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Cholecalciferol
Indications
Cholecalciferol, also known as vitamin D3, is a secosteroid produced by the skin and can also be present in certain foods such as dairy products, eggs, and fish. Its primary function is to maintain normal calcium and phosphate levels in the serum. During winter and in areas with minimal sun exposure, dietary supplementation is necessary for optimal musculoskeletal health.
The labeled indication for cholecalciferol is dietary supplementation. The off-label indications for cholecalciferol include hypothyroidism, prevention of osteoporosis, and Vitamin D insufficiency/ deficiency in both healthy patients or those with chronic kidney disease (CKD).[1]
Aside from its known role in bone mineral metabolism, various studies have found a link between cholecalciferol supplementation and favorable prognoses of different diseases such as hypertension, type 1 and 2 diabetes, cardiovascular disease, cancer, rheumatoid arthritis (RA), polycystic ovarian syndrome (POS), multiple sclerosis (MS), systemic lupus erythematosus (SLE), and various dermatologic diseases.[2]
Mechanism of Action
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Mechanism of Action
Cholecalciferol gets generated in the skin upon sun exposure. Light energy is absorbed in the skin via 7-dehydrocholesterol, where the ultraviolet B (UVB) converts 7-dehydrocholesterol to cholecalciferol, an inactive vitamin D molecule.[3]
Cholecalciferol undergoes two hydroxylation processes to activate it. The initial hydroxylation occurs in the liver via the enzyme 25-hydroxylase and results in 25-hydroxycholecalciferol, which is used to assess the body’s reserve of vitamin D because it has a longer half-life compared to 1,25-dihydroxycholecalciferol. 1,25-dihydroxycholecalciferol has a half-life of 15 hours, while 25-hydroxycholecalciferol has a half-life of 15 days.[1]
The second hydroxylation occurs in the kidneys via the enzyme 1-alpha-hydroxylase, yielding 1,25- dihydroxycholecalciferol (calcitriol), the biologically active form of vitamin D. 1,25-dihydroxycholecalciferol production in the kidneys undergoes regulation by parathyroid hormone (PTH), calcium, and phosphorus levels.[1]
Calcitriol is a hydrophobic molecule requiring a carrier protein such as vitamin D-binding protein for transport in the bloodstream. Once released, calcitriol binds intracellular vitamin D receptors (VDR) that researchers discovered to not only be in the small intestines, renal tubules, and bones but also various types of cell types such as lymphocytes, pancreatic cells, keratinocytes, parathyroid, and pituitary gland cells. The activated VDR, in turn, induces transcription activation of certain genes and suppression of others.[2]
Calcitriol is the main hormone controlling mineral homeostasis and bone function. It promotes calcium and phosphate absorption from the small intestine, increases bone mineral density by suppressing bone resorption, and increases phosphate secretion in the renal tubule.[4][5]
Hypertension
Recent studies indicated that calcitriol regulates the renin-angiotensin system (RAS) by decreasing renin expression via a VDR-mediated mechanism.[6] Other studies have shown that calcitriol has also decreased the expression of angiotensin-1 receptors in endothelial cells via the same mechanism, improving endothelial function and decreasing the severity of hypertension overall.[7]
Type 1 Diabetes
Experimental studies have shown significant improvement in fasting glucose and insulin-like growth factor 1 (IGF-1) in type 1 diabetes rat models after vitamin D supplementation.[8] Another study showed significant improvement in insulin secretion and suppression of apoptosis of pancreatic beta cells in type 1 diabetes mice models.[9] This observation was thought to be the result of its anti-inflammatory effects. A study focusing on the impact of vitamin D on inflammation concluded that vitamin D supplementation decreased inflammation markers such as TNF-alpha and IL-6 in patients with type 1 diabetes.[10]
Type 2 Diabetes
The anti-inflammatory effects of vitamin D also appear in type 2 diabetes, where it was noted to significantly reduce insulin resistance by decreasing the pancreatic oxidative stress and inflammation markers. Similarly, another study indicated that vitamin D enhances leptin levels, decreasing C reactive protein, ESR, and TNF-alpha. Several clinical trials suggested that vitamin D supplementation improved glycemic control in prediabetics, patients with diabetes, and patients with gestational diabetes.[11][12]
Cardiovascular Disease
