Vitamin D - Bone and Beyond

MALAYSIAN MENOPAUSE SOCIETY
Dr. LIEW FAH ONN
M.B.B.S. (Mal) M.R.C.O.G. (U.K.) L.L.B. (Hons) (London) Certificate in Legal Practice (Mal) Senior Consultant O&G Head of Dept. of O&G MALAYSIA President, Malaysian Menopause Society Council Member, Asia-Pacific Menopause Federation
Dr LIEW FAH ONN Novartis - PD Thistle Hotel 07-10-2012 Sun
Part 1 of 2 Vitamin D BONE & Beyond

Vitamin D SOURCES
Types of Vit. D
5 types: D1, D2, D3, D4, D5 Fat-soluble

D2 (ErgoCalciferol) D3 (CholeCalciferol)
Plants, esp fungi, yeast
Animals Skin UVB (not UVA) light 3x more potent than D2
Dr LIEW FAH ONN
Novartis - PD Thistle Hotel 07-10-2012 Sun
Vit. D - Dietary Sources
10 out of 11 RCT: 1 mcg (40 I.U.) Vit. D = 0.7 nmol up in serum 25(OH)Vit. D
Brannon. Am J Nutr 2008;88:483S-90S
Dr LIEW FAH ONN
Vitamin D FORMATION
Vit. D - Formation, Metabolism

7-DeHydroCholesterol (Skin) UVB LIGHT CholeCalciferol (D3) 25-Hydroxylase (Liver, gut) 25-HydroxyVitamin D3 (25-OH-D3) (Calcidiol) 1-Alpha-Hydroxylase (Kidney) 1,25-DiHydroxyVitamin D3 (Active) ErgoCalciferol (D2) FOOD (Animal) FOOD (Plant)
(1,25-CholeCalciferol = Calcitriol)
Bind to Vit. D receptors (VDR) BIOLOGICAL ACTIONS
Vit. D - Skin Formation
Skin produces 80% of our Vit. D needs 15 minutes of sun exposure of hands, face, arms, legs
Sunbathing: 10,000-50,000 IU when skin turns pink
Cranney J. Am J of Clin Nutr 2008;88(Suppl):513S-9S
Dr LIEW FAH ONN
Vit. D - Deficiency - Risk Factors
NON-MODIFIABLE
Skin pigmentation Covered: Religious, cultural Elderly
MODIFIABLE
High altitude Institutionalized Working indoors Sun protection, Sun screen:
SPF8 reduces SPF15 by 95% by 98%
MEDICAL
Photosensitivity Immunosuppressed Malabsorption: eg celiac disease
Vasquez A. The clinical importance of vitamin D (cholecalciferol): a paradigm shift with implications for all healthcare providers. Alternative Therapies 2004; 10(5):35
Matsuoka L. Chronic sunscreen use decreases the concentration of 25-hydroxyvitamin D: a preliminary study. Arch Dermatol 1988; 124:1802-804
Dr LIEW FAH ONN
Vitamin D RECEPTORS
Vit. D Receptors (VDR)
PRICK-SHAPE
Pancreas Reproductive: ovary, testes Intestine Cartilage Kidney Skin Heart
Adrenal Pituitary Esophagus
Dr LIEW FAH ONN
3BTL-M
Bone Breast Brain Tongue Teeth Thyroid Liver Lung Lymphocytes Muscle Macrophages Monocytes
Vitamin D Many FUNCTIONS

1. Vit. D - Functions
Dual function as a: 1) Vitamin 2) Hormone (formed in skin & acts on distant target organs, esp. gut & bones) Promotes gut absorption of calcium & phosphate Induce osteoclast (destroy) maturation: Bone remodelling Increase bone mineralization Enhances renal proximal tubular reabsorption of calcium & phosphate Decrease PTH Involved in formation & functioning of: - bones - nerves - teeth - muscles
2. Vit. D - Functions In conjunction with parathyroid gland:

1) Maintains proper levels of serum calcium & phosphorus 2) Promotes formation, calcification & repair of bones 3) Stimulates renal tubular transport of calcium & phosphorus
Modulate neuromuscular function Modulate immune system: Anti-Inflammatory Regulate cell proliferation, differentiation & apoptosis (death)
Dr LIEW FAH ONN
3. Vit. D - Other Functions Lowers BP Lowers insulin resistance Less risk of cancers: 74%
Pf eif er. JCEM 2001.86:1633-37
Hypponen. Lancet Nov 2001
AEP Vol.19 No.7 July 2009;468-83, Eur J Cancer. 2007 Jul;43(11):1701-12, American Journal of Clinical Nutrition 91 (5): 132435. 2010
Improves immunity Healthy brain aging Healthy body weight Less depression Less breast cancer: 47% less Macular degeneration: 59% less Decrease all-cause mortality (meta-analysis of 18 RCT)
Epidemiol Inf ect. 2006 Dec; 134(6):1129-40 Psychoneuroendocrinology 2009 Jun 20 Psychoneuroendocrinology 2009 Jun 20, J Alzheimer's Dis. 209May;17(1):151-9 Med Rev. 2008 Mar;13(1):6-20
Am J of Epidemiology Advance October 12, 2007
J of Allergy & Clin Immunol 2010 Jun 08
Altern
Dr LIEW FAH ONN
Vitamin D R.D.A.
Vit. D3 - R.D.A. Dosage (I.U./day) Age Group
400 300
500 200 400-800
0-22 (Male) 19-22 (Female)

Pregnant, Lactating Adult men, women Postmenopausal women
Vit. D3 = 3x more effective than D2

Trang H. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Amer Jour Clin Nutr 1998; 68:854-58 Armas L. Vitamin D2 is much less effective than vitamin D3 in human. Jour Clin Endocrinol Metab 2004; 89:5387-391
Dr LIEW FAH ONN
Vitamin D SAFE LIMITS

Vit. D - Safety Limits
Tolerable Upper Intake Level (TUIL) = 2,000 I.U./d
Non-Observed Adverse Effect Level (NOAEL) = 10,000 I.U./d

Heaney R. J Musculoskel Neuronal Interact 2006;6(4):334-8
Dr LIEW FAH ONN
Vitamin D TOXICITY
Vit. D - Toxicity 22 Vit. D trials with Adverse Events

Most trials too short to observe AE
20 trials D3 400-4,000/d
2 trials D2 5,000-10,000/d
Commonest AE (were asymptomatic): Hypercalcemia, Hypercalciuria No signif difference against placebo

Cranney. Am J Clin Nutr 2008;88(Suppl):513S-9S
Dr LIEW FAH ONN
Vit. D - Renal Stones 7 trials (Looked at incidence of renal stones)

1 Increased stones
5 NO stones
1 Non-signif difference
WHI n = 36,282 400 I.U. D3 + 100 mg Calcium vs Ca alone 5.7 events/10,000 womenexposure years
Cranney. Am J Clin Nutr 2008;88(Suppl):513S-9S
Dr LIEW FAH ONN
Vitamin D Bones FRACTURES

Vit. D - Fracture - Prevention Guyatt. Endoc Review 2002; 23(4):560-9
1966-1999 (Meta-analysis of 25 trials) Vit. D effect on BMD & fractures in postmenopausal osteoporosis (PMO)
Vit. D +/- Calcium (n=4017)
Placebo (n=4107)
BMD, Fractures after 1-5yr
Vit. D - Spine Fracture - Prevention
-37%
Vit. D - Non-Spine Fracture - Prevention
-23%
Vit. D & Fractures
Fracture risk reduced:

Vertebral Non-vertebral 37% 23%
Papadimitropoulos E. Meta-analyses of therapies for postmenopausal osteoporosis, VIII: meta-analysis of the efficacy of Vit. D treatment in preventing osteoporosis in postmenopausal women. Osteoporosis Methodology Group & The Osteoporosis Research Advisory Group. Endocr Rev 2002; 23(4):560-69
800 I.U. Vit. D vs Calcium alone or Placebo: Fracture risk reduced

Hip Non-vertebral 26% 23%
(No effect with 400 I.U. Vit. D)

Bischoff-Ferrari H. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JANA, 2005; 293(18):2257-64
Dr LIEW FAH ONN
Vitamin D Beyond Bones

Vitamin D FALLS
Vit. D - Risk of Falls

Meta-analysis: Prevent falls in elderly >65yr Vit. D +/Calcium 8 RCT n=2426 At least 3months FU
Bischoff-Ferrari H. BMJ 2009;339:b3692
Result = Need 700-800 I.U. D3/day to prevent falls

