Vitamin D has effects on bone, muscles, and non-musculoskeletal conditions. It is very common for risk groups like children, older adults, pregnant women, and immigrants to be vitamin D deficient. While vitamin D supplements can help with bone health, the evidence for other benefits is less clear. Large ongoing clinical trials are investigating the effects of vitamin D supplements on conditions like fractures, cardiovascular disease, respiratory infections, diabetes, and cancer. Recommendations for vitamin D intake vary between health organizations.

1. Vitamine D: effecten op bot,
spieren en op niet-
musculoskeletale aandoeningen
Paul Lips
Endocrinologie/Interne Geneeskunde
VU Medisch Centrum
Amsterdam
Prof.Lips

2. Prof.Lips

3. Heilzaam effect van ultraviolet licht
Tuberculose huisje
UV licht voor rachitis
Prof.Lips

4. Vitamine D en kwaliteit van leven
Rafiq R et al J Clin Endocrinol Metab 2014; 99:3136-43
Longitudinal Aging Study
Amsterdam n= 862
Instrument SF-12
Mediators: physical
performance,
depressive symptoms,
chronic diseases
Prof.Lips

5. Significance of the clinical problem
• Vitamin D deficiency is very common in risk groups:
children, adolescents, older persons (institution),
pregnant women, immigrants
• Deficiency: 25-hydroxyvitamin D < 30 nmol/l
• Optimal: 25(OH)D > 50 nmol/l (Institute of Medicine)
25(OH)D > 75 nmol/l (Endocrine Society)
• Variation in 25(OH)D measurement
• Extraskeletal effects of vitamin D?
Prof.Lips

6. Vitamine D
• Meting van 25-hydroxyvitamine D
• Vitamine D en bot
• Effecten buiten het skelet
• Aanbevelingen
Prof.Lips

7. 25(OH)D assay variations (DEQAS) and
impact on clinical decision making
Barake M et al J Clin Endocrinol Metab 2012; 97: 835-843
Prof.Lips

8. 25(OH)D assay variations and impact on
clinical decision making
Classification IDS Diasorin
25(OH)D
• < 25 nmol/l 6 % 17 %
• 25-50 nmol/l 29 % 34 %
• >50 nmol/l 65 % 49 %
Needing treatment: 35 % 51 %
(< 50 nmol/l = 20 ng/ml)
Barake M et al J Clin Endocrinol Metab 2012; 97: 835-843
Prof.Lips

9. Storende factoren
• Vitamine D bindend eiwit (DBP) beinvloedt
totale serum 25(OH)D (zwangerschap, ziekte)
• Genetische varianten van DBP
• 24,25(OH)2D kan kruisreageren, leidt tot
overschatting van 25(OH)D
Prof.Lips

10. Variation in 25(OH)D assays
Quality control
• International Vitamin D External Quality
Assessment Scheme (DEQAS); comparison to
mean value (>900 labs participate)
• Vitamin D Metabolites Quality Assurance
Program (NIH, NIST), standard sera to improve
accuracy
• Vitamin D Standardization Program (VDSP);
standardization of assays, surveys, research
Prof.Lips

11. Seasonal variation of
serum 25(OH)D in the
Longitudinal Aging Study
Amsterdam
Younger cohort 55-65 yr
Mean variation 22 nmol/l
Older cohort 65-88 yr
Mean variation 14 nmol/l
Van Schoor N et al
Osteoporos Int 2014
Prof.Lips

12. Vitamin D and bone cells
• 25(OH)D and 1,25(OH)2D reduce proliferation of
human osteoblasts and enhance differentiation,
increase alk phosphatase and osteocalcin
expression. Van der Meijden et al PLOS One 2014;9:e110283
• VDR overexpression in osteoblasts and osteocytes
prevents bone loss during vitamin D deficiency
Lam et al J Steroid Biochem Mol Biol 2014; 144: 128-31
• Osteoblast cell line culture with 25(OH)D leads to
increase of 1,25(OH)2D in medium and enhanced
osteoblast and osteocyte maturation
Turner et al J Steroid Biochem Mol Biol 2014; 144: 114-18
Prof.Lips

13. Results: increase at the femoral neck 0.8%, 95% CI 0.2-1.4 with
heterogeneity among trials
Reid et al Lancet 2014; 383: 146-55
Effects of vitamin D supplements on bone mineral
density: a systematic review and meta-analysis.
Inclusion : 23 studies (mean duration 23·5 months, comprising
4082 participants)
Baseline serum 25-hydroxyvitamin D concentration < 50
nmol/L in eight studies
Conclusion: Widespread use of vitamin D for osteoporosis
prevention in community-dwelling adults without specific risk
factors for vitamin D deficiency seems to be inappropriate.
Prof.Lips

