Vitamin D Deficiency – Myths & Facts

Vinod NaneriaChoithram Hospital & Research Centre

Indore, India

The truth is

• We are scared.• We are scared of “ N” number of diseases

associated with Vitamin D & Calcium.• Almost all reports from all corners of India

shows a deficiency state up to 80 -90%• CH&RC statistics shows 76% deficiency and

18% insufficiency out of 400 cases in affluent class.

Diseases associated with Vitamin D

Diseases associated with Vitamin D

There is a cause of Fear!

• VDR is present in the nucleus of many tissues.• In epidermal keratinocytes, activated T cells of the

immune system, antigen-presenting cells, macrophages and monocytes, and cytotoxic T cells.

• Calcitriol regulates several hundred genes throughout the body or as much as 5 percent of the human genome.

• The 1α-hydroxylase (CYP27B1) gene has been reported to be expressed in many extra-renal tissues.

How it works – not known

The cause of Fear – Extra Renal

• Extra-renal 1a-hydroxylation sites that can act as intracrine systems primarily involved in regulation of cell or tissue growth: skin, gastrointestinal tract, or glandular tissue, such as prostate and breast.

• Extra-renal CYP27B1 may be up-regulated during inflammation, or down-regulated in cancerous tissue proliferation.

• Extra-renal production of calcitriol is found in certain pathological diseases, including granulomatous conditions such as sarcoidosis, lymphoma, and tuberculosis, which can be associated with hypercalcemia.

Fear psychosis?

• ↑ Cholesterol → Coronary→ Myocardial infarct.

• ↑ B.P.→ Hypertension → Stroke.

• ↑ Uric acid → Gout → Arthritis.

• ↓ Vit D → ↓ General health → ↑ All cause mortality.

• ↓ Vit D → ↑ Osteoporosis → Fragility Fracture.

Risk Factors Diseases Clinical expressions

Hype about hip fractures?

Published in The New York Times, May 10, 2010,Company With Osteoporosis Treatment Wins the ‘Super Bowl’ By LORA KOLODNY

Courtesy of McCombs School of Business, Texas Venture Labs

Biologics MD team competing at Global Moot Corp.

Mozart's Death Was Written in the Key of (Vitamin) DJennifer Welsh, LiveScience Staff Writer Date: 06 July 2011 Time: 01:35 PM ET

If Wolfgang Amadeus Mozart had spent a few minutes basking in the sun, it might have forestalled his untimely death, researchers are saying.In many places during the winters, UVB levels in sunlight are too low to make the vitamin in our skin. Where Mozart lived, in Vienna, these low levels of UVB rays would have easily caused vitamin D deficiencies, two researchers write in a letter in the June issue of the journal Medical Problems of Performing Artists.

Mislabeling as “Vitamin”

• Contrary to common belief, vitamin d is not actually a vitamin at all. "Vitamins" by definition, are nutrients that cannot be produced by the body, but are necessary for the proper functioning of the body's tissues and organs.

• Vitamin d is produced by our bodies (when our skin is exposed to ultraviolet rays from the sun) technically, it can not be considered a vitamin.

• It is a Steroid.H1N1 – Influenza virus – Swine flue

Ray Moynihan, journalist, Iona Heath, general practitioner, David Henry, professor of clinical pharmacology.

BMJ 2002;324:886-891

• The social construction of illness is being replaced by the corporate construction of disease.

• A lot of money can be made from healthy people who believe they are sick.

• A lot of money can be made by telling healthy people that they are sick.

Change a number, create a patient

The number of people with at least one of four major medical conditions has increased dramatically in the past decade because of changes in the definitions of disease. "The new definitions ultimately label 75 percent of the adult U.S. population as diseased," according to calculations by two Dartmouth Medical School researchers.

Suddenly sick: A special report by Susan Kelleher and Duff Wilson · June 26 - June 30, 2005 http://seattletimes.nwsource.com/news/health/suddenlysick/sickdefinitions26.html

Diagnosis Old Definition New definition People under Old

People under New

% increase Year

Diabetes Fasting Sugar> 140mg/dl

Fasting > 126mg/dl

11.7 M 1.7 M 14% 1997

Hypertension BP > 160/100 BP> 140/90 38.7 M 13.5 M 35% 1997

Cholesterol > 250mg/dl > 200mg/dl 49.5 M 42.6 M 86% 1998

Obesity(BMI)

BMI> 27kg/m² BMI> 25kg/m² 70.6 M 30.5 M 43% 1998

Prehypertension

Nil 120/80 to139/89

Nil 45 M - 2003

The Number Game

Source: “Changing Disease Definitions: Implications for Disease Prevalence,”Dr.Lisa Schwartz and Steven Woloshin, Effective Clinical Practice, March/April 1999.

