Lecture at the 2017 SImpar-Isura Congress in Florence. Workshop "Feed your destiny fighting pain"

2. Vitamin D and Pain

3. Vitamin D and Pain
Summary:
1. Vit. D discovery
2. Metabolism and transformation to the active form
3. A.R. (Daily allowance)
4. Mechanism of actions
5. Epigenetics
6. Vit D and pain
7. Supplementation and treatment of deficiences
8. Safety profile of colechalciferol as source of Vit.D
9. Sinergistic activity with other natural bioactive substances

4. Rickets from Vit D deficiency
25(OH) < 10 ng/ml
Causes:
Umbalanced diet
Malabsorptions
Lack of exposition to light
Chronical liver diseases
Chronical kidney diseases
Drugs (anti convulsivants)

5. 1,25-OH cholecalciferol receptor is in every cell or our body
Norman AW, Am J Clin Nutr, 2008

6. 1,25-dihydroxyvitamin VDR receptor
Norman AW, Am J Clin Nutr, 2008
RFLPs
Fok1
Bsm1,
Taq1
Apa1
Cdx2,
poly (A)
Bgl1

8. 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

9. 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)2D
PTH (+)
Sole
(+) Basso PO2–
4
Garantisce 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

10. Nutritional
sources of
We can
obtain from
food only
< 20% of
needed
amount

11. 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.
0
2
4
6
8
10
12
Gen Feb Mar Apr Mag Giu Lug Ago Sett Nov Dic
Mesi dell'anno
%difototrasformazione

12. What Vit. D does ?
Effetti epigenetici su oltre 2000 geni
Effetti
extrascheletrici
Modulazione
della risposta
immunitaria
Modulazione
della duplicazione
cellulare
Calcemia
Fosforemia
Endotelio
Aging Infiammazione
Effetti muscolo
scheletrici
Metabolismo
osseo
Assorbimento
del calcio
Trofismo
muscolare

13. Are there other natural substances with sinergistig activity ?
Effetti epigenetici su oltre 2000 geni
Effetti
extrascheletrici
Modulazione
della risposta
immunitaria
Modulazione
della duplicazione
cellulare
Calcemia
Fosforemia
Endotelio
Aging Infiammazione
Effetti muscolo
scheletrici
Metabolismo
osseo
Assorbimento
del calcio
Trofismo
muscolare
Curcumina
Acidi grassi ῳ3
Ca, Mg, AA, Fe, Zn, Se
Vitamine gruppo B
Vit. K
Vit. C,
Echinacea
Curcumina
ῳ3, Vit B,

14. 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)

15. 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

16. 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

26. Published in 2015
10 Studies included
Lack of evidence that Vit D is more effective than placebo
Many possible biases (starting level of Vit D )

27. Can we mesure our Vit.D status ?
Interpretazione dei livelli ematici di 25(OH)D (1)
Check PTH too !!!

28. Adami et al Bone 2009
Adami et al Bone 2008 & Isaia et al OI 2003
Vit D carencies prevalence in Italy
0
10
20
30
40
50
60
70
80
90
100
<25nmol/l <35 nmol/l <50nmol/l <60 nmol/l <75 nmol/l
PrevalencePercent Italy 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.

29. 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)

30. 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

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

32. Larn 2016 Recommended intake
for the Italian poulation 2012-2014

33. Why do we develope vit D deficiences?

34. How should we treat
Vit D deficiences?
http://www.reumatismo.org/index.php/reuma/article/viewFile/reumatismo.2011.129/510

35. http://www.pacinimedicina.it/wp-
content/uploads/vitaminaD_brandi_michieliDM.pdf http://www.efsa.europa.eu/it/efsajourna
l/pub/2813

36. Vit D and mortality in the elderly
3 years follow-up
6 years follow-up
Johansson et al, Osteoporos Int, 2012

37. “ 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 aging
and does not require a disease to occur,
although it is accellerated by chronic diseases.”
Roubenoff et al, J Gerontol
2000

38. 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

39. 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)

41. 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

42. Vit D and testosterone (free and total) in men
1362 uomini
Proporz. Diretta fino a 75/85 nmol/l
Nessuna stagionalità

43. Safety profile and vit. D intoxication:

45. Synergistic activity with:
• Nsaid’s and steroids
• Omega 3
• Boswellia
• Curcumin
Inflammation
anc chronic pain
• Omega3
• Vit. B complex
• Ginko biloba
• Anti-oxidants
Peripheral
Neuropatic pain and
neurodegeneration
• Glutammine
• Probiotics and prebiotics
• Anti-oxidants
• Curcumin
Gastrointestinal
health
• Glucosammine
• Chondroitine
• Boswellia serrata
• Curcumin
Joints Health

46.  Curcuma longa
 Boswellia serrata
• Omega 3 (EPA and DHA)
 Zingiber officinale
Natural substances with anti-inflammatory activity

47. Curcumin: THE active principle of turmeric
(1,7-bis (4-hydroxy-3-méthoxy-phényl) hepta-1,6-diène-3,5-dione)
Turmeric powder
contains 3-7% of Curcuminoids
essential oils and fibers

48. 8.770 studies shows pleiotroitropic effects
of curcumin (Pubmed)

49. Inflammatory targets modulated by curcumin

50. 23
24
25
26
27
28
29
0
5
10
15
20
0
5
10
15
20
“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 )
Tassodisedimentazioneeritrocitaria(ESR)
- 11% - 8%
Significative reduction of
Disease Activity Score (DAS)
Significative reduction of
Joints pain
- 83%
- 69%
- 97% - 89%
Significative reduction of
Joints swelling
%Incidenza
%Incidenza
Curcumin
extract Diclofenac
1000 mg 100 mg
p < 0.05 p < 0.05 p < 0.05
Curcumin
extract Diclofenac
1000 mg 100 mg
Curcumin
extract Diclofenac
1000 mg 100 mg

51. 280
290
300
310
320
330
340
350
360
Ibuprofen Curcumina
° 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
Mobility
Distance covered in 6 minutes
(Time 0 and after 4 weeks)
p = 0,010
Meterswalkedin6minutes
Chronic Pain
(Time 0 and after 4
weeks)
0
1
2
3
4
5
6
Ibuprofen Curcumina
p = 0,018
%Incidence
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.
- 39%

52. 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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Maurizio Salamone, biologist
Science Manager Metagenics Italia srl.
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