14. Randomized clinical trials (n=19) of vitamin D (±
calcium) with fracture as primary outcome
Prof.Lips

15. The effect of vitamin D ± calcium on
fracture incidence: trials and meta-analyses
• Randomized controlled clinical trials n=19
5 showed decrease of fracture incidence
1 borderline decrease
1 decrease in per protocol analysis (WHI)
10 trials no effect
2 trials increase of fracture incidence (1 dose/yr)
• Meta-analyses, trial level, individual patient data n=15
Bischoff-Ferrari 2005, Boonen 2007, Jackson 2007, Tang 2007,
Cranney 2007, Reid 2008, Chung 2009, Avenell 2009, Bischoff-
Ferrari 2009, Dipart Group 2010, Bergman 2010, Lai 2010,
Chung 2011, Bischoff-Ferrari 2012, Bolland 2014
Prof.Lips

16. Annual high-dose (500 000 IU vs placebo) oral vitamin D
and falls and fractures in 2256 women >70 yrs
Sanders K et al JAMA 2010; 303: 1815-22
Prof.Lips

17. Conclusions from meta-analyses on vitamin D
and fracture prevention
Vitamin D is more effective:
• In the institutionalized than in community–living
elderly
• With a dose ≥ 800 IU/d than with < 800 IU/d
• In 80+ and 70-80 year persons than in 60-70
years.
• When compliance > 80 % than with lower
compliance.
• When combined with calcium
Tang et al Lancet 2007; 370: 657-66
Bischoff-Ferrari et al N Engl J Med 2012; 367: 40-49
Bolland et al Lancet diabetes-endocrinology 2014
Prof.Lips

18. Conclusions from meta-analyses on vitamin D
and fracture prevention (2)
• Effect on fracture prevention less than 15 % in
community dwelling elderly
• Studies are heterogeneous
• Studies have often been performed in non-
deficient persons.
• A high dose once per year has a negative effect on
fall and fracture incidence.
Tang et al Lancet 2007; 370: 657-66
Bischoff-Ferrari et al N Engl J Med 2012; 367: 40-49
Bolland et al Lancet diabetes-endocrinology 2014
Prof.Lips

19. VDR -/- mouse
• Alopecia
• Decreased longitudinal
growth, rickets
• Altered immunity
• Hypertension and
cardiac hypertrophy
• Prone to chemically
induced cancer
• Changed grooming
behaviour
Bouillon et al Endocr Rev 2008; 29: 726-76
Prof.Lips

20. Effecten buiten het skelet: Update
• Vitamine D, spierkracht en vallen
• Vitamine D en luchtweginfecties/COPD exacerbaties
• Vitamine D en bloeddruk, cardiovasculaire
uitkomsten
• Vitamine D en diabetes
• Buiten beschouwing: multiple sclerose, depressie,
kanker
Prof.Lips

21. The effect of vitamin D on fall incidence: results of
randomized clinical trials
Ref Pat vit D dose calcium Outcome
Graafmans 1997 330 400 IU/d - NS
Pfeifer 2000 148 800 IU/d 1200 mg/d - 40 %
Latham 2003 243 300,000 IU - NS
Harwood 2004 150 800 IU/d 1000 mg/d - 52 %
Flicker 2005 625 1000 IU/d 600 mg/d - 27 %
Bischoff-F 2006 445 700 IU/d 500 mg/d - 46 %(w)
Law 2006 223 100,000/3m - NS
Broe 2007 124 800 IU/d - - 72 %
Prince 2008 302 1000 IU/d 1000 mg/d - 19 %
Pfeifer 2009 242 800 IU/d 1000 mg/d - 27 %
Kärkkäinen 2009 1645 800 IU/d 1000 mg/d NS *
Sanders 2010 2256 500,000 IU/y - +15 %
*) 30 % less multiple falls
Prof.Lips

22. Exercise and vitamin D for fall prevention among
older women
Uusi-Rasi K et al JAMA Intern Med 2015; 175: 703-11
Clinical trial with factorial design
409 women 70-80 yr
- Placebo without exercise
- Vitamin D3 800 IU/d
- Placebo and exercise
- Vitamin D3 and exercise
Hazard ratios for injured fallers
were lower in exercise groups.
Vitamin D did not enhance exercise
effects on physical functioning.
Prof.Lips

