 pre-diabetes cases were ascertained during 1997-2009. The multivariate analyses included 46 diabetes cases and 337 pre-diabetes cases. The one fewer diabetes case was due to missing data on covariates on one individual.
All willing participants were followed and are presently being followed, including the diabetes and pre-diabetes cases. The follow-up rate through 2009 was 87%.
A flowchart in S1 Fig shows that no individual who was diabetic or pre-diabetic at baseline in 1977-1979 was allowed to enter the cohort of N = 903 individuals who constituted this study. As a result, the cohort was, to the standard of technology in 1977-1979 and WHO definitions of diabetes and pre-diabetes in international use, free of diabetes or pre-diabetes.
Individuals who developed diabetes during follow up were counted as incident cases to determine the hazard rate. If an individual developed only pre-diabetes, he or she was counted as a case of pre-diabetes, unless they later developed diabetes. If so, they were counted once, as a case of diabetes, to avoid counting any individual more than once. The University of California, San Diego Human Subjects Protections Program approved this study, and all participants gave written informed consent.
Data collection
During the 1997-1999 visit, participants completed standardized questionnaires that inquired about myocardial infarction, stroke, angina pectoris, and peripheral claudication, current medications, cigarette smoking, alcohol consumption, and physical exercise. Height and weight were measured using a Lipid Research Clinics calibrated stadiometer and balance- beam scale. Systolic and diastolic blood pressures were measured twice in seated subjects after a 5-minute rest period, using the standard Hypertension Detection and Follow-up Program protocol [27]. Body mass index was calculated as weight in kilograms / height in meters2. Use of vitamin D and calcium supplements at baseline was determined using a questionnaire.
The primary exposure variables were plasma concentrations of 25(OH)D and 1,25(OH)2D. Blood was obtained by venipuncture, after an overnight fast, and tubes were protected from sunlight. Plasma was separated and stored at -70°C within 30 minutes of collection. Plasma 25 (OH)D and 1,25(OH)2D concentrations were measured in the Holick-Chen Laboratory at Boston University using vitamin D competitive binding protein recognition and chemiluminescence detection (Stillwater MN, USA:Diasorin) [28]. To convert 25(OH)D from nanograms per milliliter to nanomoles per Liter, multiply nanograms/Liter times 2.5 [29].
The intra- and inter-assay coefficients of variation for the assay were 8% and 10%, respectively [28] the limit of detection was 5 ng/mL or 13 nmol/L, and the reference range was 10-52 ng/mL or 25-130 nmol/L. For 1,25(OH)2D, the intra- and inter-assay coefficients of variation were 5-10% and 10-15%, respectively; the limit of detection was 4.6 pg/mL or 12 pmol/L [28].
Case definition
Type 2 diabetes cases were defined by World Health Organization criteria of 1999 as a > 8-hour FPG, or 8-FPG > 126 mg/dL or > 7.0 mmol/L and/or 2-hour oral glucose tolerance test, or 2-OGTT, of > 200 mg/dL or > 11.1 mmol/L. Pre-diabetes was defined as 8-FPG of 100-125 mg/dL, or 5.5-6.9 mmol/L; or 2-OGTT of 140-200 mg/dL, or 7.8-11.1 mmol/L [30].
Blood specimens for 8-FPG were collected every 2 years, in all seasons. If the 8-FPG concentration ever was > 100 mg/dl or 5.5 mmol/L a 2-OGTT was performed. The measurement of 25(OH)D in plasma was performed once, in 1997-1999. The cohort had been assembled earlier, in 1972, and the participants were interviewed and examined, or completed questionnaires, every 2 years. There were 47 incident cases of diabetes and 337 incident cases of prediabetes.
Statistical analysis
Plasma 25(OH)D categories of < 30, 30-39, 40-49 and > 50 ng/ml or < 75, 75-98,100-122 and > 125 mmol/L are even multiples of 5 ng/ml, and were chosen for this analysis because they are standard and readily understandable. Covariates other than gender were continuous, including BMI, waist circumference, plasma high density lipoprotein and triglyceride concentrations. One covariate, calcium supplementation, was entered as a dichotomous covariate, because further detail was not available. Intake of vitamin D supplements could not be used as a covariate in the regression model since every participant who took a vitamin D supplement also took a calcium supplement.
Chi-square tests for categorical variables and t-tests for continuous variables were used to identify differences between participants who developed diabetes or pre-diabetes compared to those who did not. Cox proportional hazards models were used to determine hazard ratios (HRs) and 95% confidence intervals [31] for categories of 25(OH)D and 1,25(OH)2D, with adjustment for six covariates, including sex, calcium supplement use, body mass index, waist circumference, plasma high-density lipoprotein cholesterol, and triglyceride concentrations. These were all continuous scales at baseline.
Covariates for multivariate analyses were chosen using backward multivariate logistic regression including all significant variables (p < 0.05) with all exposure variables. Waist circumferences and calcium supplementation were selected as significant covariates. Plasma concentrations of 25(OH)D and 1,25(OH)2D had skewed distributions, so they were entered in multivariate models as categorical variables. Heterogeneity was evaluated by the Cochran Q test [31].
