Vitamin D Deficiency. Micol Rothman, MD Assistant Professor of Medicine Clinical Director Metabolic Bone Program University of CO-Denver

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1 Vitamin D Deficiency Micol Rothman, MD Assistant Professor of Medicine Clinical Director Metabolic Bone Program University of CO-Denver

2 50 yo woman referred for osteoporosis

3 What is striking about her bone density? Very low T and Z scores Look for a secondary cause

4 Hypogonadism Secondary causes of Premature/Surgical menopause Pituitary tumors Anorexia Turner s/ s/klinefelter s Glucocorticoid excess Immobilization Thyrotoxicosis Renal hypercalciuria osteoporosis Decreased calcium absorption celiac, lactose intolerant, gastrectomy Diabetes Mellitus Primary Hyperparathyroidism Osteomalacia Myeloma Osteogenesis Imperfecta

5 She is complaining of diffuse bone pain. H/o Crohn's disease that dates to 1981 Says she underwent gastric bypass surgery at the same time as her bowel resection due to weight gain from prednisone. Her weight from >128 lbs in one year. Taking MVI and B12, but no specific Ca/D S/p TAH/BSO, on estrogen Physical exam More info? 105 lbs Fissures on her tongue Tenderness on long bones

6 Secondary work up:lab results Serum Ca=8.5 mg/dl PTH=206 pg/ml PO4=3.7 mg/dl 24 hour urine Ca=90 mg Urine NTX= OH Vit D=<10 ng/dl Femur films were consistent with osteomalacia

7 Vitamin D Is this really an epidemic? Review of the physiology Is it more than bones? What is our goal D level? How do we get there?

8 Vitamin D: A hot topic 4800 citations on Pub Med May 2008-May % increase in a year Doubled in a decade Unanswered questions as to how much, how to replace Adams and Hewison JCEM 2010

9 Vitamin D Deficiency The older reference range of ng/ml 25(OH)VD is inadequate prevention of rickets It is estimated that 30-50% of US populations are insufficient 25(OH)D of ng/ml or deficient 25(OH)D of < 20 ng/ml Ann Epidemiol 2009;19:73 78

10 Even more common among those at risk 52% of post menopausal women receiving therapy for osteoporosis had Vitamin D levels of < 30ng/dl. 1 97% of patient hospitalized for non traumatic fractures had Vitamin D levels of <30mg/dl. 2 1 Holick MF et al JCEM Simonelli C et al J Bone Min Res 2004

11 Adult body=1 kg of Ca, 99% in bone 1% in blood, 50% free

12 Holick M. N Engl J Med 2007;357:

13 Action of PTH BONE -Osteoclast resorption -Release of Ca and Po4 from bone -Increase calcium reabsorption -Increase phosphate excretion -Increase calcitriol synthesis KIDNEY NET EFFECT: PLASMA CA INCREASED PHOSPHATE SAME/DECREASED GUT Adapted from M. McDermott -Increased calcitriol leads to Increased Ca absorption

14 What to measure 1,25(OH)VD is the active metabolite Extremely variable due to regulation by PTH PTH can fluctuate over minutes even response to a calcium ingestion 1,25(OH)VD can be normal even in VD deficiency due to shuttling of any remaining 25(OH)VD to 1,25(OH)VD by PTH (i.e. in CKD) For determination of VD levels/stores, always measure 25(OH)VD

15 Vitamin D deficiency is on the rise NHANES data from vs Mean 25 OH D went from 30 to 24ng/mL Prevalence of D<10 ng/ml went from 2% to 6%. Ginde et al Arch Intern Med 2009

16 Problems with Vitamin D Assays = reference lab (HPLC method) Ann Epidemiol 2009;19:73 78 J Clin Endocrinol Metab. 2004;89:

18 FIGURE 2. Mean age- and sex-adjusted serum concentrations of 25-hydroxyvitamin D [25(OH)D] by selected variables for non-hispanic whites aged y: the National Health and Nutrition Examination Survery (NHANES) Looker, A. C et al. Am J Clin Nutr 2008;88: Copyright 2008 The American Society for Nutrition

19 Factors leading to Vitamin D Deficiency Decreased intake Decreased absorption Decreased sunlight Skin pigmentation Sequestration Defects in 25 hydroxlyation Liver disease Anticonvulsants Defects in hydroxlyation Hypoparathyroidism Renal disease Vitamin D dependant rickets

The Vitamin D-Fat-Bone Axis Adams, J. S. et al.

