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Vitamin D is a fat-soluble vitamin that is naturally present in very few foods. It helps fight against cancer, improves physical performance, prevents osteoporosis, helps promote brain function and reduces depression. Deficiency of this vitamin may lead to brain disorders like Parkinson’s and Alzheimer’s.
What is Vitamin D?
Vitamin D, also known as the “sunshine vitamin”, is an essential fat-soluble vitamin.
It can either be obtained in the diet, through food and dietary supplements, or synthesized in the skin upon exposure to sunlight (R).
Vitamin D plays a role in calcium and phosphorus balance important in bone health, and nerve and muscle activity.
It plays a potential role in prevention and therapy of cancer and chronic conditions such as autoimmune disorders, cardiovascular disease, and infections (R).
Health Benefits of Vitamin D
It’s important to note that many of the studies regarding vitamin D are association studies, which means that deficiency is correlated with a certain issue, but doesn’t necessarily cause that issue. However, in many of these cases, the reason why people’s health is worse is because they aren’t getting enough sun, rather than being deficient in vitamin D. The sun has a lot of health benefits that are independent of vitamin D. So low vitamin D is often more of a signal that someone isn’t getting enough sun, which is the real cause of the health problem.
1) Vitamin D is Crucial to Bone Health
It promotes calcium and phosphorus absorption from the gut, calcium reabsorption in the kidney, and calcium mobilization in bone (R).
Vitamin D is needed for bone growth and formation by bone cells.
2) Vitamin D Prevents Rickets and Osteomalacia
Rickets is characterized by a delay in the mineralization of growth cartilage.
Maternal vitamin deficiency can affect skeletal development of fetuses.
In a study of 424 pregnant women, mothers with vitamin D deficiency were more likely to have fetuses with femoral bones that had rachitic features (R).
Adults with osteomalacia may experience global bone discomfort, and muscle aches and weakness (R).
Osteomalacia and rickets attributable to vitamin deficiency are preventable with adequate nutritional intake of this vitamin.
Varying doses and treatment regimes have been described with the aim is to achieve a blood level between 20 and 50 ng/mL (R).
3) Vitamin D Prevents Osteoporosis and Fractures
Studies show that in adults aged 50 years or older, vitamin D supplementation in combination with calcium has beneficial effects on bone mineral density, osteoporotic fractures and falls without evidence of harm (R, R2, R3).
In elderly women that were given 1200 mg of calcium and 800 IU of vitamin D3 daily for 3 years, the risk of hip fracture was reduced by 43%.
The risk of fracture was reduced by 32% (R).
However, annual administration of high doses of vitamin D (500 000 IU) resulted in an increased risk of falls and fractures in older community-dwelling women (R).
4) Vitamin D Can Improve Physical Performance
Clinical evidence suggests that vitamin D plays a role in muscle metabolism and function (R).
Hence the function of the muscle is either of an indirect nature or does not involve the known receptor (R).
Supplementation with this vitamin has been shown to improve muscle strength, balance, and physical performance.
Supplementation also reduced the risk of falls by more than 20% (R).
Vitamin D may increase muscle strength by improving atrophy of type II muscle fibers, which may lead to decreased falls and hip fractures (R).
Insufficiency of this vitamin is associated with increased fat infiltration in the muscles of healthy young women (R).
It may improve athletic performance in vitamin D-deficient athletes.
5) Vitamin D May Protect Against Cancer
The majority of studies found that sufficient vitamin D protects against cancer and risk of dying (R).
Vitamin D and its byproducts inhibit the spreading of cancer and cancer cell growth. It also induces cancer cell death.
Intake of 2000 IU/day of Vitamin D is associated with a reduction by 50% in the incidence of breast cancer (R).
Some studies did not show an association between higher vitamin D intakes and lower breast cancer risk in postmenopausal women.
Daily intake of 1000-2000 IU/day of this vitamin could reduce the incidence of colorectal cancer by 50% (R).
Higher intakes of vitamin D were associated with lower risks for pancreatic cancer.
Doses of 600 IU/d or more of this vitamin lowered the risk of pancreatic cancer by 41% (R).
It has been shown that low vitamin D levels are present in ovarian cancer patients, and are associated with lower overall survival rate (R).
Ultraviolet B (UVB) radiation is associated with lower risk of ovarian cancer (R).
