Continuing Education Activity

Vitamin D insufficiency and deficiency are prevalent worldwide; thus, regularly monitoring vitamin D levels is recommended for individuals at risk of such deficiencies. Cholecalciferol is a dietary supplement indicated for patients with vitamin D insufficiency or deficiency, and it also demonstrates various off-label uses. This activity comprehensively examines the indications, mechanism of action, pharmacokinetics, administration, adverse effects, drug interactions, contraindications, monitoring, and toxicity associated with cholecalciferol. This activity also highlights the roles of the interprofessional healthcare team in their coordinated efforts to enhance patient care by disseminating knowledge among healthcare professionals and patients about the significance of routinely monitoring vitamin D levels, thereby optimizing patient outcomes with cholecalciferol therapy.

Objectives:

• Identify patients at risk of vitamin D insufficiency or deficiency through thorough medical assessments.
• Implement evidence-based strategies for cholecalciferol supplementation, considering dosage forms and personalized treatment plans.
• Select optimal dosage forms and formulations of cholecalciferol tailored to individual patient needs.
• Collaborate with interprofessional healthcare teams to optimize patient outcomes with cholecalciferol therapy and educate patients on the importance of routine vitamin D level monitoring and proper cholecalciferol use.

Indications

Vitamin D insufficiency and deficiency are prevalent worldwide; thus, regular monitoring of vitamin D levels is recommended for individuals at risk of insufficiency and deficiency. Vitamin D deficiency is associated with an increased risk of cardiovascular disease, type 2 diabetes, cancer, depression, and cognitive impairment.[1] Individuals experiencing mild vitamin D deficiency may exhibit symptoms such as fatigue, joint pains, and depression. In cases of severe deficiency, adults may develop osteomalacia, whereas children may be affected by rickets disease.

Cholecalciferol, commonly known as vitamin D3, is a dietary supplement prescribed for individuals with vitamin D insufficiency or deficiency. Widely utilized in clinical practice, it also finds numerous off-label uses.

FDA-Approved Indications

Cholecalciferol, also known as vitamin D3, is a prohormone indicated for use as a dietary supplement.[2]

Off-Label Uses

Proven benefits from off-label uses in certain clinical trials include preventing bone loss or treating osteoporosis in postmenopausal women, preventing falls in older adults, and preventing fractures.[3][2] Other uses explored in clinical trials that were not beneficial are listed below.[2]

• Preventing and treating hypertension and multiple sclerosis
• Reducing mortality in patients with heart failure
• Mitigating statin-induced myalgia
• Preventing diabetes and improving glycemic control
• Averting depression or alleviating depression symptoms
• Preventing cognitive decline and dementia
• Managing asthma and chronic obstructive pulmonary disease
• Preventing and treating infectious diseases, such as tuberculosis and upper respiratory tract infections
• Preventing colorectal and breast cancer

Mechanism of Action

Vitamin D–binding protein and albumin facilitate the transport of cholecalciferol to vitamin D receptors (VDRs),[4] which are present in most body tissues.[5]

Calcitriol, the active metabolite of cholecalciferol, binds to VDRs,[6] which leads to the transcription of vitamin D–dependent genes. These genes activate osteoclasts and promote bone resorption and mobilization of calcium and phosphate from the bone into the bloodstream.[7][6] In addition, in the intestines, calcitriol promotes the absorption of calcium and phosphorus into the bloodstream.

Pharmacokinetics

Cholecalciferol is a prohormone that can be obtained from exogenous sources such as supplements or foods of animal origin.[8] Endogenously, the skin synthesizes cholecalciferol.[9] Upon exposure to ultraviolet B (UVB) radiation from sunlight, the skin converts 7-dehydrocholesterol to cholecalciferol. As tanning beds emit UVA, not UVB,[10] they do not promote vitamin D synthesis.

