Vitamin D Deficiency – 7 Interesting Facts

What is Vitamin D Deficiency

Vitamin D deficiency is when your body does not have enough vitamin D. Vitamin D is important because:

  • It helps your body use other minerals that your body needs.
  • It helps keep your bones strong and healthy.
  • It may help to prevent some diseases.
  • It helps your heart and other muscles work well.

You can get vitamin D by:

  • Eating foods with vitamin D in them.
  • Drinking or eating milk or other foods that have had vitamin D added to them.
  • Taking a vitamin D supplement.
  • Being in the sun.

Not getting enough vitamin D can make your bones become soft. It can also cause other health problems.

Interesting Facts

  1. Vitamin D deficiency is a condition defined by low circulating levels of vitamin D
    • Exact threshold level of 25-hydroxyvitamin D that constitutes deficiency is controversial, but achieving a level of at least 12 to 20 ng/mL (30-50 nmol/L) is considered adequate for bone health 1 2 3 4 5
  2. Circulating vitamin D levels depend on dietary calcium amount, sun exposure, degree of adiposity, and genetic factors
  3. Most patients with vitamin D deficiency are asymptomatic
  4. Severe vitamin D deficiency can lead to osteomalacia in adults
  5. Treat for vitamin D deficiency if levels of 25-hydroxyvitamin D are less than 10 ng/mL (25 nmol/L) or 10 to 20 ng/mL (25-50 nmol/L) in the presence of certain bone diseases, symptoms suggestive of vitamin D deficiency, or risk factors for vitamin D deficiency 2
  6. Routine vitamin D supplementation to prevent deficiency is recommended in certain populations (eg, patients who are elderly, have little exposure to sunlight, have chronic liver or kidney disease, have had bariatric surgery, have other causes for reduced absorption or increased catabolism of vitamin D)
  7. Routine vitamin D supplementation is not recommended in the general population as it does not reduce incidence of cancer, cardiovascular disease, diabetes, or death in community-dwelling adults and does not reduce fracture rates in individuals who are not at high risk for fracture 1

Pitfalls

  • Intentional exposure to natural or artificial UV radiation for the purpose of treating vitamin D deficiency is not advised owing to the increased risk of skin cancer, including melanoma 7
  • No amount of vitamin D is able to compensate for inadequate total calcium intake

Terminology

Clinical Clarification

  • Vitamin D deficiency is a condition defined by low circulating levels of vitamin D 8
    • Optimal vitamin D nutritional status is a subject of controversy and threshold levels to define vitamin D deficiency vary by professional society 4 5
      • 25-hydroxyvitamin D level less than 10 ng/mL (25 nmol/L), per National Osteoporosis Society 2
      • 25-hydroxyvitamin D level less than 12 ng/mL (30 nmol/L), per National Academy of Medicine (Institute of Medicine) 3 8
      • 25-hydroxyvitamin D level less than 20 ng/mL (50 nmol/L), per Endocrine Society 9
  • According to the National Osteoporosis Society, levels above 20 ng/mL (50 nmol/L) are sufficient for almost everyone 2 3
  • While not considered vitamin D deficiency, the National Osteoporosis Society suggests 25-hydroxyvitamin D levels of 10 to 20 ng/mL (25-50 nmol/L) may be inadequate for some people 2
  • The Endocrine Society uses the term vitamin D insufficiency to describe levels 25-hydroxyvitamin D levels between 21 and 29 ng/mL (52.5-72.5 nmol/L) 9
  • Physiology
    • Vitamin D is an essential steroid hormone that exists in the body in multiple forms
      • 25-hydroxycholecalciferol (calcidiol) and 1,25-dihydroxycholecalciferol (calcitriol) are the main forms
    • Vitamin D can be obtained from dietary sources of vegetal (vitamin D₂ or ergocalciferol) or animal origin (vitamin D₃ or cholecalciferol), or through conversion of 7-dehydrocholesterol into cholecalciferol (vitamin D₃) by UVB exposure in the skin
    • In the liver, cholecalciferol is converted into 25-hydroxyvitamin D
      • 25-hydroxyvitamin D concentration depends on nutritional supply or synthesis in the skin after exposure to UVB light
    • In the kidney, 25-hydroxyvitamin D is converted to 1,25-dihydroxyvitamin D
    • 1,25-dihydroxyvitamin D is considered to be the biologically active form and its concentration is highly regulated
  • Units for 25-hydroxyvitamin D levels are expressed as ng/mL or nmol/L; the conversion between them is [nmol/L] = 2.5 × [ng/mL] 8