Vitamin D CANCER
Cancers associated with Low Exposure to Sunlight
Breast
Ovary Uterus Prostate Bladder Kidney
Esophagus
Stomach Pancreas Colon, Rectum Lung Non-Hodgkin lymphoma
Grant W. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer 2002; 94(6):1867-75
Grant proposes: If supplement with Vit. D or adequate exposure to UV light:

save 23,000 Americans a year by a reduction in cancer mortality
Grant W. The association of solar ultraviolet B (UVB) with reducing risk of cancer: multif actorial ecologic analysis of geographic variation in age-adjusted cancer mortality rates. Anticancer Res 2006; 26:2687-699
Dr LIEW FAH ONN
Cancers associated with Low Exposure to Sunlight
If serum 25 OH-Vit D = 55 ng/mL, in a year may prevent: Cancer Colorectal N. America 60,000 The World 250,000
Breast
85,000
350,000
Garland C. What is the dose-response relationship between vitamin D and cancer risk? Nutrition Reviews 2007; 65(8):S91-S95
Dr LIEW FAH ONN
Vitamin D DEFICIENCY & Conditions

1. Vit. D - Deficiency associated with

Ann Epidem 2009;19:446-454, Eur J Cancer. 2007 Jul;43(11):1701-12
Hypertension: 3x more AHA BP. Conf erence 2009 High cholesterol Heart attack, atherosclerosis: 2x more Framingham (Circulation Jan 2008), Scragg, R. Int
J. Epidemiol 1990; 19(3):559-63
Heart arrhythmia (Atrial fibrillation) Stroke: 2x more Achives of Neurology March 2011 Epilepsy Ali. Am Pharmacother 2004; 38(6):1002-5,Psychoneuroendocrinology 2009 Jun 20 Parkinson's, Alzheimer's disease Psychoneuroendocrinology 2009 Jun 20 Depression Lansdown. Psychopharm 1998; 135(4):319-23, J Alzheimer's Dis. 209May;17(1):151-9 Infections: respiratory Epidemiol Inf ect. 206 Dec; 134(6):1129-40 Unexplained body pain (Fibromyalgia) Metabolic syndrome Cancer: Breast, bladder, kidney, GB, liver, lung
Eur J Cancer. 2007 Jul;43(11):1701-12
Dr LIEW FAH ONN

Epidemiologically: GI Disorders
Ann Epidem 2009;19:446-454, AEP Vol.19 No.7 July 2009;468-483
Gastric reflux B 12 deficiency Poor stomach motility Gallstones

Hypponen. Lancet Nov 2001, Chiu, K. Am J. Clin Nutr 2004; 79:820-5
Diabetes mellitus: 57% more
Decreased good colonic bacteria with bloating etc. Constipation Stomach, esophageal cancer Colon cancer: 72% more Pancreatic cancer: 45% more
Dr LIEW FAH ONN
Eur J Cancer. 2007 Jul;43(11):1701-12
Cancer Epid Biomarkers & Prevention 15 (9): 168895. 2006
Am J Clin Nutr 85(6):1586-91 2007
Epidemiologically: AutoImmune Disorders

Ann Epidem 2009;19:446-454
Rheumatoid arthritis SLE Ulcerative Colitis Psoriasis Celiac Disease Asthma Allergies, atopy Multiple Sclerosis Cardiovascular disease
Psychoneuroendocrinology 2009 Jun 20
Respir Res. 2009 Oct 24;10(1):98
Respir Res. 2009 Oct 24;10(1):98
Psychoneuroendocrinology 2009 Jun 20, Goldberg. Med Hypotheses, 1986: 21(2):193-200
Daniel MR. Pharmacotherapy 2009; 29(9) 177e-179e
Dr LIEW FAH ONN
Vitamin D SUMMARY
Summary
D3 preferred 400-800 I.U./day 15 minutes sunlight a day Many benefits beyond bone health
Dr LIEW FAH ONN
Part 2 of 2 Calcium BONE & Beyond

Calcium R.D.A.
Calcium
Years mg. a day 25-50 or Male 1000
51+ 1200
11-24 1200-1500
Pregnant 1200-1500
BreastFeed 1200-1500
Vit D 400-800 I.U. a day

Calcium - Tolerable Upper Limits (mg.)

