Vitamin D and Pain

Vitamin D and Pain

Summary:1. Vit. D discovery 2. Metabolism and transformation to the active form3. A.R. (Daily allowance)4. Mechanism of actions5. Epigenetics6. Vit D and pain7. Supplementation and treatment of deficiences8. Safety profile of colechalciferol as source of Vit.D9. Sinergistic activity with other natural bioactive substances

Rickets from Vit D deficiency25(OH) < 10 ng/ml

Causes:

Umbalanced dietMalabsorptionsLack of exposition to lightChronical liver diseasesChronical kidney diseasesDrugs (anti convulsivants)

1,25-OH cholecalciferol receptor is in every cell or our body

Norman AW, Am J Clin Nutr, 2008

1,25-dihydroxyvitamin VDR receptor

Norman AW, Am J Clin Nutr, 2008

RFLPs Fok1 Bsm1,Taq1 Apa1 Cdx2, poly (A) Bgl1

Vit. D – Ormon D Pleiotropin D – Epigenetic agent D

Colecalciferol• Not active precursor, not hydroxilated

Calcidiol o 25(HO)Vit D - D2.• Inactive• Used for blood tests

Calcitriol o 1,25(HO) Vit.D - D3• Active form

25(OH)D=25-idrossivitamina D; 1,25(OH)2D=1,25-diidrossivitamina D

Cute (80%)Fegato

Rene

Dieta (~20%) Vitamina D3

Vitamina D2

Intestino Osso

ProD3 PreD3 Vitamina D3

25(OH)D

1,25(OH)2DPTH (+)

UVBSole

(+) Basso PO2–

4Garantisce un assorbimento

ottimale di calcio e fosforo Garantisce una

mineralizzazione ottimaleMantiene concentrazioni ottimali di calcio e

fosforo sierici

Funzioni metaboliche Funzioni neuromuscolari

Promuove la differenziazione

cellulare

modificato da Holick MF Osteoporos Int 1998

Vitamin D Metabolism

Nutritional sources of

We can obtain from food only< 20% of needed amount

80% of our Vit. D is comes from the sun light exposure and only from March to October in middle hours of the day at our

latitude.

024681012

Gen Feb Mar Apr Mag Giu Lug Ago Sett Nov Dic Mesi dell'anno

% d

i fot

otra

sfor

maz

ione

What Vit. D does ?Effetti epigenetici su oltre 2000 geni

Effetti extrascheletrici

Modulazione della risposta immunitaria

Modulazione della duplicazione

cellulare

CalcemiaFosforemia Endotelio

Aging Infiammazione

Effetti muscolo scheletrici

Metabolismo osseo

Assorbimento del calcio

Trofismo muscolare

Are there other natural substances with sinergistig activity ?

Effetti epigenetici su oltre 2000 geni

Effetti extrascheletrici

Modulazione della risposta immunitaria

Modulazione della duplicazione

cellulare

CalcemiaFosforemia Endotelio

Aging Infiammazione

Effetti muscolo scheletrici

Metabolismo osseo

Assorbimento del calcio

Trofismo muscolare

CurcuminaAcidi grassi ῳ3

Ca, Mg, AA, Fe, Zn, SeVitamine gruppo BVit. K

Vit. C, EchinaceaCurcuminaῳ3, Vit B,

Pleiotropic activity on more than 2.100 genes with scheletric and extra- scheletric activities

(1) Heaney et Al. Am. J. Nutr, 2003(2) Vitamin D for Health: A Global Perspective Arash Hossein-nezhad, Michael F. Holick Mayo Clinic proceedings.

Mayo Clinic 1 July 2013 (volume 88 issue 7 Pages 720-755 DOI: 10.1016/j.mayocp.2013.05.011)

Vit D and immunomodulation

Endocrinol Metab Clin North Am. 2010 Jun;39(2):365-79, Vitamin D and the immune system: new perspectives on an old theme. Hewison M

Effects of vitamin D on innate and adaptive immunity

Schematic representation of the principal innate and adaptive immune responses to a pathogenic challenge, and the positive or negative regulation of these responses by vitamin D. TLR, toll like receptor; DC, dendritic cell, M , macrophage; T-cell, T-lymphocyte; cyto T-cell, cytotoxic T-cell; B-cell, B-lymphocyte; Treg, regulatory T-cell

Vit. D and immunomodulation

Miller J, Gallo RL. Vitamin D and innate immunity, Dermatol. Therapy, 2010; 23:13-22

LA PRESENZA DI VITAMINA D E’ NECESSARIA PER L’ATTIVAZIONE DEI LINFOCITI B E PER IL RECLUTAMENTO DEI MACROFAGI

Published in 201510 Studies includedLack of evidence that Vit D is more effective than placeboMany possible biases (starting level of Vit D )

Can we mesure our Vit.D status ?Interpretazione dei livelli ematici di 25(OH)D (1)

Check PTH too !!!

