Continuing Education Activity

Vitamin D is a fat-soluble nutrient essential for bone development and maintenance, as it enhances calcium, magnesium, and phosphate absorption. A circulating 25-hydroxyvitamin D level above 30 ng/mL is necessary to ensure adequate levels of the unmodified molecule. Deficiency can lead to various complications, most notably rickets in children and osteoporosis in adults. Milk fortification with vitamin D in the 1930s effectively eradicated rickets worldwide, yet deficiency remains widespread, warranting screening in high-risk populations. Studies have shown conflicting associations between vitamin D deficiency and cancer, cardiovascular disease, diabetes, autoimmune disorders, and depression.

The evaluation of vitamin D deficiency involves measuring serum levels of the 25-hydroxy form, with values below 20 ng/mL indicating deficiency and levels between 20 and 30 ng/mL suggesting insufficiency. Management includes supplementation with vitamin D2 or D3, tailored to the severity of deficiency, along with dietary modifications and adequate sun exposure. High-risk populations, such as individuals with limited sun exposure, older adults, and people with malabsorption disorders, require routine screening and monitoring to ensure optimal vitamin D status.

This activity for healthcare professionals is designed to enhance learners' proficiency in evaluating and managing vitamin D deficiency. Participants will deepen their understanding of the condition's risk factors, etiology, pathophysiology, and symptomatology, as well as the recommended strategies for its diagnosis and treatment. Improved clinical capabilities will enhance teamwork within an interprofessional team caring for patients with vitamin D deficiency, ensuring good outcomes.

Objectives:

• Identify the risk factors causing vitamin D deficiency in patients presenting with suggestive signs and symptoms.

• Select the appropriate diagnostic tools for suspected vitamin D deficiency cases.

• Implement individualized approaches for managing vitamin D deficiency or insufficiency.

• Collaborate with the interprofessional team to educate, treat, and monitor patients with vitamin D deficiency to improve patient outcomes.

Introduction

Vitamin D is a fat-soluble nutrient essential for calcium homeostasis and bone metabolism. Deficiency of this beneficial substance can lead to nutritional rickets in children and osteomalacia in adults.[1] In the 1930s, North America began fortifying milk with vitamin D to eradicate dietary rickets in children.[2] The recommended daily intake for adults ranges from 400 to 800 international units (IU).[3] However, subclinical vitamin D deficiency remains prevalent worldwide, affecting up to 1 billion people in both developed and developing countries.[4] Subclinical vitamin D deficiency is linked to osteoporosis, increased risk of falls, and fragility fractures. Recent observational studies have shown a potential correlation between vitamin D deficiency and cancer, cardiovascular disease, diabetes, autoimmune diseases, and depression.[5]

The optimal blood concentration of vitamin D remains controversial. According to the 2019 Endocrine Society guidelines, vitamin D sufficiency is defined as having a serum total 25-hydroxyvitamin D level greater than 30 ng/mL (50 nmol/L). Vitamin D insufficiency is defined as having a total 25-hydroxyvitamin D level between 12 and 20 ng/mL (30 to 50 nmol/L), while vitamin D deficiency is defined as having a level below 12 ng/mL (30 nmol/L).

Etiology

Since few foods, such as fatty fish livers and fortified products, are significant sources of vitamin D, the dermal synthesis of vitamin D becomes the primary source of cholecalciferol (vitamin D3). Both cholecalciferol and ergocalciferol (vitamin D2) are converted into their respective 25-hydroxy forms—25-hydroxyvitamin D2 and 25-hydroxyvitamin D3—in the liver by hepatic 25-hydroxylase. These forms are further converted into the most active vitamin D metabolite, 1,25-dihydroxyvitamin D, by the enzyme 1α-hydroxylase in the kidneys. This active form enhances calcium absorption in the intestines, promotes bone resorption, and reduces renal excretion of calcium and phosphate.[6] Cytochrome P450 mixed-function oxidases catalyze all hydroxylation steps.[7]

Vitamin D deficiency can result from a range of causes, potentially disrupting one or more stages of vitamin D activation. The following are the most important factors:

• Decreased dietary intake or absorption: Certain malabsorption syndromes, such as celiac disease, short bowel syndrome, gastric bypass, inflammatory bowel disease, chronic pancreatic insufficiency, and cystic fibrosis, may lead to vitamin D deficiency. Older individuals are more likely to take lower amounts of vitamin D orally.[8]
• Decreased sun exposure: About 20 minutes of sunshine daily, with over 40% of skin exposed, is required to prevent vitamin D deficiency.[9] However, cutaneous synthesis of vitamin D declines with aging. Dark-skinned individuals have less cutaneous vitamin D synthesis. Decreased exposure to the sun, as seen in individuals who are institutionalized or have prolonged hospitalizations, can also lead to vitamin D deficiency.[10] Individuals who use sunscreens consistently reduce the opportunity for effective sun exposure.
• Decreased endogenous synthesis: Individuals with chronic liver conditions, such as cirrhosis, can have defective 25-hydroxylation, leading to a deficiency of active vitamin D.[11] Defects in 1α-25-hydroxylation can be seen in renal failure and hypoparathyroidism.[12][13]
• Increased hepatic catabolism: Medications such as phenobarbital, carbamazepine, dexamethasone, nifedipine, spironolactone, clotrimazole, and rifampin induce hepatic p450 enzymes, which accelerate the degradation of vitamin D into inactive metabolites.[14]
• End-organ resistance: Hereditary vitamin D-resistant rickets may cause end-organ resistance to this nutrient.[15]

Epidemiology

Vitamin D deficiency is a global public health issue, affecting approximately 1 billion people worldwide. Nearly 50% of some populations experience vitamin D insufficiency. The highest prevalence of deficiency is found among older adults, individuals with obesity, nursing home residents, and hospitalized patients. Individuals with obesity have a 35% higher prevalence of vitamin D deficiency, regardless of latitude or age.[16] In the United States, about 50% to 60% of nursing home residents and hospitalized patients are vitamin D-deficient.[17][18]

Individuals who have higher skin melanin content or practice extensive skin coverage, particularly in Middle Eastern countries, may also be at greater risk. In the United States, 47% of African American infants and 56% of Caucasian infants have vitamin D deficiency, while over 90% of infants in Iran, Turkey, and India are affected. Among adults, 35% of those in the U.S. are vitamin D deficient, whereas more than 80% of adults in Pakistan, India, and Bangladesh experience deficiency. In the U.S., 61% of older adults are deficient, compared to 90% in Turkey, 96% in India, 72% in Pakistan, and 67% in Iran.[19]

Vitamin D deficiency is also prevalent in individuals with chronic kidney disease. Hemodialysis, concomitant liver disease, or a prior liver transplant can increase this risk, affecting 85% to 99% of such patients.[20] Individuals admitted to intensive care units have higher rates of deficiency, which correlates with increased disease severity, morbidity, and mortality.[21]

Pathophysiology

Vitamin D is crucial for calcium homeostasis and bone metabolism, with its skeletal effects well-established. In cases of chronic or severe vitamin D deficiency, reduced intestinal absorption of calcium and phosphorus leads to lower blood calcium levels.[22] Diminished blood calcium triggers parathyroid hormone (PTH) production and secondary hyperparathyroidism. Elevated PTH levels stimulate osteoclast activity, which accelerates bone turnover, promotes phosphaturia, and causes thinning and porosity of cortical bone.[23] These effects can lead to osteomalacia and osteoporosis in adults and osteomalacia and rickets in children.

