1. Vitamin D Deficiency Elaine Wendt, MD January 4, 2010

2. 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

3. 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

4. Holick M. N Engl J Med 2007;357:266-281 Metabolism of 25-Hydroxyvitamin D to 1,25-Dihydroxyvitamin D for Nonskeletal Functions

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

6. Prevalence of Vitamin D Deficiency Elderly in US and Europe 40-100% Children 30-50% Adult inpatients over 80%

7. 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) Sufficiency50-250 (20-100) Excess>250 (100) Intoxication> 375 (150)

8. 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

9. Causes of Vitamin D Deficiency Heritable disorders- rickets Acquired disorders

10. Holick M. N Engl J Med 2007;357:266-281 Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism

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

12. Inadequate sun exposure or supplementation Children Preventative 400- 1000 IU D3 daily sensible sun exposure 1000-2000 IU D3 daily is safe Treatment of Deficiency 50000 IU of D2 every week for 8 weeks Adults (non lactating) Preventative 800-1000 IU D3 daily 50000 IU of D2 every 2-4 weeks Sensible sun exposure Use of a tanning bed or UVB radiation device 10000 IU of D3 daily is safe for 5 months Treatment of deficiency 50000 IU of D2 every week for 8 weeks, repeat for another 8 weeks if 25, OH Vitamin D level < 30 ng/ml

13. Pregnant or lactating adults Preventative 1000-2000 IU of D3 daily 50000 IU of D2 every 2 weeks up 4000 IU of D3 is safe for 5 months Maintenance dose is 50000 IU of D2 every 2-4 weeks Treatment of Deficiency 50000 IU of D2 every week for 8 weeks Repeat for another 8 weeks if 25-OH vitamin D level <30 ng/ml

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

15. Holick M. N Engl J Med 2007;357:266-281 Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism

16. Malabsorption Syndromes Prevention Adequate exposure to sun or UV radiation 50000 IU D2 daily, every other day, or every other week Up to 10000 IU D3 daily is safe for 5 months Maintenance is 50000 IU D2 weekly ◦ Treatment of Deficiency UVB irradiation 50000 IU D2 every day or every other day

17. Obesity Preventative 1000-2000 IU D3 daily 50000 IU of D2 every 1-2 weeks Maintenance dos is 50000 IU D2 every 1, 2, or 4 weeks Treatment of Deficiency 50000 IU D2 every week for 8-12 weeks Repeat if 25-OH vitamin D level < 30 ng/ml

18. Increased Catabolism Anticonvulsants Glucocorticoids HAART Antirejection medications

19. Holick M. N Engl J Med 2007;357:266-281 Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism

20. Drugs that activate steroid and xenobiotic receptor, drugs used in transplantation Preventative 50000 IU of vitamin D2 every other day or every week Maintenance is 50000 IU of D2 every 1, 2, or 4 weeks Treatment of Deficiency 50000 IU D2 every 2 weeks for 8- 10 weeks, or every week if 25-OH vitamin D level <30 ng/ml

21. Breast-feeding Poor vitamin D content in human milk

22. Breastfeeding Preventative 400 IU D3 daily Sensible sun exposure 1000-2000 IU D3 daily safe Maintenance dose is 400-1000 IU of D3 daily Treatment of Deficiency 200000 IU D3 every 3 months 600000 IU D3 IM, repeat 12 weeks 1000-2000 IU D2 or D3 daily with calcium supplementation

23. Decreased synthesis of 25-OH vitamin D Liver failure

24. Holick M. N Engl J Med 2007;357:266-281 Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism

25. Increased Urinary Loss of 25-OH Vitamin D Nephrotic Syndrome

26. Holick M. N Engl J Med 2007;357:266-281 Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism

27. Nephrotic Syndrome Preventive 1000-2000 IU D3 daily 50000 IU D2 once or twice weekly Maintenance is 50000 IU D2 every 2 or 4 weeks Treatment of Deficiency 50000 IU D2 weekly for 8-12 weeks Repeat if 25-OH vitamin D level <30 ng/ml

28. 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

29. Holick M. N Engl J Med 2007;357:266-281 Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism

30. Chronic Kidney Disease Stages 2 and 3 Prevention Control serum phosphate 1000 IU D3 daily 50000 IU D2 every 2 weeks Maintenance dose 50000 IU D2 every 2-4 weeks May also need to treat with an active vitamin D analog when sufficiency is obtained Treatment of Deficiency 50000 IU D2 once weekly for 8 weeks Repeat if 25-OH vitamin D level <30 ng/ml

31. Chronic Kidney Disease Stages 4 and 5 Prevention 1000 IU D3 daily 50000 IU D2 every 2 weeks Need to treat with 1,25 dihydroxyvitamin D3, or active analog Treatment of Deficiency 0.25-1 ug calcitriol BID 1-2 ug paricalcitriol IV every 3 days Doxecalciferol 10-20 ug three times weekly or 2- 6 ug IV three times weekly

32. 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

33. Treatment of Vitamin D Defiency Rickets Vitamin D (ergocalciferol) Double dose vitamin D3: 800 IU daily for 3-4 months OR Vitamin D 1000-10000 IU daily for 8-12 weeks, then 400-1000 IU daily OR D2 100000- 600000 IU daily or 50000 D2 weekly for 8 weeks Calcium 30-75 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

34. Acquired Disorders Tumor- induced Osteomalacia Primary hyperparathyroidism Granulomatous Disorders Hyperthyroidism

35. Primary or tertiary Hyperparathyroidism Prevention 800-1000 IU D3 daily 50000 IU D2 every 2 weeks Maintenance 50000 IU D2 every 2-4 weeks Treatment of deficiency 50000 IU D2 once weekly for 8 weeks, Repeat is 25-OH vitamin D < 30 ng/ml

36. Granulomatous disorders and some lymphomas Prevention 400 IU D3 daily 50000 IU D2 monthly Treatment of Deficiency 50000 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

37. References N Engl J Med 2007;357:266-81. Pediatrics 2008;122:398-417.