Absorption: The intestinal absorption of vitamin D occurs not only through passive diffusion but also through other mechanisms involving membrane carriers.[11] As cholecalciferol shares a structural resemblance with cholesterol,[12] it utilizes an additional absorption mechanism that involves its transportation through cholesterol carriers.[11]

Data on the effect of food on vitamin D absorption are conflicting. A particular study indicated that vitamin D absorption improves when patients take it with the largest meal of the day.[13] Given its fat-soluble nature, vitamin D absorption is enhanced when patients take it with a high-fat meal.[14] However, other studies indicate no correlation between vitamin D absorption and concurrent food intake, including high-fat consumption.[15]

Distribution: As a fat-soluble vitamin, vitamin D exhibits the highest distribution in adipose tissue and, to a lesser extent, in muscles and the liver.[16] The adipose tissue stores cholecalciferol in its original form.[17] Due to cholecalciferol's affinity to adipose tissue, people with high body fat are at higher risk of vitamin D deficiency, as it can lower vitamin D plasma levels.

Metabolism: Cholecalciferol is inactive.[18] In the liver, the enzyme 25-hydroxylase converts cholecalciferol originating from diet or sunlight to 25-hydroxyvitamin D3 (or 25(OH)D3) via hydroxylation. Vitamin D–binding proteins transport 25(OH)D3 from the liver to the kidneys.[6] The parathyroid hormone stimulates the activation of cholecalciferol in the kidneys.[19] In the kidneys, the enzyme 1-alpha-hydroxylase hydroxylates 25(OH)D3 to 1,25-dihydroxyvitamin D3 (1,25(OH)₂D3), which is also known as calcitriol.[9]

Calcitriol is a biologically active hormone. Although nonrenal calcitriol synthesis occurs, most calcitriol synthesis occurs in the kidneys. Therefore, the conversion of 25(OH)D to 1,25(OH)D is decreased in advanced kidney disease.[20][21] Patients with chronic kidney disease (CKD), as early as stage 3, may require supplementation with the active form of vitamin D.[21]

Fibroblast-like growth factor-23 (FGF23) is a hormone originating from the bones.[22] FGF23 plays a crucial role in vitamin D homeostasis, with elevated levels of 1,25(OH)₂D stimulating FGF23 release. FGF23, in turn, inhibits the hydroxylation of 25(OH)D3 in the kidneys and activates enzymes that lead to the degradation of vitamin D.

The half-life of 1,25(OH)₂D is 15 hours, whereas that of 25(OH)D is 15 days.[16]

Elimination: Bile acid secretions from the liver transport cholecalciferol to the intestine.[23] Subsequently, the intestines excrete cholecalciferol in the feces.[24] 

Administration

Available Dosage Forms and Strengths

Cholecalciferol is offered in various strengths and dosage forms, including solid and liquid formulations. Cholecalciferol is available as capsules, oral tablets, chewable tablets, sublingual liquid, and oral liquid. One microgram of cholecalciferol is equivalent to 40 international units.[25]

Adult Dosage

Vitamin D deficiency or insufficiency: According to the Kidney Disease Improving Global Outcomes (KDIGO) guideline, most studies define vitamin D deficiency as a 25(OH)D serum level <20 ng/mL and vitamin D insufficiency as a serum level of 21 to 29 ng/mL.[26] The target vitamin D level is >30 ng/mL. A study analyzing data from national surveys in the United States found that maintaining a 25(OH)D serum concentration of 30 ng/mL or more is associated with a reduced incidence of metabolic syndrome and diabetes when compared to a 25(OH)D serum concentration of <12 ng/mL.[27]

The appropriate dose of cholecalciferol depends on the extent of vitamin D deficiency or insufficiency. Maintenance dosing for addressing vitamin D deficiency and insufficiency is highly individualized and influenced by factors such as the target level and concurrent comorbidities, which might affect cholecalciferol metabolism and absorption.[28]

Healthy adults with vitamin D insufficiency (serum 25(OH)D level of 20 to 30 ng/mL): Patients with vitamin D insufficiency are advised to take cholecalciferol 1000 to 2000 international units once daily.[29]

Healthy adults with vitamin D deficiency (serum 25(OH)D level of <20 ng/mL): Patients with vitamin D deficiency are advised to adhere to the regimen as mentioned below.[29]

• Patients with a serum 25(OH)D level of 12 to 20 ng/mL should take 2000 international units of cholecalciferol daily.

• Symptomatic patients with a serum 25(OH)D level of <12 ng/mL should receive 30,000 international units of cholecalciferol per week.

• Asymptomatic patients with a serum 25(OH)D level of <12 ng/mL should receive 4000 to 5000 international units of cholecalciferol daily.

• Clinicians should monitor 25(OH)D levels every 12 weeks for patients receiving cholecalciferol at an equivalent dose of >2000 international units per day.

CKD patients with vitamin D deficiency or insufficiency: The KDIGO guideline recommends treating vitamin D deficiency or insufficiency in CKD patients similarly to the general population if there is no severe hyperparathyroidism. Clinicians should regularly monitor serum levels of vitamin D, calcium, and phosphate. On the other hand, CKD patients with significantly elevated parathyroid hormone are recommended to receive calcitriol or vitamin D analogs rather than cholecalciferol.[30]

Secondary hyperparathyroidism: Secondary hyperparathyroidism in CKD patients may involve the use of cholecalciferol, although it is not the preferred option. Calcium supplements combined with active vitamin D, such as alfacalcidol and calcitriol, are recommended to address secondary hyperparathyroidism.[31]

Osteoporosis prevention: The National Osteoporosis Foundation (NOF) recommends a daily oral intake of cholecalciferol at a dosage of 800 to 1000 international units for adults aged 50 or older.[32]

Specific Patient Populations

Hepatic impairment: Cholecalciferol does not require dosage adjustment for individuals with hepatic impairment.

Renal impairment: Cholecalciferol does not require dosage adjustment for individuals with renal impairment.

Pregnancy considerations: The American College of Obstetrics and Gynecology (ACOG) and Institute of Medicine (IOM) recommend daily vitamin D supplementation of 600 international units during pregnancy.[33] This dosage maintains the requirements of both the developing fetus and the pregnant woman. The developing fetus requires vitamin D, potentially leading to decreased vitamin D levels in pregnant women.[34] In the case of pregnancy with vitamin D deficiency, which is 25(OH)D <20 ng/mL, the ACOG guideline recommends a daily intake of 1000 to 2000 international units of vitamin D.

Breastfeeding considerations: Unlike infant formulas fortified with vitamin D, breast milk lacks adequate vitamin D for infants.[35] Therefore, breastfed infants must supplement 400 international units of vitamin D daily to prevent rickets.

Alternatively, supplementing the breastfeeding mother with 6400 international units of vitamin D daily can adequately provide vitamin D to exclusively breastfed infants through breast milk.[36]

Pediatric patients: The World Health Organization (WHO) recommends vitamin D supplementation for children at risk of deficiency, such as those with limited exposure to sunlight.[37] The Endocrine Society and IOM recommend supplementing children aged 1 to 18 with 600 to 1000 international units of vitamin D daily. Experts do not generally recommend regular testing of vitamin D levels in children.

Older patients: As vitamin D deficiency increases the risk of bone fractures,[38] older patients with vitamin D deficiency should receive calcium and cholecalciferol to reduce the risk of fractures. Studies indicate that a daily intake of 800 to 1000 international units of cholecalciferol and 1000 mg of calcium can reduce the risk of fractures by 8% to 12%.

Adverse Effects

Although cholecalciferol is generally considered safe, its adverse effects can occur due to high vitamin D levels.[39] High-loading doses of cholecalciferol, ranging from 300,000 to 600,000 international units, have been associated with falls and fractures.[40] Therefore, the NOF guideline recommends limiting the use of such high doses to symptomatic patients or those at risk of hypocalcemia due to potent antiresorptive therapy.[40][41]

Drug-Drug Interactions

Bile acid sequestrants—colestipol and cholestyramine—interact with cholecalciferol in 2 ways.[42] As cholecalciferol is a fat-soluble vitamin, bile acid sequestrants bind to it and decrease its absorption. In addition, bile acid sequestrants promote the excretion of bile acids.

