11Bikle vitamin D more than good for bones - UCSF CME · VITAMIN D: MORE THAN GOOD FOR BONES Daniel...
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3/19/10 1 VITAMIN D: MORE THAN GOOD FOR BONES Daniel D Bikle, MD, PhD Professor of Medicine and Dermatology UCSF and SFVAMC P Ca 1,25(OH)2D FGF23 P Ca PTH FGF23 Liver Kidney
Transcript of 11Bikle vitamin D more than good for bones - UCSF CME · VITAMIN D: MORE THAN GOOD FOR BONES Daniel...
3/19/10
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VITAMIN D: MORE THAN GOOD FOR BONES
Daniel D Bikle, MD, PhD Professor of Medicine and Dermatology
UCSF and SFVAMC
P Ca
1,25(OH)2D
FGF23
P Ca
PTH
FGF23
Liver Kidney
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SERUM LEVELS OF MAJOR VITAMIN D METABOLITES
RNA!Polymerase II!RXR!VDR!
Coactivator!complex!
Initiation!complex!
Translation!Start Site!
1,25(OH)2D!
mRNA!
Protein!
Classical Actions: Bone Mineral Homeostasis
The Players
25 OHD
1,25(OH)2D
FGF23
Blood
Ca, P
Kidney
Gut
Ca P Ca P Ca
Bone
Urine
PTH
Parathyroid Glands
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Classical Actions: Bone Mineral Homeostasis
Hormonal Feedback Loops
25 OHD
1,25(OH)2D
Bone
Kidney
FGF23 PTH
Parathyroid Glands
Gut
Classical Actions: Bone Mineral Homeostasis
Mineral Feedback Loops
25 OHD
1,25(OH)2D
Blood
Ca, P
Gut
Kidney
P Ca
FGF23
Parathyroid Glands
Bone
PTH
Urine
Classical Actions: Bone Mineral Homeostasis
Mineral Feedback Loops
NON CLASSIC TISSUE DISTRIBUTION OF VDR • Hematolymphopoietic • Activated T and B lymphocytes • Lymph nodes • Macrophages • Monocytes • Spleen • Thymus • Reticular cells • Lymphocytes • Tonsillar dendritic cells • Unactivated lymphocytes • Muscle • Heart • Atria1 myoendocrine cells • Muscle cells • Skeletal muscle • Smooth muscle • Pyloric sphincter • Reproductive • Amnion • Chorioallantoic membrane • Eggshell gland” • Epididymis • Mammary gland • Alveolar and duct cells • Ovary • Oviduct • Placenta • Prostate • Testis • Seminiferous tubule/Sertoli cells • Interstitial tissue/Leydig cells • Uterus (mammalian) • Yolk sac
• Nervous • Brain • Hippocampus • Cerebellum • Purkinje cells • Granule cells • Bed nucleus • Stria terminalis • Amygdala central nucleus • Sensory ganglia • Spinal cord • Endocrine tissues • Adrenal medulla • Cortex • Pancreas • bCells Pituitary • Thyroid • Follicular cells • C Cells • Parathyroid gland • Skin • Epidermis • Fibroblasts • Hair follicles • Keratinocytes • Melanocytes • Sebaceous glands • Other tissues: • Alimentary tract epithelium • Bladder • Choroid plexus • Endothelial cells • Gills • Liver • Lung • Parotid gland From MR Walters Endocrine Reviews 13:719, 1992
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Tissue RNA Protein Activity
Proximal tubules ** ** ***
Epidermis, hair follicle (keratinocytes) ** ** **
Placenta ** ** n.d.
Brain (purkinje cells) ** ** n.d.
Pancreas (beta cells) ** ** *
Colon ** ** n.d.
Breast * ** *
Ovary * * *
Endothelium ** ** *
Dendritic cells *** *** ***
Macrophages *** *** ***
Adrenal medulla * * n.d.
Parathyroid * * n.d.
TISSUE DISTRIBUTION OF CYP27B1 (1OHASE)
From Townsend et al J Ster Bioc Mol Biol:97: 103-109, 2005
VITAMIN D DEFICIENCY IS NOT RARE
The percent of the older population reaching 80 nmol/l serum vitamin D
Age 60+ in NHANES III
Bischoff-Ferrari HA et al. American Journal of Medicine 2004
%
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VITAMIN D DEFICIENCY WITH AGING
• Decreased vitamin D production in the skin • Decreased vitamin D intake in the diet • Decreased vitamin D absorption by intestine • Decreased 1,25D production by the kidney • Decreased intestinal response to 1,25D
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GI DISEASE BIG CAUSE OF VITAMIN D DEFICIENCY: OFTEN UNRECOGNIZED
INCIDENCE OF BONE DISEASE IN GI DISORDERS
• Postgastrectomy: up to 70%, increases with age
• Celiac Disease: up to 80% if untreated • Crohns Disease: up to 30%, affects the
young • Bariatric surgery: up to 60%, depending
on procedure
THE 25(OH)D CONTINUUM
0 25 50 75 100 125 150 (nmol/L)
rickets/osteomalacia osteoporosis
normal
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WHAT IS THE BASIS FOR CHOOSING 80nmol/l TO
DEFINE VITAMIN D SUFFICIENCY?
NB: the conversion factor between ng/ml and nmol/L is 2.5.
32ng/ml=80nmol/L
VITAMIN D STATUS & Ca ABSORPTION
What is the desirable serum 25-OHD level for optimal lower extremity function?
0 20 40 60 80 100 120 140 160 180 200 220 240 3.5
4
4.5
0 20 40 60 80 100 120 140 160 180 200 220 240
14
15
16 8-foot walk Repeated sit-to-stand
25-OHD nmol/l 25-OHD nmol/l
Bischoff-Ferrari HA et al Am J Clin Nutr 2004;80:752–758.
Sec Sec
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Long-Term Effect of Vitamin D and Calcium on the Rate of Falling in ambulatory Older Persons
• 246 women, 199 men • Age: 65 years+ • Randomized, double-blind,
controlled trial – Calcium 500 mg/day
+ vitamin D 700 IU/day – Placebo
• 3-year duration • Mean serum 25(OH)D
67 nmol/l at baseline
Adapted from Bischoff-Ferrari HA et al Archives of Internal Medicine 2006
P < 0.05
inactive all
Effect was neutral in men
Forest Plot Meta-analysis: Effect of vitamin D on falls
Bischoff-Ferrari HA et al.; JAMA 2004
pooled corrected OR = 0.78; 95% CI [0.64, 0.92]
700 IU
u800 IU
400 IU
(n= 1237)
800 IU
0.5 µg
1 µg
800 IU
Serum 25(OH)D and Hip BMD
• NHANES-III • Adults Age
20 – 49 yrs • LOWESS plot
of slope of BMD on 25(OH)D
Bischoff-Ferrari HA. Am J Med 2004; 116: 634-9.
Non-Hispanic whites
African-Americans
Hispanics
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Fracture Efficacy by achieved 25(OH)D levels Hip fracture
Bischoff-Ferrari HA et al. JAMA 2005
Any non-vertebral fracture
Meta-regression: p = 0.02 Meta-regression: p = 0.03
Record RR = 1.01 WHI RR = 0.88
46 to 59 21 to 62
NON CLASSIC TARGET TISSUES AND RESPONSES PROVIDE ADDITIONAL
REASONS FOR MAINTAINING ADEQUATE VITAMIN D LEVELS
• Prodifferentiation, Antiproliferative Actions
• Regulation of Specific Hormone Secretion
• Modulation of Immune Function
CANCER EPIDERMIS
Proliferation
Differentiation
Differentiation Proliferation
25OHD
1,25(OH)2D - +
-
+ -
1,25(OH)2D3
D3
7DHC
25OHD3
-
Adequate 25OHD may protect against cancer and various hyperproliferative diseases of the skin
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CALCIPOTRIENE + UVB RX OF PSORIASIS
From Rogers Dermatol Nursing 18:258-61, 2006
BREAST CANCER MORTALITY
• US breast CA deaths (1970 – 1994) vs. solar UV exposure
• Grant, WB Cancer 2002; 94:1867–75
COLORECTAL CANCER
• Nurses’ Health Study • ages 46–78 • nested case-control study • 193 incident cases • 25(OH)D measured
twice, prior to diagnosis • Feskanich et al., Cancer
Epidemiol Biomarkers Prev 2004 13:1502–08
25(OH)D Quintiles (with medians*)
P = 0.02
*ng/mL
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Lappe et al AJCN 85:1586-91, 2007
