Vitamin D Deficiency Elaine Wendt, MD January 4, 2010

Importance of vitamin D Deficiency In utero and during childhood, can cause growth retardation and skeletal deformities In adulthood, can cause osteopenia, osteoporosis, osteomalacia, muscle weakness and increase risk of fracture

Other risk associations Common cancers such as breast, prostate, colon, and NH lymphoma Autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, Type 1diabetes, and Crohn’s disease Infectious diseases such as TB Cardiovascular disease such as HTN and CHF Muscle aches and bone pains Mental illness such as schizophrenia and depression

Holick M. N Engl J Med 2007;357: Metabolism of 25-Hydroxyvitamin D to 1,25-Dihydroxyvitamin D for Nonskeletal Functions

Functions of 1,25 Dihydroxyvitamin D Regulates cellular proliferation, differentiation, apoptosis, and angiogenesis Potent immunomodulator Inhibits renin synthesis Increases insulin production Increases myocardial contractility

Prevalence of Vitamin D Deficiency Elderly in US and Europe % Children 30-50% Adult inpatients over 80%

Vitamin D Status in Relation to 25 (OH)-D Levels Vitamin D Status25 (OH)- D Level, nmol/L (ng/ml) Severe Deficiency< 12.5 (5) Deficiency< 37.5 (15) Insufficiency37.5 – 50 (15-20) Sufficiency (20-100) Excess>250 (100) Intoxication> 375 (150)

Causes of Vitamin D Deficiency Reduced skin synthesis Decreased bioavailability Increased catabolism Breast-feeding Decreased synthesis of 25-OH Vit D Increased urinary loss of 25-OH Vit D Decreased synthesis of 1,25 dihydroxyvitamin D

Causes of Vitamin D Deficiency Heritable disorders- rickets Acquired disorders

Holick M. N Engl J Med 2007;357: Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism

Reduced Skin Synthesis Sunscreen use Skin pigmentation Aging Season, latitude, and time of day Patients with skin grafts for burns

Inadequate sun exposure or supplementation Children Preventative IU D3 daily sensible sun exposure IU D3 daily is safe Treatment of Deficiency IU of D2 every week for 8 weeks Adults (non lactating) Preventative IU D3 daily IU of D2 every 2-4 weeks Sensible sun exposure Use of a tanning bed or UVB radiation device IU of D3 daily is safe for 5 months Treatment of deficiency IU of D2 every week for 8 weeks, repeat for another 8 weeks if 25, OH Vitamin D level < 30 ng/ml

Pregnant or lactating adults Preventative IU of D3 daily IU of D2 every 2 weeks up 4000 IU of D3 is safe for 5 months Maintenance dose is IU of D2 every 2-4 weeks Treatment of Deficiency IU of D2 every week for 8 weeks Repeat for another 8 weeks if 25-OH vitamin D level <30 ng/ml

Decreased bioavailability Malabsorption from disease or cholesterol medications Obesity- sequestration of vitamin D in body fat

Holick M. N Engl J Med 2007;357: Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism

Malabsorption Syndromes Prevention Adequate exposure to sun or UV radiation IU D2 daily, every other day, or every other week Up to IU D3 daily is safe for 5 months Maintenance is IU D2 weekly ◦ Treatment of Deficiency UVB irradiation IU D2 every day or every other day

Obesity Preventative IU D3 daily IU of D2 every 1-2 weeks Maintenance dos is IU D2 every 1, 2, or 4 weeks Treatment of Deficiency IU D2 every week for 8-12 weeks Repeat if 25-OH vitamin D level < 30 ng/ml

Increased Catabolism Anticonvulsants Glucocorticoids HAART Antirejection medications

Holick M. N Engl J Med 2007;357: Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism

Drugs that activate steroid and xenobiotic receptor, drugs used in transplantation Preventative IU of vitamin D2 every other day or every week Maintenance is IU of D2 every 1, 2, or 4 weeks Treatment of Deficiency IU D2 every 2 weeks for weeks, or every week if 25-OH vitamin D level <30 ng/ml