As cholecalciferol is a fat-soluble vitamin, orlistat—a lipase inhibitor—binds to cholecalciferol from food or supplementation, resulting in decreased absorption of cholecalciferol.[42]

Contraindications

Cholecalciferol is contraindicated in patients with inherited 24-hydroxylase deficiency.[43] In this rare genetic mutation, the catabolism of cholecalciferol decreases, which may lead to vitamin D–dependent hypercalcemia.[44]

Monitoring

Clinicians determine vitamin D status by measuring the 25(OH)D serum concentration.[27] Laboratories report vitamin D levels in ng/mL or nmol/L, and to convert from ng/mL to nmol/L, one can multiply by 2.496.

Routine testing for vitamin D status in the general population is not a standard practice. However, screening for vitamin D deficiency or insufficiency proves beneficial in individuals with specific risk factors, including malnutrition, malabsorption, and hepatic and renal diseases.[45]

KDIGO guidelines recommend monitoring calcium, phosphorus, parathyroid hormone, and alkaline phosphatase in patients with CKD stage 3 or more.[46]

Toxicity

On average, individuals need approximately 15 to 20 minutes of sun exposure per day to synthesize vitamin D.[29] The likelihood of vitamin D toxicity from excessive sunlight exposure is low, as the skin naturally degrades excess vitamin D.

Signs and Symptoms of Overdose

Although rare, cholecalciferol toxicity occurs when serum 25(OH)D levels exceed 220 nmol/L.[47] Symptoms of cholecalciferol toxicity are nonspecific and may include confusion, vomiting, abdominal pain, polydipsia, polyuria, and dehydration.[48]

Cholecalciferol toxicity may result in hypercalcemia and hypercalciuria, potentially leading to complications such as nephrolithiasis, nephrotoxicity, and hyperphosphatemia.[39]

Management of Overdose

Supportive therapy involves discontinuing cholecalciferol and stabilizing the patient, which represents the first step in treating cholecalciferol toxicity. Pharmacological intervention for hypercalcemia may become necessary, with examples of such therapies being loop diuretics or bisphosphonates. In instances of life-threatening hypercalcemia, intermittent hemodialysis may be required.[49]

Enhancing Healthcare Team Outcomes

Vitamin D insufficiency and deficiency are prevalent worldwide. Hence, it is crucial to raise awareness among healthcare professionals about the significance of regularly monitoring vitamin D levels and provide patient education on the subject. The highest prevalence of vitamin D deficiency is observed among African Americans (82.1%), Hispanics (62.9%), adults with obesity, pregnant women, and children aged between 1 and 11.[50] Obesity (BMI over 30) is strongly associated with low vitamin D levels, potentially attributed to reduced sun exposure due to limited mobility. Moreover, bariatric surgery or gastric bypass procedures elevate the risk of malabsorption of fat-soluble vitamins such as A, D, E, and K.[51] 

Ensuring sufficient vitamin D supplementation for children prevents rickets and osteomalacia. In the United States, the production of vitamin D–fortified milk has been ongoing since 1933, following the recommendation of the American Medical Association Council on Foods.[52] However, relying solely on food fortification is often inadequate, especially for individuals with limited sun exposure.

Although cholecalciferol is readily available as a supplement, an interprofessional healthcare team approach is crucial for ensuring proper use and correct dosing regimens. Clinicians prescribe cholecalciferol based on assessments involving 25(OH)D serum levels, clinical signs, and patient history. Pharmacists are crucial in aiding patients in selecting the appropriate dosage form of cholecalciferol, checking for potential drug interactions, and providing guidance on proper administration. Nurses are essential in follow-up care, assessing patient adherence to therapy, and monitoring symptoms. A collaborative effort among all healthcare team members is crucial to coordinate actions and optimize patient outcomes with cholecalciferol therapy.

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References

1.

Galesanu C, Mocanu V. VITAMIN D DEFICIENCY AND THE CLINICAL CONSEQUENCES. Rev Med Chir Soc Med Nat Iasi. 2015 Apr-Jun;119(2):310-8. [PubMed: 26204630]

2.

Haines ST, Park SK. Vitamin D supplementation: what's known, what to do, and what's needed. Pharmacotherapy. 2012 Apr;32(4):354-82. [PubMed: 22461123]

3.

Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011 Apr 09;377(9773):1276-87. [PMC free article: PMC3555696] [PubMed: 21450337]

4.