In addition to its anti-inflammatory effect on the endothelial cells and its regulation of the RAS, vitamin D also exerts its positive effects on the cardiovascular system by its antithrombotic effects. Vitamin D was shown to downregulate the expression of prothrombotic factors such as thrombospondin, plasminogen activator inhibitor-1, and tissue factors such as vascular smooth muscle cell-derived tissue factor (VSMC-derived TF) via a VDR-mediated mechanism.[13] Vitamin D was also discovered to have an antihypertrophic effect on the myocardium by inhibiting pro-hypertrophic calcineurin, cardiac RAS, nuclear factor of activated T cells (NFAT), and myocardial proliferation. Multiple studies on VDR knockout mice have indicated myocardial hypertrophy.[14] Randomized clinical trials have found an inverse relationship between serum 25-hydroxycholecalciferol level and the number of cardiovascular disease (CVD) events and mortality.[15]
Cancer
Vitamin D has been noted to have an inhibitory effect on angiogenesis, proliferation, and metastasis of cancer cells. In a study on the effect of vitamin D on gastric cancer cell proliferation, the research showed that vitamin D inhibited the growth of gastric cancer cells by p21 stimulation and CDK2 suppression, which are important cell cycle regulatory molecules.[16] Degradation of the extracellular matrix is an important step in cancer cell metastasis. In a study on the effect of vitamin D on cancer cell metastasis, researchers noted that vitamin D exerted an anti-metastatic effect by downregulating proteases that break down the extracellular matrix and upregulating protease inhibitors that inhibit that process.[17] More importantly, vitamin D was also discovered to regulate angiogenesis in several mechanisms. One study indicated that vitamin D downregulates vascular endothelial growth factor (VEGF).[18] Another mechanism by which vitamin D interferes with cancer cell angiogenesis is by inhibiting the proinflammatory NF-κB signaling pathway, which induces angiogenic factors.[19]
Polycystic Ovarian Syndrome
Vitamin D deficiency is common in patients with polycystic ovarian syndrome.[20] Several clinical trials have indicated that vitamin D supplementation resulted in menstrual cycle regulation, lowering of triglycerides levels, and improvement of follicular development.[21] A reduction of inflammatory markers and oxidative stress was observed following vitamin D supplementation and had links to the improvement seen in patients with PCOS.[22]
Similarly, several experimental studies and RCTs have attributed the positive effects of vitamin D on other diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, atopic dermatitis, and psoriasis its anti-oxidative and anti-inflammatory functions.[2]
Administration
Adults
Vitamin D Deficiency/Insufficiency
The optimum level of Vitamin D remains controversial. The Institute of Medicine (IOM) defines it as over 20 ng/mL, whereas others define it as over 30 ng/mL or a range between 25 to 80 ng/mL.[23] The American Geriatric Society and Endocrine Society define vitamin D insufficiency as levels ranging between 20 to 29.9 ng/mL, while vitamin D deficiency as levels <20 ng/mL.
Vitamin D Insufficiency in Healthy Adults (Serum 25-hydroxyvitamin D level of 20 to 30 ng per mL/50 to 75 nmol per L)
Oral supplements of 1000 to 2000 units once daily. Serum vitamin D levels could be reassessed in 3 months.[24]
Vitamin D Deficiency in Healthy Adults (Serum 25-hydroxyvitamin D level of less than 20 ng per mL/50 nmol per L)
Dosing with 2000 units once daily with a 3-month vitamin D serum level reassessment. If the target level has not been reached, 2000 units once daily or 50000 units once weekly for 6 to 8 weeks.[24][25]
Maintenance dosing for both vitamin D deficiency and insufficiency is very patient-specific and depends on the target level and other comorbidities that may affect its metabolism and absorption.[25]
Vitamin D Deficiency/Insufficiency in Chronic Kidney Disease (CKD) Patients
The current recommendation indicates treating vitamin D deficiency/insufficiency in CKD patients without severe hyperparathyroidism, similarly to the general population. Regular blood tests to monitor vitamin D, calcium, phosphate serum levels are advised. On the other hand, CKD patients with severely elevated parathyroid hormone (PTH) are recommended to receive calcitriol or vitamin D analogs rather than cholecalciferol.[26]
Hypoparathyroidism
Calcium supplements, combined with active vitamin D, such as alfacalcidol and calcitriol, are recommended for hypoparathyroidism. Cholecalciferol or ergocalciferol are also options.[27]
Osteoporosis Prevention
Oral dosage is 800 to 1000 units daily for adults greater than or equal to 50 years old.
