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

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

50 yo woman referred for osteoporosis

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

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

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 285-- -->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

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=100 25 OH Vit D=<10 ng/dl Femur films were consistent with osteomalacia

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?

Vitamin D: A hot topic 4800 citations on Pub Med May 2008-May 2009 15% increase in a year Doubled in a decade Unanswered questions as to how much, how to replace Adams and Hewison JCEM 2010

Vitamin D Deficiency The older reference range of 10-55 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 21 29 29 ng/ml or deficient 25(OH)D of < 20 ng/ml Ann Epidemiol 2009;19:73 78

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 2005 2 Simonelli C et al J Bone Min Res 2004

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

Holick M. N Engl J Med 2007;357:266-281

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

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

Vitamin D deficiency is on the rise NHANES data from 1988-1994 1994 vs 2001-2004. 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

Problems with Vitamin D Assays = reference lab (HPLC method) Ann Epidemiol 2009;19:73 78 J Clin Endocrinol Metab. 2004;89:3152 3157

FIGURE 2. Mean age- and sex-adjusted serum concentrations of 25-hydroxyvitamin D [25(OH)D] by selected variables for non-hispanic whites aged 20-59 y: the National Health and Nutrition Examination Survery (NHANES) 2003-2004 Looker, A. C et al. Am J Clin Nutr 2008;88:1519-1527 Copyright 2008 The American Society for Nutrition

Factors leading to Vitamin D Deficiency Decreased intake Decreased absorption Decreased sunlight Skin pigmentation Sequestration Defects in 25 hydroxlyation Liver disease Anticonvulsants Defects in 1-251 hydroxlyation Hypoparathyroidism Renal disease Vitamin D dependant rickets

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

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 1994 2 Jackson et al NEJM 2006 3 Grant A Lancet 2006

500,000 Units Yearly Sanders, K. M. et al. JAMA 2010;303:1815-1822. Copyright restrictions may apply.

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

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

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 1.11-2.36) 1 Peak protection from CV death level 35-40 ng/ml? 2 1 Wang et al Circulation 2008 2 Kim et al Am J Cardiol 2008

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 2009 3 Danescu LG Endocrine 2009 4 Adams and Hewson JCEM 2010

PTH AND VITAMIN D: Where did the target of 30mg/ml come from? Holick, M. F. et al. J Clin Endocrinol Metab 2005;90:3215-3224

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

NOF:Adult Recommendations Adults< 50 400-800 (IU) of vitamin D daily Adults> 50 800-1,000 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.

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.

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 >10 000 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 400 1000 IU/day for infants, 1000 1500 1500 IU/day for children 1 101 10 years of age, and 1500 2000 IU/day for teenagers and adults. M Holick Clinical Chemistry. 2010;56:729-731.)

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 20-30 ng/ml, add 1000-2000 IU per day and recheck in three months

Ann Epidemiol 2009;19:73 78 J Clin Densitometr. 1998;1:201 204 Patients received 50K units of ergocalciferol once/week for 8 weeks

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. 2010 May 3.

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

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;93:3735-3740 Copyright 2008 The Endocrine Society