Classification

  • Vitamin D forms 8
    • Vitamin D: calciferol
    • Vitamin D₂: ergocalciferol
    • Vitamin D₃: cholecalciferol
    • 25-hydroxyvitamin: calcidiol, no distinction between D₂ and D₃ forms
    • 1,25-dihydroxyvitamin D₃: calcitriol

Diagnosis

Clinical Presentation

History

  • Most patients with mild to moderate vitamin D deficiency are asymptomatic
    • Any symptoms that do occur are often vague and ascribing them to a low vitamin D level can be erroneous
  • Patients with prolonged and severe vitamin D deficiency–related disorders (eg, osteomalacia) may present with: 2
    • Musculoskeletal pain
    • Hyperalgesia or paresthesia
    • Proximal muscle weakness
    • Waddling gait
    • History of fracture
    • Coexisting hypocalcemia, which may cause muscle cramping or myalgias

Physical examination

  • Most patients with mild to moderate vitamin D deficiency have no characteristic examination findings
  • Severe vitamin D deficiency may have musculoskeletal findings or findings related to hypocalcemia
    • Genu varum (outward bowing of the lower legs)
    • Proximal muscle weakness (symmetrical)
    • Chvostek sign (twitching of facial muscles in response to tapping over the area of the facial nerve)
    • Trousseau sign (carpal spasm caused by inflating the blood pressure cuff to a level above systolic pressure for 3 minutes) 10
    • Fasciculations and/or tremors
    • Muscle spasms
    • Tetany

Causes and Risk Factors

Causes

  • Insufficient dietary vitamin D (cholecalciferol [D₃] or ergocalciferol [D₂])
    • Malnutrition
  • Inadequate cutaneous production of cholecalciferol
    • Seasonal or permanent residence in far northern or southern latitudes
    • Patients who are institutionalized or homebound
    • Sunscreen use
    • Dark skin pigmentation
  • Inability to process vitamin D due to renal or liver failure
    • Conversion of vitamins D₂ and D₃ into active compounds requires a 2-step enzymatic hydroxylation process
      • First step occurs with 25-hydroxylase activity in the liver, and second step occurs with 1α-hydroxylase activity in the kidney
      • Level of hepatic and renal dysfunction required for this enzymatic dysfunction is significant (cirrhosis and renal failure, respectively)
  • Intestinal malabsorption of vitamin D due to:
    • Exocrine pancreatic insufficiency
    • Inflammatory bowel disease
    • Sarcoidosis
    • Amyloidosis
    • Celiac disease
    • Cystic fibrosis
    • History of bariatric surgery or small-intestine resection
  • Drug-induced impairment of vitamin D action or drug-provoked vitamin D catabolism due to:
    • Phenobarbital
    • Phenytoin
    • Rifampin
    • Highly active antiretroviral therapy
  • 1α-hydroxylase deficiency

Risk factors and/or associations

Age
  • 65 years or older with limited mobility 11
    • Decreased vitamin D skin production due to low exposure to UV light
Genetics
  • Hereditary vitamin D–dependent rickets (present in childhood) 12
    • Vitamin D–dependent rickets type 1A results from abnormalities in the CYP27B1 gene, coding for 25-hydroxyvitamin D₃–1α-hydroxylase
    • Vitamin D–dependent rickets type 1B results from abnormalities in the CYP2R1 gene, coding for 25-hydroxylase
  • Variants at loci involved in cholesterol synthesis, hydroxylation, and vitamin D transport contribute to the variability of serum concentrations of 25-hydroxyvitamin D; these include CYP2R1DHCR7, and CYP24A1 13
Ethnicity/race
  • Dark skin pigmentation (eg, black, Hispanic, and Asian populations)
    • Reduces natural vitamin D₂ and D₃ production by the epidermis
Other risk factors/associations
  • Obesity
    • Low vitamin D levels often exist owing to sequestration of vitamin D in adipose tissue
  • Factors reducing exposure of skin to solar UVB rays (decreased vitamin D skin production due to low exposure to UV light)
    • Living in high latitudes (above 33° north or below 33° south)
    • Patients who live in institutions
    • Cultural practices that encourage covering most or all of the skin
    • Lactose intolerance, causing avoidance of milk
      • Vitamin D fortification of milk-substitute products (eg, soy milk, almond milk, rice milk) is not universal

