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Conservative Vitamin D Consensus from Central Europe - April 2022

Clinical Practice in the Prevention, Diagnosis and Treatment of Vitamin D Deficiency: A Central and Eastern European Expert Consensus Statement

Nutrients 2022,14, 1483. https://doi.org/10.3390/nu14071483
Pawel Pludowski1'* , Istvan Takacs 2, Mihail Boyanov 3 , Zhanna Belaya 4 , Camelia C. Diaconu 5 ,
Tatiana Mokhort6 , Nadiia Zherdova 7, Ingvars Rasa 8, Juraj Payer 9 and Stefan Pilz 1

Abstract:

Vitamin D deficiency has a high worldwide prevalence, but actions to improve this public health problem are challenged by the heterogeneity of nutritional and clinical vitamin D guidelines, with respect to the diagnosis and treatment of vitamin D deficiency. We aimed to address this issue by providing respective recommendations for adults, developed by a European expert panel, using the Delphi method to reach consensus. Increasing the awareness of vitamin D deficiency and efforts to harmonize vitamin D guidelines should be pursued. We argue against a general screening for vitamin D deficiency but suggest 25-hydroxyvitamin D (25(OH)D) testing in certain risk groups. We recommend a vitamin D supplementation dose of 800 to 2000 international units (IU) per day for adults who want to ensure a sufficient vitamin D status. These doses are also recommended for the treatment of vitamin D deficiency, but higher vitamin D doses (e.g., 6000 IU per day) may be used for the first 4 to 12 weeks of treatment if a rapid correction of vitamin D deficiency is clinically indicated before continuing, with a maintenance dose of 800 to 2000 IU per day. Treatment success may be evaluated after at least 6 to 12 weeks in certain risk groups (e.g., patients with malabsorption syndromes) by measurement of serum 25(OH)D, with the aim to target concentrations of 30 to 50 ng/mL (75 to 125 nmol/L).

Table 4. Statement regarding screening of vitamin D deficiency in adults

Screening of vitamin D deficiency should be considered in the following patients/individuals or condition
Osteoporosis; Osteomalacia; Musculoskeletal pain; Chronic kidney disease; Hepatic failure; Malabsorption syndromes (e.g., cystic fibrosis, inflammatory bowel diseases, bariatric surgery, radiation enteritis); Hyperparathyroidism; Chronic treatment with medications that influence vitamin D metabolism (e.g., antiseizure medications, glucocorticoids, AIDS-medications, antifungal agents, cholestyramine); Chronic autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis); Pregnant and lactating women; Institutionalized or hospitalized patients; Older adults (>65 years) in general; Older adults with history of falls or nontraumatic fractures; Granuloma-forming disorders (e.g., sarcoidosis, tuberculosis, histoplasmosis, berylliosis, coccidiomycosis); Obesity (BMI > 30kg/m2); dark skin pigmentation.
25(OH)D is recommended as a laboratory marker for the diagnosis of vitamin D deficiency.

In patients with diagnosed vitamin D deficiency (25(OH)D <20 ng/mL (<50 nmol/L) ) and suspected related health issues, serum calcium, phosphate, alkaline phosphatase, parathyroid hormone (PTH), creatinine, and serum magnesium levels should be considered for evaluation; in particular in individuals with a 25(OH)D concentration of <10 ng/mL (<25 nmol/L).

  • A 25(OH)D concentration of <20 ng/mL (<50 nmol/L) is considered a vitamin D deficiency
  • A 25(OH)D concentration of >20 ng/mL (>50 nmol/L) and <30 ng/mL (<75 nmol/L) is considered as vitamin D insufficiency
  • A 25(OH)D concentration of 30-50 ng/mL (75-125 nmol/L) is considered as vitamin D sufficiency
  • A 25(OH)D concentration of >50-60 ng/mL (125-150 nmol/L) is considered as safe but not as a target level
  • A 25(OH)D concentration of >60-100 ng/mL (150-250 nmol/L) is considered as area of uncertainty with potential benefits or risks.
  • A 25(OH)D concentration of >100 ng/mL (250 nmol/L) is considered as oversupply/vitamin D toxicity