Bikle DD. Vitamin D: Production, Metabolism and Mechanisms of Action. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. MDText.com, Inc.; South Dartmouth (MA): Dec 31, 2021. [PubMed: 25905172]

5.

Khazai N, Judd SE, Tangpricha V. Calcium and vitamin D: skeletal and extraskeletal health. Curr Rheumatol Rep. 2008 Apr;10(2):110-7. [PMC free article: PMC2669834] [PubMed: 18460265]

6.

Sirajudeen S, Shah I, Al Menhali A. A Narrative Role of Vitamin D and Its Receptor: With Current Evidence on the Gastric Tissues. Int J Mol Sci. 2019 Aug 05;20(15) [PMC free article: PMC6695859] [PubMed: 31387330]

7.

Kinyamu HK, Gallagher JC, Balhorn KE, Petranick KM, Rafferty KA. Serum vitamin D metabolites and calcium absorption in normal young and elderly free-living women and in women living in nursing homes. Am J Clin Nutr. 1997 Mar;65(3):790-7. [PubMed: 9062531]

8.

Benedik E. Sources of vitamin D for humans. Int J Vitam Nutr Res. 2022 Mar;92(2):118-125. [PubMed: 34658250]

9.

Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014 Mar 20;21(3):319-29. [PMC free article: PMC3968073] [PubMed: 24529992]

10.

Woo DK, Eide MJ. Tanning beds, skin cancer, and vitamin D: An examination of the scientific evidence and public health implications. Dermatol Ther. 2010 Jan-Feb;23(1):61-71. [PubMed: 20136909]

11.

Silva MC, Furlanetto TW. Intestinal absorption of vitamin D: a systematic review. Nutr Rev. 2018 Jan 01;76(1):60-76. [PubMed: 29025082]

12.

Reboul E, Goncalves A, Comera C, Bott R, Nowicki M, Landrier JF, Jourdheuil-Rahmani D, Dufour C, Collet X, Borel P. Vitamin D intestinal absorption is not a simple passive diffusion: evidences for involvement of cholesterol transporters. Mol Nutr Food Res. 2011 May;55(5):691-702. [PubMed: 21280209]

13.

Mulligan GB, Licata A. Taking vitamin D with the largest meal improves absorption and results in higher serum levels of 25-hydroxyvitamin D. J Bone Miner Res. 2010 Apr;25(4):928-30. [PubMed: 20200983]

14.

Dawson-Hughes B, Harris SS, Lichtenstein AH, Dolnikowski G, Palermo NJ, Rasmussen H. Dietary fat increases vitamin D-3 absorption. J Acad Nutr Diet. 2015 Feb;115(2):225-230. [PubMed: 25441954]

15.

Borel P, Caillaud D, Cano NJ. Vitamin D bioavailability: state of the art. Crit Rev Food Sci Nutr. 2015;55(9):1193-205. [PubMed: 24915331]

16.

Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr. 2008 Aug;88(2):582S-586S. [PubMed: 18689406]

17.

Park CY, Han SN. The Role of Vitamin D in Adipose Tissue Biology: Adipocyte Differentiation, Energy Metabolism, and Inflammation. J Lipid Atheroscler. 2021 May;10(2):130-144. [PMC free article: PMC8159757] [PubMed: 34095008]

18.

Ponchon G, Kennan AL, DeLuca HF. "Activation" of vitamin D by the liver. J Clin Invest. 1969 Nov;48(11):2032-7. [PMC free article: PMC297455] [PubMed: 4310770]

19.

Khundmiri SJ, Murray RD, Lederer E. PTH and Vitamin D. Compr Physiol. 2016 Mar 15;6(2):561-601. [PubMed: 27065162]

20.

Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, Hewison M. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab. 2001 Feb;86(2):888-94. [PubMed: 11158062]

21.

Williams S, Malatesta K, Norris K. Vitamin D and chronic kidney disease. Ethn Dis. 2009 Autumn;19(4 Suppl 5):S5-8-11. [PMC free article: PMC2878736] [PubMed: 20077598]

22.