PROSPECTIVE TRIAL WITH VITAMIN D
CANCERS BY SITE AND TREATMENT GROUP
Site Placebo (n = 288)
Calcium only
(n = 445)
Vitamin D plus calcium
(n = 446) Placebo (n = 266)
Calcium only
(n = 416)
Vitamin D plus calcium
(n = 403)
Breast(n) 8 6 5 7 6 4
Colon (n) 2 0 1 2 0 0
Lung (n) 3 3 1 3 2 1
Lymph, leukemia, myeloma (n)
4 4 2 4 4 2
Uterus (n) 0 2 1 0 1 0
Other (n) 3 2 3 2 2 1
Total1 20 (6.9) 17 (3.8) 13 (2.9) 18 (6.8) 15 (3.6) 8 (2.0)
Years 1-5 Years 2-5
L
25 OHD
1,25(OH)2D
Bone
Kidney
FGF23 PTH
Parathyroid Glands
Hormonal Regulation by and of 1,25(OH)2D
Renin
Insulin
Pancreas
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25(OH)D & SERUM iPTH*
*after Thomas et al., 1998 NEJM;338:777–783
290 consecutive pts. on a general medical ward – MGH
PTH minimum
Vitamin D/Calcium Interactions
S Adami et al Bone 42:267-270, 2008
TWO FINNISH STUDIES ASSOCIATING 25OHD LEVELS AND DEVELOPMENT OF TYPE 2 DM (highest quartile 69nM vs lowest quartile 22nM)
Knekt et al E;pidemiology 19:666-671, 2008
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Effect of calcium and vitamin D on progression to DM
Pittas et al Diabetes Care 30:980-86, 2007 500mg Ca + 700u D3 placebo
Vitamin D in the aetiology of type 2 diabetes: published studies in humans
Study parameters Study design
Type of subjects studied (age at study) Study results
Vitamin D intake via supplementation 2,000 IU/day (50 g) for 1 month
Observational
Vitamin D-deficient women (adulthood)
Improved glucose tolerance and improved beta cell function
Vitamin D intake via supplementation 2,000 IU/day for 6 months
Case-control
Vitamin D-deficient subjects (adulthood) Improved insulin secretion
Vitamin D intake via single i.m. injection 100,000 IU/day
Case-control
Vitamin D-deficient subjects (adulthood) Improved insulin and C-peptide responses
1,25(OH)2D3 treatment 0.5 g/day for 21 days (or +500 mg Ca2+)
Case-control
Uraemic women (adulthood)
Improved first-phase insulin secretion and insulin sensitivity
1,25(OH)2D3 treatment 1 g/day for 4 days Case-control
Type 2 diabetic women (adulthood)
Improved insulin and C-peptide responses to Sustacal (Mead Johnson, Evansville, IN, USA)
Hypovitaminosis (<5 ng/ml) Observational
Type 2 diabetic women (adulthood)
Decreased 25-hydroxyvitamin D3 levels decreased beta cell function
Vitamin D intake via supplementation 1,332 IU/day for 1 month
Case-control
Type 2 diabetic women (adulthood) Improved first-phase insulin secretion
Vitamin D intake via single i.m. injection 300,000 IU/day
Observational
Type 2 diabetic men and women (adulthood) Increased insulin resistance
From C Mathieu et al. Diabetologia 48:1247-57, 2005
Pilz, S. et al. (2009) Vitamin D status and arterial hypertension: a systematic review Nat. Rev. Cardiol. doi:10.1038/nrcardio.2009.135
The antihypertensive effects of vitamin D
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Findings from cross‑sectional studies of 25(OH)D and blood pressure
Pilz, S. et al. (2009) Nat. Rev. Cardiol. 6:621
ASSOCIATION OF 25OHD LEVELS WITH DEVELOPMENT OF MI
Giovannucci et al Arch Int Med 168:1174-1180, 2008
LOWEST ALL CAUSE MORTALITY ASSOCIATED WITH 25OHD BETWEEN 30-40ng/ml
Melamed et al Arch Intern Med 168:1629-1637, 2008
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VITAMIN D and IMMUNE FUNCTION
DEFINITIONS
• Adaptive Immunity: Mediated by cells specialized in antigen presentation, eg. dendritic cells, and by cells responsible for antigen recognition, eg. T and B lymphocytes
• Innate immunity: Characterized by rapid responses largely based on proinflammatory mediators such as cytokines, chemokines, and reactive oxygen species triggered by recognition of stereotyped patterns in infectious microorganisms by toll-like receptors found in many cells.
