Vitamin D and Calcium
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1 Vitamin D and Calcium American Association of Clinical Endocrinologists Marina Del Rey, CA September 15, 2018 Albert Shieh, MD MS Assistant Clinical Professor Department of Medicine Division of Endocrinology UCLA
2 None Conflicts of Interest
3 What is the role of vitamin D in the musculoskeletal system
4 Vitamin D in the Media d deficiency supplements.html
5 USPSTF 2018: Vitamin D +/ Calcium and Fractures US Preventive Services Task Force. Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community Dwelling AdultsUS Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(15): doi: /jama
6 Vitamin D Synthesis and Metabolism 7-dehydrocholesterol UVB skin 37 vitamin D3 25-hydroxyvitamin D3 CYP27b1 liver 1,25-dihydroxyvitamin D3 kidney, placenta, macrophages, bone? CYP24a1 CYP24a1 side chain cleavage VDR
7 Classical Vitamin D Endocrinology Heaney, R. P. (2008). Vitamin D and calcium interactions: functional outcomes. The American journal of clinical nutrition, 88(2), 541S 544S.
8 Classical Vitamin D Endocrinology Steingrimsdottir L, Gunnarsson O, Indridason OS, Franzson L, Sigurdsson G. Relationship Between Serum Parathyroid Hormone Levels, Vitamin D Sufficiency, and Calcium Intake. JAMA. 2005;294(18): doi: /jama
9 Classical Vitamin D Endocrinology Priemel, M., von Domarus, C., Klatte, T. O., Kessler, S., Schlie, J., Meier, S.,... & Amling, M. (2010). Bone mineralization defects and vitamin D deficiency: Histomorphometric analysis of iliac crest bone biopsies and circulating 25 hydroxyvitamin D in 675 patients. Journal of Bone and Mineral Research, 25(2),
10 Who Benefits from Vitamin D and Calcium US Preventive Services Task Force. Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community Dwelling AdultsUS Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(15): doi: /jama
11 Who Benefits from Vitamin D and Calcium? Dawson Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med. 1997;337(10):
12 Who Benefits from Vitamin D and Calcium? Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med, 1992;327:
13 Who Benefits from Vitamin D and Calcium? Macdonald, H. M., Reid, I. R., Gamble, G. D., Fraser, W. D., Tang, J. C., & Wood, A. D. (2018). 25 Hydroxyvitamin D Threshold for the Effects of Vitamin D Supplements on Bone Density Secondary Analysis of a Randomized Controlled Trial. Journal of Bone and Mineral Research.
14 How much vitamin D do we need?
15 Recommended 25(OH)D Targets Recommended 25OHD Outcome of Interest (ng/ml) Institute of Medicine 20 Skeletal health Endocrine Society 30 Skeletal health National Osteoporosis Foundation 30 Skeletal health American Geriatrics Society 30 Skeletal health Falls Ross, A. C., Manson, J. E., Abrams, S. A., Aloia, J. F., Brannon, P. M., Clinton, S. K.,... & Shapses, S. A. (2011). The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. The Journal of Clinical Endocrinology & Metabolism, 96(1), Holick, M. F., Binkley, N. C., Bischoff Ferrari, H. A., Gordon, C. M., Hanley, D. A., Heaney, R. P.,... & Weaver, C. M. (2011). Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 96(7), J Am Geriatr Soc 62: , 2014.