Diagnostic Procedures

Primary diagnostic tools

  • History and physical examination may suggest vitamin D deficiency but diagnosis is made by laboratory testing
  • Laboratory measurement of serum 25-hydroxyvitamin D (calcidiol) level 14
    • Serum 25-hydroxyvitamin D (calcidiol) level is the best indicator of overall vitamin D status
    • Reflects total vitamin D from dietary intake, sunlight exposure, and adipose tissues; subsequently stored in the liver
    • Measurement of serum 1,25-dihydroxyvitamin D levels are not useful for determining vitamin D deficiency; they are used to monitor certain conditions

Laboratory

  • Serum 25-hydroxyvitamin D level 9 15
    • Primary diagnostic test for vitamin D deficiency and best indicator of vitamin D status for most patients
      • Deficiency is defined as a 25-hydroxyvitamin D level less than 10 ng/mL (25 nmol/L), per National Osteoporosis Society 2 (2018) or less than 12 ng/mL (30 nmol/L), per National Academy of Medicine (Institute of Medicine) 2011 3 8
      • Endocrine Society 2011 guideline defined deficiency as 25-hydroxyvitamin D level 9 less than 20 ng/mL (50 nmol/L)
      • Levels above 20 ng/mL (50 nmol/L) are considered sufficient for almost all populations 2
    • The most accurate laboratory methodology uses assays of high performance liquid chromatography or tandem mass spectrometry; radioimmunoassay is an acceptable alternative method 8
  • Serum 1,25-dihydroxyvitamin D level
    • Measurement of 1,25-dihydroxyvitamin D is primarily indicated to monitor the following conditions, which include acquired and inherited disorders in the metabolism of 25-hydroxyvitamin D and phosphate: 9
      • Chronic kidney disease
      • Hereditary phosphate-losing disorders
      • Oncogenic osteomalacia
      • Pseudovitamin D–deficiency rickets
      • Vitamin D–resistant rickets
      • Chronic granuloma-forming disorders, such as sarcoidosis and some lymphomas
    • Accurate interpretation of serum 1,25-dihydroxyvitamin D level can be complex, as levels are regulated by factors beyond vitamin D alone (such as parathyroid hormone); therefore, consultation with endocrinologist or nephrologist is recommended 8
  • Serum calcium level 2
    • Obtain results for patients with vitamin D deficiency 1 month after starting supplementation
    • In chronic and severe cases of vitamin D deficiency, hypocalcemia can occur owing to diminished calcium absorption from the small intestine, secondary to low 1,25-dihydroxyvitamin D levels
    • Calcium levels can also fall within the reference range if secondarily elevated parathyroid hormone levels induce sufficient calcium mobilization from bone and calcium reabsorption from the kidney
    • Calcium levels must be monitored closely in patients using calcitriol (eg, for renal or liver disease) throughout therapy owing to the high likelihood of hypercalcemia
    • Calcium level must be corrected for albumin
      • Corrected total calcium level = measured total calcium level + (0.8 × [4 − measured albumin level in g/dL]) 16

Imaging

  • Plain radiography
    • Indicated in patients with vitamin D–associated rickets or osteomalacia to assess bone structure
    • May show nontraumatic fractures at high stress points
    • Characteristic findings in osteomalacia include pseudofractures (radiolucent bands) ranging from a few millimeters to centimeters in length, most visible near the femoral neck or pelvis 17

Differential Diagnosis

Most common

  • Based on symptoms
    • Osteoarthritis
      • Joints most commonly affected are the distal interphalangeal, neck, lower back, knees, and hips, whereas joint-specific arthralgias are not observed in vitamin D deficiency
      • Arthralgias from osteoarthritis worsen during activity and improve with rest, which is typically not the case with arthralgias related to vitamin D deficiency
      • Radiographic findings of joint space loss, osteophyte formation, cysts, and subchondral sclerosis can indicate osteoarthritis, but laboratory testing of vitamin D levels is definitive since the 2 conditions can coexist 18
      • Primarily differentiated by serum 25-hydroxyvitamin D level
    • Fibromyalgia19
      • Chronic pain syndrome characterized by widespread musculoskeletal pain
      • In contrast to isolated vitamin D deficiency, fibromyalgia is accompanied by fatigue, sleep disturbances, headaches, and cognitive and mood disturbances
      • Diagnosis is clinical and largely based on 2 sets of self-reported assessments: the widespread pain index and the symptom severity score
      • Definitively differentiated by 25-hydroxyvitamin D levels
    • Polymyositis 20
      • Idiopathic inflammatory myopathy characterized by subacute onset, over weeks to months, of proximal muscle weakness
      • Morning stiffness, weight loss, and fever are common, which is not expected in isolated vitamin D deficiency
      • Gottron papules (papules and plaques over bony prominences of the metacarpal phalangeal joints) are found in most patients with polymyositis; a heliotrope rash is evident in those with coexisting dermatomyositis
      • Polymyositis is diagnosed based on scoring of the Bohan and Peter criteria, which include symmetrical weakness of limb girdle muscles, elevated creatine phosphokinase level, myopathic pattern on EMG, and muscle biopsy showing evidence of inflammation 21 22
      • Definitively differentiated by 25-hydroxyvitamin D levels