6) Vitamin D is Beneficial for Brain Development and Function
Studies indicate that this vitamin is important for brain development.
It may protect brain cells through detoxification pathways (production of antioxidant glutathione, inhibition of nitric oxide).
Epidemiological studies show that low concentrations of vitamin D are associated with:
- diagnosis of dementia and Alzheimer’s disease (R).
- higher rates of psychotic experiences and schizophrenia (R, R2, R3).
7) Vitamin D Improves Cognitive Functions
While other studies suggest that blood levels of this vitamin do not influence cognitive or emotional functioning.
8) Vitamin D Reduces Depression
Deficiency of vitamin D was associated with an 8–14% increase in the prevalence of depression.
Also, some studies showed that supplementation of this vitamin neither worsened nor improved depressive symptoms.
In elderly postmenopausal women, there was no effect of hormone therapy and vitamin D either individually or in combination on depression (R).
9) Vitamin D Reduces Risk of Parkinson’s Disease
Vitamin D deficiency may contribute to the development of Parkinson’s disease.
Higher vitamin D blood levels are associated with reduced risk of developing Parkinson’s disease.
Individuals with a blood vitamin concentration of at least 50 nmol/l had a 65% lower risk than those with values under 25 nmol/l (R).
10) Vitamin D Plays a Role in Alzheimer’s Disease
Vitamin D deficiency is prevalent in Alzheimer’s disease and dementia patients.
Blood levels of this vitamin less than 50 nmol/L were associated with a higher risk of Alzheimer’s disease and dementia (R).
11) Vitamin D is Beneficial in Multiple Sclerosis
Higher vitamin D blood levels protect from developing multiple sclerosis.
Also, higher vitamin D levels were associated with a reduced worsening and recurrence of multiple sclerosis symptoms.
Optimal blood concentrations of this vitamin may decrease disease-related complications, including increased bone degradation, fractures, and muscle weakness (R).
Increased sun exposure during ages 6–15 years is associated with a decreased risk of multiple sclerosis.
Multiple sclerosis occurs less often if this vitamin abundant, as in sunny climates, high altitudes, and areas with dietary rich in fish oils (R).
Vitamin D has anti-inflammatory action in multiple sclerosis.
12) Vitamin D Improves Sleep Quality
Vitamin D could be important for sleep disorders (R).
Higher concentrations of this vitamin were associated with better maintenance of sleep (R).
In the National Health and Nutrition Examination Survey (NHANES) study, lower vitamin levels were associated with shorter sleep duration (R).
Some studies suggest improved sleep quality with vitamin D supplementation.
Studies have reported a high prevalence of this vitamin deficiency in obstructive sleep apnea syndrome.
This is a widespread disorder characterized by episodes of breathing cessation due to upper airway tract obstruction during sleep (R).
More studies are needed to prove this relationship between sleep quality and vitamin D supplementation.
13) Vitamin D Reduces the Risk of Cardiovascular Disease
A study showed that this vitamin supplementation or UVB irradiation may lower blood pressure, improve blood pressure control, and regress heart enlargement (R).
However, some studies show the opposite findings.
Daily supplementation with 800 IU vitamin D for 12 weeks did not impact blood pressure, renin and fat concentrations, markers of cardiovascular disease (R).
Study of healthy postmenopausal women, given 400 IU/day or 1000 IU/day vitamin D for a period of 1 year, showed no significant benefit to heart disease risk (R).
14) Vitamin D Reduces Blood Pressure
Skin exposure to UVB radiation is associated with lower blood pressure (R, R2, R3).
Blood pressure is affected by variations in skin color, geographic region and season (R, R2, R3).
Blood pressure was significantly decreased after 6 weeks of therapy in individuals receiving UVB therapy (R).
This vitamin decreases activity of the renin-angiotensin system.
In vitamin D deficient elderly women, there was a 9% decrease in systolic blood pressure (by 13 mmHg) with supplemental vitamin D and calcium compared with calcium alone (R).
Studies including more than 1800 patients found an increased risk of high blood pressure in those with vitamin D level <50 nmol/L compared to those >75 nmol/L (R).
15) Vitamin D May Decrease the Risk of Type 1 and Type 2 Diabetes
Vitamin D plays a role in insulin production and secretion from pancreatic cells (R).