For a sensitivity analysis of whether the association of plasma 25(OH)D with diabetes was explained by traditional, widely accepted diabetes risk factors, four additional analyses were performed using risk scores for propensity to develop diabetes that were calculated using algorithms developed by the Centers for Disease Control and Prevention based on NHANES-III Third National Health and Nutrition Examination Survey data [32] and ARIC, the Atherosclerosis Risk in Communities study [33].
These scores were used to adjust the hazard rates for diabetes risk factors including age, waist circumference, history of gestational diabetes, family history of diabetes, weight, height, blood pressure, and regular exercise for the NHANES-III risk score [32]; and age, sex, race, hypertension, smoking history, resting pulse, parental history of diabetes, height, weight and waist circumference for the ARIC risk score [33].
Subgroup analyses stratified for the presence of hyperparathyroidism, regular strenuous exercise, metabolic syndrome, and high vs. low diabetes risk score according to the NHANE- S-III and ARIC algorithms were performed to identify any effect modifiers of the association between vitamin D metabolite concentrations and diabetes risk. Allp-values were two-tailed. All analyses were conducted using SAS Version 9.2 (SAS Institute, Cary, NC). Anonymized data are in S1 Table.
Results according to continuous variable at baseline are shown in Table 1. Median follow-up time until diagnosis of diabetes or pre-diabetes was as follows: 4.5 years for diabetes cases; 4.1 years for pre-diabetes cases; and 12.5 years for the total cohort. Range of age of the cohort at baseline was 38-97 years, with a mean of 74 years. Body mass index, waist circumference, fasting plasma glucose, triglyceride concentrations and systolic blood pressure were higher in individuals who became cases of diabetes during the follow-up period than in those who did not, as shown in Table 1.
Use of vitamin D and calcium supplements at baseline was lower in individuals who became diabetes cases than in those who did not. Plasma HDL-cholesterol concentration at baseline was lower in individuals who became diabetes or pre-diabetes cases than in those who did not develop diabetes.
Results according to discrete variables at baseline are shown in Table 2. Males constituted 70% of diabetes cases but only 49% of pre-diabetes cases. Alcohol use, smoking, and self- reported regular strenuous exercise were not significantly associated with incidence of diabetes or pre-diabetes, but there was a borderline adverse trend of higher alcohol use by cases of prediabetes.
Use of calcium supplements at baseline was associated with lower risk of diabetes (p < 0.05). There was a borderline trend linking use of vitamin D supplements at baseline with lower incidence of diabetes (p = 0.06).
As shown in Table 3, a plasma 25(OH)D concentrations > 30 ng/ml or 75 nmol/L was associated with approximately 70% lower incidence of diabetes compared with < 30 ng/ml or 75 nmol/L at baseline. A concentration of 30-39 ng/ml or 75-99 nmol/L was associated with HR = 0.31 and 40-49 ng/ml or 100-124 nmol/L was associated with HR = 0.29 as shown in
Table 1. Baseline characteristics of diabetes cases, pre-diabetes cases and non-cases in the Rancho Bernardo cohort, 1997-1999.
Table 2. Baseline characteristics of non-cases, type 2 diabetes mellitus cases and pre-diabetes cases in the Rancho Bernardo cohort, discrete variables, 1997-1999.
Table 3. Hazard ratios with 95% confidence intervals of type 2 diabetes mellitus (DM) incidence by categories of plasma vitamin D metabolite concentrations in the Rancho Bernardo cohort, 1997-1999.
Fig 1. Hazard ratios were progressively lower in each stratum from the lowest 25(OH)D concentration of < 30 ng/ml or 75 nmol/L to the highest, of > 50 ng/ml or 125 nmol/L. The highest levels of 25(OH)D had an 81% lower incidence rate of diabetes, or HR = 0.19. Each 10 ng/ ml or 25 nmol/L higher 25(OH)D was associated with a HR = 0.64.
The association of 25(OH)D with pre-diabetes was weak compared to that with diabetes (Fig 2). For 40-49 ng/ml or 100-124 nmol/L, the p-heterogeneity was 0.025 between the two HRs in diabetes and pre-diabetes risk; for > 50 ng/ml or 125 nmol/L, p-heterogeneity was 0.039. 25(OH)D concentrations > 50 ng/ml or 125 nmol/L were significantly associated with lower incidence of pre-diabetes. The HR was 0.66.
There were N =241 deaths of participants, leaving N = 662 alive through the end of the follow-up period. The mean 25(OH)D concentration in those who died was 38.9 ng/ml, or 97.3 nmol/L. The mean in those who lived was 43.0 ng/ml, or 107.5 nmol/L.
An analysis was performed of the inverse association between serum 25(OH)D and hazard ratios for diabetes according to whether the individual was taking a calcium supplement at baseline, as shown in Table 4. This revealed that the association between 25(OH)D and risk of diabetes may have been slightly stronger in participants who took calcium supplements at baseline. In those who took supplements, there was a hazard ratio of 0.55 with 95% CI of 0.310.99 for each 10 ng/ml or 25 nmol/L increase in serum 25(OH)D. By contrast, in participants who took no calcium at baseline, the hazard ratio was 0.69 with 95% CI 0.49-0.98 for each 10 ng/ml or 25 nmol/L increase in serum 25(OH)D. The slightly lower hazard ratio suggests that calcium might enhance the effect of 25(OH)D, but the difference according to calcium supplement use was not statistically significant. The association of plasma 25(OH)D with risk of diabetes persisted after exclusion of individuals taking calcium and/or vitamin D supplements.