23. Vitamin D dose and fall prevention: a
randomized controlled clinical trial
• Ref D: 24000 IU/month (800 IU/d),
• High D: 60000 IU/month (2000 IU/d)
• Combined D: 24000 IU/month + calcidiol 300 ug/month
• Lower extremity strength: no difference between groups
• 275 falls: 141 in first 6 and 134 in second 6 months
• 24000 IU: lowest n of falls and % of fallers
• Lower replete range 50-75 nmol/l (median 67) optimal
• Conclusion: Ref D (lower dose) is optimal!!
Bischoff-Ferrari H Vitamin D Workshop Delft 2015
Prof.Lips

24. Vitamin D and peak expiratory flow in 454 men from the
Longitudinal Aging Study Amsterdam
Van Schoor et al J Clin Endocrinol Metab 2012; 97:2164-71
Multivariate
longitudinal
association between
serum 25(OH)D and
PEF in men
25(OH)D
PEF
Prof.Lips

25. Vitamin D for the prevention of acute
respiratory infection in older adults (ViDiFlu):
increased risk for upper resp infection
Martineau et al Thorax 2015, june 10 10.1136
2.4 mg (96,000 IU) once per 2 month for 1 year
Prof.Lips

26. Vitamin D vs placebo in 250 adults with asthma
(ViDiAs); 120,000 IU per 2 months
Martineau et al Thorax 2015; 70: 451-7
Prof.Lips

27. Vitamin D vs placebo in patients with COPD (ViDiCo)
Martineau et al Lancet Resp Med 2015; 3: 120-30
240 patients with COPD
Randomized to:
- Vitamin D3 120,000 IU/2 months
- Placebo
Study duration 1 year
Outcomes:
- First exacerbation
- First upper respiratory infection
Subgroup analysis in patients
with
Serum 25(OH)D < 50 nmol/l
vs > 50 nmol/l
< 50
> 50
Prof.Lips

28. Systematic review: vitamin D and
cardiometabolic outcomes
• Significant associations between
vitamin D status and diabetes risk,
incident hypertension, and incident
cardiovascular disease.
• In randomized trials with vitamin D,
effects on glycemia,blood pressure
(see figure) and cardiovascular
outcomes were not significant.
• Pittas AG et al Ann Intern Med 2010;
152: 307-314
Prof.Lips

29. Vitamin D supplementation and systolic blood pressure:
individual patient data meta-analysis
Beveridge LA JAMA Intern Med 2015; 175: 745-54
Prof.Lips

30. Effect of vitamin D and calcium on pancreatic β-cell
function, and insulin sensitivity
Mitri J et al Am J Clin Nutr 2011; 94: 486-94
Vitamin D3 2000 IU/d vs placebo for 16 weeks in 92 adults with high risk.
Disposition index: insulin secretion x insulin sensitivity
Prof.Lips

31. Effects of calcium and vitamin D suplementation on
metabolic profiles in vitamin D insufficient people with
type 2 diabetes: a randomized controlled trial
• 118 patients with type 2 diabetes, serum 25(OH)D < 75 nmol/l,
factorial design, 8 weeks
Vitamin D 50,000 IU/wk + calcium plac
Vitamin D plac + calcium 1000 mg/d
Vitamin D 50,000 IU/wk + calcium 1000 mg/d
Vitamin D plac + calcium plac
Tabesh M et al Diabetologia 2014; 57: 2038-47
Prof.Lips

32. 120 overweight
subjects with
prediabetes
25(OH)D< 50 nmol/l
Vitamin D3 1200 IU/d
vs placebo
Posthoc: when
25(OH)D > 60 nmol/l
insulinogenic index
Effect of vitamin D supplementation on insulin sensitivity
in vitamin D–deficient non-Western immigrants in the
Netherlands: a randomized placebo-controlled trial
Oosterwerff et al Am J Clin Nutr 2014; 100:152-60
Prof.Lips

33. Effect of vitamin D supplementation on glycemic
control in 275 patients with Type 2Diabetes (SUNNY
Trial): A randomized placebo-controlled trial
Krul-Poel et al. Diabetes Care 2015;38:1420
Prof.Lips

34. Conclusie vitamine D en diabetes
• Een aantal gerandomiseerde trials laat enig effect
zien van vitamine D3 op insuline afgifte en
resistentie.
• De effecten zijn vooral zichtbaar bij patienten met
vitamine D deficientie.
• De effecten zijn gering bij een groep die al zonder
meer voor vitamine D in aanmerking komt.
• Klinisch van belang?
Prof.Lips