A study found that an intake of 2,000 IU of this vitamin during the first year of life diminished the risk of developing type 1 diabetes (R).
The Diabetes Autoimmunity Study in the Young (DAISY) reported an increased presence of antibodies against pancreatic cells in newborns of mothers with low intake of this vitamin during pregnancy (R).
In the Women’s Health Study, an intake of 511 IU/day of vitamin D or more was associated with a lower risk of type 2 diabetes (R).
It may have a role in delaying the progression to diabetes in adults at high risk of type 2 diabetes.
Supplementation was associated with improved function of pancreatic cells (R).
It also had an effect on the rise of Hb A1C (shows average blood sugar levels over a period of weeks/months) that occurs over time (R).
16) Vitamin D Prevents Obesity and Metabolic Syndrome
There is a genetic evidence that higher body mass index (BMI) leads to lower vitamin D status (R).
12 week supplementation with 25 μg of vitamin D in overweight and obese women decreased body fat mass by 7%, but did not affect body weight and waist circumference (R).
Obese African Americans are at particularly high risk for this vitamin deficiency.
Physicians should consider routine supplementation or screening of these patients for low vitamin D levels (R).
Higher blood levels of vitamin D were associated with a decrease in the prevalence of the components of metabolic syndrome (elevated blood pressure, elevated triglycerides, and reduced high-density lipoprotein cholesterol) in postmenopausal women (R).
17) Vitamin D has Anti-Inflammatory Role
Studies have shown potent effects of vitamin D on both innate and adaptive immunity.
Effects of vitamin D on immune system include:
- Inhibits B cell production, and antibody secretion (R, R2)
- Decreases T cell growth, inhibits T cell activation and IL-2 production (R, R2)
- Results in a shift from a Th1 to a Th2 phenotype (R, R2)
- Regulates the activity of monocytes/macrophages (R, R2)
- Inhibits dendritic cells production and growth (R, R2)
- Decreases the secretion of inflammatory cytokines IL-1, IL-2, IL-6, IL-8, IL-17, TNF-α, IFN-γ, and IL-12 (R, R2, R3, R4)
- Increases cytokines IL-10 and IL-4 (R, R2, R3, R4)
- Inhibits production of IgE by B cells and enhances production of IL-10 by dendritic cells and T cells, playing an important role in allergic immune responses (R, R2)
- Reduces the expression of MHC class II, CD40, CD80, and CD86 (R, R2)
- Decreases TGF-beta (contributes to tissue repair by promoting tissue fibrosis) (R, R2, R3, R4)
- Crucial for T Cell activation (R)
- Regulates differentiation of CD4+ T cells (decreases Th1 and Th17 cell production, and increases Th2 and Treg cell production) (R, R2)
- Increases CD8+ T Cells, important in controlling viruses, intracellular bacteria, and cancer (R, R2)
- Increases Natural Killer T Cells (R)
- Releases antimicrobials in response to an infection such as cathelicidin and beta defensin 4 (R, R2)
18) Vitamin D May Be Beneficial For Inflammatory Bowel Disease and Celiac Disease
Inflammatory bowel disease (IBD) is a chronic inflammation of the gut, and includes Crohn’s disease and ulcerative colitis.
Studies in mice indicate that this vitamin plays a crucial role in this disease (R).
Vitamin D has an anti-inflammatory effect in patients with IBD.
Study showed a 32% decrease in CRP (C-reactive protein) levels and 46% decrease in ESR (erythrocyte sedimentation rate) in patients receiving vitamin D (R).
1200 IU/d vitamin D supplementation reduced recurrence of Crohn’s disease from 29% to 13% (R).
Low vitamin D level is associated with higher risk of polyps and adenomas in the colon, common complications of ulcerous colitis (R).
Almost 60% of patients with celiac disease were found to be vitamin D deficient or insufficient (R).
19) Vitamin D Plays a Role in Cystic Fibrosis
Low blood vitamin D levels are commonly found in patients with cystic fibrosis (CF).
Its deficiency occurs in 25–33% of patients with late-stage CF (R).
Absorption of this vitamin is reduced in patients with CF due to insufficient pancreatic enzymes (R).
Also, CF patients have increased oxidant and P450 activity, which could lead to faster degradation of vitamin D (R).
95% of cystic fibrosis patients required 1800 IU/day of vitamin D to achieve blood concentration above 25 ng/ml (R).
