vitamin d and calcium - syllabus.aace.comsyllabus.aace.com/...vitamind_calcium_ca2018am.pdf ·...
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Vitamin D and CalciumAmerican Association of Clinical Endocrinologists
Marina Del Rey, CA September 15, 2018
Albert Shieh, MD MSAssistant Clinical ProfessorDepartment of MedicineDivision of Endocrinology
UCLA
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Conflicts of Interest
• None
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What is the role of vitamin D in the musculoskeletal system
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Vitamin D in the Media
https://www.nytimes.com/2017/04/10/health/vitamin‐d‐deficiency‐supplements.html
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USPSTF 2018: Vitamin D +/‐ Calcium and Fractures
US Preventive Services Task Force. Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures inCommunity‐Dwelling AdultsUS Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(15):1592–1599. doi:10.1001/jama.2018.3185
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Vitamin D Synthesis and Metabolism
7-dehydrocholesterol
vitamin D3 25-hydroxyvitamin D3
1,25-dihydroxyvitamin D3CYP27b1
liver
kidney, placenta,macrophages, bone?
37°
skinUVB
CYP24a1
CYP24a1
side chain
cleavage
VDR
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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.
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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):2336–2341. doi:10.1001/jama.294.18.2336
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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), 305‐312.
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Who Benefits from Vitamin D and Calcium
US Preventive Services Task Force. Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures inCommunity‐Dwelling AdultsUS Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(15):1592–1599. doi:10.1001/jama.2018.3185
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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):670‐676.
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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;327:1637‐42.
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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 andMineral Research.
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How much vitamin D do we need?
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Recommended 25(OH)D Targets
Recommended 25OHD(ng/ml)
Outcome of Interest
Institute of Medicine 20 Skeletal health
Endocrine Society 30 Skeletal health
National Osteoporosis Foundation 30 Skeletal health
American Geriatrics Society 30 Skeletal healthFalls
• 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), 53‐58.
• 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), 1911‐1930.
• J Am Geriatr Soc 62:147–152, 2014.
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Recommended Vitamin D IntakeVitamin D Calcium
Institute of Medicine51‐70 years71+ years
600 IU800 IU
1000 mg (M); 1200 mg (F)1200 mg
Endocrine Society51‐70 years71+ years
1500‐2000 IU1500‐2000 IU
N/A
National Osteoporosis Foundation51‐70 years71+ years
800‐1000 IU800‐1000 IU
1000 mg (M); 1200 mg (F)1200 mg
American Geriatrics Society65+ years >1000 IU N/A
• 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), 53‐58.
• 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), 1911‐1930.
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Target 25(OH)D in Patients on Anti‐resorptive Therapy
(Taking 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), 2479‐2487.
(Taking bisphosphonates)
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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), 3215‐3224.
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What are ways to correct vitamin D deficiency?
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Vitamin D2 vs. D3
D2 D3
Source Plant sources‐ UV irradiation of
ergosterol
Animal sources‐ UV irradiation of 7‐
dehydrocholesterol
Molecular weight 399 384
Binding affinity for DBP Less More
Half life of 25(OH)D 13.9 + 2.6 days 15.1 + 3.1 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), 3373‐3381.
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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), 677‐681.
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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), 4339‐4345.
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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), 854‐858.
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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.
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Vitamin D3 vs. 25(OH)D3
D3 25(OH)D3
Intestinal absortpion 79% 93%
Hydrophobic/hydrophilic More hydrophobic More hydrophilic
Half‐life 30‐45 days 10‐13 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.
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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 calcifediolon total and free 25‐hydroxyvitamin D and parathyroid hormone. The Journal of Clinical Endocrinology & Metabolism, 102(4), 1133‐1140.
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When Might 25(OH)D3 Be More Effective than D3?
• Obesity• Fat malabsorption• Decreased CYP2R1 efficiency• CKD
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Is free 25(OH)D a better marker of vitamin D status than total 25(OH)D?
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Total vs. Free 25(OH)D
DBP‐bound87%
Albumin‐bound12%
Free<1%
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Free Hormone Hypothesis
Most tissuesBlood
Cell
Megalin‐expressing tissuesBlood
Cell
DBP
DBP
Alb
25OHD25OHD
25OHD25OHD
25OHD25OHD
25OHD25OHD
25OHD25OHD
25OHD25OHD
1,25(OH)2D1,25(OH)2D
Vitamin D Receptor
DBP
DBP
Alb
25OHD25OHD
25OHD25OHD
25OHD25OHD
25OHD25OHD
25OHD25OHD
25OHD25OHD
1,25(OH)2D1,25(OH)2D
Vitamin D Receptor
DBP 25OHD25OHD
Megalin
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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), 1695‐1696.
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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), 2226‐2234.
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Associations of Change in Total vs. Free 25(OH)D with Change in PTH
Percent change in PTH (95% CI) per unit increment change in serum total v. free 25D
Mean (95% CI) p‐value
Total 25DUnadjusted Adjusted for D2 v. D3Adjusted for D2 v. D3, change in 1,25D & calcium
‐0.507 (‐1.124, 0.110)‐0.516 (‐1.230, 0.197)‐0.498 (‐1.269, 0.273)
0.20.20.2
Free 25DUnadjustedAdjusted for D2 v. D3Adjusted for D2 v. D3, change in 1,25D & calcium
‐3.383 (‐6.247, ‐0.519)‐3.366 (‐6.463, ‐0.268)‐3.384 (‐6.594, ‐0.175)
0.020.030.03
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), 3070‐3078.
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When Might Free 25(OH)D Be More Useful Than Total 25(OH)D?
• Liver cirrhosis• Older adults (multiple co‐morbidities)• Pregnancy
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How does 25(OH)D assay affect clinical care?
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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
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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.
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How much calcium do we need?
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Recommended Calcium IntakeVitamin D Calcium
Institute of Medicine51‐70 years71+ years
600 IU800 IU
1000 mg (M); 1200 mg (F)1200 mg
Endocrine Society51‐70 years71+ years
1500‐2000 IU1500‐2000 IU
N/A
National Osteoporosis Foundation51‐70 years71+ years
800‐1000 IU800‐1000 IU
1000 mg (M); 1200 mg (F)1200 mg
American Geriatrics Society65+ years >1000 IU N/A
• 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), 53‐58.
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Calcium and Cardiovascular Disease