Adami et al Bone 2009Adami et al Bone 2008 & Isaia et al OI 2003

Vit D carencies prevalence in Italy

0102030405060708090

100

<25nmol/l <35 nmol/l <50nmol/l <60 nmol/l <75 nmol/l

Prev

alen

ce P

erce

ntItaly Elderly Italy Young

Severe vitamin D deficiency is found in > 50% of elderly subjects and inadequate levels in >95%.Inadequate 25OHD values are found in > 50% of young “healthy” subjects.

Valore medio della 25(OH)D

Pazienti con valori di 25(OH)D <30 ng/mL

Pazienti con valori di 25(OH)D <12 ng/mL

16.8 ± 13.1 ng/mL (range 0.3-69.1)

78.3% (235/300)

41% (123/300)

Delle Sedie A et al, Clinical Cases in Mineral and Bone Metabolism 2006

Patients with rheumatologic diseases show lower values of vit. D (N=300)

EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA); Scientific Opinion on the Tolerable Upper Intake Level of vitamin D. EFSA Journal 2012;10(7):2813. [45 pp.] doi:10.2903/j.efsa.2012.2813. Available online: www.efsa.europa.eu/efsajournal

Scientific Opinion on the Tolerable Upper Intake Level of vitamin D1 EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)

In two studies in men, intakes between 234 and 275 μg/day were not associated with hypercalcaemia, and a no observed adverse effect level (NOAEL) of 250 μg/day was established

Upper Intake Level of vitamin D μg U.I.

Infants (0-1) 25 μg 1.000

Children (1-10) 50 μg 2.000

Adolescents (11-17) 100 μg 4.000

Adults 100 μg 4.000

Pregnant women 100 μg 4.000

Effect of cholecalcifelrol supplementation on blood 25(OH)Vit.D level

Larn 2016 Recommended intake for the Italian poulation 2012-2014

Why do we develope vit D deficiences?

How should we treatVit D deficiences?

http://www.reumatismo.org/index.php/reuma/article/viewFile/reumatismo.2011.129/510

http://www.pacinimedicina.it/wp-content/uploads/vitaminaD_brandi_michieliDM.pdf

http://www.efsa.europa.eu/it/efsajournal/pub/2813

Vit D and mortality in the elderly

3 years follow-up

6 years follow-up

Johansson et al, Osteoporos Int, 2012

“ Sarcopenia is a term that denotes the decline in muscle mass and strength that

occurs with healthy aging.”Rosenberg, Am. J. Clin. Nutr.

1989

“ Sarcopenia is part of normal agingand does not require a disease to occur,

although it is accellerated by chronic diseases.”

Roubenoff et al, J Gerontol 2000

Relation of vit D deficiency to cardiovascular risk factors, disease status, and incident cv events(death, heart failure, coronary artery disease/myocardial infarction, stroke)

Anderson et al, Am J Cardiol, 2010

Association between low serum 25-hydroxy-vitamin D and depression in a large sample of healthy adults: the Cooper Center Longitudinal StudyMayo Clinic Proceedings, 2011

Vit D deficiency and depression

Livelli più alti di vitamina D erano associati ad un rischio minore di depressione, al contrario, invece, di stati carenziali che sono risultati associati a maggiore probabilità di depressione, soprattutto nei soggetti che in passato avevano già sofferto di tale malattia.