Treatment

Goals

  • Correct vitamin D deficiency; ideally, increase 25-hydroxyvitamin D levels to greater than 20 ng/mL (50 nmol/L) 1 2 3
    • Endocrine Society guidelines recommend higher target of 30 ng/mL (75 nmol/L) but this is not universally accepted 9
  • Reverse any clinical consequences of vitamin D deficiency if present
  • Avoid vitamin D toxicity

Disposition

Recommendations for specialist referral

  • Refer to endocrinologist or nephrologist for complex cases, particularly where use of calcitriol is necessary

Treatment Options

Indications for treatment 2

  • 25-hydroxyvitamin D level less than 10 ng/mL (25 nmol/L)
  • 25-hydroxyvitamin D levels of 10 to 20 ng/mL (25-50 nmol/L) and any of the following:
    • Fragility fracture
    • Documented osteoporosis or high fracture risk
    • Treatment with antiresorptive medication for bone disease
    • Symptoms suggestive of vitamin D deficiency
    • Increased risk of developing vitamin D deficiency owing to reduced exposure to sunlight, religious/cultural dress code, or dark skin color
    • Elevated parathyroid hormone
    • Treatment with antiepileptic drugs or oral glucocorticoids

Treatment consists of vitamin D dietary supplements 2 23

  • There are 2 forms: plant-based D₂ (ergocalciferol) and animal-derived D₃ (cholecalciferol); either may be used to prevent or treat vitamin D deficiency 23
  • However, vitamin D₃ is considered the treatment of choice for vitamin D deficiency according to the National Osteoporosis Society 2
    • Evidence suggests vitamin D₃ may be more effective in raising serum levels to the desired threshold
      • Vitamin D₃ is cleared less rapidly and is more bioavailable than vitamin D₂
  • Dietary sources alone of vitamin D are not currently recommended as a reliable means of vitamin D supplementation 24
  • Vitamin D therapy in either form can be given daily, weekly, or monthly with equal effectiveness, based on patient preference 25
    • Annual high-dose depot vitamin D therapy and activated vitamin D preparations (eg, calcitriol) are not recommended for most patients; they may be ineffective and have a risk of toxicity 2 26
    • Cumulative dose is more important than drug treatment interval
  • Also ensure dietary calcium intake is adequate
    • Men and premenopausal women with vitamin D deficiency should consume 1000 mg of calcium daily; postmenopausal women with vitamin D deficiency should consume 1200 mg calcium daily 27 28
    • Calcium plus vitamin D is effective in preventing bone fracture and falls and reducing mortality in older adults, whereas vitamin D supplementation alone does not confer similar benefits 2 27 28

Treatment guidance

  • For patients requiring rapid correction of vitamin D deficiency (eg, those with symptomatic disease; those about to start treatment with potent antiresorptive agent such as zoledronate, denosumab, or teriparatide) 2
    • Recommended treatment regimen is based on fixed loading doses followed by regular maintenance therapy
    • A loading dose of approximately 300,000 units vitamin D in total can be given either as separate weekly or daily doses over 6 to 10 weeks
      • Loading regimen options include:
        • 50,000 units (tablets, capsules, or liquid) once weekly for 6 weeks (300,000 units)
        • 40,000 units once weekly for 7 weeks (280,000 units)
        • 1000 units orally, 4 times per day for 10 weeks (280,000 units)
        • 800-unit capsules, 5 times per day given for 10 weeks (280,000 units)
      • Calcium/vitamin D combinations should not be used
    • Maintenance therapy of vitamin D in doses equivalent to 800 to 2000 units daily (up to a maximum of 4000 units daily) is then given daily or higher doses given intermittently
  • For patients requiring less urgent correction of vitamin D deficiency and when prescribing vitamin D supplements in combination with an oral antiresorptive agent
    • Start maintenance therapy without initial loading doses
  • Populations requiring greater doses of vitamin D to correct vitamin D deficiency include: 9
    • Obese people (BMI of 30 kg/m² or higher)
    • Patients on medications that reduce vitamin D levels (eg, anticonvulsants, glucocorticoids)
    • Patients with conditions that cause vitamin D malabsorption (eg, chronic pancreatitis, inflammatory bowel disease, amyloidosis, sarcoidosis, celiac disease, cystic fibrosis)
    • People with a history of bariatric surgery or small-intestine resection 29
      • Treat with 3000 to 6000 to 10,000 units of vitamin D₃ daily or 50,000 units of vitamin D₂ 1 to 3 times weekly
  • Other populations that might use calcitriol instead of vitamin D₂ or D₃ include those with:
    • Vitamin D–dependent rickets
    • Chronic kidney disease 30
    • Liver failure

Drug therapy

  • Oral forms of vitamins D₂ and D₃ should be taken with a meal containing fat to ensure maximum absorption
  • Vitamin D₃ (cholecalciferol)
    • For treatment of vitamin D deficiency
      • Vitamin D Oral capsule; Adults: 25 to 50 mcg (1,000 to 2,000 International Units) PO daily. Up to 1,250 mcg (50,000 International Units) PO every week for 6 weeks has been studied. In malabsorption syndromes, higher doses may be required; consider a vitamin D analog.
    • For routine vitamin D supplementation
      • Vitamin D Oral capsule; Adults and Geriatrics 18 to 70 years: 15 mcg/day (600 International Units/day) PO is the RDA for vitamin D in adults and elderly up to 70 years of age.
      • Vitamin D Oral capsule; Geriatrics older than 70 years: 20 mcg/day (800 International Units/day) PO is the RDA for vitamin D in elderly older than 70 years of age.
  • Vitamin D₂ (ergocalciferol)
    • For treatment of vitamin D deficiency
      • Vitamin D (Ergocalciferol) Oral capsule; Adults: 25—50 mcg (1000—2000 IU) PO daily. Up to 1250 mcg (50,000 IU) PO once weekly for 6 weeks has been studied. In malabsorption syndromes, higher doses may be required; consider a vitamin D analog.
    • For routine vitamin D supplementation
      • Vitamin D (Ergocalciferol) Oral capsule; Adults and Geriatrics 18 to 70 years: 15 mcg/day (600 International Units/day) PO.
      • Vitamin D (Ergocalciferol) Oral capsule; Geriatrics older than 70 years: 20 mcg/day (800 International Units/day).
  • Calcitriol
    • Usually limited to patients with vitamin D–dependent rickets, chronic kidney disease, or liver failure
      • For vitamin D deficiency due to vitamin D–dependent rickets
        • Calcitriol Oral solution; Adults: Initially, 0.25 mcg PO once daily; increase by 0.25 mcg daily at 4 to 8 week intervals if needed. Usual dose range is 0.5 to 1 mcg once daily.
      • For vitamin D deficiency in patients who have chronic kidney disease with hypocalcemia and secondary hyperparathyroidism
        • Calcitriol Oral solution; Adults: Initially, 0.25 mcg PO once daily; increase by 0.25 mcg daily at 4 to 8 week intervals if needed. Usual dose range is 0.5 to 1 mcg once daily.

Nondrug and supportive care

  • Nutritional counseling
    • Dietary sources of vitamin D include supplements and food
    • Food sources of vitamin D include salmon, sardines, tuna, cod liver oil, and egg yolk
      • In the United States, fluid milk is voluntarily fortified with 400 units of vitamin D per quart (or 385 units/L) 8
    • Dietary supplements are in the form of vitamin D₂ or vitamin D₃
      • In the United States, supplement doses range from 1000 to 5000 units of vitamin D₃ and up to 50,000 units of vitamin D₂ 8
      • In Canada, dosage levels of vitamin D (any form) above 1000 units are obtainable only with a prescription 8

Comorbidities

  • Cardiovascular disease (eg, hypertension, peripheral vascular disease, metabolic syndrome, coronary artery disease, heart failure)
    • Low 25-hydroxyvitamin D levels are associated with the presence of cardiovascular disease but not as a risk factor for the development of cardiovascular diseases 8
    • Routine supplementation with vitamin D has not been shown to provide cardiovascular benefits 1 31 32