Overall agreement 100%, consensus endorsed

Table 5. Statement regarding prevention of vitamin D deficiency in adults
  • In healthy adults without other risk factors, a supplementation of 800-2000 IU/day, for those who want to achieve a targeted/measured 25(OH)D concentration, should be considered during wintertime (mainly November-April) due to insufficient endogenous dermal vitamin D synthesis and depending on the body weight.
  • Due to decreased skin synthesis in elderly (>65 years), a supplementation of 800-2000 IU/day is recommended throughout the year.
  • In hospitalized/institutionalized individuals, a supplementation of 800-2000 IU/day is recommended throughout the year.
  • Women planning a pregnancy should start or maintain the vitamin D supplementation as recommended for healthy adults without other risk factors (800-2000 IU/day). The vitamin D supplementation should be continued throughout pregnancy and lactation.
  • In certain patients/individuals or conditions 2-3 times higher vitamin D dosages, without using vitamin D doses above the UL of 4000 IU/day, are recommended for prevention compared to healthy adults without other risk factors:
    • Malabsorption (e.g., cystic fibrosis, inflammatory bowel diseases, bariatric surgery, radiation enteritis)
    • Obesity (BMI > 30 kg/m2)
    • Dark skin pigmentation
  • As vitamin D metabolites are stored in fat and other tissues and gradually released into the blood circulation,
    • a daily or weekly or monthly supplementation regimen is equally effective and safe, if monthly doses are not exceedingly high, for the prevention of vitamin D deficiency.
  • A tailored approach for vitamin D administration, involving the patients' preferences of the supplementation regimen (daily, weekly, monthly) might enhance the adherence to preventive vitamin D supplementation.
  • For the prevention of vitamin D deficiency, the supplementation of oral cholecalciferol (vitamin D3) is recommended.
Table 6. Statement regarding treatment of vitamin D deficiency in adults.
  • It is recommended to initiate a vitamin D deficiency treatment at a 25(OH)D concentration of <20 ng/mL (<50 nmol/L). At a concentration of <30 ng/mL (<75 nmol/L) a treatment may be considered.
  • Individuals with diagnosed vitamin D deficiency can be initially treated with higher vitamin D dosages compared to the preventive dosages recommended for the general population, if a rapid correction of the 25(OH)D concentration is clinically indicated. As initial dose for the treatment of vitamin D deficiency in patients without other risk factors, a dosage of 6000 IU, equivalent to a daily dosage, is recommended.
  • In certain individuals or conditions, higher vitamin D dosages, up to 10,000 IU, equivalent to a daily dosage, are recommended for treatment compared to healthy adults without other risk factors (Endocrine Society recommendation) [14]:
    • Malabsorption (e.g., cystic fibrosis, inflammatory bowel diseases, bariatric surgery, radiation enteritis)
    • Chronic treatment of medications that influence vitamin D metabolism (e.g., antiseizure medications, glucocorticoids, AIDS-medications, antifungal agents, cholestyramine)
    • Obesity (BMI > 30 kg/m2)
  • A treatment duration of 4-12 weeks is recommended, depending on the severity of vitamin D deficiency.
  • A tailored approach for vitamin D administration, involving the patients' preferences of the treatment regimen (daily, weekly, monthly) might enhance the adherence to the therapy.
  • As soon as a 25(OH)D concentration of 30-50 ng/mL (75-125 nmol/L) is achieved, a maintenance dose of 800-2000 IU/day is recommended, that can also be used as an initial treatment dose if there is no requirement for a rapid correction of vitamin D deficiency.
  • Approx. 6-12 weeks after start of the treatment, the effectiveness may be evaluated by measurement of the 25(OH)D concentration particularly in certain risk groups with e.g., malabsorption syndrome.
  • For the treatment of vitamin D deficiency in adults, oral cholecalciferol (vitamin D3) is preferred.
  • Calcifediol may be used instead of vitamin D in certain conditions, including obesity or malabsorption.
  • Calcitriol and active vitamin D analogues may be considered in special patient groups.
  • In certain risk groups (e.g., patients with severe malabsorption), parenteral vitamin D treatment can be considered.
Calcifediol ($$ and generally only by prescription)