Age
0-6 mth
Male
Female
Pregnant Lactating
1000 1500
2500
7-12 mth
1- yr 9- yr 19- yr 51- yr
3000
2500
2000
Committee to Review Dietary Ref erence Intakes f or Vitamin D and Calcium, Food and Nutrition Board, Institute of Medicine. Dietary Ref erence Intakes f or Calcium and Vitamin D. Washington, DC: National Academy Press, 2010
Dr LIEW FAH ONN
Calcium ABSORPTION
Calcium & Absorption
35 30 25 20 15 10 5 0 Gluconate Lactate Citrate Phosphate
Dr LIEW FAH ONN
Calcium Calcium-Sandoz 600 +Vitamin D3

Each tablet contains:
Calcium Lactate Gluconate 1358mg Calcium Carbonate 1050mg
Elemental calcium: 600mg

Vitamin D3: 400 I.U.
Dr LIEW FAH ONN
Calcium
What is Calcium Lactate Gluconate (CLG)?
Highly soluble salt of calcium, calcium gluconate & calcium lactate Developed by Sandoz, Switzerland
Bioavailability of CLG can reach 30%, which is equal or even superior to bioavailability of milk calcium
Neutral taste
Calcium What Helps Absorption

Calcium - What Helps Absorption-01
Protein, meat
Dr LIEW FAH ONN
Acidic food, Citrus fruits, Vitamin C
Dr LIEW FAH ONN
Dr LIEW FAH ONN
Ca-C 1000 Sandoz
Dr LIEW FAH ONN
Composition of Ca-C 1000 Sandoz

Each Effervescent tablet (orange) contains:
1000mg
327mg
Calcium Lactate-Gluconate
Calcium Carbonate
1000mg
Vitamin C
Equivalent to 260 mg of elemental Calcium

Combine goodness of Vitamin C & Calcium in one effervescent tablet
Alternative for people with swallowing problems
Pleasant orange flavor

Calcium What Decreases Absorption

Calcium - what Decreases Absorption
Iron pills
Vegetables: phytic acid, oxalic acid
Tea, Caffeine, Alcohol
Dr LIEW FAH ONN
Calcium Well-Known Functions

Calcium - Functions
Mineralization of bones, teeth, nails: less risk for osteoporosis Clotting Factor IV Nerve conduction Muscle contraction, strength Vascular contraction & dilation Hormonal secretion eg. PTH, calcitonin Decrease BP Allender PS, Cutler JA, Follmann D, Cappuccio FP, Pryer J, Elliott P. Dietary calcium and blood pressure.
Ann Intern Med 1996;124:825-31, Bucher HC, Cook RJ, Guyatt GH, Lang JD, Cook DJ, Hatala R, et al. Ef f ects of dietary calcium supplementation on blood pressure. JAMA 1996;275:1016-22, McCarron D, Reusser M. Finding consensus in the dietary calcium-blood pressure debate. J Am Coll Nutr 1999;18:398S-405S
Less colon cancer risk Wu K, Willett WC, Fuchs CS, Colditz GA, Giovannucci EL. Calcium intake and risk of
colon cancer in women and men. J Natl Cancer Inst 2002;94:437-46, Weingarten MA, Zalmanovici A, Yaphe J. Dietary calcium supplementation f or preventing colorectal cancer and adenomatous polyps. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003548
Less symptoms of PMS Risk of pre-eclampsia: -55% Hof myer GJ et al. Cochrane Database Syst Rev 2010 Aug 4; 8: CD001059
Risk of preterm delivery: -24% Hof myer GJ et al. Cochrane Database Syst Rev 2010 Aug 4; 8: CD001059
Calcium Cardiovascular Risks

Calcium & Cardiovascular Risk

Calcium supplements with or without vitamin D & risk of cardiovascular events: reanalysis of the Womens Health Initiative (WHI) limited access dataset & meta-analysis
15 trials
British Medical Journal 2011;342:d2040
16,718 women
Mark J Bolland, senior research fellow, Andrew Grey, associate professor, Alison Avenell, clinical research fellow, Greg D Gamble, research fellow, Ian R Reid, professor of medicine & endocrinology
30% increased risk of myocardial infarction if Calcium supplements (but not for dietary calcium)
No significant increase in strokes
Calcium & Cardiovascular Risk
24,000 people aged 35-64yr
23 May 2012
Possible reduction of risk of MI with higher dietary Calcium
820mg Calcium/day = 31% lower MI risk