Fig 2. Hazard ratio for pre-diabetes according to plasma 25(OH)D concentration at baseline, Rancho Bernardo CA, 1997-2009.
Table 5. Hazard ratios with 95% confidence intervals of type 2 diabetes incidence by categories of plasma 25(OH)D concentration adjusted for different combinations of confounding factors for diabetes, Rancho Bernardo cohort, 1997-2009.
Regarding multiple regression analyses of the associations of vitamin D supplements vs. calcium supplements, it was not possible to absolutely separate the association of vitamin D supplementation compared to the association with calcium supplementation. This was because all individuals who took vitamin D supplements also took calcium.
As shown in Table 5, the association of low 25(OH)D with high incidence of diabetes persisted after adjustment for NHANES-III and ARIC diabetes risk scores. The association of low 25(OH)D with high risk of diabetes also persisted after stratification for PTH level, regular strenuous exercise, and metabolic syndrome (Table 6).
The inverse association of 25(OH)D with diabetes was stronger in individuals with hyperparathyroidism or who exercised regularly (p- heterogeneity = 0.006 and 0.046, respectively) (Table 5). Among those with hyperparathyroidism, those with 25(OH)D > 30 ng/ml had lower risk of diabetes (HR = 0.06, 95% CI 0.02-0.25). Among those reporting no exercise, those with 25(OH)D > 30 ng/ml also had lower risk (HR = 0.35, 95% CI 0.16-0.80). The association of 25(OH)D > 30 ng/ml with diabetes persisted despite metabolic syndrome or high NHANES III or CDC risk scores (HR = 0.42, 95% CI 0.17-1.00; HR = 0.33 95% CI 0.13-0.84; and HR = 0.39 95% CI = 0.18-0.85, respectively.
Plasma 1,25(OH)2D concentrations were not associated with incidence of diabetes or prediabetes (Table 3). Graphs are available from the authors.
Individuals with a 25(OH)D concentration > 30 ng/ml or 75 nmol/L had only one-third the incidence of diabetes as those with < 30 ng/ml or 75 nmol/L. Those with a somewhat higher concentration of 25(OH)D > 50 ng/ml or 125 nmol/L had a much lower HR of 0.2.
The association of 25(OH)D with diabetes persisted after exclusion of participants who reported at baseline that they usually took vitamin D or calcium supplements. The inverse association of a higher 25(OH)D concentration > 30 ng/ml or 75 nmol/L was consistent among individuals in higher traditional risk groups for diabetes such as those having metabolic syndrome or established diabetes risk factors according to standard scores for predicting risk of diabetes that are used by CDC and other organizations to predict incidence of diabetes. These include obesity and lack of regular exercise.
Table 6. Hazard ratios with 95% confidence intervals of type 2 diabetes mellitus (DM) incidence by plasma 25(OH)D levels after stratification for PTH levels, regular strenuous exercise, metabolic syndrome, and DM risk scores.
The finding of the present study that 25(OH)D concentration had a significantly inverse association with risk of diabetes is biologically plausible. Mice with the vitamin D receptor (VDR) null phenotype have higher incidence rates of diabetes [34], suggesting that the vitamin D pathway may be relevant to the pathogenesis of diabetes. Pancreatic beta cells have VDR, and vitamin D metabolites stimulate the pancreas to produce insulin [35].
Active metabolites of vitamin D also have been shown in animal models to protect pancreatic beta cells from cytokine-induced inflammation and apoptosis [34].
Only the 25(OH)D concentration was associated with lower risk of diabetes in the present study. One of the reasons may be the stability of 25(OH)D in circulation. 25(OH)D has a 75-fold longer half-life than 1,25(OH)2D [36]. Circulating 25(OH)D is also stable with respect to time, even in stored frozen plasma [37].
Although the number of cases of diabetes was much smaller than that of pre-diabetes, 25 (OH)D levels were strongly inversely associated with risk of diabetes and weakly inversely associated with risk of pre-diabetes. This could be because pre-diabetes is a relatively mild condition, and includes many individuals who did not become diabetic.
Another possible reason is that people with pre-diabetes may be healthier due to better lifestyle behaviors. In our study, pre-diabetes participants were more likely to use vitamin D supplements and had higher HDL-cholesterol levels, lower triglyceride levels, BMI, and waist circumference, and were less likely to smoke cigarettes compared to diabetes patients.
The inverse association of 25(OH)D with diabetes was much stronger in individuals with hyperparathyroidism and who regularly exercised strenuously as shown in Table 5. Hyperparathyroidism, regardless of cause, is a common concern in the aged, particularly in women, due to renal deterioration, low estrogen, low calcium intake, and, on occasion, use of furosemide [38, 39]. It is also adversely associated with glucose tolerance and insulin resistance [40,41].
In our cohort, individuals with hyperparathyroidism were likely to have higher risk for diabetes as shown in Table 5. Nevertheless, our finding that a higher 25(OH)D concentration has a beneficial effect on risk of diabetes is encouraging to older people. The beneficial effect of higher 25(OH)D could be due to improving insulin sensitivity and anti-inflammatory effects [40, 41[[40,41] although the exact mechanisms by which a higher 25(OH)D concentration lowers diabetes risk remain unclear.