Special populations

  • Obese patients
    • Low vitamin D levels often exist owing to sequestration of vitamin D in adipose tissue
    • Obese adults need at least 2 to 3 times more vitamin D (at least 6000-10,000 units/day) to treat and prevent vitamin D deficiency 33
      • Consider adjusting vitamin D replacement therapy according to body size 33
      • Equation to estimate additional daily dose (beyond recommended daily intake) of vitamin D₃ is needed: additional daily vitamin D₃ dose (units) = (weight [kg] × desired change in 25[OH]D level × 2.5) −10 33
  • Patients with chronic kidney disease and dialysis-dependent renal failure
    • Patients with chronic kidney disease and GFR less than 30 mL/minute have reduced renal 1α-hydroxylation activity and are at risk of hypocalcemia and secondary hyperparathyroidism
    • Owing to reduced renal 1α-hydroxylation activity, patients with chronic kidney disease are typically given vitamin D replacement with active 1,25-dihydroxvitamin D (calcitriol) or a related analog 34
      • Use of active vitamin D therapy in chronic kidney disease appears to improve survival and slow progression to end-stage renal disease 34
    • Under the guidance of a nephrologist, treat vitamin D deficiency in patients with chronic kidney disease using nutritional vitamin D₂ or vitamin D₃, as well as active vitamin D
      • Nutritional vitamin D₂ or D₃ can be considered if documented vitamin D deficiency exists
    • Vitamin D supplements are not routinely recommended in the absence of deficiency 35
      • Safety and efficacy of nutritional vitamin D supplementation are not established in patients with chronic kidney disease or who are on dialysis but do not have documented vitamin D deficiency
  • Patients with chronic liver disease
    • Owing to impaired hepatic 25-hydroxylation, patients with liver failure are often vitamin D deficient 36
    • Calcium (1000-1200 mg/day) and vitamin D (400-800 units/day) supplements are routinely recommended for patients with cholestatic liver disease 37
  • Patients who have had bariatric surgery
    • Very high doses of vitamin D are required after bariatric surgery, ranging from a minimum of 3000 units daily to 50,000 units 3 times daily in cases of severe malabsorption 9
    • Optimal dose of vitamin D after bariatric surgery has not been identified; thus, vitamin D replacement recommendations vary across professional society clinical practice guidelines
      • Endocrine Society Clinical Practice Guideline (2011) 9
        • First phase (weeks 1-2, liquids): oral vitamin D 50,000 units/day
        • Second phase (weeks 3-6, soft food): calcitriol D 1000 units/day
        • For severe malabsorption: 50,000 units vitamin D 1 to 3 times daily
      • American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery (2019) 29
        • After most bariatric procedures (eg, Roux-en-Y gastric bypass, laparoscopic sleeve gastrectomy, laparoscopic adjustable gastric banding), give vitamin D dose of 3000 units/day, titrate to more than 30 ng/mL
        • In cases of severe malabsorption: oral D₂ or D₃ may need to be as high as 50,000 units 1 to 3 times weekly or even daily; more recalcitrant cases may require concurrent oral calcitriol
  • Pregnant women
    • Vitamin D supplementation is not recommended for pregnant women to improve maternal and perinatal outcomes 38
    • Pregnant women should be advised that sunlight is the most important source of vitamin D 38
    • Pregnant women should be encouraged to receive adequate nutrition, which is best achieved through consumption of a healthy, balanced diet 38
    • For pregnant women with documented vitamin D deficiency, vitamin D supplements may be given at the current recommended nutrient intake of 200 units (5 mcg) per day 38
    • Uncertainties exist regarding the effects of vitamin D supplementation (particularly effects on preterm birth) and other associated benefits or harms of vitamin D when combined with other vitamins and minerals (particularly calcium) 38 39
      • Supplementation with vitamin D alone: 39
        • Probably reduces the risk of preeclampsia, gestational diabetes, and low birth weight
        • Possibly reduces the risk of severe postpartum hemorrhage
        • Does not significantly alter the risk of preterm birth
      • Supplementation with vitamin D and calcium together probably reduces the risk of preeclampsia but may increase the risk of preterm birth 39