Risk of MI with supplements only = 2x higher No risk for stroke
Does taking Calcium cause More Stones ?
Dr LIEW FAH ONN
Women's Health Initiative (WHI) 2002 36,282 post-menopausal women Randomly assigned Take supplements of Calcium 1000 mg PLUS Vit. D 400 I.U. with meals or Take placebo pills For 7 years RESULT Development of kidney stones was 17% more common among women taking supplements than among those in placebo group.
Calcium does NOT cause more stones
Recent review of medical literature Journal of the American College of Nutrition 27-Oct-2008 concluded
"most of the studies show no increase in stone risk with high calcium intake (from either diet or supplements)"
THANK YOU

Vitamin D - Bone and Beyond

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MALAYSIAN MENOPAUSE SOCIETY

Dr. LIEW FAH ONN

Part 1 of 2 Vitamin D BONE & Beyond

5 types: D1, D2, D3, D4, D5 Fat-soluble

Plants, esp fungi, yeast

Animals Skin UVB (not UVA) light 3x more potent than D2

Dr LIEW FAH ONN

Novartis - PD Thistle Hotel 07-10-2012 Sun

Vit. D - Dietary Sources

Dr LIEW FAH ONN

Novartis - PD Thistle Hotel 07-10-2012 Sun

Vit. D - Formation, Metabolism

Vit. D - Skin Formation

Dr LIEW FAH ONN

Novartis - PD Thistle Hotel 07-10-2012 Sun

Vit. D - Deficiency - Risk Factors

Dr LIEW FAH ONN

Novartis - PD Thistle Hotel 07-10-2012 Sun

Vit. D Receptors (VDR)

Novartis - PD Thistle Hotel 07-10-2012 Sun

Vitamin D Many FUNCTIONS

2. Vit. D - Functions In conjunction with parathyroid gland:

Dr LIEW FAH ONN

Novartis - PD Thistle Hotel 07-10-2012 Sun

Hypponen. Lancet Nov 2001

Am J of Epidemiology Advance October 12, 2007

J of Allergy & Clin Immunol 2010 Jun 08

Dr LIEW FAH ONN

Novartis - PD Thistle Hotel 07-10-2012 Sun

Vit. D3 - R.D.A. Dosage (I.U./day) Age Group

0-22 (Male) 19-22 (Female)

Vit. D3 = 3x more effective than D2

Dr LIEW FAH ONN

Novartis - PD Thistle Hotel 07-10-2012 Sun

Vitamin D SAFE LIMITS

Vit. D - Safety Limits

Tolerable Upper Intake Level (TUIL) = 2,000 I.U./d

Non-Observed Adverse Effect Level (NOAEL) = 10,000 I.U./d

Dr LIEW FAH ONN

Novartis - PD Thistle Hotel 07-10-2012 Sun

Vit. D - Toxicity 22 Vit. D trials with Adverse Events

Commonest AE (were asymptomatic): Hypercalcemia, Hypercalciuria No signif difference against placebo

Dr LIEW FAH ONN

Novartis - PD Thistle Hotel 07-10-2012 Sun

Vit. D - Renal Stones 7 trials (Looked at incidence of renal stones)

Dr LIEW FAH ONN

Novartis - PD Thistle Hotel 07-10-2012 Sun

Vitamin D Bones FRACTURES

Vit. D - Fracture - Prevention Guyatt. Endoc Review 2002; 23(4):560-9

Vit. D - Spine Fracture - Prevention

Vit. D - Non-Spine Fracture - Prevention

Vit. D & Fractures

Fracture risk reduced:

800 I.U. Vit. D vs Calcium alone or Placebo: Fracture risk reduced

(No effect with 400 I.U. Vit. D)

Dr LIEW FAH ONN

Novartis - PD Thistle Hotel 07-10-2012 Sun

Vitamin D Beyond Bones

Vit. D - Risk of Falls

Result = Need 700-800 I.U. D3/day to prevent falls

Cancers associated with Low Exposure to Sunlight

Grant proposes: If supplement with Vit. D or adequate exposure to UV light:

Dr LIEW FAH ONN