Individuals who were doing regular strenuous exercise were likely to have a lower HR associated with higher 25(OH)D concentration (Table 6). A similar association was present in those with higher levels of PTH (Table 6). Skeletal muscle has VDR [42]. Strenuous exercise itself has a favorable effect in controlling diabetes through increasing glucose utilization in muscle and insulin sensitivity [43].
The present study has several limitations. The study participants were relatively healthy middle to upper-middle class Caucasians, who had good access to health care. As a result, our findings may not be generalizable to other populations.
Rancho Bernardo, located 16 miles north of San Diego, CA, has sunny weather throughout the year. This natural environment helps the participants maintain higher 25(OH)D concentrations in blood without vitamin D supplementation. Previous studies have shown that 95% of 25(OH)D is a product of photosynthesis of vitamin D3 in the skin [44], and it is probable that there is more sunlight reaching the members of this community than members of previously studied communities.
Generalizability with certainty to areas less sunny than southern California could be examined by repeating the study. However, an association in the same direction as found in this study was present in another cohort whose members lived throughout the U.S. [45], although the association was not found in another cohort [46]. The present study will help resolve the question of whether the association is present in men and in older women.
It is also possible that the higher concentrations observed in this study might have been due to differences in laboratory assay techniques. The competitive binding protein assay may produce higher 25(OH)D results compared with radioimmunoassay and high-performance liquid chromatography [36,47]. Concentrations of 25(OH)D and 1,25(OH)2D found in the Rancho Bernardo cohort may not be directly comparable to those in studies using different assays.
On the other hand, routine assays accurately rank individuals across the range of 25(OH)D levels [36], suggesting internal validity. Values for 25(OH)D were measured on a single blood specimen, but are known to have seasonal variation [48]; this may have weakened the observed association between these measures and incidence of diabetes. Nearly all other studies showing an association between 25(OH)D concentration and diabetes have also used a single measurement.
Comparison of the present study with a recent well-designed multi-center cohort study by Schafer et al. [20] of 25(OH)D and risk of diabetes in older adults is useful. The study by Schafer et al., in contrast to the present study, did not report the existence of an association of plasma 25(OH)D with risk of diabetes. It would be of value to try to explain the differences between that study and this one that might account for the differences in results.
Both studies used approximately the same well-established and highly respected cohort study design. The difference is unlikely to be merely a matter of a deficiency in basic study design. Both studies were performed by highly experienced research teams. Both studies ruled
out the existence of diabetes at baseline. Both used well-regarded statistical methods, such as t- tests, chi-square tests and Cox proportional hazards regression. Both used either stratification and/or multiple regression to control for confounding.
There were more similarities between these studies than differences, but there were a few differences that may be instructive. One is that the study by Schafer et al. was conducted at 4 centers located mainly in the Northern and mid-Atlantic tiers of the US: Minneapolis, Pittsburgh, Baltimore, and Portland OR. These studies had a median latitude of 43 degrees N. This can be compared with the 33 degrees N latitude of Rancho Bernardo. Winter conditions can be harsh in these four areas, but winters in Rancho Bernardo are extremely mild. The mean 25 (OH)D concentration was 23 ng/ml or 58 nmol/L in the Schafer et al. study, compared to 42 ng/ml or 105 nmol/L in the present study. It might be that the 25(OH)D concentrations in the subjects in the previous study tended to be in a range that is below the range in which 25(OH) D is inversely related to incidence of diabetes.
The present Rancho Bernardo cohort has the highest median 25(OH)D of any cohort study to date. This suggests a chance that there may be a threshold in the dose-response curve between 25(OH)D and incidence of diabetes. If a threshold for benefit from higher 25(OH)D exists, the present study suggests that it may be at about 30 ng/ml or 75 nmol/L. Thresholds are common features of dose-response curves [11]. Substantial numbers of subjects with serum 25(OH)D > 30 ng/ml or 75 nmol/L were not present in any cohorts previously studied, but were present in the Rancho Bernardo cohort.
Finally, an inverse association of 25(OH)D with risk of diabetes that was identified in the study by Schafer et al. lost its statistical significance after adjustment for BMI and other covariates. This adjustment is logical if BMI itself is the adverse factor. But if BMI happens to be a link in a possible causal chain from obesity to lower 25(OH)D to incidence of diabetes, the adjustment may have at least partially washed out the association that was found in the age- and clinic location-adjusted data in that study.
Based on the above contrasts between well-designed cohort studies such as that of Schafer et al. [20] and the present study, it is evident that more research is needed to delineate the contributory roles of BMI per se and of 25(OH)D to risk of diabetes. Such contributory roles may not be mutually exclusive, and the results of both studies could possibly be accurate. Metaanalyses may help provide context for understanding the diversity of findings of studies such as these [11, 13, 21, 22].
On the other hand, the present study has several strengths. The standard A. B. Hill criteria for causality in observational studies [49] were applied to the results of the present study, and the association of higher plasma 25(OH)D with lower risk of diabetes met most of the Hill criteria. The study was a prospective cohort study of individuals who were healthy volunteers when they enrolled, but developed diabetes during the study. The cohort study tends to have lower risk of reverse causation than a case-control study. Even when the hazard ratios were adjusted using regression and standard risk scoring systems for classical risk factors for diabetes, the findings persisted and remained similar in strength.
