Weak support of IoM position of Vitamin D – 2018

The IOM—Endocrine Society Controversy on Recommended Vitamin D Targets: In Support of the IOM Position

From a chapter in Vitamin D (Fourth Edition) Volume 1: Biochemistry, Physiology and Diagnostics 2018, Pages 1065-1089
Roger Bouillon1, Cliff Rosen2
1 Katholieke Universiteit Leuven, Leuven, Belgium;
2 Maine Medical Center Research Institute- Scarborough, ME, United States

http://dx.doi.org/10.1016/B978-0-12-809965-0.00058-6
Entire PDF is available free at Sci-Hub  10.1016/B978-0-12-809965-0.00058-6

INTRODUCTION
Vitamin D Supplementation to Prevent Rickets
VITAMIN D STATUS AND BONE HEALTH IN ADULTS AND THE ELDERLY
Vitamin D Status and Serum 1,25-Dihydroxyvitamin D3
Vitamin D Status and Parathyroid Function
Vitamin D Status and Intestinal Calcium Absorption
Vitamin D Status and Bone Mineral Density
Vitamin D Status and Fracture Risk
VITAMIN D AND EXTRASKELETAL HEALTH
Skin Diseases
Cancer
Immune System and Vitamin D Status
Diabetes, Metabolic Syndrome, and Vitamin D Status
Muscle Function and Vitamin D Status
Vitamin D in Pregnancy and the Perinatal Period
Mortality
Conclusions: Extraskeletal Effects of Vitamin D
LESSONS FROM RECENTLY UPDATED GUIDELINES ON VITAMIN D SUPPLEMENTATION
VITAMIN D AND HUMAN HEALTH: WHAT IS THE OPTIMAL VITAMIN D STATUS