20) Vitamin D is Beneficial in Atopic Dermatitis
Atopic dermatitis affects up to 20% of children and up to 3% of adults (R).
Vitamin D deficiency could be associated with the prevalence of atopic dermatitis (R).
Vitamin supplementation may improve disease symptoms and severity.
21) Vitamin D is Effective Therapy for Psoriasis Patients
A daily dose of 35,000 IU of this vitamin is a safe and effective therapy for psoriasis patients (R).
Topical vitamins calcipotriol and/or tacalcitol are considered as first-line treatment for mild-to-moderate psoriasis.
22) Vitamin D May Benefit Thyroid Dysfunction
Deficiency may exacerbate the onset and/or development of Graves’ disease
Correction of the deficiency may be able to reverse it (R).
Vitamin D deficiency severity was associated with duration of the disease, thyroid gland size, and antibody levels (R).
23) Vitamin D Reduces Severity of Asthma
Lower vitamin levels are associated with increased markers of allergy and asthma severity (R).
24) Vitamin D Affects Chronic Obstructive Pulmonary Disease
Lower blood vitamin levels were associated with a higher risk of COPD (R).
Its deficiency is associated with increased risk of lung infections, causing worsening of COPD (R).
Vitamin D regulates airway contraction and inflammation (R).
25) Vitamin D Reduces Risk of Tuberculosis
Blood levels of this vitamin are lower in tuberculosis patients comparing to healthy individuals (R).
26) Vitamin D has Negative Effect on Sarcoidosis
Increased level of this vitamin is associated with disease activity (R).
Elevated vitamin levels require chronic immunosuppressive therapy in patients with sarcoidosis (R).
Patients with sarcoidosis do not benefit from vitamin D supplementation (R).
27) Vitamin D Decreases the Risk of Respiratory Tract Infections
Lower levels of vitamin D are related to increased risk of respiratory infections (R).
Studies showed a decrease in respiratory tract infections in children taking 600 to 700 IU/d vitamin D supplementation (R).
Supplementation with 1200 IU/d prevents against influenza A in school children between December and March (R).
Supplementation with this vitamin (at 300 IU daily) significantly reduced the risk of acute respiratory infections by 50% among Mongolian children with vitamin D deficiency in winter (R).
However, a monthly dose of 100 000 IU of vitamin D in healthy adults did not significantly reduce the incidence or severity of upper respiratory tract infections (R).
28) Vitamin D Plays a Role in Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) activity is associated with lower vitamin D blood levels (R).
Vitamin D supplementation has an effect on the immune system in patients with SLE.
It decreases memory B cells, effector Th1 and Th17 cells, and increases Tregs (R).
29) Vitamin D is Beneficial in Rheumatoid Arthritis
Vitamin D supplementation suppresses Th17 cell cytokines and has the effect potential to treat patients with RA (R).
Vitamin D deficiency is present in 30-63% of people with rheumatoid arthritis (R).
Greater intake of vitamin D may be associated with a lower risk of rheumatoid arthritis in older women (R).
Low blood levels are associated with rheumatoid arthritis symptoms and severity.
Supplementation of 500 IU/day to patients with early rheumatoid arthritis along with anti-rheumatic therapy results in higher pain relief (R).
30) Vitamin D Protects Kidney Function
Chronic kidney disease patients have a higher prevalence of vitamin D deficiency compared to the general population (R).
Vitamin D deficiency or insufficiency is frequent after renal transplantation (R).
The VITALE study (VITamin D supplementation in renAL transplant recipients) showed that high doses of vitamin D prevent posttransplant bone loss without causing adverse events (R).
It can protect kidney from injury in patients with diabetic kidney disease (R).
31) Vitamin D is Beneficial in HIV Disease
Vitamin D deficiency is common among individuals infected with human immunodeficiency virus (HIV).
HIV-infected patients with abnormally low vitamin D levels had shorter survival than other HIV-infected subjects (R).
This vitamin improves HIV-associated immunity.
High doses of vitamin D supplementation decreases virus production, and increases white blood cells (R).
32) Vitamin D Affects Male Fertility
Studies on mice show beneficial effects of vitamin D on male reproductive system (R).
Male mice who lack vitamin D receptors suffer from infertility.
Vitamin D is important for sperm production, growth, and survival (R).