Indian SceneAuthors No. Of Patients Deficiency Insufficiency Year / Journal

Arya V et al. 78.3 Osteoporosis Int. 2004 Jan

Marwaha R.K. et al

1346 1228 (91.2%) 92 (6.8%). J Assoc Physicians India. 2011

Vupputuri MR el al

105 94.3% Am J Clin Nutr. 2006 Jun;83

Harinarayan CV.Harinarayan CV et al

164

Rural M/FUrban M/F

52%

44%, /70%, 62%, / 75%,

30%

39.5%, /29%, 26% / 19%,

Osteoporosis Int. 2005 AprAm J Clin Nutr. 2007 Apr;85

Shivane VK et al

1137 100% Postgrad Med J. 2011 Aug;87(1030

Indian scene

• A high prevalence of clinical and biochemical hypovitaminosis D exists in apparently healthy schoolchildren in northern India.Am J Clin Nutr. 2005 Aug;82(2):477-82. Marwaha R et el

• We observed a high prevalence of physiologically significant hypovitaminosis D among pregnant women and their newborns.Am J Clin Nutr. 2005 May;81(5):1060-4. High prevalence of vitamin D deficiency among pregnant women and their newborns in northern India.

Sachan A et al.

Why South Asian are deficient? Dr. Nikhil Tandon – AIIMS ND

• vitamin D deficiency epidemic across South Asia, including India and Pakistan. He also offered insight into some of the possible reasons:"A lack of exposure to sunshine, genetic traits and dietary habits, skin pigmentation and traditional clothing, as well as air pollution and limited outdoor activity in urban populations.“

• High Oxalates & Phytates in the food make unabsorbable calcium salts in the intestine.

second annual 1st Asia-Pacific Osteoporosis Meeting in Singapore

Millions Of U.S. Children Low In Vitamin D

• The researchers found that 7.6 million children across the U.S., were vitamin D deficient, while another 50.8 million, were vitamin D insufficient.

• Low vitamin D levels were especially common in children who were older, female, African-American, Mexican-American, obese, drank milk less than once a week, or spent more than four hours a day watching TV, playing videogames, or using computers.

Global scene?

50% of World PopulationWhy worry ?

Vitamin D - One outfit for All

• Anti aging,• Anti cancer,• Anti diabetes,• Anti infective,• Anti depressant,• Anti hypertensive,• Cardiac protective

National Osteoporosis Foundation Vitamin D Recommendations

• Deficiency is when 25-hydroxyvitamin D blood level of below 10 ng/ml (25nmol)

• Insufficiency is defined as a 25-hydroxyvitamin D blood level between 10 ng/ml - 30 ng/ml

• Sufficiency is defined as a 25-hydroxyvitamin D blood level of 30ng/ml or higher

Multiply ng/ml by 2.5 to get nmol/litre

Serum 25-Hydroxyvitamin D [25(OH)D] Concentrations and Health* [1]

nmol/L**

ng/mL* Health status

<30 <12 Associated with vitamin D deficiency, leading to rickets in infants and children and osteomalacia in adults

30–50 12–20 Generally considered inadequate for bone and overall health in healthy individuals

≥50 ≥20 Generally considered adequate for bone and overall health in healthy individuals

>125 >50 Emerging evidence links potential adverse effects to such high levels, particularly >150 nmol/L (>60 ng/mL)

* Serum concentrations of 25(OH)D are reported in both nanomoles per liter (nmol/L) and nanograms per milliliter (ng/mL). ** 1 nmol/L = 0.4 ng/mL

< 25

25- 75

75 - 250

>250

Relationship between serum PTH and 25(OH)D levels demonstrate a plateau in suppression of PTH when the 25(OH)D level reaches approximately 30 ng/mL.This is the rationale for selecting 30 ng/mL as the cut-off value. Vitamin D level < 10 ng/ml will lead to rickets & osteomalasia. This is another cut-off point. Anything below is severe deficiency.

Why 30ng/ml optimal

Recommendations: Calcium

• Bone forming EAR RDA– Infancy 500 – 800mg 700- 1000mg– Growth spurts 800 -1000mg 1000 – 1200mg

• Bone maintenance– Male 800 – 1000mg 1000 – 1300mg– Female

• Pregnancy• Lactation• Menopause

• Bone decay– Above 65 1000mg 1300mg– Osteoporosis

Age Male Female Pregnancy Lactation

0–12 months*400 IU

(10 mcg)400 IU

(10 mcg)

1–13 years600 IU

(15 mcg)600 IU

(15 mcg)

14–18 years600 IU

(15 mcg)600 IU

(15 mcg)600 IU

(15 mcg)600 IU

(15 mcg)

19–50 years600 IU

(15 mcg)600 IU

(15 mcg)600 IU

(15 mcg)600 IU

(15 mcg)

51–70 years600 IU

(15 mcg)600 IU

(15 mcg)

>70 years800 IU

(20 mcg)800 IU

(20 mcg)

* Adequate Intake (AI)

Recommended Dietary Allowances (RDAs) for Vitamin D [1]

COMMITTEE TO REVIEW DIETARY REFERENCE INTAKES FOR VITAMIN D AND CALCIUM

2010

Summary IOM 2010

• Outcomes related to cancer, cardiovascular disease, hypertension, diabetes, metabolic syndrome, falls, physical performance, immune functioning, autoimmune disorders, infections, neuropsychological functioning, and preeclampsia could not be linked reliably with calcium or vitamin D intake and were often conflicting.

Exception: measures related to bone health.

Summary IOM 2010

• Although data related to cancer risk and vitamin D are potentially of interest, a relationship between cancer incidence and vitamin D (or calcium) nutriture is not adequately and causally demonstrated at present;

• indeed, for some cancers, there appears to be an increase in incidence associated with higher serum 25-hydroxyvitamin D (25OHD) concentrations or higher vitamin D intake.

The U turn

• A U-shaped response curve describes the relationship between serum 25(OH)D and various disease risks.

• Finnish study, the risk of prostate cancer increases below 40 nmol/L and above 60 nmol/L .

• In women from the United States, Finland and China, mortality for 7 types of cancer (endometrial, esophageal, gastric, kidney, non-Hodgkin's lymphoma, pancreatic, ovarian) increases below 45 nmol/L and above 124 nmol/L.

The U turn

• Another transnational study reported that the risk of pancreatic cancer is higher above 100 nmol/L.

• The Framingham Heart Study concluded that cardiovascular disease risk increases below 50 nmol/L and above 62.5 nmol/L,

• The NHANES III found higher all-cause mortality above 122.5 nmol/L.

• Perhaps most worrisome, animal and human studies have indicated a U-shaped response curve for lifespan, with premature ageing associated with both too little and too much vitamin D.

Adverse outcome of high dosage

Factors affecting – Vitamin D synthesis

• Latitude No effect• Skin color No effect• Dietary habit + ve effect• Age + ve effect• Life style + ve effect• Lab errors! No standardization.

The Latitude

White – developed countries

The UVB exposure around the glob

By: Tavera-Mendoza

The Latitude

• Surprisingly, geographic latitude does not consistently predict average serum 25(OH)D levels in a population.

• Ample opportunities exist to form vitamin D (store it in the liver and fat) from exposure to sunlight during the spring, summer, and fall months even in the far north latitudes.

• Long lengthy days,• Thin, low level, less cloudy atmosphere: > UV

penetration.

Ultraviolet (UV) B radiation with a wavelength of 290–320 nanometers penetrates uncovered skin and converts cutaneous 7-dehydrocholesterol to previtamin D3, which in turn becomes vitamin D3. Season, time of day, length of day, cloud cover, smog, skin melanin content, and sunscreen are among the factors that affect UV radiation exposure and vitamin D synthesis.

Sun Exposure

Sun Exposure

• Approximately 5–30 minutes of sun exposure between 10 AM and 3 PM at least twice a week to the face, arms, legs, or back without sunscreen lead to sufficient vitamin D synthesis.

• Minimal Erythrismal Dose. • White skin synthesis more vit D than

Black/Brown during short time exposure.

SkinType General Pigment Sunburn

I Light Pale white or freckled Always

II Fair White Usually

III Medium White to Light Brown Sometimes

IV Olive Moderate Brown Rarely

V Brown Dark Brown Very Rarely

VI Black Very Dark Brown to Black

Never

Sub-Saharan African, Indian, Southern European, and Northern European

Skin Colour Adaptation

1,25, (HO)2 vitamin D3 level kept at a constant level regardless of skin colour

Sun exposure

• Prolonged exposure of the skin to sunlight does not produce toxic amounts of vitamin D3 because of photoconversion of previtamin D3 and vitamin D3 to inactive metabolites.