ADAPTIVE IMMUNITY
Vitamin D suppresses
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Adaptive Immunity
CYP27B1
Macrophage or Keratinocyte
Dendritic Cell
1,25(OH)2D
25OHD +
+
- -
-
Examples of VDR agonist treatment in animal models of autoimmune diseases
Experimental models
Main effects
Arthritis Decreased incidence and severity of collagen-induced or Lyme arthritis, also when given at disease onset
Autoimmune diabetes Inhibition of insulitis and reduction of diabetes, even when given after islet infiltration
Experimental allergic encephalomyelitis Prevention and treatment of disease, inhibition of relapses
Inflammatory bowel disease Significant amelioration of symptoms, block of disease progression
Psoriasis Inhibition of leukocyte activation and amelioration of histological and clinical signs of disease in human psoriatic skin grafts transplanted to SCID mice
Systemic lupus erythematosus Inhibition of proteinuria, prevention of skin lesions
From L Adorini Cell Immunol 233:115-124, 2005
INNATE IMMUNITY
Vitamin D potentiates
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TLR
Innate Immunity
Macrophage or Keratinocyte
+
Schauber, J. et al. J. Clin. Invest. 2007;117:803-811
TWO EXAMPLES OF INNATE IMMUNITY REGULATED BY VITAMIN D
VITAMIN D & INNATE IMMUNITY*
Cyp27B1 VDR 1,25D
*Liu et al., Science 2006
Cathelicidin Cyp24
25OHD
Mycobacterium
Courtesy of Robert Heaney
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CIRCULATING 25OHD LEVELS IMPORTANT
*Liu et al., Science 2006
serum 25(OH)D: 22 nmol/L
serum 25(OH)D: 78 nmol/L
Courtesy of Robert Heaney
VITAMIN D & TUBERCULOSIS*
• 67 pts with pulmonary TB
• standard treatment for all
• in addition, randomized to either vit D 10,000 IU/d or placebo
*Nursyam et al., Acta Med Indones 2006
• P = 0.002
Courtesy of Robert Heaney
Schauber, J. et al. J. Clin. Invest. 2007;117:803-811
THE INNATE IMMUNE RESPONSE IS LACKING IN THE ANIMAL UNABLE TO
PRODUCE 1,25(OH)2D
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HOW TO TREAT VITAMIN D DEFICIENCY
VITAMIN D SOURCES
25(OH)D RESPONSE TO ORAL D3
D3 dose (IU/d)
10,000
5,000
1,000 0
• 66 males
• aged 38.7 yr (± 11.2 )
• dosed with vit D3 from October through February
100IU D3 daily increases 25OHD3 by 1ng/ml Heaney et al AJCN 77:204-210, 2003
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D2 vs. D3*
• single oral dose • 50,000 IU • D2 or D3
• n = 10 in each group
*Armas et al., 2004
D3
D2
SUMMARY • Vitamin D deficiency is not rare—Vitamin D itself is
the best treatment • The levels of vitamin D required to prevent rickets or
osteomalacia are inadequate to optimize BMD, intestinal calcium absorption and muscle function resulting in increased falls and fractures
• Newly recognized functions such as cancer prevention, insulin secretion, adaptive and innate immunity also may require higher than “normal” vitamin D levels
• The target 25OHD level is around 80nmol/l or 32ng/ml