The results of this study suggest that targeting a plasma 25(OH)D concentration in the range of 50 ng/ml or 125 nmol/L might be useful in attempting to reduce the incidence rate of diabetes. However, it is thought by some workers that there may be an unknown degree of risk associated with maintaining 25(OH)D in this range. The main possible risk is one of hypercalcemia [50]. Another could be the chance of a higher risk of ischemic heart disease [50]. Results
regarding whether such a risk exists have been mixed [50]. There have been no known reports of complications of vitamin D supplementation or high plasma 25(OH)D in our cohort.
There are still unresolved concerns about the desirable plasma target for 25(OH)D. At this moment, the authors would tentatively suggest that the target be no less than 40 ng/ml or 100 nmol/L. Other analysts considering the same data could reasonably choose other desired targets, such as 30 ng/ml or 75 nmol/L proposed by the Endocrine Society [51].
In conclusion, the higher plasma 25(OH)D concentrations of > 50 ng/ml or 125 nmol/L in this cohort were independently associated with 80% lower incidence rates of diabetes. However, a target threshold of 50 ng/ml or 125 nmol/L is considerably above that recently recommended by an expert consensus panel that considered all known benefits and risks of vitamin D, and suggested instead a threshold of 30 ng/ml or 75 nmol/L [51]. As a result the possibility of a threshold higher than 30 ng/ml or 75 nmol/L should be approached with caution, pending replication of the findings [50].
Our study does not solve the basic question of whether individuals may need to seek vitamin D supplementation if needed to maintain a concentration of 30 ng/ml or 75 nmol/L, despite the possibility of any toxicity. A recent placebo-controlled randomized trial of a vitamin D weekly bolus supplement for pre-diabetes patients failed to prove a beneficial effect on 5-year incidence of diabetes [52]. Sufficient 25(OH)D levels obtained naturally from sunlight and food, not supplementation, might be more relevant than supplementation to reduce risk of diabetes. Larger cohort studies or long-term clinical trials would be desirable to help confirm whether this association is causal.
This study used a single measurement of 25(OH)D during a longitudinal study, since no other measurements were available. These measurements may have been more representative of serum levels during the 12.5 years of follow-up if two or more measurements had been made. The single measurement would have been of greatest concern if the study had found no association, since the absence of an association could have been due to use of a single measurement.
However an inverse association of 25(OH)D with incidence of diabetes was detected in this study despite the use of a single baseline measurement. It is possible that more associations could have been detected if there were more measurements of 25(OH)D during follow-up. On the other hand, 25(OH)D concentrations tend to be somewhat stable over time in adults [3]. The question of stability of season-specific 25(OH)D concentrations in adults over periods of 5 years or longer should be further studied in cohorts that have used multiple measurements during follow-up [3].
Both major metabolites of vitamin D were studied to determine whether an association was present for both. Only a low concentration of 25(OH)D is usually associated with diseases that are due to vitamin D-deficiency [1]. However the authors measured the 1,25(OH)2D concentration to confirm that the association was only for 25(OH)D and not present for 1,25(OH)2D. 1,25(OH)2D is tightly homeostatically regulated, and typically does not vary greatly among individuals [1, 29].
Serum 25(OH)D is generally accepted as the standard measure of vitamin D nutrition [1]. Most tissues can enzymatically convert it to 1,25(OH)2D [1]. In retrospect, measurement of 25 (OH)D alone would have been adequate to test for an inverse association between vitamin D nutritional status and risk of diabetes. This study found no association of 1,25(OH)2D with risk of type 2 diabetes. We therefore do not suggest any benefit from measuring 1,25(OH)2D in future studies of the etiology of type 2 diabetes.
A decision was made in 1997 to include all members of the cohort who were alive. No sampling was done, so there was no design need for a formal sample size calculation. Lower than optimal power may have caused this study to miss the chance of detecting a true association,
such as an inverse association between plasma 25(OH)D and risk of type 2 diabetes. However this association emerged as statistically significant. Still, the size of the present cohort may have been inadequately large to detect associations with other covariates. Therefore this study should not be used to rule out such associations.
Vitamin D supplementation only occurred in participants who were also taking calcium supplements. Therefore it was not practical to perform a separate analysis for vitamin D supplements.
Supporting information
S1 Fig. Flowchart of participants. (TIFF)
S1 Table. Data, anonymized. (XLSX) No such attachment on this page
Short URL = is.gd/DiabetesD
]]>Diabetes Care, . 2020 Nov 8;dc201485., doi: 10.2337/dc20-1485. .
Zhenzhen Wan 1 2, Jingyu Guo 3, An Pan 4, Chen Chen 4, Liegang Liu 5 2, Gang Liu 5 2
Vitamin D appears to both prevent and treat diabetes
Number of articles in both categories of Diabetes and:
Objective: The evidence regarding vitamin D status and mortality among diabetes is scarce. This study aimed to examine the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with all-cause and cause-specific mortality among adults with diabetes.