Monitoring

  • Check adjusted plasma calcium 1 month after completing the loading regimen or after starting lower dose vitamin D supplementation 2
    • Development of hypercalcemia after vitamin D treatment has begun can be a sign of a coexisting primary hyperparathyroidism
  • Routine monitoring of plasma 25-hydroxyvitamin D is not generally required according to National Osteoporosis Society guidelines 2
    • May be appropriate in patients with symptomatic vitamin D deficiency, malabsorption, or suspected poor drug compliance
      • Check levels after a minimum treatment duration of 3 months but preferably after 6 months 2
  • The Endocrine Society recommends monitoring 25-hydroxyvitamin D level every 8 weeks until serum level of 30 ng/mL is achieved; once maintenance therapy begins, recheck 25-hydroxyvitamin D serum levels every 3 to 6 months thereafter 9
  • For adults with vitamin D deficiency and underlying conditions that require treatment with calcitriol: 9
    • Careful monitoring of serum calcium levels in patients using calcitriol (eg, those with acquired and inherited disorders of vitamin D and phosphate metabolism, renal disease, or liver disease) is necessary owing to greater susceptibility for developing hypercalcemia in such patients
    • Monitor both 1,25-dihydroxyvitamin D and calcium levels
    • 25-hydroxyvitamin D levels do not reflect vitamin D status in these patients
  • For adults with conditions that cause extrarenal production of 1,25-dihydroxyvitamin D: 9
    • Perform serial monitoring of 25-hydroxyvitamin D and serum calcium levels during treatment with vitamin D to prevent hypercalcemia
    • Hypercalciuria and hypercalcemia are usually observed when the 25-hydroxyvitamin D level is above 30 ng/mL

Complications and Prognosis

Complications

  • Complications of disease
    • Secondary hyperparathyroidism 40
      • Vitamin D deficiency impairs intestinal calcium and phosphorus absorption, resulting in an increase in parathyroid hormone levels
      • Secondary hyperparathyroidism maintains serum calcium level in the reference range at the expense of mobilizing calcium from the skeleton and increasing phosphorus wasting in the kidneys
      • Parathyroid hormone–mediated osteoclastic activity causes a generalized decrease in bone mineral density, resulting in osteoporosis
      • Parathyroid hormone–mediated phosphaturia results in a low calcium-phosphorus product, causing a mineralization defect in the skeleton
        • In young children who have little mineral in their skeleton, this defect results in a variety of skeletal deformities classically known as rickets
        • In adults, skeletal deformities are not observed, but the mineralization defect still occurs, and this condition is referred to as osteomalacia
    • Osteomalacia
      • Deficient mineralization from chronically low vitamin D states leads to:
        • Cartilage abnormalities at the growth plate before epiphyseal closure in children (rickets)
        • Accumulation of osteoid after epiphyseal closure in adults (osteomalacia)
        • Chronic kidney failure (renal osteodystrophy)
      • Compromised bone stability can lead to fractures at high stress points
      • Resulting bone abnormalities (eg, bowing of the legs, spinal deformities) may require bracing or surgery
    • Osteoporosis
      • Increases risk of bone fracture, particularly in those at greater risk of falling, such as geriatric patients 41
      • Treatment includes vitamin D and calcium repletion, with consideration of antiresorptive agents (eg, zoledronate, denosumab) after normal vitamin D levels have been established
  • Complications of treatment
    • Vitamin D toxicity
      • Rare event caused by inadvertent ingestion of excessively high amounts of vitamin D
      • Symptoms include nausea, vomiting, anorexia, constipation, and headaches; hypercalcemia, hypercalciuria, kidney stones, and ectopic calcifications of soft tissues can develop 4
      • Those sensitive to vitamin D supplementation include patients with chronic granulomatous disorders, patients with chronic fungal infections, and some patients with lymphoma in whom activated macrophages produce 1,25-dihydroxyvitamin D in an unregulated manner 40
      • Suggested upper limit of 10,000 units/day of vitamin D for most adults 9
      • Safe upper value for serum 25-hydroxyvitamin D level to avoid hypercalcemia is not certain; upper limit of 100 ng/mL is suggested 9

Prognosis

  • Prognosis of vitamin D deficiency is good, assuming recognition and treatment using adequate repletion regimens

Screening and Prevention

Screening

Routine screening for vitamin D deficiency in healthy asymptomatic individuals is not recommended 1 2 15

Screening for vitamin D deficiency is recommended in at-risk populations and situations in which correcting vitamin D deficiency before specific treatment is appropriate 42

  • Unless the risk factor condition deteriorates or a new risk factor occurs, one-time screening is adequate