History and Physical

The majority of patients with vitamin D deficiency are asymptomatic. However, even mild, chronic vitamin D deficiency can lead to chronic hypocalcemia and secondary hyperparathyroidism, increasing the risk of osteoporosis, falls, and fractures, particularly in older individuals.[24] Prolonged and severe vitamin D deficiency can cause symptoms related to secondary hyperparathyroidism, including bone pain, arthralgia, myalgia, fatigue, muscle twitching (fasciculations), and weakness.[25] Chronic vitamin D deficiency may also result in fragility fractures and osteoporosis. In children, symptoms of vitamin D deficiency can include irritability, lethargy, developmental delay, bone changes, and fractures.[26]

Evaluation

High-risk individuals should be evaluated for vitamin D deficiency by obtaining total serum 25-hydroxyvitamin D. However, the optimal serum levels of 25-hydroxyvitamin D remain controversial.[27] Significant differences in mineral metabolism exist across different races. For instance, African Americans tend to have higher bone density and a lower fracture risk compared to other racial groups. Additionally, the effects of calcium and vitamin D supplementation in non-White populations have not been fully evaluated or reported. The International Society for Clinical Densitometry and the International Osteoporosis Foundation recommend maintaining serum 25-hydroxyvitamin D levels of at least 30 ng/mL to minimize the risk of falls and fractures in older individuals.[28]

Although the maximum safe upper level of serum 25-hydroxyvitamin D is not well-established, levels above 100 ng/mL may pose a risk of toxicity due to secondary hypercalcemia. Hypervitaminosis D, characterized by levels exceeding 150 ng/mL, is considered toxic.[29] When vitamin D deficiency is diagnosed, clinicians must assess for secondary hyperparathyroidism by obtaining PTH and serum calcium levels.

Treatment / Management

Vitamin D is available in several formulations. Notably, vitamin D3 is more efficacious than vitamin D2 when used to achieve optimal 25-hydroxyvitamin D levels, making it the preferred agent for correcting deficiencies of this nutrient.[30]

Prevention of Vitamin D Deficiency

Adults younger than 65 who do not receive adequate sun exposure year-round should consume 400 to 800 IU of vitamin D3 daily to prevent deficiency. For adults aged 65 and older, a daily intake of 800 to 1,000 IU of vitamin D3 is recommended to prevent deficiency and reduce the risk of fractures and falls.[31] Supplementation exceeding 4,000 IU daily is not recommended for adults replete with this vitamin.

Management of Vitamin D Deficiency

The amount of vitamin D required to address deficiencies depends largely on the condition's severity and underlying risk factors. Vitamin D2 is synthetic and less stable during storage than vitamin D3. However, vitamin D3 is more effective in raising serum 25-hydroxyvitamin D levels.[32]

For a serum level below 12 ng/mL, initial supplementation for 8 weeks with either vitamin D2 or D3 is recommended. Options include 6,000 IU (150 mcg) daily or 25,000 to 50,000 IU (625-1250 mcg) weekly. Once the serum 25-hydroxyvitamin D level exceeds 30 ng/mL, a daily maintenance dose of 1,000 to 2,000 IU is recommended. For high-risk adults who are vitamin D-deficient, such as African Americans, Hispanics, people with obesity, individuals taking certain medications, and patients with malabsorption syndrome, a higher initial dose of 10,000 IU (250 mcg) daily may be necessary. A maintenance dose of 3,000 to 6,000 IU daily is recommended after reaching a serum 25-hydroxyvitamin D level of 30 ng/mL.

For serum levels between 12 and 20 ng/mL, supplementation with 800 to 1,000 IU (20-25 mcg) daily should be initiated, and levels should be repeated after 3 months to ensure correction. The recommended daily dose should be continued once levels have normalized. For serum levels between 20 and 30 ng/mL, supplementation with 600 to 800 IU (15-20 mcg) daily is typically considered sufficient.

Children with vitamin D deficiency should receive 2,000 IU of vitamin D3 daily or 50,000 IU of vitamin D3 once weekly for 6 weeks. Once the serum 25-hydroxyvitamin D level exceeds 30 ng/mL, a maintenance dose of 1,000 IU daily is recommended. According to the American Academy of Pediatrics, 400 IU of vitamin D supplementation should be given to breastfed infants and children who consume less than 1 L of vitamin D-fortified milk a day.[33]

Calcitriol may be considered for individuals whose deficiency persists despite treatment with vitamin D2 or D3. Serum calcium levels should be closely monitored in these individuals due to the increased risk of hypercalcemia secondary to calcitriol use. Calcitriol does not require activation by 1α-hydroxylase in the kidney, making it the preferred option for individuals with advanced kidney failure or hypoparathyroidism.[34]