Latic N, Erben RG. FGF23 and Vitamin D Metabolism. JBMR Plus. 2021 Dec;5(12):e10558. [PMC free article: PMC8674776] [PubMed: 34950827]

23.

Dawson PA. Role of the intestinal bile acid transporters in bile acid and drug disposition. Handb Exp Pharmacol. 2011;(201):169-203. [PMC free article: PMC3249407] [PubMed: 21103970]

24.

DeLuca HF. Metabolism of vitamin D: current status. Am J Clin Nutr. 1976 Nov;29(11):1258-70. [PubMed: 187053]

25.

Vieth R, Kimball S, Hu A, Walfish PG. Randomized comparison of the effects of the vitamin D3 adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients. Nutr J. 2004 Jul 19;3:8. [PMC free article: PMC506781] [PubMed: 15260882]

26.

Jean G, Souberbielle JC, Chazot C. Vitamin D in Chronic Kidney Disease and Dialysis Patients. Nutrients. 2017 Mar 25;9(4) [PMC free article: PMC5409667] [PubMed: 28346348]

27.

Ganji V, Tangpricha V, Zhang X. Serum Vitamin D Concentration ≥75 nmol/L Is Related to Decreased Cardiometabolic and Inflammatory Biomarkers, Metabolic Syndrome, and Diabetes; and Increased Cardiorespiratory Fitness in US Adults. Nutrients. 2020 Mar 10;12(3) [PMC free article: PMC7146199] [PubMed: 32164233]

28.

Dawson-Hughes B, Mithal A, Bonjour JP, Boonen S, Burckhardt P, Fuleihan GE, Josse RG, Lips P, Morales-Torres J, Yoshimura N. IOF position statement: vitamin D recommendations for older adults. Osteoporos Int. 2010 Jul;21(7):1151-4. [PubMed: 20422154]

29.

Khan QJ, Fabian CJ. How I treat vitamin d deficiency. J Oncol Pract. 2010 Mar;6(2):97-101. [PMC free article: PMC2835491] [PubMed: 20592785]

30.

Uhlig K, Berns JS, Kestenbaum B, Kumar R, Leonard MB, Martin KJ, Sprague SM, Goldfarb S. KDOQI US commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD-Mineral and Bone Disorder (CKD-MBD). Am J Kidney Dis. 2010 May;55(5):773-99. [PubMed: 20363541]

31.

Brandi ML, Bilezikian JP, Shoback D, Bouillon R, Clarke BL, Thakker RV, Khan AA, Potts JT. Management of Hypoparathyroidism: Summary Statement and Guidelines. J Clin Endocrinol Metab. 2016 Jun;101(6):2273-83. [PubMed: 26943719]

32.

Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R., National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014 Oct;25(10):2359-81. [PMC free article: PMC4176573] [PubMed: 25182228]

33.

Urrutia RP, Thorp JM. Vitamin D in pregnancy: current concepts. Curr Opin Obstet Gynecol. 2012 Mar;24(2):57-64. [PMC free article: PMC3709246] [PubMed: 22327734]

34.

Pérez-López FR, Pilz S, Chedraui P. Vitamin D supplementation during pregnancy: an overview. Curr Opin Obstet Gynecol. 2020 Oct;32(5):316-321. [PubMed: 32487800]

35.

O'Callaghan KM, Taghivand M, Zuchniak A, Onoyovwi A, Korsiak J, Leung M, Roth DE. Vitamin D in Breastfed Infants: Systematic Review of Alternatives to Daily Supplementation. Adv Nutr. 2020 Jan 01;11(1):144-159. [PMC free article: PMC7442322] [PubMed: 31552417]

36.

Hollis BW, Wagner CL, Howard CR, Ebeling M, Shary JR, Smith PG, Taylor SN, Morella K, Lawrence RA, Hulsey TC. Maternal Versus Infant Vitamin D Supplementation During Lactation: A Randomized Controlled Trial. Pediatrics. 2015 Oct;136(4):625-34. [PMC free article: PMC4586731] [PubMed: 26416936]

37.