At-risk populations 43

  • People aged 65 years and older 2
  • People who have low or no exposure to the sun (eg, those who cover their skin for cultural reasons, those who are confined indoors for long periods) 2
  • People who have darker skin (eg, people of African, African-Caribbean, or South Asian origin) 2 44
  • Patients with diseases that cause vitamin D malabsorption, including:
    • Inflammatory bowel disease
    • Granulomatous disease (eg, sarcoidosis, tuberculosis)
    • History of bariatric surgery or small-intestine resection
    • Cystic fibrosis
    • Celiac disease
    • Some forms of cancer 43
  • Patients using medications that increase catabolism of vitamin D, including:
    • Anticonvulsants
    • Antifungals (eg, ketoconazole)
    • Cholestyramine
    • Rifampin
  • Patients with chronic kidney disease
  • Patients with liver failure
  • Patients with osteoporosis 9
  • Obese patients 9
  • Pregnant and lactating women 9

Screening tests

  • Both the National Osteoporosis Society and Endocrine Society guidelines recommend screening the following groups with serum 25-hydroxyvitamin D measurement: 2 9
    • Patients with musculoskeletal symptoms that could be attributed to vitamin D deficiency
    • Patients suspected of having bone diseases that may be improved with vitamin D treatment, including:
      • Osteomalacia
      • Osteoporosis
    • Patients with bone diseases before specific treatment in which correcting vitamin D deficiency may be necessary 2
      • Osteoporosis
        • Screen the subset of patients with osteoporosis who are starting treatment with a potent antiresorptive agent (eg, zoledronate, denosumab) to avoid the development of hypocalcemia
        • However, routine screening is unnecessary in patients with osteoporosis or fragility fracture in which a decision has already been made to coprescribe vitamin D supplementation with an oral antiresorptive treatment
      • Paget disease
        • Screen before starting a bisphosphonate to avoid development of hypocalcemia
      • Hyperparathyroidism 9
        • Screen before parathyroidectomy
    • The Endocrine Society also recommends screening in the wider range of at-risk patients described above 44

Prevention

  • Routine vitamin D supplementation in healthy adults is not recommended 1
    • Supplementation has not been shown to reduce the incidence of cancer, cardiovascular disease, diabetes, or death in community-dwelling adults and does not reduce fracture rates in individuals who are not at high risk for fracture 1
      • Specifically, the US Preventive Services Task Force recommends against daily supplementation with 400 units or less of vitamin D₃ and 1000 mg or less of calcium for the primary prevention of fractures in community-dwelling postmenopausal women; evidence was insufficient to determine benefits and harms of higher doses and supplementation in men and premenopausal women 9 45
    • Most people can maintain adequate vitamin D levels through safe sunlight exposure and diet 2
      • In the United States and Canada, milk is fortified with vitamin D, as are some bread products, orange juices, cereals, yogurts, and cheeses 9
      • Cod liver oil, salmon, and sardines are rich in vitamin D 9
      • Intentional sun exposure is not universally recommended owing to the risk of UV radiation–induced skin cancers
  • Vitamin D dietary reference intakes to maintain adequate levels of 25-hydroxyvitamin D: 8
    • Adults aged 19 to 70 years: 600 units/day
      • Recommended daily allowance during pregnancy and lactation is also 600 units/day
    • Adults older than 70 years: 800 units/day
  • The National Osteoporosis Society recommends a daily supplement containing 400 units of vitamin D for people aged 65 years and older and those who have minimal exposure to the sun 2
    • The Endocrine Society recommends 800 units of vitamin D per day for the prevention of falls and fractures in patients aged 65 years and older; however, to raise the blood levels of 25-hydroxyvitamin D above their 30 ng/ml target may require at least 1500 to 2000 units/day 9
  • Patients who have undergone bariatric surgery or who have other causes for reduced absorption or increased catabolism of vitamin D should be prescribed vitamin D supplementation to prevent deficiency 46
    • American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery recommend vitamin D supplements of 3000 units/day (titrated to therapeutic 25-hydroxyvitamin D levels greater than 30 ng/mL) for patients who have undergone bariatric surgery 29

Follow these instructions at home:

  • Take medicines and supplements only as told by your doctor.
  • Eat foods that have vitamin D. These include:
    • Dairy products, cereals, or juices with added vitamin D. Check the label for vitamin D.
    • Fatty fish like salmon or trout.
    • Eggs.
    • Oysters.
  • Do not use tanning beds.
  • Stay at a healthy weight. Lose weight, if needed.
  • Keep all follow-up visits as told by your doctor. This is important.

Contact a doctor if:

  • Your symptoms do not go away.
  • You feel sick to your stomach (nauseous).
  • You throw up (vomit).
  • You poop less often than usual or you have trouble pooping (constipation).

Sources

1: LeFevre ML et al: Vitamin D screening and supplementation in community-dwelling adults: common questions and answers. Am Fam Physician. 97(4):254-60, 2018

Cross Reference