Research design and methods: This study included 6,329 adults with diabetes from the Third National Health and Nutrition Examination Survey (NHANES III) and NHANES 2001-2014. Death outcomes were ascertained by linkage to National Death Index records through 31 December 2015. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% CIs for mortality from all causes, cardiovascular disease (CVD), and cancer.
Results: The weighted mean (95% CI) level of serum 25(OH)D was 57.7 (56.6, 58.8) nmol/L, and 46.6% had deficient vitamin D (<50 nmol/L [20 ng/mL]). Higher serum 25(OH)D levels were significantly associated with lower levels of glucose, insulin, HOMA of insulin resistance, HbA1c, blood lipids, and C-reactive protein at baseline (all P trend < 0.05). During 55,126 person-years of follow-up, 2,056 deaths were documented, including 605 CVD deaths and 309 cancer deaths.
After multivariate adjustment, higher serum 25(OH)D levels were significantly and linearly associated with lower all-cause and CVD mortality: there was a
per one-unit increment in natural log-transformed 25(OH)D (both P < 0.001).
Compared with participants with 25(OH)D <25 nmol/L, the multivariate-adjusted HRs and 95% CI for participants with 25(OH)D >75 nmol/L were
Conclusions: Higher serum 25(OH)D levels were significantly associated with lower all-cause and CVD mortality. These findings suggest that maintaining adequate vitamin D status may lower mortality risk in individuals with diabetes.
Vitamin D Deficiency in Pediatric Patients Using Antiepileptic Drugs: Systematic Review With Meta-Analysis
Review J Pediatr (Rio J), 2020 Mar 11, DOI: 10.1016/j.jped.2020.01.004
Cíntia Junges 1, Tania Diniz Machado 2, Paulo Ricardo Santos Nunes Filho 3, Rudimar Riesgo 2, Elza Daniel de Mello 2
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Objectives: To measure the prevalence of vitamin D deficiency (through the 25-hydroxyvitamin D metabolite) in pediatric patients using antiepileptic drugs.
Source of data: Meta-analysis of studies identified through search in the PubMed, Embase, LILACS, and Cochrane Library databases, on February 19, 2019.
Summary of data: A total of 748 articles were identified, 29 of which were relevant to the objectives of this study. The prevalence of vitamin D deficiency found was 0.32 (95% CI=0.25-0.41; I2=92%, p<0.01). In the subgroup analyses, the most significant results were observed in the group of patients using cytochrome P450-inducing antiepileptic drugs, with a prevalence of 0.33 (95% CI=0.21-0.47; I2=86%, p<0.01) and, considering the study design, in the subgroup of cohort studies, with a prevalence of 0.52 (95% CI=0.40-0.64; I2=76%, p<0.01).
Conclusions: Taking into account the deleterious effects of vitamin D deficiency on the bone health of individuals using antiepileptic drugs, it is suggested to include in their care 25-hydroxyvitamin D monitoring, cholecalciferol supplementation, and treatment of the deficiency, when present.
Effect of high dose vitamin d supplementation on vitamin d nutrition status of pre-pubertal children on anti-epileptic drugs – A randomized controlled trial
Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2018.11.007
Background and aims
Patients on long term anti-epileptic drug therapy are prone for Vitamin D deficiency for a myriad of reasons. The aim of this research was to study the effect of high dose vitamin D supplementation on vitamin D nutrition status of children newly started on anti-epileptic drug therapy.
Materials
This randomized controlled trial was conducted in a tertiary care Children's Hospital at New Delhi from November 2011 to March 2013. Eighty three children in the age group 5–10 years newly started on anti-epileptic drugs (AED) were randomized into two groups; group A – the intervention group, to whom 60,000 IU vitamin D3 was given orally/month under direct supervision along with AED for a period of 6 months, and group B- the control group, to whom AED without vitamin D3 was given. Serum 25(OH)D, ionized calcium (iCa), total calcium (tCa), inorganic phosphate (iP), alkaline phosphatase (ALP) and parathyroid hormone (PTH) levels were assayed at baseline and at the end of 6 months and were compared within and between the two groups.
Results
The mean 25(OH)D in Group A was maintained at 6 months follow up [ 26 ng/ml, 95% CI 20–34 ng/ml] compared to baseline [25 ng/ml, 95% CI −19 to 33 ng/ml] [ p = 0.83]. In group B, there was a significant decrease in 25(OH)D levels at 6 months [13 ng/ml (95% CI 9 ng/ml–17 ng/ml)] compared to baseline [18 ng/ml (95% CI 13–24 ng/ml)] [p = 0.01]. At 6 months, mean serum 25(OH)D was significantly higher in group A as compared to group B (p = 0.005).
Conclusion: To conclude, oral administration of 60,000 IU vitamin D3/month is sufficient to maintain serum 25(OH)D level and prevent development of vitamin D deficiency in children newly started on AED over a period of 6 months. Non supplementation leads to the lowering of serum 25(OH)D in these children.
Trial Registration Number: CTRI/2017/08/009234.
The impact of Antiepileptic drugs on Vitamins levels in epileptic patients.
Curr Pharm Biotechnol. 2018 Aug 15. doi: 10.2174/1389201019666180816104716
Shaikh AS1, Guo X1, Li Y2, Cao L2, Liu X2, Li P1, Zhang R1, Guo R1.