Corsello A, Spolidoro GCI, Milani GP, Agostoni C. Vitamin D in pediatric age: Current evidence, recommendations, and misunderstandings. Front Med (Lausanne). 2023;10:1107855. [PMC free article: PMC10060648] [PubMed: 37007781]

38.

Smith LM, Gallagher JC. Dietary Vitamin D Intake for the Elderly Population: Update on the Recommended Dietary Allowance for Vitamin D. Endocrinol Metab Clin North Am. 2017 Dec;46(4):871-884. [PMC free article: PMC5821124] [PubMed: 29080640]

39.

Razzaque MS. Can adverse effects of excessive vitamin D supplementation occur without developing hypervitaminosis D? J Steroid Biochem Mol Biol. 2018 Jun;180:81-86. [PubMed: 28734988]

40.

Aspray TJ, Bowring C, Fraser W, Gittoes N, Javaid MK, Macdonald H, Patel S, Selby P, Tanna N, Francis RM., National Osteoporosis Society. National Osteoporosis Society vitamin D guideline summary. Age Ageing. 2014 Sep;43(5):592-5. [PubMed: 25074538]

41.

Shalit R, Tripto-Shkolnik L. SEIZURES ASSOCIATED WITH ZOLEDRONIC ACID (ZA) THERAPY: A CASE REPORT AND REVIEW OF THE LITERATURE. AACE Clin Case Rep. 2020 Nov-Dec;6(6):e315-e318. [PMC free article: PMC7685415] [PubMed: 33244492]

42.

Robien K, Oppeneer SJ, Kelly JA, Hamilton-Reeves JM. Drug-vitamin D interactions: a systematic review of the literature. Nutr Clin Pract. 2013 Apr;28(2):194-208. [PMC free article: PMC5623087] [PubMed: 23307906]

43.

Pludowski P, Takacs I, Boyanov M, Belaya Z, Diaconu CC, Mokhort T, Zherdova N, Rasa I, Payer J, Pilz S. Clinical Practice in the Prevention, Diagnosis and Treatment of Vitamin D Deficiency: A Central and Eastern European Expert Consensus Statement. Nutrients. 2022 Apr 02;14(7) [PMC free article: PMC9002638] [PubMed: 35406098]

44.

Cappellani D, Brancatella A, Morganti R, Borsari S, Baldinotti F, Caligo MA, Kaufmann M, Jones G, Marcocci C, Cetani F. Hypercalcemia due to CYP24A1 mutations: a systematic descriptive review. Eur J Endocrinol. 2021 Dec 10;186(2):137-149. [PubMed: 34735369]

45.

Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: when to test and how to treat. Mayo Clin Proc. 2010 Aug;85(8):752-7; quiz 757-8. [PMC free article: PMC2912737] [PubMed: 20675513]

46.

Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl (2011). 2017 Jul;7(1):1-59. [PMC free article: PMC6340919] [PubMed: 30675420]

47.

Bischoff-Ferrari HA. How to select the doses of vitamin D in the management of osteoporosis. Osteoporos Int. 2007 Apr;18(4):401-7. [PubMed: 17151835]

48.

Marcinowska-Suchowierska E, Kupisz-Urbańska M, Łukaszkiewicz J, Płudowski P, Jones G. Vitamin D Toxicity-A Clinical Perspective. Front Endocrinol (Lausanne). 2018;9:550. [PMC free article: PMC6158375] [PubMed: 30294301]

49.

Lim K, Thadhani R. Vitamin D Toxicity. J Bras Nefrol. 2020 Apr 03;42(2):238-244. [PMC free article: PMC7427646] [PubMed: 32255467]

50.

Forrest KY, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res. 2011 Jan;31(1):48-54. [PubMed: 21310306]

51.

Vanlint S. Vitamin D and obesity. Nutrients. 2013 Mar 20;5(3):949-56. [PMC free article: PMC3705328] [PubMed: 23519290]

52.

Institute of Medicine (US) Panel on Micronutrients. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. National Academies Press (US); Washington (DC): 2001. [PubMed: 25057538]

Disclosure: Nazik Al-Hashimi declares no relevant financial relationships with ineligible companies.

Disclosure: Sherly Abraham declares no relevant financial relationships with ineligible companies.