• In addition, sunlight-induces production of melanin, which reduces production of vitamin D3 in the skin.

People with dark skinGreater amounts of the pigment melanin in the epidermal layer result in darker skin and reduce the skin's ability to produce vitamin D from sunlight.It is not clear that lower levels of 25(OH)D for persons with dark skin have significant health consequences.

Skin color & Melanin synthesis is protective adaptation.It can not itself be a cause of deficiency for normal habitat.

Dark Skin• Among young, tanned Hawaiians with 22.4 hours per

week of unprotected sun exposure, 51% were found to have serum 25(OH)D below 75 nmol/L (30ng/ml).

• A study from south India found levels below 50 nmol/L in 44% of the men and in 70% of the women. The subjects were "agricultural workers starting their day at 8am and working outdoors until 5pm with their face, chest, back, legs, arms, and forearms exposed to sunlight“ .

Extreme Examples

• Eskimo – extreme North – high latitude.

• African(sub Saharan) – at Equater plane - dark skin.

VDD in Eskimo

• Vit. D deficiency is common among northern Native peoples.

• Higher latitudes that prevent vitamin D synthesis most of the year.

• Darker skin that blocks solar UVB. • Wear thick cloths.• Fewer dietary sources of vitamin D. • Vitamin D levels are clearly lower, it is less clear

that these lower levels indicate a deficiency.

VDD in Eskimo - compensation

• There is in fact evidence that the Eskimos have compensated for decreased production of vitamin D through increased conversion to its most active form and through receptors that bind more effectively.

• The Eskimos have normal serum calcium despite low serum 25(OH)D and a calcium-deficient diet.

– Vitamin D deficiency among northern Native Peoples: a real or apparent problem? (Int J Circumpolar Health 2011; 70(x):xxx-xxx Peter Frost

Adaptations to low vitamin D • This may be why nearly half of African Americans are

classified as vitamin D deficient and yet few show signs of calcium deficiency.

• In fact, this population has less osteoporosis, fewer fractures and a higher bone mineral density than do Euro-Americans.

• The same apparent contradiction emerges from a survey of East African immigrant children in Australia.

• None had rickets despite very low serum 25(OH)D, with 87% of them having less than 50 nmol/L and 44% having less than 25 nmol/L

Adaptations: cont….• Darker-skinned humans seem to cope with low levels

of vitamin D by using this vitamin more efficiently or by increasing calcium and phosphorus absorption via other means. Thus, a single UVB exposure produces less vitamin D3 in black subjects than in whites.

• The difference narrows, however, after liver hydroxylation to 25(OH)D, and

• disappears after kidney hydroxylation to 1,25(OH)2D. The most active form of vitamin D is thereby kept at a constant level regardless of skin colour.

Adaptations: cont….

• To summarise, there are many possible reasons why some human populations have managed to survive and even thrive despite apparently deficient levels of vitamin D.

This vitamin may be less necessary!

– because stores of calcium and phosphorus are used more efficiently,

– because these elements are absorbed from the gut via alternate metabolic pathways,

– because vitamin D is transported more efficiently through the bloodstream and into target tissues,

– because the vitamin D receptor binds more strongly to this molecule, or

– because 25(OH)D is converted to 1,25(OH)2D at a higher rate.

Example of Physiological adaptations

• During pregnancy:– Increase calcium absorption from early days.– Hypercalciurea,– Real risk of Renal stone, if supplemented,– Calcium transportation occurs in 3rd trimester.– Total 1,25,(HO)2 D3 doubles up.– DBP increases in plasma.– No change in BMD

Example of Physiological adaptations

During lactation: Total calcium in the milk comes from mother’s skeleton.

Mother’s BMD goes down – but recovers fully after cessation of lactation later on.

Mother is ready for next pregnancy.An adolescent (pregnancy + lactation) mother have

better BMD than a nulliparous woman.

Physiological adaptations

• People living in Northern Europe have better vitamin D level than their counter part living in southern Europe (Who are more close to equatorial plane).

• The response to sun exposure is very quick in white population than in black as an adaptation.

Example of Physiological adaptations

• African Americans living in deferent geographical location are Vitamin D deficient.

• They have High BMD• They are resistant to Osteoporosis and

Fragility fractures.

African Sub- Saharan

• Increased pigmentation reducing vitamin D production in the skin.

• Mean 25(OH)D levels are lower. • Blacks have higher PTH levels and a high

prevalence of secondary hyperparathyroidism.• Higher average levels of 1,25(OH)2D and lower

urinary calcium excretion but not higher biochemical indices of bone turnover.