Calcidiol, a major circulating metabolite of cholecalciferol, may be considered in patients with severe hepatic dysfunction, as it does not require activation by 25-hydroxylase in the liver. The recommended dose ranges from 30 to 200 μg daily.[35]

Differential Diagnosis

The differential diagnosis of vitamin D deficiency should include the following conditions:

• Celiac sprue
• Cystic fibrosis
• End-stage liver disease
• Inadequate sunlight exposure
• Lack of dietary intake
• Use of antiepileptic medications

A comprehensive approach that includes these conditions in the differential diagnosis is necessary for properly identifying and managing vitamin D deficiency.

Pertinent Studies and Ongoing Trials

A meta-analysis of 18 randomized controlled trials (RCTs) involving over 57,000 participants found that daily vitamin D supplementation reduced total mortality rates.[36] The Women’s Health Initiative revealed that calcium and vitamin D supplementation decreased the risk of total cancer, breast cancer, and colorectal cancer but did not affect total mortality.[37] One RCT demonstrated that supplements combining calcium with vitamin D significantly reduced the risk of all cancers in postmenopausal women.[38] Additionally, a meta-analysis of 3 RCTs found that vitamin D supplementation reduced the rate of COPD exacerbations in patients with vitamin D levels below 25 nmol/L.[39]

Toxicity and Adverse Effect Management

Vitamin D is fat-soluble. Toxicity is possible, though rarely observed. Hypervitaminosis D typically results from excessive oral intake rather than excessive sunlight exposure. Toxicity has been reported when serum 25-hydroxyvitamin D levels exceed 88 ng/mL. Acute intoxication can lead to hypercalcemia, which may cause symptoms such as confusion, anorexia, vomiting, polyuria, polydipsia, and muscle weakness. Chronic toxicity can result in nephrocalcinosis and bone pain.

Prognosis

The prognosis of vitamin D deficiency varies depending on severity and underlying conditions. With appropriate supplementation, most individuals can restore normal vitamin D levels and avoid complications. However, prolonged deficiency may lead to bone disorders, fractures, and increased susceptibility to infections.

Complications

Vitamin D deficiency can produce bone disorders, such as osteomalacia and osteoporosis, increasing the risk of fractures. Insufficiency of this nutrient may also contribute to muscle weakness, increasing the risk of falls, especially in older adults. Long-term deficiency is associated with a greater risk of chronic conditions, including cardiovascular disease and autoimmune disorders.

Deterrence and Patient Education

The skeletal benefits of vitamin D supplementation are widely accepted for children and adults with vitamin D levels below 20 ng/mL, especially for those with levels below 12 ng/mL. Modest benefits in the management of osteoporosis have also been proven in older adults.[40]

Although numerous observational studies suggest a potential link between vitamin D and various extraskeletal outcomes, the causal relationship remains unclear. Large randomized clinical trials, including VITAL, ViDA, and D2d, with over 30,000 participants combined, showed that vitamin D supplementation in adults replete with vitamin D (baseline serum 25-hydroxyvitamin D >50 nmol/L) does not prevent cardiovascular events, cancer, and type 2 diabetes mellitus or reduce mortality.[41][42][43][44][45] Recent trials have similarly failed to demonstrate vitamin D's benefit in preventing falls in older adults.[46][47][48]

Despite the evidence, many individuals with vitamin D deficiency do not receive supplementation. Meanwhile, numerous individuals replete with this substance continue supplementation despite the lack of benefits shown in clinical trials.[49]

Enhancing Healthcare Team Outcomes

Vitamin D deficiency is frequently overlooked in both outpatient and inpatient settings. The U.S. Preventive Services Task Force (USPSTF) does not recommend universal screening for vitamin D levels. However, screening for vitamin D deficiency in asymptomatic high-risk individuals is essential to prevent future complications. High-risk populations include nursing home residents, older adults, women with osteoporosis, African American and Hispanic individuals, hospitalized patients, and people with chronic kidney disease, chronic liver disease, or malabsorption syndromes.