1 Institute of Clinical Pharmacology, Qilu Hospital of Shandong University, Jinan. China.
2 Department of Neurology, Qilu Hospital of Shandong University, Jinan. China.
BACKGROUND:
The impact of antiepileptics on serum vitamin levels is controversial and uncertain. With no clear conclusions on the impact of antiepileptics on serum levels of vitamins, there is a need for further clinical studies in order to ascertain the impact of old and newer antiepileptic drugs on serum levels of vitamins in epileptic patients, thus accomplishing a suitable usage of vitamins supplementation.
OBJECTIVE:
The intention of the present research is to confirm the hypothesis of whether or not vitamin levels are altered with antiepileptic drugs. The study also aims to reveal which vitamin levels are particularly more altered, are vitamin levels affected by gender and the type and number of antiepileptics used.
METHODS:
The present research was piloted in collaboration with the Department of Neurology in Qilu Hospital of Shandong University. A total of 63 serum samples of epileptic patients receiving antiepileptics as monotherapy or polytherapy were requested for analysis of nine vitamin serum levels. Total nine vitamins (B1, B2, B6, B9, B12, A, C, D and E) in epileptic patients receiving antiepileptic drugs were analyzed. The serum results of all vitamins were compiled and evaluated with SPSS.
RESULTS:
It was alarmingly found that serum levels of vitamin D were particularly very low in almost all (90%) epileptic patients in this study. Notably, serum levels of vitamin C and vitamin B1 were also below reference range in 72% and 46% epileptic patients, respectively. The remaining vitamins were almost in reference range for most of the patients. In our study, mean and frequency of vitamin D, C and B1 levels do not vary too much among different gender groups. The patients receiving newer antiepileptic drugs displayed a slightly increased serum vitamin D levels in comparison to the patients receiving older antiepileptic drugs. We found low vitamin D, C and B1 serum levels in patients who were on monotherapy as in comparison with patients on polytherapy.
CONCLUSION:
The most significant and surprising finding of this study revealed that serum vitamin D levels in particular were very low in almost all patients and in some patients vitamin B1 serum levels were also below the reference range. More importantly, it is first time reported here that vitamin C serum levels were also below reference range in the majority of these Chinese epileptic patients. It is recommended that all these vitamins should be regularly monitored in addition to therapeutic drug monitoring of antiepileptic drugs. Additional clinical trials are required for further evaluation. It is also recommended that epileptic patients with low serum levels of these vitamins may be prescribed vitamins supplementations with antiepileptic drugs in order to control their seizures more effectively and efficiently.
Effect of Antiepileptic Therapy on Serum 25(OH)D3 and 24,25(OH)2D3 Levels in Epileptic Children
Ann Nutr Metab. 2016;68(2):119-27. doi: 10.1159/000443535. Epub 2016 Jan 27.
He X1, Jiang P, Zhu W, Xue Y, Li H, Dang R, Cai H, Tang M, Zhang L, Wu Y.
Institute of Clinical Pharmacy and Pharmacology, Second Xiangya Hospital, Changsha, China.
BACKGROUND:
Vitamin D deficiency is not only associated with the adverse effects of chronic treatment with antiepileptic drugs (AEDs), but also with epilepsy. Although emerging evidence suggests that AEDs can accelerate the vitamin D catabolism, resulting in suboptimal vitamin D status, there are a limited number of studies examining the vitamin D status in epileptic patients, especially in first-episode or AEDs-naïve children.
METHODS:
Determined with high-performance liquid chromatography-tandem mass spectrometry, circulating 25(OH)D3 and 24,25(OH)2D3 levels, and 24,25(OH)2D3:25(OH)D3 ratio were compared between AEDs-treated epileptic (n = 363) and control (n = 159) children. To further figure out whether the patients were in a vitamin D deficient prone state even before treatment, epileptic children before their initiation of treatment (n = 51) were enrolled into a follow-up study.
RESULTS:
A significant decrease of 25(OH)D3 and 24,25(OH)2D3 levels, but a significant increase of 24,25(OH)2D3:25(OH)D3 ratio was observed in epileptic children, compared with controls. Baseline 25(OH)D3, 24,25(OH)2D3 and 24,25(OH)2D3:25(OH)D3 ratio in the follow-up group were similar to those in controls, but significantly changed with 2 months of AED therapy.
CONCLUSIONS:
Disturbed vitamin D levels were possibly the consequence of AED therapy, rather than the contributing factor of epilepsy. Collectively, circulating vitamin D levels should be monitored and corrected in AEDs-treated epileptic children.
Vitamin D for the Treatment of Epilepsy: Basic Mechanisms, Animal Models and Clinical Trials
Front. Neurol. | doi: 10.3389/fneur.2016.00218
Kevin Pendo2 and Christopher M. DeGiorgio, MD1*
1 University of California, USA, 2 Princeton, USA
There is increasing evidence supporting dietary and alternative therapies for epilepsy, including the ketogenic diet, modified Atkins diet, and omega-3 fatty acids. Vitamin D is actively under investigation as a potential intervention for epilepsy. Vitamin D is fat soluble steroid which shows promise in animal models of epilepsy. Basic research has shed light on the possible mechanisms by which Vitamin D may reduce seizures, and animal data support the efficacy of Vitamin D in rat and mouse models of epilepsy. Very little clinical data exists to support the treatment of human epilepsy with Vitamin D, but positive findings from preliminary clinical trials warrant larger Phase I and II clinical trials in order to more rigorously determine the potential therapeutic value of Vitamin D as a treatment for human epilepsy.