• The fracture risk is lower and BMD is high.

African Sub- Saharan

• Biochemical indices of bone formation osteocalcin levels are lower.

• The black skeleton is resistant to the bone-resorbing effects of PTH, whereas renal sensitivity to PTH is maintained or perhaps even enhanced.

• Vitamin D supplementation studies in black women have shown inconsistent benefits to BMD.

• Skeletal and renal adaptations to vitamin D deficiency in blacks might be so effective that vitamin D supplementation might not confer any further benefit to the black skeleton.

What is the truth?

• We are deficient as per IOM recommendation.• These recommendations are for USA &

Canada as their main source of Vit D is diet.• They are not applicable to us.• We don’t need high calcium & Vitamin D.• The association of D3+Calcium with other

diseases are still under observational stage.• We have less incidence of Osteoporosis.

We have better adaptability to so called low levels of D

Where Do we stand?

Recommendations

• Our diagnosis of deficiency state should be clinical.

• H/o cramps, Proximal muscle myopathy + Deep bone tenderness.

• If possible Lab assistance, serum calcium, alkaline phosphatase, serum phosphate, urinary excretion of calcium & phosphates, 25(HO)D3, & PTH.

• Taking > Vit D + Calcium may be toxic.

Goswami R et al, AIIMS – New Delhi

• 28 Indians with low serum 25(OH)D (mean 13.5 nmol/l) on screening during January-March 2005. Serum parathyroid hormone (PTH) level was supranormal in 30 % of them.

• Oral supplementation with 60,000 IU cholecalciferol per week + 1g elemental Ca daily for 8 weeks.

Goswami R et al, AIIMS – New Delhi

• At 8 weeks the mean 25(OH)D levels increased to 82.4 nmol/l and serum PTH normalized in all. Twenty-two of the twenty-three subjects had 25(OH)D levels >49.9 nmol/l.

• At 1 year, the mean 25(OH)D level drop to 24.7 nmol/l & all subjects were 25(OH)D deficient. Five subjects with supranormal iPTH at baseline showed recurrence of biochemical hyperparathyroidism.

Supplementations have temporary effect

Goswami R et al, AIIMS – New Delhi• After initial supplementation Vit. D level return to

baseline with in one year.• For sustained improvement in 25(OH)D levels

supplementation has to be ongoing after the initial cholecalciferol loading.

Pattern of 25-hydroxy vitamin D response at short (2 month) and long (1 year) interval after 8 weeks of oral supplementation with cholecalciferol in Asian Indians with chronic hypovitaminosis D.

Br J Nutr. 2008 Sep;100(3):526-9. Epub 2008 Feb 6.

Do we need extra calcium/ vitamin D?

Recommendations: NICE,NOGG,CKS, NHS

• Due to a lack of supporting evidence, vitamin D supplementation for active people younger than 65 years of age is not recommend.

• People older than 65 years of age and those at risk of vitamin D deficiency should aim for a daily vitamin D intake of 10 - 20 micrograms (400 -800 units).

Recommendations: NICE,NOGG,CKS, NHS

• Evidence suggests that vitamin D alone is not effective in reducing fractures in older people (when compared with placebo),

• It can reduce the risk of falls in people 60 years of age and older living in institutionalized care or in the community.

• For elderly people who are housebound or living in a nursing home, a higher dose of 20 micrograms (800 units), along with a daily dose of 1.0 g to 1.2 g calcium, is recommended to reduce the risk of fractures.

Suggestions

• Supplementation of Vitamin D & Calcium should be considered on clinical suspicion.

• Aches & pain, cramps, night restless legs, frequent muscle pulls, knee pain.

• Clinically deep bone tenderness – shin tender.• Proximal muscle weakness.• Low serum calcium + high Alk PO4, low Vit. D,

high PTH + Urinary excretion of Ca + P.

Bottom line:-

• We must treat all deficiency status.

• Requirement of regular supplementation in apparently healthy individuals with Calcium and or Vitamin D at present does not appears logical for Indians.

DISCLAIMER

• Information contained and transmitted by this presentation is based on review of literature from internet and form Institute of Medicine summary on DRI for Vitamin D & Calcium.

• It is intended for use only by the students of orthopaedic surgery.

• Many Gif/Jpeg files are taken from Internet/Textbooks. • Views and opinion expressed in this presentation are personal. • For any confusion please contact the sole author for

clarification. • Every body is allowed to copy or download and use the

material best suited to him.• There is No financial involvement in preparation of this PPT.• For any correction or suggestion please contact

naneria@yahoo.com