Blood levels of this vitamin are associated with sperm motility.
Men with vitamin D deficiency (blood levels <20 ng/mL) had less motile sperm compared with men with high levels.
Also, blood levels above 50 ng/mL were associated with decreased sperm production and quality.
33) Vitamin D is Beneficial in Pregnancy and Lactation
Vitamin D deficiency was high in a diverse group of women during pregnancy, affecting 97% of African Americans, 81% of Hispanics, and 67% of Caucasians.
Its deficiency in pregnant women may affect both the women and newborns.
Vitamin D sufficiency may protect from spontaneous preterm birth risk (R).
Vitamin D deficiency during pregnancy is associated with:
- An increased risk of preeclampsia, the leading cause of maternal and neonatal morbidity and mortality (R, R2).
- Almost 4 times the odds of primary cesarean section (R).
- Bacterial vaginosis, a highly prevalent vaginal infection that is associated with adverse pregnancy outcomes (R).
Vitamin D supplementation of 4000 IU/day for pregnant women is safe. It is effective in achieving sufficiency in all women and their newborns and associated with fewer adverse events of pregnancy (R).
It was thought for decades that breast milk was ‘naturally’ low in vitamin D.
Since vitamin D is transferred into the milk, the mother needs a daily source of vitamin D in order to provide her infant with enough substrate to avoid deficiency (R).
An intake of 6400 IU/day of vitamin D provides enough vitamin D to a breastfeeding infant (R).
34) Vitamin D Improves Clinical Manifestations of Polycystic Ovary Syndrome
Women with polycystic ovary syndrome (PCOS) have low vitamin D blood levels
PCOS is accompanied by a high risk of cardiovascular diseases.
Low-dose vitamin D is used as an additional therapy for PCOS and cardiovascular diseases (R).
35) Vitamin D Influences Hair Loss
Studies show an important role of vitamin D receptor in hair loss (R).
The function of vitamin D receptor is essential for the maintenance of normal hair cycle.
Screening patients with hair loss for vitamin D deficiencies seems to be of value for the possibility of supplementing these patients with vitamin D.
Supplementation may be useful to grow hair in case of its deficiency (R).
Active vs Inactive Forms
There are two forms of vitamin D: vitamin D2 and vitamin D3.
Vitamin D2 (ergocalciferol) is produced in plants, fungi, and yeasts.
Vitamin D3 (cholecalciferol) is synthesized in the skin and consumed in animal-based foods (R).
Both forms of vitamin D are biologically inactive and must be activated in the body.
In the liver, vitamin D is converted to calcidiol (25-hydroxyvitamin D [25(OH)D]), the major circulating form of vitamin D, and the indicator of vitamin D status (R).
In the kidneys, calcidiol is converted to calcitriol (1,25-dihydroxy vitamin D [1,25(OH)2D]), the active form of vitamin D (R).
In order to regulate bodily functions, calcitriol binds to vitamin D receptor (VDR) in the cytoplasm of target cells, and goes to the nucleus and binds with the retinoic acid X receptor (RXR).
This complex regulates the expression of vitamin D regulated genes (R).
Vitamin D levels can be increased by getting more natural sunlight, in food or supplements. Sun is the best method for increasing vitamin D.
Most of the vitamin D3 in humans is derived from the synthesis in the skin.
Factors affecting UV radiation exposure and vitamin D synthesis include the season of the year, latitude, clouds, smog, aging, skin color, use of sunscreen, clothing, and amount of skin exposed (R, R2).
Very few foods in nature contain vitamin D.
Major food sources are fatty fish (salmon, tuna, mackerel), cod liver oil, beef liver, egg yolks, cheese, and mushrooms (shiitake, portabella) (R).
Some foods are fortified with vitamin D. These include milk, soy milk, yogurt, margarine, orange juice, and cereals (R).
Both the United States and Canada mandate the fortification of infant formula with vitamin D: 40–100 IU/100 kcal in the United States and 40–80 IU/100 kcal in Canada (R).
In supplements, vitamin D is available in two forms, D2 (ergocalciferol) and D3 (cholecalciferol) (R).
Vitamin D3 is approximately 87% more effective in raising and maintaining the vitamin D levels in the body than vitamin D2.
Most multivitamins contain 400 IU of vitamin D, and single ingredient vitamin D supplements are available for additional supplementation.