21 Varying Results for D and Fracture Cauley et al Annals Int Med 2008

22 Does Vitamin D improve fracture risk? Nursing home residents with a mean level of 14 with 800 IU of D and 1200 mg of Calcium 25% risk reduction in hip and non vertebral fractures. 1 WHI 2 study compared Vitamin D3 400 IU and Calcium 1000mg with improvement However women who were most consistent with their Ca and D had a 29% risk reduction RECORD 3 showed no improvement, but levels only went to 24.8 ng/dl. 1 Chapuy et al BMJ Jackson et al NEJM Grant A Lancet 2006

23 500,000 Units Yearly Sanders, K. M. et al. JAMA 2010;303: Copyright restrictions may apply.

24 The importance of Vitamin D Ann Epidemiol 2009;19:73 78

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

26 Non-bone effects: Cardiovascular Cardiovascular data: 1700 Framingham offspring 25 OH D <15 ng/ml more likely to have CV event (hazard ratio 1.62 CI ) 1 Peak protection from CV death level ng/ml? 2 1 Wang et al Circulation Kim et al Am J Cardiol 2008

27 Non-bone effects of Vitamin D Upper respiratory tract infections 1 Related to development of T1DM 3 Less dementia? Chronic pain? 1 Ginde et al Arch Int Med Danescu LG Endocrine Adams and Hewson JCEM 2010

28 PTH AND VITAMIN D: Where did the target of 30mg/ml come from? Holick, M. F. et al. J Clin Endocrinol Metab 2005;90:

29 Sources of Vitamin D Solar UV-B B (sunlight) Naturally occurring food sources Salmon 400 IU/3.5 oz Cod liver oil 400 IU/tsp Egg yolks 20 IU Fortified foods in US Milk 100 IU/serving Cereal 100 IU/serving Orange Juice 100 IU/serving Yogurt 100 IU/serving Holick M Mayo Clinic Proc 2006

30 NOF:Adult Recommendations Adults< (IU) of vitamin D daily Adults> ,000 IU of vitamin D daily. Experts disagree on the safe upper limit for vitamin D. It is difficult to get too much vitamin D unless a person is taking a prescription dose of the vitamin. In that case, healthcare providers can easily monitor a person s s vitamin D level with a blood test.

31 AAP: Pediatric Recommendations Changed from 200 IU (2003) to 400 IU (2008) 400 IU daily for: Breastfed and partially breastfed infants Older children consuming<1 quart per day of vitamin D-fortified formula or milk Adolescents who do not obtain 400 IU of vitamin D per day through foods Children with increased risk of vitamin D deficiency, such as those taking certain medications, may need higher doses of vitamin D. Consider measuring vitamin D levels in pregnancy.

33 Expert opinion:holick It would be premature at this time to monitor everyone s s serum 25(OH)D concentration so that it is >40 µg/l. Vitamin D intoxication is usually not observed until > IU of vitamin D are ingested per day for >5 months No downside to increasing everyone s s vitamin D intake by increasing the consumption of foods that naturally contain or are fortified with vitamin D. Dietary sources are not adequate taking taking a vitamin D supplement and taking advantage of the beneficial effect of sun exposure will help guarantee vitamin D sufficiency I recommend IU/day for infants, IU/day for children years of age, and IU/day for teenagers and adults. M Holick Clinical Chemistry. 2010;56: )

34 What we do If the level is<10 ng/dl, supplement with 50,000 IU twice a week for three months and then recheck If the level is <20 ng/ml, supplement with 50,000 IU once a week for three months and then recheck If the level is ng/ml, add IU per day and recheck in three months

35 Ann Epidemiol 2009;19:73 78 J Clin Densitometr. 1998;1: Patients received 50K units of ergocalciferol once/week for 8 weeks

36 Limited resources: What if you can t t check levels? 68 nursing home patients received a minimum of 5 months of daily 2000 IU vitamin D(3) supplementation. 94.1% had a 25(OH)D(3) level in excess of 80 nmol/l after a minimum of 5 months of daily 2,000 IU vitamin D(3) supplementation. No residents had 25(OH)D(3) levels in a toxic range. Schwalfenberg and Genuis Mol Nutr Food Res May 3.

37 Back to the patient Due to her malabsorption,, has required 50,000 IU 3 times a week. Clinical sx and bone density improved

39 FIG. 3. Change in BMD 1 yr after RYGB, presented as percent change (and SEM) in BMD from preoperative baseline at each measurement site Fleischer, J. et al. J Clin Endocrinol Metab 2008;93: Copyright 2008 The Endocrine Society

Shon E. Meek, M.D., Ph.D. Assistant Professor of Medicine

Shon E. Meek, M.D., Ph.D. Assistant Professor of Medicine meek.shon@mayo.edu 2016 MFMER 3561772-1 Update on Vitamin D Shon Meek MD, PhD 20 th Annual Endocrine Update January 30-Feb 3, 2017 Disclosure Relevant