From the end of the conclusion section
"Recently, our group has received an IND for a Phase I study of Vitamin D3 in drug-resistant epilepsy to study the safety, preliminary efficacy and potential cardiac benefits of Vitamin D3 5000 IU/day in drug-resistant epilepsy."
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Vitamin D Deficiency in Children With Newly Diagnosed Idiopathic Epilepsy
J Child Neurol October 2015 vol. 30 no. 11 1428-1432
Fatma Mujgan Sonmez, MD1⇑, Ahsen Donmez, MD2, Mehmet Namuslu, MD3
Metin Canbal, MD4, Emel Orun, MD2
1Department of Child Neurology, Turgut Ozal University, Ankara, Turkey
2Department of Pediatrics, Turgut Ozal University, Ankara, Turkey
3Department of Biochemistry, Turgut Ozal University, Ankara, Turkey
4Department of Family Medicine, Turgut Ozal University, Ankara, Turkey
Fatma Mujgan Sonmez, MD, Department of Child Neurology, Turgut Ozal University, Alparslan Turkes Caddesi, No: 57 Emek, Ankara 06560, Turkey. Email: mjgsonmez at yahoo.com
14 ng for newly diagnosed vs 23 ng for controls
Suspect that newly diagnosed have not had Vitamin D depleting drugs
Note:
Several studies have shown a link between vitamin D deficiency and epilepsy. This study includes 60 newly diagnosed idiopathic epilepsy patients and 101 healthy controls (between the ages of 5 and 16). Each group was also divided into two subgroups according to seasonal changes in terms of months of longer versus shorter daylight. We retrospectively evaluated the levels of calcium, phosphorus, alkaline phosphatase, parathyroid hormone, and 25-OH vitamin-D3 in the study participants. Levels below 20 ng/ml were defined as vitamin D deficiency and levels of 20-30 ng/ml as insufficiency. There were no significant differences in age, gender distribution and levels of calcium, phosphorus, alkaline phosphatase and parathyroid hormone between the groups. The level of 25-OH vitamin-D3 in the patient group was significantly lower when compared to the control group (p < 0.05) (14.07 ± 8.12 and 23.38 ± 12.80 ng/ml, respectively). This difference also held true when evaluation was made according to seasonal evaluation (12.38 ± 6.53 and 17.64 ± 1.14 in shorter daylight and 18.71 ± 9.87 and 30.82 ± 1.04 in longer daylight).
There are a variety of idiopathic epilepsy syndromes. Children with idiopathic epilepsy may have generalized or partial seizures.
Many, although not all, idiopathic epilepsy syndromes are benign and the child will eventually grow out of them.
Relatives of a child with idiopathic epilepsy often have a history of seizures.
What are other terms for idiopathic epilepsy?
An older term for idiopathic epilepsy is primary epilepsy. The terms “idiopathic epilepsy” and “cryptogenic epilepsy” are sometimes used interchangeably, especially in older books and articles.
What causes idiopathic epilepsy?
By definition, there is no apparent underlying cause of idiopathic epilepsy, such as a structural problem with the brain or a metabolic disorder. It is possible that idiopathic epilepsy is caused by tiny abnormalities at the cellular level. We are now learning that many, although not all, idiopathic epilepsy syndromes have an associated genetic component.
In most cases, the exact way in which epilepsy is inherited is unclear. However, some researchers estimate that genes could account for 70% to 90% of the tendency to develop epilepsy.
What epilepsy syndromes are idiopathic?
How many other children have idiopathic epilepsy?
Idiopathic epilepsy is common; about 30% of childhood epilepsy is idiopathic.
Together, idiopathic and cryptogenic epilepsy account for 55% to 75% of cases of childhood epilepsy.
It is difficult to be precise, because different researchers define these terms differently.
How is idiopathic epilepsy treated?
Idiopathic epilepsy is treated with anti-epileptic drugs.
What is the outlook for a child with idiopathic epilepsy?
The outlook for a child with idiopathic epilepsy depends on the specific condition and how well the seizures respond to treatment.
Several idiopathic epilepsy syndromes, such as childhood absence epilepsy and BECTS, usually go away on their own.
With other syndromes, though, the child may need to take anti-epileptic drugs all his life.
Elizabeth J. Donner, MD, FRCPC, 2/4/2010
About one percent of Americans have some form of epilepsy, and nearly four percent (1 in 26) will develop epilepsy at some point in their lives. The number of Americans who have epilepsy is greater than the number who have multiple sclerosis, Parkinson's disease, and cerebral palsy combined.
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Should vitamin D supplementation routinely be prescribed to children receiving antiepileptic medication?
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Some graphics from the web
Incidence Doubling in a Decade
Update Dec 2016 - US Drug Enforcement Agency put CBD into the class of addicting drugs which include cocaine - so CBD is unlikely to stiil be on Amazon
Suspect that there are several types of Epilepsy, and that not all benefit from CBD
New title for this page April 2019. caused the visitor count to reset.