Some experts argue that calcifediol (=25(OH)D3, calcidiol) may also be used to correct vitamin D deficiency in certain conditions. The use of calcifediol seems to be more justified in obese people, people with malabsorption syndromes, people with liver disease, patients suffering from chronic kidney disease (stage 3 or 4), and those in all conditions where rapid correction of vitamin D deficiency is required [82-84]. Furthermore, calcifediol use may also be beneficial in patients taking medications that disrupt the hepatic cytochrome P-450 enzyme system, including those taking glucocorticoids, anticonvulsants, anticancer drugs, or antiretroviral drugs [82-85]. The increase in serum 25(OH)D is markedly reduced in patients with obesity (high BMI) and in patients with malabsorption syndromes treated with cholecalciferol, but with calcifediol, the 25(OH)D increase is not significantly different according to BMI or according to the presence, or absence, of malabsorption syndromes. Moreover, the increase in serum 25(OH)D is faster, and the dose-response curve is more linear with the use of calcifediol versus vitamin D3, and when stopping treatment, the decline in 25(OH)D concentration is faster after calcifediol compared to vitamin D3 [75,82-84]. While accumulating evidence suggests that calcifediol may be an attractive alternative to "native" vitamin D, due to the lack of experience with this molecule in Central and Eastern European countries, at this stage, we continue to recommend vitamin D3 (cholecalciferol) [75]. Cholecalciferol and calcifediol appear, so far, as equal molecules in the fight with vitamin D deficiency. However, RCT data are still missing on the superior benefit of calcifediol versus vitamin D, with reference to hard clinical outcomes, but more data on this topic may be available in the future [75,84,85].
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  81. Gupta, N.; Farooqui, K.J.; Batra, C.M.; Marwaha, R.K.; Mithal, A. Effect of oral versus intramuscular Vitamin D replacement in apparently healthy adults with Vitamin D deficiency. Indian J. Endocrinol. Metab. 2017, 21,131-136. [CrossRef]
  82. Sosa Henriquez, M.; Gomez de Tejada Romero, M.J. Cholecalciferol or Calcifediol in the Management of Vitamin D Deficiency. Nutrients 2020,12,1617. [CrossRef]
  83. Quesada-Gomez, J.M.; Bouillon, R. Is calcifediol better than cholecalciferol for vitamin D supplementation? Osteoporos. Int. 2018, 29,1697-1711. [CrossRef]
  84. Perez-Castrillon, J.L.; Duenas-Laita, A.; Brandi, M.L.; Jodar, E.; Del Pino-Montes, J.; Quesada-Gomez, J.M.; Cereto Castro, F.; Gomez-Alonso, C.; Gallego Lopez, L.; Olmos Martinez, J.M.; et al. Calcifediol is superior to cholecalciferol in improving vitamin D status in postmenopausal women: A randomized trial. J. Bone Miner. Res. 2021, 36,1967-1978. [CrossRef]
  85. Bischoff-Ferrari, H.A.; Dawson-Hughes, B.; Orav, E.J.; Staehelin, H.B.; Meyer, O.W.; Theiler, R.; Dick, W.; Willett, W.C.; Egli, A. Monthly High-Dose Vitamin D Treatment for the Prevention of Functional Decline: A Randomized Clinical Trial. JAMA Intern. Med. 2016,176,175-183. [CrossRef]
  86. Bollerslev, J.; Rejnmark, L.; Zahn, A.; Heck, A.; Appelman-Dijkstra, N.M.; Cardoso, L.; Hannan, F.M.; Cetani, F.; Sikjaer, T.; Formenti, A.M.; et al. European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders. Eur. J. Endocrinol. 2022, 186, R33-R63. [CrossRef]
  87. Bischoff-Ferrari, H.A.; Willett, W.C.; Orav, E.J.; Lips, P.; Meunier, P.J.; Lyons, R.A.; Flicker, L.; Wark, J.; Jackson, R.D.; Cauley, J.A.; et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N. Engl. J. Med. 2012,367, 40-49. [CrossRef]
  88. Bolland, M.J.; Grey, A.; Avenell, A. Effects of vitamin D supplementation on musculoskeletal health: A systematic review, meta-analysis, and trial sequential analysis. Lancet Diabetes Endocrinol. 2018, 6, 847-858. [CrossRef]
  89. Carmel, A.S.; Bockman, R.S. Vitamin D and bisphosphonate response. Osteoporos. Int. 2014, 25, 2155. [CrossRef]
  90. Reid, I.R.; Horne, A.M.; Mihov, B.; Stewart, A.; Garratt, E.; Wong, S.; Wiessing, K.R.; Bolland, M.J.; Bastin, S.; Gamble, G.D. Fracture Prevention with Zoledronate in Older Women with Osteopenia. N. Engl. J. Med. 2018, 379, 2407-2416. [CrossRef]
  91. Li, S.; Xi, C.; Li, L.; Long, Z.; Zhang, N.; Yin, H.; Xie, K.; Wu, Z.; Tian, J.; Wang, F.; et al. Comparisons of different vitamin D supplementation for prevention of osteoporotic fractures: A Bayesian network meta-analysis and meta-regression of randomised controlled trials. Int. J. Food Sci. Nutr. 2021, 72, 518-528. [CrossRef]
  92. Ganmaa, D.; Enkhmaa, D.; Nasantogtokh, E.; Sukhbaatar, S.; Tumur-Ochir, K.E.; Manson, J.E. Vitamin D, respiratory infections, and chronic disease: Review of meta-analyses and randomized clinical trials. J. Intern. Med. 2021. [CrossRef]
  93. Iuliano, S.; Poon, S.; Robbins, J.; Bui, M.; Wang, X.; De Groot, L.; Van Loan, M.; Zadeh, A.G.; Nguyen, T.; Seeman, E. Effect of dietary sources of calcium and protein on hip fractures and falls in older adults in residential care: Cluster randomised controlled trial. BMJ 2021, 375, n2364. [CrossRef]
  94. Appel, L.J.; Michos, E.D.; Mitchell, C.M.; Blackford, A.L.; Sternberg, A.L.; Miller, E.R., 3rd; Juraschek, S.P.; Schrack, J.A.; Szanton, S.L.; Charleston, J.; et al. The Effects of Four Doses of Vitamin D Supplements on Falls in Older Adults: A Response- Adaptive, Randomized Clinical Trial. Ann. Intern. Med. 2021,174,145-156. [CrossRef]
  95. Zittermann, A.; Ernst, J.B.; Prokop, S.; Fuchs, U.; Dreier, J.; Kuhn, J.; Knabbe, C.; Birschmann, I.; Schulz, U.; Berthold, H.K.; et al. Effect of vitamin D on all-cause mortality in heart failure (EVITA): A 3-year randomized clinical trial with 4000 IU vitamin D daily. Eur. Heart J. 2017, 38, 2279-2286. [CrossRef]
  96. Gnagnarella, P.; Muzio, V.; Caini, S.; Raimondi, S.; Martinoli, C.; Chiocca, S.; Miccolo, C.; Bossi, P; Cortinovis, D.; Chiaradonna, F.; et al. Vitamin D Supplementation and Cancer Mortality: Narrative Review of Observational Studies and Clinical Trials. Nutrients 2021,13, 3285. [CrossRef]
  97. Charoenngam, N.; Holick, M.F. Immunologic Effects of Vitamin D on Human Health and Disease. Nutrients 2020,12,2097. [CrossRef]
  98. Hajhashemy, Z.; Shahdadian, F.; Moslemi, E.; Mirenayat, F.S.; Saneei, P. Serum vitamin D levels in relation to metabolic syndrome: A systematic review and dose-response meta-analysis of epidemiologic studies. Obes. Rev. 2021, 22, e13223. [CrossRef]
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  100. Hahn, J.; Cook, N.R.; Alexander, E.K.; Friedman, S.; Walter, J.; Bubes, V.; Kotler, G.; Lee, I.M.; Manson, J.E.; Costenbader, K.H. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ 2022, 376, e066452. [CrossRef]
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  102. Jolliffe, D.A.; Camargo, C.A., Jr.; Sluyter, J.D.; Aglipay, M.; Aloia, J.F.; Ganmaa, D.; Bergman, P; Bischoff-Ferrari, H.A.; Borzutzky, A.; Damsgaard, C.T.; et al. Vitamin D supplementation to prevent acute respiratory infections: A systematic review and meta-analysis of aggregate data from randomised controlled trials. Lancet Diabetes Endocrinol. 2021, 9,276-292. [CrossRef]
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Vitamin D Life