Pediatrics
Rickets Prevention
- Breastfed infants: Oral 400 units daily starting from a few days of age until 12 months of age when the infant gets weaned to greater than or equal to 1000 mL daily vitamin D-fortified formula or whole milk
- Formula-fed infants: oral 400 units daily for infants ingesting less than 1000 mL daily vitamin D-fortified formula[28]
Rickets Treatment
- Infants: oral 2000 units daily for three months
- Children: oral 3000 to 6000 units daily for three months
- Adolescents: oral 6000 units daily
The maintenance dosage of oral 400 to 600 units daily is also a recommendation.[28]
Vitamin D Deficiency in Patients with Cystic Fibrosis
- Infants: oral 400 to 500 units daily
- Children 10 years and under: oral 800 to 1000 units daily
- Children over10 years: oral 800 to 2000 units daily
Adverse Effects
Although rare, cholecalciferol has a few adverse effects that include hypercalcemia, hypercalciuria which could lead to nephrolithiasis, nephrotoxicity, and hyperphosphatemia.[29]
Contraindications
The FDA classified cholecalciferol as a pregnancy drug category C under its prior pregnancy classification system, indicating that teratogenicity risks cannot be ruled out, and clinicians should only use this agent when benefits outweigh risks.[30]
Monitoring
While on cholecalciferol, it is advised to monitor the levels of alkaline phosphatase, BUN to creatinine ratio, calcium (free and total), magnesium, and phosphate. It is also essential to ensure that patients are not confusing cholecalciferol with other sound-alike or look-alike medications such as alfacalcidol and ergocalciferol.
Toxicity
Despite its safety, excessive use can lead to Vitamin D toxicity, which manifests with nausea, vomiting, decreased appetite, fatigue, weight loss, constipation, dehydration, irritability, and confusion. Those symptoms are still observable for more than two months after drug discontinuation and largely derive from the effects of hypercalcemia.[5][31][5]
Enhancing Healthcare Team Outcomes
Vitamin D insufficiency (level between 20 and 29.9 ng/mL) and deficiency (a level below 20 ng/mL) are widespread worldwide. Spreading awareness among healthcare professionals regarding the importance of regular vitamin D level monitoring as well as patient education about vitamin D is crucial. Groups that have been shown to have the highest prevalence of vitamin D deficiency include African Americans (82.1%), Hispanics (62.9%), obese adults, pregnant women, and children between 1 and 11 years of age.[32] Obesity (BMI over 30) strongly correlates with low vitamin D levels. This correlation could be due to decreased mobility, hence reduced sun exposure, as well as being eligible for bariatric or gastric bypass procedures, which put patients at risk for malabsorption of fat-soluble vitamins A, D, E, and K.[33]
Adequate supplementation of vitamin D to children is especially important, not only to prevent rickets and osteomalacia but also because there has been growing evidence that vitamin D deficiency has links to chronic diseases in adulthood such as coronary artery disease, hypertension, diabetes, and cancer.[34] In the United States, vitamin D-fortified milk has been in production since 1933, based on the recommendation of the American Medical Association Council on Foods.[35] Food fortification by itself is still not sufficient, especially in those with limited sun exposure. Hence, vitamin D supplementation is widely available both over the counter (1000 to 5000 IU) and via prescription (50000 IU).[36]
Even though it is a vitamin and available as a supplement, cholecalciferol use and dosing benefit greatly from the efforts of an interprofessional healthcare team approach; the clinician will be responsible for prescribing or recommending the drug, based on testing or clinical signs/patient history. Patients may not be aware of the various forms of vitamin D, and as a result, either over or underdose because of this knowledge gap, so the pharmacist should help guide them in making a selection in tandem with the wishes of the treating clinician. Nursing can perform a follow-up and assess patient compliance and therapeutic effectiveness. All team members need to coordinate their efforts to optimize patient outcomes with cholecalciferol therapy. [Level 5]
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