Vitamin D: Bolus Is Bogus—A Narrative Review

In this review we summarize the impact of bolus versus daily dosing of vitamin D on 25(OH)D and 1,25(OH)2D levels, as well as on key countervailing factors that block vitamin D functions at the cellular level. Further, we discuss the role of bolus versus daily dosing of vitamin D for several health outcomes, including respiratory infections and coronavirus disease 2019 (COVID‐19), rickets, falls and fractures, any cancer, and cancer‐related mortality. This discussion appears timely because bolus doses continue to be tested for various disease outcomes despite a growing amount of evidence suggesting lack of efficacy or even detrimental effects of bolus dosing of vitamin D for outcomes where daily dosing at modest levels was effective in the vitamin D deficient. As a result, these discordant results may bias health recommendations for vitamin D if the recommendations are based on meta‐analyses combining both daily and bolus dosing trials. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

[1]  P. Płudowski,et al.  Vitamin D Deficiency in Older Patients—Problems of Sarcopenia, Drug Interactions, Management in Deficiency , 2021, Nutrients.

[2]  R. Pranata,et al.  Low Serum 25-hydroxyvitamin D (Vitamin D) Level Is Associated With Susceptibility to COVID-19, Severity, and Mortality: A Systematic Review and Meta-Analysis , 2021, Frontiers in Nutrition.

[3]  F. Petrelli,et al.  Therapeutic and prognostic role of vitamin D for COVID-19 infection: A systematic review and meta-analysis of 43 observational studies , 2021, The Journal of Steroid Biochemistry and Molecular Biology.

[4]  M. Chakhtoura,et al.  The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis , 2021, Metabolism.

[5]  C. Apovian,et al.  Association of Vitamin D Status With Hospital Morbidity and Mortality in Adult Hospitalized Patients With COVID-19 , 2021, Endocrine Practice.

[6]  Z. Mekonnen,et al.  The Impact of Vitamin D Level on COVID-19 Infection: Systematic Review and Meta-Analysis , 2021, Frontiers in Public Health.

[7]  R. Mancini,et al.  Circulating Vitamin D levels status and clinical prognostic indices in COVID-19 patients , 2021, Respiratory Research.

[8]  B. Gualano,et al.  Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial. , 2021, JAMA.

[9]  R. Quinton,et al.  Perspective: Vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: implications for COVID-19. , 2021, Clinical medicine.

[10]  H. Brenner.  Vitamin D Supplementation to Prevent COVID-19 Infections and Deaths—Accumulating Evidence from Epidemiological and Intervention Studies Calls for Immediate Action , 2021, Nutrients.

[11]  J. Pascual,et al.  Calcifediol treatment and COVID-19-related outcomes , 2021, The Journal of clinical endocrinology and metabolism.

[12]  C. Mantzoros,et al.  Vitamin D Status Is Associated With In-Hospital Mortality and Mechanical Ventilation: A Cohort of COVID-19 Hospitalized Patients , 2021, Mayo Clinic Proceedings.

[13]  H. Brenner,et al.  Vitamin D supplementation to the older adult population in Germany has the cost‐saving potential of preventing almost 30 000 cancer deaths per year , 2020, Molecular oncology.

[14]  J. Manson,et al.  Vitamin D and Clinical Cancer Outcomes: A Review of Meta‐Analyses , 2020, JBMR plus.

[15]  D. Chandramohan,et al.  Vitamin D for Growth and Rickets in Stunted Children: A Randomized Trial , 2020, Pediatrics.

[16]  M. Kloc,et al.  Effects of vitamin D on macrophages and myeloid-derived suppressor cells (MDSCs) hyperinflammatory response in the lungs of COVID-19 patients , 2020, Cellular Immunology.

[17]  S. Wimalawansa,et al.  Putative roles of vitamin D in modulating immune response and immunopathology associated with COVID-19 , 2020, Virus Research.

[18]  J. Manson,et al.  Effect of Vitamin D Supplementation, Omega-3 Fatty Acid Supplementation, or a Strength-Training Exercise Program on Clinical Outcomes in Older Adults: The DO-HEALTH Randomized Clinical Trial. , 2020, JAMA.

[19]  L. Zgaga.  Heterogeneity of the Effect of Vitamin D Supplementation in Randomized Controlled Trials on Cancer Prevention. , 2020, JAMA network open.

[20]  A. Abrishami,et al.  Possible association of vitamin D status with lung involvement and outcome in patients with COVID-19: a retrospective study , 2020, European Journal of Nutrition.

[21]  J. Manson,et al.  The vitamin D for COVID-19 (VIVID) trial: A pragmatic cluster-randomized design , 2020, Contemporary Clinical Trials.

[22]  M. Holick,et al.  SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels , 2020, PloS one.

[23]  Linda LL Benskin.  A Basic Review of the Preliminary Evidence That COVID-19 Risk and Severity Is Increased in Vitamin D Deficiency , 2020, Frontiers in Public Health.

[24]  R. Bouillon,et al.  “Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study” , 2020, The Journal of Steroid Biochemistry and Molecular Biology.

[25]  S. Pilz,et al.  The effect of vitamin D on fibroblast growth factor 23: a systematic review and meta-analysis of randomized controlled trials , 2020, European Journal of Clinical Nutrition.

[26]  C. Chen,et al.  The importance of vitamin d metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19 , 2020, Journal of Translational Medicine.

[27]  S. Azer.  COVID-19: pathophysiology, diagnosis, complications and investigational therapeutics , 2020, New Microbes and New Infections.

[28]  H. Brenner,et al.  Vitamin D Insufficiency and Deficiency and Mortality from Respiratory Diseases in a Cohort of Older Adults: Potential for Limiting the Death Toll during and beyond the COVID-19 Pandemic? , 2020, Nutrients.

[29]  David A. Jolliffe,et al.  Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials , 2020, medRxiv.

[30]  A. Gorohovski,et al.  Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study , 2020, medRxiv.

[31]  J. Manson,et al.  VITamin D and OmegA-3 TriaL (VITAL): Effects of Vitamin D Supplements on Risk of Falls in the US Population , 2020, The Journal of clinical endocrinology and metabolism.

[32]  D. Gatti,et al.  Pharmacokinetics of Oral Cholecalciferol in Healthy Subjects with Vitamin D Deficiency: A Randomized Open-Label Study , 2020, Nutrients.

[33]  J. Pell,et al.  Vitamin D concentrations and COVID-19 infection in UK Biobank , 2020, Diabetes & Metabolic Syndrome: Clinical Research & Reviews.

[34]  W. Grant,et al.  Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths , 2020, Nutrients.

[35]  Eun-Kyeong Jo,et al.  Vitamin D-Cathelicidin Axis: at the Crossroads between Protective Immunity and Pathological Inflammation during Infection , 2020, Immune network.

[36]  R. Rezvani,et al.  Efficacy of high-dose versus low-dose vitamin D supplementation on serum levels of inflammatory factors and mortality rate in severe traumatic brain injury patients: study protocol for a randomized placebo-controlled trial , 2019, Trials.

[37]  M. Meremikwu,et al.  Vitamin D, calcium or a combination of vitamin D and calcium for the treatment of nutritional rickets in children , 2017 .

[38]  C. Lawes,et al.  Effect of monthly high-dose vitamin D supplementation on acute respiratory infections in older adults: A randomized controlled trial. , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[39]  D. Bennett,et al.  Vitamin D and Calcium for the Prevention of Fracture , 2019, JAMA network open.

[40]  P. Mecocci,et al.  Effects of Weekly Supplementation of Cholecalciferol and Calcifediol Among the Oldest-Old People: Findings From a Randomized Pragmatic Clinical Trial , 2019, Nutrients.

[41]  L. Liu,et al.  Vitamin D does not improve lung function decline in COPD: a meta-analysis. , 2019, European review for medical and pharmacological sciences.

[42]  B. Boucher,et al.  Why Secondary Analyses in Vitamin D Clinical Trials Are Important and How to Improve Vitamin D Clinical Trial Outcome Analyses—A Comment on “Extra-Skeletal Effects of Vitamin D, Nutrients 2019, 11, 1460” , 2019, Nutrients.

[43]  Y. Zayed,et al.  Role of vitamin D supplementation for primary prevention of cancer: Meta-analysis of randomized controlled trials. , 2019, Journal of Clinical Oncology.

[44]  J. Manson,et al.  Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials. , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[45]  C. Lawes,et al.  Adverse events from large dose vitamin D supplementation taken for one year or longer , 2019, The Journal of Steroid Biochemistry and Molecular Biology.

[46]  J. Manson,et al.  Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease , 2019, The New England journal of medicine.