16 Recommended Vitamin D Intake Institute of Medicine years 71+ years Endocrine Society years 71+ years National Osteoporosis Foundation years 71+ years Vitamin D 600 IU 800 IU IU IU IU IU Calcium 1000 mg (M); 1200 mg (F) 1200 mg N/A American Geriatrics Society 65+ years >1000 IU N/A 1000 mg (M); 1200 mg (F) 1200 mg Ross, A. C., Manson, J. E., Abrams, S. A., Aloia, J. F., Brannon, P. M., Clinton, S. K.,... & Shapses, S. A. (2011). The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. The Journal of Clinical Endocrinology & Metabolism, 96(1), Holick, M. F., Binkley, N. C., Bischoff Ferrari, H. A., Gordon, C. M., Hanley, D. A., Heaney, R. P.,... & Weaver, C. M. (2011). Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 96(7),
17 Target 25(OH)D in Patients on Anti resorptive Therapy (Taking Bisphosphonates) bisphosphonates) Carmel, A. S., Shieh, A., Bang, H., & Bockman, R. S. (2012). The 25 (OH) D level needed to maintain a favorable bisphosphonate response is 33 ng/ml. Osteoporosis International, 23(10),
18 Target 25(OH)D in Patients on Anti resorptive Therapy Holick, M. F., Siris, E. S., Binkley, N., Beard, M. K., Khan, A., Katzer, J. T.,... & de Papp, A. E. (2005). Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. The Journal of Clinical Endocrinology & Metabolism, 90(6),
19 What are ways to correct vitamin D deficiency?
20 Vitamin D2 vs. D3 Source D2 Plant sources UV irradiation of ergosterol Molecular weight Binding affinity for DBP Less More D3 Animal sources UV irradiation of 7 dehydrocholesterol Half life of 25(OH)D days days Jones, K. S., Assar, S., Harnpanich, D., Bouillon, R., Lambrechts, D., Prentice, A., & Schoenmakers, I. (2014). 25 (OH) D2 half life is shorter than 25 (OH) D3 half life and is influenced by DBP concentration and genotype. The Journal of Clinical Endocrinology & Metabolism, 99(9),
21 D2 v D3: 1,000 IU daily x11 weeks Holick, M. F., Biancuzzo, R. M., Chen, T. C., Klein, E. K., Young, A., Bibuld, D.,... & Tannenbaum, A. D. (2008). Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25 hydroxyvitamin D. The Journal of Clinical Endocrinology & Metabolism, 93(3),
22 D2 v. D3: 2,000 IU/day x8 weeks Lehmann, U., Hirche, F., Stangl, G. I., Hinz, K., Westphal, S., & Dierkes, J. (2013). Bioavailability of vitamin D2 and D3 in healthy volunteers, a randomized placebo controlled trial. The Journal of Clinical Endocrinology & Metabolism, 98(11),
23 D2 v. D3: 4,000 IU daily x14 days Trang, H. M., Cole, D. E., Rubin, L. A., Pierratos, A., Siu, S., & Vieth, R. (1998). Evidence that vitamin D3 increases serum 25 hydroxyvitamin D more efficiently than does vitamin D2. The American journal of clinical nutrition, 68(4),
24 D2 v D3: 50,000 IU weekly x10 weeks Shieh, A., Chun, R. F., Ma, C., Witzel, S., Meyer, B., Rafison, B.,... & Adams, JS. (2016). Effects of high dose vitamin D2 versus vitamin D3 on total and free 25 hydroxyvitamin D and markers of calcium balance. The Journal of Clinical Endocrinology & Metabolism, jc 2016.
25 Vitamin D3 vs. 25(OH)D3 D3 25(OH)D3 Intestinal absortpion 79% 93% Hydrophobic/hydrophilic More hydrophobic More hydrophilic Half life days days Volume of distribution Larger Smaller Quesada Gomez, J. M., & Bouillon, R. (2018). Is calcifediol better than cholecalciferol for vitamin D supplementation?. Osteoporosis International, 1 15.