35. Megatrials with multiple outcomes,
currently going on
Consortium number dose outcome
ViDA 5110 100,000IU/m fract, CVD, ARI
VITAL 28,875 2000 IU/d cancer, CVD
TIPS-3 5,500 60,000 IU/m CVD, fract, cancer
FIND 18,000 3200 vs 1600 vs P CVD, cancer
DO-HEALTH 2,152 2000 IU/om-3/exerc fract,BP,infect/decl
D-Health 25,000 60,000 IU/m CVD, DM, cancer
VIDI-Kids 6,750 60,000 IU/m tuberculosis
Results are expected between 2016 and 2020
Investigators: R Scrag, JE Manson, S Yusuf, TP Tuomainen, H Bischoff-Ferrari,
R Neale, A Martineau,
Prof.Lips

36. Cod liver oil for the prevention of rickets
Prof.Lips

37. RDA, upper limit of intake (UL) according to the Institute of
Medicine and requirement and UL according to the
Endocrine Society.
Inst of Med Endocrine Soc
Age RDA UL Requirement UL
Children 1-8 yr 600 2500 600-1000 4000
Children 9-18 yr 600 4000 600-1000 4000
Adults 19-70 yr 600 4000 1500-2000 10,000
Adults > 70 yr 800 4000 1500-2000 10,000
Pregnancy 600 4000 1500-2000 10,000
Lactation 600 4000 1500-2000 10,000
Prof.Lips

38. Gezondheidsraad 2012: aanbevelingen
• Dagelijks 10 g (400 IU) extra voor:
- kinderen t/m 4 jaar
- vrouwen 4-50 jaar, mannen 4-70 jaar met donkere huid
en weinig zonblootstelling.
- gesluierde vrouwen tot 50 jaar
- zwangeren, borstvoeding
- vrouwen 50-70 jaar
• Dagelijks 20 g (800 IU) extra voor:
- alle ouderen vanaf 70 jaar
Gezondheidsraad 2012; publicatie 2012/15
Prof.Lips

39. Effect of vitamin D3 400 or 800 IU/day vs control on
serum 25(OH)D and PTH in institutionalized elderly
800
400
cont
cont
Lips et al J Clin Endocrinol Metab 1988
400
800
• Randomized clinical trial
• Serum 25(OH)D by HPLC
and CPB.
• No non-responders
• Non-linear increase
Prof.Lips

40. Dose response to vitamin D supplementation
in postmenopausal women
Gallagher JC et al Ann Intern Med 2012; 156: 425-37
Prof.Lips

41. A reverse J-shaped associaton of all-cause mortality with
serum 25-hydroxyvitamin D in 247,574 subjects from
general practices
Durup et al J Clin Endocrinol Metab 2012; Epub
Prof.Lips

42. • Pieter Brueghel: De val van Icarus
Prof.Lips

43. Overdosering vitamine D
• Diermodellen: FGF23 -/- muis heeft hoge spiegels van
1,25(OH)2D, hoog Ca en PO4, botresorptie,
vaatverkalking en vervroegde veroudering.
• Cohortonderzoek en klinische trials wijzen op een U-
vormig verband: te veel vitamine D leidt tot meer
vallen en fracturen, en mogelijk hogere mortaliteit.
Prof.Lips

44. Conclusies
• De optimale 25-hydroxyvitamine D-spiegel voor
botstofwisseling en spierfunctie is 50 tot 80 nmol/l.
• De nauwkeurigheid van 25(OH)D bepalingen is nog
steeds onvoldoende. Internationale programma’s
zoals DEQAS en VDSP brengen hierin verbetering.
• Vitamine D en calcium supplementen kunnen ca 15
% van de heup- en niet-wervelfracturen voorkomen
bij ouderen in instellingen.
• Vitamine D kan mogelijk vallen voorkomen.
Prof.Lips

45. Conclusies (2)
• Vitamine D heeft mogelijk een preventief effect op
luchtweginfecties/exacerbaties bij COPD.
• Vitamine D heeft mogelijk een gering effect op
insuline afgifte en gevoeligheid.
• Met een dosis vitamine D3 1 dd 800 IE is de 25(OH)D
spiegel bij 95 % van de behandelden boven 50
nmol/l.
• Het verband tussen dosis en effect is voor vitamine D
waarschijnlijk U-vormig. Er is een optimum en
daarboven een negatief effect.
Prof.Lips