[47]  David A. Jolliffe,et al.  Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis. , 2019, Health technology assessment.

[48]  A. Avenell,et al.  Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis. , 2018, The lancet. Diabetes & endocrinology.

[49]  E. Giovannucci,et al.  Monthly High-Dose Vitamin D Supplementation and Cancer Risk: A Post Hoc Analysis of the Vitamin D Assessment Randomized Clinical Trial , 2018, JAMA oncology.

[50]  John H. White,et al.  Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions , 2018, Endocrine reviews.

[51]  R. Kumar,et al.  Comparison of the effect of daily versus bolus dose maternal vitamin D3 supplementation on the 24,25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 ratio. , 2018, Bone.

[52]  R. Bouillon,et al.  Is calcifediol better than cholecalciferol for vitamin D supplementation? , 2018, Osteoporosis International.

[53]  Leila C. Kahwati,et al.  Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force , 2018, JAMA.

[54]  S. Wimalawansa.  Associations of vitamin D with insulin resistance, obesity, type 2 diabetes, and metabolic syndrome , 2018, The Journal of Steroid Biochemistry and Molecular Biology.

[55]  L. D. de Groot,et al.  Dose-response effects of supplementation with calcifediol on serum 25-hydroxyvitamin D status and its metabolites: A randomized controlled trial in older adults. , 2017, Clinical nutrition.

[56]  Jia-Guo Zhao,et al.  Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis , 2017, JAMA.

[57]  C. Lawes,et al.  Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial. , 2017, The lancet. Diabetes & endocrinology.

[58]  A. Ginde,et al.  High‐Dose Monthly Vitamin D for Prevention of Acute Respiratory Infection in Older Long‐Term Care Residents: A Randomized Clinical Trial , 2017, Journal of the American Geriatrics Society.

[59]  J. Tang,et al.  Efficacy of High-Dose Vitamin D Supplements for Elite Athletes , 2017, Medicine and science in sports and exercise.

[60]  A. Hanff,et al.  Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men , 2016 .

[61]  C. Weaver,et al.  Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis from the National Osteoporosis Foundation , 2015, Osteoporosis International.

[62]  Dean Y. Li,et al.  Dietary Vitamin D and Its Metabolites Non-Genomically Stabilize the Endothelium , 2015, PloS one.

[63]  O. Phan,et al.  Vitamin D: A Review on Its Effects on Muscle Strength, the Risk of Fall, and Frailty , 2015, BioMed research international.

[64]  J. Binongo,et al.  The effect of a single, large bolus of vitamin D in healthy adults over the winter and following year: a randomized, double-blind, placebo-controlled trial , 2014, European Journal of Clinical Nutrition.

[65]  J. Alvarez,et al.  Large, single-dose, oral vitamin D supplementation in adult populations: a systematic review. , 2014, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[66]  C. Wagner,et al.  Clinical review: The role of the parent compound vitamin D with respect to metabolism and function: Why clinical dose intervals can affect clinical outcomes. , 2013, The Journal of clinical endocrinology and metabolism.

[67]  J. Bacchetta,et al.  Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25‐dihydroxyvitamin D in human monocytes , 2013, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[68]  R. Heaney.  Vitamin D--baseline status and effective dose. , 2012, The New England journal of medicine.

[69]  W. Willett,et al.  A pooled analysis of vitamin D dose requirements for fracture prevention. , 2012, The New England journal of medicine.

[70]  P. Glendenning,et al.  Effects of three‐monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: A randomized controlled trial , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[71]  W. Willett,et al.  Oral supplementation with 25(OH)D3 versus vitamin D3: Effects on 25(OH)D levels, lower extremity function, blood pressure, and markers of innate immunity , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[72]  Rongwei Fu,et al.  Primary Care–Relevant Interventions to Prevent Falling in Older Adults: A Systematic Evidence Review for the U.S. Preventive Services Task Force , 2010, Annals of Internal Medicine.

[73]  R. Kalyani,et al.  Vitamin D Treatment for the Prevention of Falls in Older Adults: Systematic Review and Meta‐Analysis , 2010, Journal of the American Geriatrics Society.

[74]  M. Hewison.  Vitamin D and the immune system: new perspectives on an old theme. , 2010, Endocrinology and metabolism clinics of North America.

[75]  B. Dawson-Hughes,et al.  High-dose vitamin D supplementation: too much of a good thing? , 2010, JAMA.