Ai pazienti coinvolti veniva somministrato un questionario per valutare una possibile storia precedente di depressione e venivano valutati i seguenti parametri: • livelli sierici di 25(OH)D •sintomi depressivi, misurati mediante indice di depressione CES-D (Center for Epidemiologic Studies Depression Scale; un punteggio uguale o superiore a 10 indica depressione)

100 –

90 –

80 –

70 –

60 –

50 –

40 –

30 –

20 –

10 –

0

% asthmatic children with a desiderable level of Vitamin D

(at least 30 to 40 ng/mL)

9.3%

Verona = 45°

Vitamin D Serum Levels and Markers of Asthma Control in Italian Children Chinellato J Pediatr 2011;158:437

75 asthmatic children

25-hydroxyvitamin D

Spirometry

asthma control, according to GINA guidelines and with Childhood Asthma Control Test

Vit D and testosterone (free and total) in men

1362 uominiProporz. Diretta fino a 75/85 nmol/lNessuna stagionalità

Safety profile and vit. D intoxication:

Synergistic activity with:

• Nsaid’s and steroids• Omega 3• Boswellia• Curcumin

Inflammation anc chronic pain

• Omega3• Vit. B complex• Ginko biloba• Anti-oxidants

PeripheralNeuropatic pain

and neurodegeneration

• Glutammine• Probiotics and prebiotics• Anti-oxidants• Curcumin

Gastrointestinal health

• Glucosammine• Chondroitine• Boswellia serrata• Curcumin

Joints Health

Curcuma longa

Boswellia serrata

• Omega 3 (EPA and DHA)

Zingiber officinale

Natural substances with anti-inflammatory activity

Curcumin: THE active principle of turmeric

(1,7-bis (4-hydroxy-3-methoxy-phenyl) hepta-1,6-diene-3,5-dione)

Turmeric powdercontains 3-7% of Curcuminoidsessential oils and fibers

8.770 studies shows pleiotroitropic effects of curcumin (Pubmed)

Inflammatory targets modulated by curcumin

23

24

25

26

27

28

29

02468

1012141618

02468

101214161820

“Randomized, single blind study on efficacy and tolerability of curcumin in patients with reumatoid poliarthritis “Chandran et al. A Randomized, Pilot Study to Assess the Efficacy and Safety of Curcumin in Patients with Active Rheumatoid Arthritis. Phytother. Res. 2012;26:1719–1725.

° n = 45 : curcumin n =15 ; diclofenac n = 15 ; curcumin and diclofenac n = 15° 8 weeks , 1000 mg curcumin (BCM-95 ) e 100 mg diclofenac

Curcumin vs. NSAID’ (diclofenac )

Tass

o di

sedi

men

tazio

ne e

ritro

cita

ria (E

SR)

- 11% - 8%

Significative reduction ofDisease Activity Score (DAS)

Significative reduction ofJoints pain

- 83%- 69%

- 97% - 89%

Significative reduction ofJoints swelling

% In

cide

nza

% In

cide

nza

Curcuminextract Diclofenac1000 mg 100 mg

p < 0.05 p < 0.05 p < 0.05

Curcuminextract Diclofenac1000 mg 100 mg

Curcuminextract Diclofenac1000 mg 100 mg

Ibuprofen Curcumina280290300310320330340350360

° n = 367 : curcumin extract n = 182 ; ibuprofen n = 185° After 4 weeks 1500 mg curcumin (2 capsuls 3x/die) e 1200 mg ibuprofen (2 capsuls 3x/die).° Simple turmeric extract

MobilityDistance covered in 6 minutes

(Time 0 and after 4 weeks)

p = 0,010

Met

ers w

alke

d in

6 m

inut

es

Chronic Pain(Time 0 and after 4

weeks)

Ibuprofen Curcumina0

1

2

3

4

5

6

p = 0,018

% In

cide

nce

1200 mg 1500 mg 1200 mg 1500 mg)

- 41%+ 14% + 11%

Curcumin vs. NSAID’ (ibuprofen)

“Efficacy and safety of curcumin vs. Ibuprofen in patients with knee arthrosis : a multicentric study“Kuptniratsaikul V et al. Efficacy and safety of Curcuma domestica extracts compared with ibuprofen in patients with knee osteoarthritis: a multicenter study. Clin Interv Aging. 2014 Mar 20;9:451-8.

Curcuma polvere

Curcumina principio attivo (1)

Fitosoma (1)

Oli (1)

Ciclodestrina (1)

Forma micellare o Solubilizzata (2)

X 9,5 – 51,1

X 57,7

X 335

X 1350

X 7,3

Source: • (1) Jäger et al, Nutrition Journal 2014, 13:11, comparative absorption of curcumin formulations.• (2) Schiborr et al, Mol. Nutr. Food Res. 2014, 58, 516-527.

X 1

Biodisponibilità vs. Curcuma

Bioavailability of IMPROVED Curcumins

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