Intake of ordinary doses of vitamin D3 supplements seems to be associated with decreases in the overall risk of dying (R).
Vitamin D taken orally is absorbed in the gut with the aid of bile salts.
It is transported to the blood by chylomicrons and taken up by the liver or storage tissues (fat tissue and muscles) (R).
There are many factors that affect vitamin D absorption resulting in large differences in the bioavailability of vitamin D supplements in some populations (R).
Also, individuals taking medications that bind bile acid (such as cholestyramine) will also have impaired vitamin D absorption (R).
Obesity is also associated with decreased vitamin D levels (R).
Vitamin D is most efficiently absorbed when consumed with food containing fat.
Taking vitamin D with the largest meal improves absorption, and results in a 50% increase in blood levels of vitamin D (R).
Infants and children aged 0-1 yr should have a daily intake of at least 400 IU of vitamin D (R).
Children 1 yr and older and adolescents should have a daily intake of 600 IU of vitamin D.
Adults aged 19–70 and over 70 yr require at least 600 and 800 IU/d, respectively, of vitamin D to maximize bone health and muscle function, and prevent falls and fractures.
Pregnant and lactating women require at least 600 IU/d of vitamin D.
Many health professionals recommend 2000 IU or more a day.
Obese and children and adults on anticonvulsant medications, glucocorticoids, antifungals, and medications for AIDS should be given at least two to three times more vitamin D for their age group to satisfy their body’s vitamin D requirement.
Vitamin D deficiency is the most common nutritional deficiency worldwide in both children and adults.
The blood level of 25(OH)D is the best method to determine vitamin D status (R).
Studies suggest that blood 25(OH)D levels between 30 ng/mL and 60 ng/mL are associated with lower risks of adverse health outcomes, including cardiovascular disease, cancers and autoimmune diseases (R).
Causes of vitamin D deficiency:
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Vitamin D deficiency can come from:
- Inadequate sun exposure
- Geographical locations (latitude and altitudes), atmospheric conditions (air pollution, the presence of clouds), and seasonal changes influence the intensity of UVB radiation and thus vitamin D production in skin (R).
- People with a dark skin, African Americans and Hispanic Americans. Higher skin melanin content reduces the skin’s ability to make vitamin D (R, R2).
- Wearing protective clothing and hats, and applying sunscreens, reduce skin exposure to sunlight (R, R2, R3).
- Women in the Middle East and North Africa who wear a headscarf or cover all skin. 96% had blood vitamin D levels less than 20 ng/mL, and 60% had vitamin D levels below 12 ng/mL (R, R2).
- Malabsorption of vitamin D
- Patients with gut disease including Crohn’s disease, ulcerous colitis, celiac disease, cystic fibrosis (R, R2, R3).
- Cholestatic and non-cholestatic liver disease (R).
- Low vitamin D intake
- Low vitamin D diet without fortified food or supplements (R).
- Strict vegan diet (R).
- Chronic kidney disease leads to reduced synthesis of 1,25-dihydroxy-vitamin D and an increased loss of 25-hydroxyvitamin D in urine (R).
- Obesity (R).
- The elderly have a reduced capacity to synthesize vitamin D in the skin and are more likely to stay indoors or use sunscreen (R, R2).
- Pregnant women (R).
- Infants who are exclusively breastfed and do not receive vitamin D supplementation (R).
- Medication: glucocorticoids, antiepileptic drugs, rifampin, antiretroviral therapy (R).
People who are vitamin D deficient may not have any symptoms at all or symptoms may be vague.
Vitamin D deficiency manifests as fatigue, symmetric low back pain, throbbing bone pain, muscle weakness and aches, sweating, digestive problems, obesity, mood swings, and impaired immunity.
Vitamin D toxicity is extremely rare but potentially serious condition.
It occurs from high intakes of supplements (>50,000 IU/d) for a long period of time.
Toxicity does not occur from dietary intake or prolonged sun exposure (R).
Vitamin D is a fat-soluble vitamin, and it is stored in fat tissues. Therefore, toxic effects may last for months after stopping supplementation (R).
Vitamin D supplementation must be considered carefully in patients with granulomatous diseases such as sarcoidosis and Crohn’s disease (active phase), metastatic bone disease, and Williams syndrome (infantile hypercalcemia) (R, R2, R3, R4).
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