[76]  J. Simpson,et al.  Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. , 2010, JAMA.

[77]  Ngaire Kerse,et al.  Interventions for preventing falls in older people in nursing care facilities and hospitals. , 2010, The Cochrane database of systematic reviews.

[78]  Sarah P Zuber,et al.  Interventions to Prevent Falls in Older Adults , 2010 .

[79]  T. S. Wilkinson,et al.  The human cathelicidin LL-37 preferentially promotes apoptosis of infected airway epithelium. , 2010, American journal of respiratory cell and molecular biology.

[80]  W. Willett,et al.  Benefit–risk assessment of vitamin D supplementation , 2010, Osteoporosis International.

[81]  J B Wong,et al.  Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials , 2009, BMJ : British Medical Journal.

[82]  G. Hunninghake,et al.  Respiratory Epithelial Cells Convert Inactive Vitamin D to Its Active Form: Potential Effects on Host Defense1 , 2008, The Journal of Immunology.

[83]  D. Moher,et al.  Systematic review of the benefits and harms of calcitriol and alfacalcidol for fractures and falls , 2008, Journal of Bone and Mineral Metabolism.

[84]  F. Richy,et al.  Differential Effects of D-Hormone Analogs and Native Vitamin D on the Risk of Falls: A Comparative Meta-Analysis , 2008, Calcified Tissue International.

[85]  C. Cooper,et al.  Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial. , 2007, Rheumatology.

[86]  S. Sen,et al.  The effect of cholecalciferol (vitamin D3) on the risk of fall and fracture: a meta-analysis. , 2007, QJM : monthly journal of the Association of Physicians.

[87]  J. Adams,et al.  Extra-renal 25-hydroxyvitamin D3-1α-hydroxylase in human health and disease , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[88]  J. Adams,et al.  Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease. , 2007, The Journal of steroid biochemistry and molecular biology.

[89]  David Feldman,et al.  Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. , 2005, Cancer research.

[90]  L. Shih,et al.  19-Nor-1,25(OH)2D2 (a novel, noncalcemic vitamin D analogue), combined with arsenic trioxide, has potent antitumor activity against myeloid leukemia. , 2005, Cancer research.

[91]  S. Nicosia,et al.  Induction of Ovarian Cancer Cell Apoptosis by 1,25-Dihydroxyvitamin D3 through the Down-regulation of Telomerase* , 2004, Journal of Biological Chemistry.

[92]  S. Nicosia,et al.  p27Kip1 Stabilization and G1 Arrest by 1,25-Dihydroxyvitamin D3 in Ovarian Cancer Cells Mediated through Down-regulation of Cyclin E/Cyclin-dependent Kinase 2 and Skp1-Cullin-F-box Protein/Skp2 Ubiquitin Ligase* , 2004, Journal of Biological Chemistry.

[93]  Bess Dawson-Hughes,et al.  Effect of Vitamin D on falls: a meta-analysis. , 2004, JAMA.

[94]  D. Reardon,et al.  The vitamin D3 analog EB 1089 enhances the antiproliferative and apoptotic effects of adriamycin in MCF-7 breast tumor cells , 2000, Breast Cancer Research and Treatment.

[95]  R. Doll,et al.  Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial , 2003, BMJ : British Medical Journal.

[96]  T. Gaschott,et al.  Short-chain fatty acids and colon cancer cells: the vitamin D receptor--butyrate connection. , 2003, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[97]  C. Paraskeva,et al.  Apoptosis is induced by the active metabolite of vitamin D3 and its analogue EB1089 in colorectal adenoma and carcinoma cells: possible implications for prevention and therapy. , 2000, Cancer research.

[98]  K. Miyazono,et al.  Convergence of transforming growth factor-beta and vitamin D signaling pathways on SMAD transcriptional coactivators. , 1999, Science.

[99]  M. Campbell,et al.  Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafluoride vitamin D3 analogue involves the induction of p21waf1, p27kip1 and E-cadherin. , 1997, Journal of molecular endocrinology.

[100]  A. Mackay,et al.  Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells , 1996, The Journal of Steroid Biochemistry and Molecular Biology.

[101]  T. Nikaido,et al.  Inhibitory effect of 220-oxa-1,25-dihydroxyvitamin D3 on the proliferation of pancreatic cancer cell lines. , 1996, Gastroenterology.