26 D3 vs 25(OH)D3: 60 mcg vs. 20 mcg/day Shieh, A., Ma, C., Chun, R. F., Witzel, S., Rafison, B., Contreras, H. T.,... & Adams, J. S. (2017). Effects of cholecalciferol vs calcifediol on total and free 25 hydroxyvitamin D and parathyroid hormone. The Journal of Clinical Endocrinology & Metabolism, 102(4),
27 When Might 25(OH)D3 Be More Effective than D3? Obesity Fat malabsorption Decreased CYP2R1 efficiency CKD
28 Is free 25(OH)D a better marker of vitamin D status than total 25(OH)D?
29 Total vs. Free 25(OH)D Albuminbound 12% Free <1% DBP bound 87%
30 Free Hormone Hypothesis Blood Most tissues Megalin expressing tissues Blood DBP 25OHD DBP 25OHD Alb 25OHD Alb 25OHD DBP 25OHD DBP 25OHD 25OHD 25OHD 25OHD 25OHD Cell 25OHD Cell Megalin 25OHD DBP 25OHD 1,25(OH) 2 D 1,25(OH) 2 D Vitamin D Receptor Vitamin D Receptor
31 Total vs. Free 25(OH)D in Multi racial/ethnic Populations Nielson, C. M., Jones, K. S., Chun, R. F., Jacobs, J., Wang, Y., Hewison, M.,... & Pauwels, S. (2016). Role of assay type in determining free 25 hydroxyvitamin D levels in diverse populations. New England Journal of Medicine, 374(17),
32 Correlations Between Total and Free 25(OH)D Nielson, C. M., Jones, K. S., Chun, R. F., Jacobs, J. M., Wang, Y., Hewison, M.,... & Pauwels, S. (2016). Free 25 hydroxyvitamin D: impact of vitamin D binding protein assays on racial genotypic associations. The Journal of Clinical Endocrinology & Metabolism, 101(5),
33 Associations of Change in Total vs. Free 25(OH)D with Change in PTH Total 25D Unadjusted Adjusted for D2 v. D3 Adjusted for D2 v. D3, change in 1,25D & calcium Free 25D Unadjusted Adjusted for D2 v. D3 Adjusted for D2 v. D3, change in 1,25D & calcium Percent change in PTH (95% CI) per unit increment change in serum total v. free 25D Mean (95% CI) p value ( 1.124, 0.110) ( 1.230, 0.197) ( 1.269, 0.273) ( 6.247, 0.519) ( 6.463, 0.268) ( 6.594, 0.175) Shieh, A., Chun, R. F., Ma, C., Witzel, S., Meyer, B., Rafison, B.,... & Hewison, M. (2016). Effects of high dose vitamin D2 versus D3 on total and free 25 hydroxyvitamin D and markers of calcium balance. The Journal of Clinical Endocrinology & Metabolism, 101(8),
34 When Might Free 25(OH)D Be More Useful Than Total 25(OH)D? Liver cirrhosis Older adults (multiple co morbidities) Pregnancy
35 How does 25(OH)D assay affect clinical care?
36 Common 25(OH)D Assays Immunoassay High variability Measures 25(OH)D2 and 25(OH)D3 together Some assays underestimate 25(OH)D2 LC:MS:MS Considered gold standard Less variability Measures 25(OH)D2 and 25(OH)D3 individually
37 25(OH)D: Immunoassay vs. LC:MS:MS Binkley, N., & Carter, G. D. (2017). Toward clarity in clinical vitamin D status assessment: 25 (OH) D assay standardization. Endocrinology and metabolism clinics of North America.
38 How much calcium do we need?
39 Recommended Calcium Intake Institute of Medicine years 71+ years Endocrine Society years 71+ years National Osteoporosis Foundation years 71+ years Vitamin D 600 IU 800 IU IU IU IU IU Calcium 1000 mg (M); 1200 mg (F) 1200 mg N/A American Geriatrics Society 65+ years >1000 IU N/A 1000 mg (M); 1200 mg (F) 1200 mg Ross, A. C., Manson, J. E., Abrams, S. A., Aloia, J. F., Brannon, P. M., Clinton, S. K.,... & Shapses, S. A. (2011). The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. The Journal of Clinical Endocrinology & Metabolism, 96(1), Holick, M. F., Binkley, N. C., Bischoff Ferrari, H. A., Gordon, C. M., Hanley, D. A., Heaney, R. P.,... & Weaver, C. M. (2011). Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 96(7),
40 Calcium and Cardiovascular Disease
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