Interview covering 30+ Vitamin D topics
Consensus Vitamin D category
68 Vitamin D consensus publications
11 reasons why doctors reluctant to accept vitamin D
Co-factors (such as Magnesium and Omega-3) not mentioned
Incorrectly states that loading doses should not be used

Overview Loading of vitamin D  A few examples

4,000 IU max - yet > 100 Amazon suppliers sell 5,000 IU capsules
  • And many also sell 10,000 IU and 50,000 IU capsules
No mention of getting more vitamin D to cells by activation of Vitamin D Receptor
No mention of other important forms of Vitamin D: topical, nanoemulsion, gut-friendly
No mention of taking vitamin D with biggest meal of the day
  • Staying in small intestine longer increases response by about 30%
No indication of health problems that require more than 40 ng of vitamin D
Vitamin D Treats
150 ng Multiple Sclerosis *
80 ng Cluster Headache *
Reduced office visits by 4X *
70 ngSleep *
60 ngBreast Cancer death reduced 60%
Preeclampsia RCT
50 ng COVID-19
Fertility
Psoriasis
Infections Review
Infection after surgery
40 ng Breast Cancer 65% lower risk
Depression
ACL recovery
Hypertension
Asthma?
30 ng Rickets

* Evolution of experiments with patients, often also need co-factors

No prevention of health problems
  • They do not test until after the health problem already exists
No consideration that people lacking sun will need more vitamin D
  • Excessive Clothing, 2nd shift workers, unable to get outdoors,
Incorrectly states that Vitamin D test should be made again after 6-12 weeks
  • Responses to low vitamin D doses often do not plateau for 25+ weeks
Incorrectly states 800 IU can maintain a 50 ng level
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Conservative Vitamin D Consensus from Central Europe - April 2022        
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