SUMMARY OF RECOMMENDATIONS

1. There is unanimity that serum concentrations below 10-12 ng are a risk factor for rickets and osteomalacia. This severe deficiency is still highly prevalent around the world (overall estimated to affect more than 5% of the world population except in equatorial areas (Table 57A.5). This deficiency is a situation comparable with iodine or vitamin A deficiency and is in principle easily preventable. Therefore, national and international organizations should implement strategies to eradicate this deficiency and its complications in the near future. The WHO should take the lead but requires that its member states first request that this is a top priority. We do not expect that the coauthors of the present debate, arguing for higher overall vitamin D status, would disagree with our conclusion which is in fact unanimously found in all guidelines. We suggest generalizing daily supplementation with 400 IU/day for all infants and young children (to age 3 or 4).
2. We think that serum 25(OH)D concentrations between 10 and 20 ng/mL can lead to deleterious compensatory biochemical consequences such as increased PTH secretion or decreased production of systemic or locally produced 1,25(OH)2D. Such levels are unlikely to have marked effects on intestinal calcium absorption but may in some individuals have long-term consequences for bone (bone loss and fragility fractures) and maybe muscle function and falls, especially, in the elderly. This may not be a problem for all subjects. Indeed, guidelines recommending serum levels of 25(OH)D of >20 ng/mL clearly state that this covers the need of 97.5% of the target population and is therefore in principle not necessary for everybody. About a third of the world population has levels below 20 ng/mL (Table 57A.5) but this does, therefore, not imply that one third of the world population is really vitamin D deficient as levels between 10 and 20 ng/mL are probably sufficient for half of them [230,231]. However, at present, no methods exist to define who is in need of the higher or lower range of these levels; the guidelines recommend that the target groups should take a daily dose of vitamin D of 600-1000 IU. This dose has been identified as safe and efficient to reach the target concentrations in whites and African-Americans but there are some data that this may have to be slightly increased for other populations such as in the Middle East [232]. According to most recent guidelines this should be implemented fairly systematically in all elderly subjects and even more so in the oldest-old. Daily supplementation could be the preferred method for most of them as they frequently also need some degree of supplementation with calcium. The same 25(OH)D level is also recommended in the majority of the recently updated guidelines for older children and adults. This can and is usually achieved by safe sun exposure and dietary vitamin D intake in the large majority of cases but for some countries or specific target groups a supplementation strategy is needed. There is, however, no cure-all strategy as this depends on climate, skin color, dietary habits, lifestyle, and cultural or other traditions. The implementation of these strategies should be the primary responsibility of national or regional authorities. We hope that our “competing coauthors" of Chapter 57B in the present deliberations will support our recommendations in line with the consensus of most guidelines.
3. We believe that there is at present no evidence that serum levels higher than 30 (up to 40 or maybe 50) ng/mL convey additional health benefits although such levels are probably safe for the large majority of humans. The benefits claimed by others (and our competing coauthors) are based on extrapolations or association studies. Indeed most RCTs that used doses of >2000 IU/day were of course able to generate higher 25(OH)D levels but could not demonstrate (and certainly not consistently) additional benefits for bone, muscle, metabolic, CV, or other hard end points (for overview up to 2011 see [233]). Some studies even suggested that subjects randomized to 800 IU/day (or equivalent per month) were better off than the ones on the higher dosages [189].
   Very high levels as found in East African native populations should not be taken as optimal levels but are more likely the maximal levels nature allows amidst plenty of sunlight as to avoid vitamin D toxicity. In these populations, serum 25(OH)D virtually never exceeds 60 ng/mL, and we consider such levels to be the results of a very long defense mechanism during the evolution of primates and men. We strongly recommend that this level should not be exceeded by dietary supplementation.
   Note: Vitamin D levels of East African tribes East Africans often have >60ng
   Strategies to achieve serum 25(OH)D levels well above 30 ng/mL in more than 97.5% of the target population are extremely difficult as 2000 IU/day is by far not sufficient for all.
      Interesting reasoning. > 2,000 IU may be toxic, need > 2,000 IU to get > 30ng, Therefore > 30 ng must not be useful
   Therefore, to achieve such a high target while avoiding high “upper natural" concentrations, requires individualized follow-up and regular monitoring of serum 25(OH)D. In the absence of proven safety and efficacy such investments of health care resources should be avoided. In addition, long-term oral intake of such high doses of vitamin D has never been found or tested in natural circumstances. As there are a large number of ongoing trials testing the safety and efficacy of higher dosages our recommendations are of course open to revision pending the results of these studies. Levels higher than 45 ng/mL may generate side effects such as falls and fractures and maybe even small increases in mortality rates. Although we consider this conclusion to be at present still speculative, this should, nevertheless, be a signal not to pursue such levels. Levels higher than 80-100 ng may cause true vitamin D intoxication.
4. The consequences of vitamin D status on maternal outcome and long-term outcome of the offspring are still incompletely understood. Appropriate studies in pregnant or lactating women should be a top priority as they frequently have shown a (very) low vitamin D status. While awaiting the results of such studies, we recommend that the guidelines for vitamin intake and vitamin D status applicable for that age group should be carefully implemented. The use of very high doses of vitamin D to replace the vitamin D supplementation of infants or to prevent possible diseases in the offspring is at present not to be recommended without extensive furthers studies.

HIGHLIGHTS

• Vitamin D deficiency is frequent around the world.
• 25(OH)D is a biomarker for exposure to the combined supply of dietary and endogenously produced vitamin D and low or very high concentrations are not equivalent to diseases but risk factors for diseases. Whether assays that measure free 25(OH)D may provide additional information is so far not established.
• There is fairly large unanimity about the definition of severe vitamin D deficiency (as revealed by serum 25(OH) D levels below 10 ng/mL or 25 nmol/L).
• More preclinical and clinical research is needed to address the outstanding questions.

It is possible to define clear priorities such as

1. Top priority: eradicate rickets around the world
2. Optimize vitamin D status to at least serum 25(OH)D concentrations of 20 ng/mL for all elderly subjects and even more so in the oldest-old
3. Subjects who for whatever reason must or want to avoid exposure to UV-B sunlight should take vitamin D supplements to bring their serum 25(OH)D above 10 and preferably above 20 ng/mL.
4. Be aware of risks of excess vitamin D