Breast-feeding Poor vitamin D content in human milk

Breastfeeding Preventative 400 IU D3 daily Sensible sun exposure IU D3 daily safe Maintenance dose is IU of D3 daily Treatment of Deficiency IU D3 every 3 months IU D3 IM, repeat 12 weeks IU D2 or D3 daily with calcium supplementation

Decreased synthesis of 25-OH vitamin D Liver failure

Holick M. N Engl J Med 2007;357: Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism

Increased Urinary Loss of 25-OH Vitamin D Nephrotic Syndrome

Holick M. N Engl J Med 2007;357: Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism

Nephrotic Syndrome Preventive IU D3 daily IU D2 once or twice weekly Maintenance is IU D2 every 2 or 4 weeks Treatment of Deficiency IU D2 weekly for 8-12 weeks Repeat if 25-OH vitamin D level <30 ng/ml

Decreased Synthesis of 1,25- dihydroxyvitamin D Chronic kidney disease Stages 2 and 3- hyperphosphatemia increases fibroblast growth factor 23, which decreases 25 OH vitamin D-1- hydroxylase activity Stages 4 and 5- inability to produce adequate amounts of 1,25- dihydroxy- vitamin D

Holick M. N Engl J Med 2007;357: Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism

Chronic Kidney Disease Stages 2 and 3 Prevention Control serum phosphate 1000 IU D3 daily IU D2 every 2 weeks Maintenance dose IU D2 every 2-4 weeks May also need to treat with an active vitamin D analog when sufficiency is obtained Treatment of Deficiency IU D2 once weekly for 8 weeks Repeat if 25-OH vitamin D level <30 ng/ml

Chronic Kidney Disease Stages 4 and 5 Prevention 1000 IU D3 daily IU D2 every 2 weeks Need to treat with 1,25 dihydroxyvitamin D3, or active analog Treatment of Deficiency ug calcitriol BID 1-2 ug paricalcitriol IV every 3 days Doxecalciferol ug three times weekly or 2- 6 ug IV three times weekly

Heritable disorders- Rickets Pseudovitamin D deficiency rickets Vitamin D-resistant rickets Vitamin D-dependent rickets Type 3 Autosomal dominant hypophosphatemic rickets X-linked hypophosphatemic rickets

Treatment of Vitamin D Defiency Rickets Vitamin D (ergocalciferol) Double dose vitamin D3: 800 IU daily for 3-4 months OR Vitamin D IU daily for 8-12 weeks, then IU daily OR D IU daily or D2 weekly for 8 weeks Calcium mg/kg daily of elemental calcium in 3 divided doses ( start at higher dose and wean down over 2-4 weeks) Monitoring of Therapy At 1 month: calcium, phosphorus, alkaline phosphatase (ALP) At 3 months: calcium, phosphorus, magnesium, ALP, PTH, 25(OH)-D, urine calcium/creatinine ratio, recheck radiographic findings At 1 year and annually: 25(OH)-D

Acquired Disorders Tumor- induced Osteomalacia Primary hyperparathyroidism Granulomatous Disorders Hyperthyroidism

Primary or tertiary Hyperparathyroidism Prevention IU D3 daily IU D2 every 2 weeks Maintenance IU D2 every 2-4 weeks Treatment of deficiency IU D2 once weekly for 8 weeks, Repeat is 25-OH vitamin D < 30 ng/ml

Granulomatous disorders and some lymphomas Prevention 400 IU D3 daily IU D2 monthly Treatment of Deficiency IU D2 weekly for 4 weeks, need to keep 25- OH vitamin D level between 20 and 30 ng/ml. >30 ng/ml can result in hypercalciuria and hypercalcemia

References N Engl J Med 2007;357: Pediatrics 2008;122: