Calcium en vitamine D:

Calcium en vitamine D:
hoeveel en voor iedereen?
Evelien Gielen, MD PhD
Centrum voor Metabole Botziekten, UZ Leuven
Afdeling Gerontologie en Geriatrie, UZ Leuven
Overzicht
•
•
•
•
•
•
Inleiding
Botmetabolisme
Fractuurpreventie met calcium en vitamine D
Calcium: hoeveel en voor wie?
Vitamine D: hoeveel en voor wie?
Besluit
Overzicht
•
•
•
•
•
•
Inleiding
Botmetabolisme
Fractuurpreventie met calcium en vitamine D
Calcium: hoeveel en voor wie?
Vitamine D: hoeveel en voor wie?
Besluit
Bot is levend weefsel
Bot wordt voortdurend vernieuwd …
Osteoblast
Osteoclast
Osteoblast
Osteoclast
Actieve botombouweenheid (BMU)
Bot wordt voortdurend vernieuwd …
Osteoblast
Osteoclast
Botaanmaak
Botafbraak
Actieve botombouweenheid (BMU)
Normaal bot
… om microfracturen te verwijderen
Reproduced with permission from Seeman. Advances in Osteoporotic Fracture Management 2: 2-8, 2002;
Fyhrie. Bone 15:105-109, 1994
Onevenwicht tussen botaanmaak en botafbraak …
Osteoblast
Osteoclast
Actieve botombouweenheid (BMU)
↑
Botaanmaak ↓ Botafbraak
Botafbraak
Osteoporose
… ligt aan de basis van botverlies
Totale heup BMD (g/cm2)
1.2
1.1
 2 SD
1.0
 1 SD
Mean
0.9
0.8
0.7
0.6
0.5
0.4
30
40
50
60
70
80
90
Leeftijd (jaren)
Meunier. Clin Ther 1999; 1025-1044
Osteoporose en osteoporotische breuken
Overzicht
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•
•
•
•
•
Inleiding
Botmetabolisme
Fractuurpreventie met calcium en vitamine D
Calcium: hoeveel en voor wie?
Vitamine D: hoeveel en voor wie?
Besluit
Botmetabolisme
Normaal serum Calcium2+
Botmetabolisme bij ouderen
Leeftijdsgebonden deficiëntie
van calcium en vitamine D
Negatieve calciumbalans
Botmetabolisme bij ouderen
Age‐related calcium and vitamin D insufficiency
Negative calcium balance
Secondary hyperparathyroidism
Secondary hyperparathyroidism
Increased bone turnover
Increased bone turnover
Loss of bone quality and subsequent fractures in women and men
Overzicht
•
•
•
•
•
•
Inleiding
Botmetabolisme
Fractuurpreventie met calcium en vitamine D
Calcium: hoeveel en voor wie?
Vitamine D: hoeveel en voor wie?
Besluit
Ca en vit D beschermt tegen breuken
Weight
(%)
Relative Risk
(95% CI)
38.9%
0.74 (0.60‐0.91))
Dawson‐Hughes et al. 1997
0.2%
0.36 (0.02‐8.78)
Chapuy et al. 2002
6.5%
0.62 (0.36‐1.07))
Porthouse et al. 2005
2.8%
0.71 (0.31‐1.64)
RECORD Trial Group. 2005
10.9%
1.14 (0.76‐1.73))
WHI Trial Group. 2006
40.7%
0.88 (0.72‐1.08)
100.0%
0.82 (0.71‐0.94)
Favors
Treatment
Favors
Placebo
(calcium & vitamin D)
Chapuy et al. 1994
Pooled Estimate
N = 45.509
0.1
0.5
1.0
1.5
2.0
p=0.0005
Relative Risk (95% CI) of Hip Fracture
Boonen. JCEM 2007; 92: 1415-1423
Ca en vit D beschermt tegen breuken als
Weight
(%)
Relative Risk
(95% CI)
38.9%
0.74 (0.60‐0.91))
Dawson‐Hughes et al. 1997
0.2%
0.36 (0.02‐8.78)
Chapuy et al. 2002
6.5%
0.62 (0.36‐1.07))
Porthouse et al. 2005
2.8%
0.71 (0.31‐1.64)
RECORD Trial Group. 2005
10.9%
1.14 (0.76‐1.73))
WHI Trial Group. 2006
40.7%
0.88 (0.72‐1.08)
100.0%
0.82 (0.71‐0.94)
Favors
Treatment
Favors
Placebo
(calcium & vitamin D)
Chapuy et al. 1994
Pooled Estimate
N = 45.509
0.1
0.5
1.0
1.5
2.0
p=0.0005
Relative Risk (95% CI) of Hip Fracture
Boonen. JCEM 2007; 92: 1415-1423
1. in combinatie
Weight
(%)
Favors
Placebo
Favors
Treatment
Relative Risk
(95% CI)
(vitamin D alone)
Lips et al. 1996
31.1%
1.21 (0.83‐1.75)
Meyer et al. 2002
30.1%
1.08 (0.73‐1.57)
Trivedi et al. 2003
13.0%
0.87 (0.49‐1.56)
RECORD Trial Group. 2005
25.8%
1.14 (0.75‐1.72)
100.0%
1.10 (0.89‐1.36)
Pooled Estimate
N = 9083
P=0.38 (NS)
0.1
0.5
1.0
5.0
10.0
Relative Risk (95% CI) of Hip Fracture
Boonen. JCEM 2007; 92: 1415-1423
2. in de juiste dosis
Vitamin D 800 IU/d
Favours Vitamin D
Vitamin D 400 IU/d
Favours control
Favours control
Favours Vitamin D
Meyer et al. 2002
Chapuy et al. 2002
Meunier et al. 1994
Lips et al. 1996
Trivedi et al. 2003
Pooled 0.74 (0.61‐0.88) 0.2
0.5
1.0
5.0
Relative risk (95% CI) of hip fractures
Pooled 1.15 (0.88‐1.50)
0.2
0.5
1.0
5.0
Relative risk (95% CI) of hip fractures
Bischoff-Ferrari. JAMA 2005; 293: 2257-2264
3. volgehouden
70
NTX (pBCE/mmol)
60
50
40
30
20
10
Startwaarden
Tijdens calcium
& vitamine D
Na calcium
& vitamine D
Prestwood. Osteoporos Int 1996; 314-319
3. volgehouden
BMD (% of baseline)
Femoral neck BMD
4.0
3.0
2.0
1.0
0.0
‐1.0
‐2.0
Discontinuation
4.0
3.0
2.0
1.0
0.0
‐1.0
‐2.0
P<0.05
0
12
24
36
48
60
0
12
24
36
Time (months)
Calcium (500 mg) & vitamin D (700 IU)
Placebo
Dawson-Hughes. Am J Clin Nutr 2000
48
4. gericht toegediend
Cumulative hazard
0.3
Placebo
Calcium (1000 mg)
Vitamine D3 (800 IU)
Combination treatment
0.2
All fractures
NS
N = 5292
0.1
0
0
10
20
30
40
50
60
70
Time (months)
NS = not significant
RECORD Trial Group - Lancet 2005
4. gericht toegediend
Serum 25(OH)D, nmol/L
100
80
60
20 ng/ml
50 nmol/L
40
20
0
Adults
<70 years
Independent
elderly
Institutionalized Hip fracture
elderly
patients
Lips. Endocr Rev 2001; 22: 477-501
4. gericht toegediend
Mean serum 25‐hydroxyvitamin D concentrations for the USA for 2005–2006, by age and sex
20 ng/ml
Rosen. Nat Rev Endocrinol 2013; 434-438
4. gericht toegediend
Favors
Treatment
Institutionalized
Relative Risk
(95% CI)
Favors
Placebo
(calcium & vitamin D)
Chapuy et al. 1992
0.74 (0.65‐0.97)
Chapuy et al. 2002
0.62 (0.36‐1.07)
0.71 (0.55‐0.91)
Subtotal
Community‐dwelling
Jackson et al. 2006
0.97 (0.92‐1.03)
Dawson‐Hughes et al. 1997
0.46 (0.23‐0.90)
Porthouse et al. 2005
1.08 (0.61‐1.91)
Porthouse et al. 2005
0.96 (0.64‐1.43)
Salovaara et al. 2010
0.84 (0.63‐1.13)
0.92 (0.78‐1.07)
Subtotal
0.2
1.0
5.0
Relative Risk (95% CI) of Fracture
Chung. Ann Intern Med 2011; 155: 827-838
Overzicht
•
•
•
•
•
•
Inleiding
Botmetabolisme
Fractuurpreventie met calcium en vitamine D
Calcium: hoeveel en voor wie?
Vitamine D: hoeveel en voor wie?
Besluit
Dietary reference intake for Calcium
Recommended dietary
allowance (mg/day)
Upper level intake
(mg/day)
1-3 years
700
2500
4-8 years
1000
2500
9-13 years
1300
3000
14-18 years
1300
3000
19-30 years
1000
2500
31-50 years
1000
2500
51-70 years ♂
1000
2000
51-70 years ♀
1200
2000
> 70 years
1200
2000
IOM Report 2011
Cardiovascular Auckland Calcium Study
risk of calcium supplements
Potential vascular events reported by
postmenopausal women
Calcium group
1000 mg per day
(n=732)
Placebo group
(n=739)
p-value
Relative risk
(95% CI)
Angina
88
99
0.05
0.71 (0.50-1.01)
Myocardial infarction
45
19
0.01
2.24 (1.20-4.17)
Transient ischaemic attack
42
27
0.10
1.59 (0.93-2.72)
Stroke
52
34
0.14
1.44 (0.90-2.31)
Sudden death
4
1
0.22
4.04 (0.45-36.0)
Angina, chest pain, MI or sudden death
155
135
0.68
0.94 (0.72-1.24)
Myocardial infarction, stroke or sudden death
101
54
0.01
1.66 (1.15-2.40)
Death
34
29
0.52
1.18 (0.73-1.92)
NNT to prevent 1 symptomatic fracture: 55
NNH to cause 1 acute myocardial infarction: 44
Auckland Calcium Study, 1471 postmenopausal women, mean age 74 y
Bolland. BMJ 2008;336:262-266
2010 meta-analysis of Bolland et al.
Calcium supplements (without co-administered vitamin D)
are associated with an increased risk of myocardial infarction
Cumulative incidence (%)
6
5
Calcium (≥ 500 mg per day)
Placebo
+ 31 %
4
3
2
1
HR 1.31 (95% CI 1.02-1.67)
0
0
6
8151 patients in 5 trials, mean age 73 y
12
18
24
30
36
42
48
54
60
Time (months)
Bolland. BMJ 2010; 341: c3691
2011 meta-analysis of Bolland et al.
Calcium with vitamin D supplements
increase the risk of myocardial infarction and stroke
Favors Ca & D
N = 20.090
Favors placebo
Weight (%)
Myocardial infarction
1.21 (1.01-1.44)
RECORD trial. 2005
18
Lappe et al. 2007
1
WHI CaD trial. 2007
81
Stroke
1.20 (1.00-1.43)
RECORD trial. 2005
23
Lappe et al. 2007
2
WHI CaD trial. 2007
75
20.090 patients in 3 trials
Relative Risk (95% CI)
0.5
1.0
2
3
Bolland. BMJ 2011; 342: d2040
Are calcium supplements associated with
an increased cardiovascular risk?
Calcium supplements: evidence in perspective
Calcium supplements (with or without vitamin D) may be
associated with an increased risk of myocardial infarction …
… but several limitations of the meta-analyses of Bolland et al.
have to be taken into account
o
o
o
statistical outcomes are borderline significant
cardiovascular events were not registered in a standardized manner
no ↑ cardiovascular risk in other observational trials, RCTs and meta-analyses
Gielen. Age ageing 2012; 41: 576-580
Calcium supplements: evidence in perspective
Cumulative event rate
In a 5-year RCT with 4.5-year follow-up, the calcium group did not have
a higher risk of death or hospitalization from atherosclerotic vascular disease
Intention-to-treat analysis
(1460 postmenopausal women)
0.3
Placebo
Calcium (2x 600 mg per day)
NS
HR 0.92 (CI 0.74-1.15)
0.2
0.1
0
0
Calcium Intake Fracture Outcome Study
20
40
60
80
100
Time to the first event (months)
Lewis. J Bone Miner Res 2011; 26: 35-41
Calcium supplements: evidence in perspective
Calcium supplements (with or without vitamin D) may be
associated with an increased risk of myocardial infarction …
… but several limitations of the meta-analyses of Bolland et al.
have to be taken into account
o
o
o
o
statistical outcomes are only borderline significant
cardiovascular events were not registered in a standardized manner
no ↑ cardiovascular risk in other observational trials, RCTs and meta-analyses
mechanistically speculative  acute elevation of serum calcium?
Gielen. Age ageing 2012; 41: 576-580
Calcium supplements: evidence in perspective
Calcium Intake Fracture Outcome Study
Calcium 1000 mg 1x per day
6
Calcium 600 mg 2x per day
Placebo
5
SS
4
3
2
1
0
0
RR 2.24 (CI 1.20-4.17)
10
20
30
40
50
Time to the first event (months)
60
Cumulative event rate
Proportion (%) with verified
myocardial infarction
Auckland Calcium Study
0.3
Placebo
NS
0.2
0.1
HR 0.92 (CI 0.74-1.15)
0
0
20
40
60
80
100
Time to the first event (months)
Bolland. BMJ 2008; 336: 262-266; Lewis. J Bone Miner Res 2011; 26: 35-41
Calcium supplements: evidence in perspective
The risk of myocardial infarction might be increased by taking calcium supplements
and might be reduced by a moderately higher dietary calcium intake
N = 23.980
mean age = 35-64 years
mean follow-up = 11 years
* p < 0.05
Myocardial infarction
Cardiovascular mortality
Mean
513 mg/day
675 mg/day
820 mg/day
1130 mg/day
1.00 (ref)
0.94 (0.70-1.25)
0.69 (0.50-0.94)*
0.85 (0.63-1.16)
101
91
70
92
1.00 (ref)
1.34 (0.95-1.88)
1.15 (0.80-1.65)
1.18 (0.82-1.72)
65
75
61
66
Non-use of supplements
Calcium supplement
1.00 (ref)
1.86 (1.17-2.96)*
256
20
1.00 (ref)
1.02 (0.51-2.00)
184
9
Quartile
Dietary
calcium intake 1 (low)
2
3
4 (high)
Supplements
Hazard ratio (95% confidence interval)
and number of cases
Li. Heart 2012; 98: 920-925
and cardiovascular
risk: conclusion
CalciumCalcium
supplements
and cardiovascular
risk: conclusion
•
Safety questions about the use of supplemental calcium +/- vitamin D have been raised.
•
There is no conclusive evidence that calcium supplements increase cardiovascular risk.
•
Individuals who do not obtain sufficient dietary calcium intake should not be advised to
avoid calcium supplements because of concerns about a potential increased
cardiovascular risk.
•
Nevertheless, it seems appropriate
o
to target supplementation to subgroups that will most benefit from supplementation
o
to correct calcium deficiency preferably by enhancing dietary intake
•
Efficacy of more frequent, lower dosing schedules need further study.
Heaney. Adv Nutr 2012; 3: 763-71
Dietary reference intake for Calcium
Recommended dietary
allowance (mg/day)
Upper level intake
(mg/day)
1-3 years
700
2500
4-8 years
1000
2500
9-13 years
1300
3000
14-18 years
1300
3000
19-30 years
1000
2500
31-50 years
1000
2500
51-70 years ♂
1000
2000
51-70 years ♀
1200
2000
> 70 years
1200
2000
Dietary + supplemental intake
IOM Report 2011
Dietary Calcium intake
• 300 mg from healthy diet
• 180 mg per glass of milk (150/ml)
• 360 mg per slice of cheese (30g)
• 180 mg per portion (125g)
• 90-100 mg Contrex/Hépar (200 ml)
Calcium supplements
+ Citric acid
Elemental calcium
Calcium carbonate
Calcium citrate
1000 mg
2500 mg
4750 mg
500 mg (max single dose)
1250 mg
2375 mg
Max per tablet
1250 mg
950 mg
Cheaper
Requires stomach acid for
absorption
Readily absorbed with and
without stomach acid
Less GI side effects (?)
Pill burden
Nephrolithiasis
Bauer. NEJM 2013; 369: 1537-1543; Harvey JBMR 1988; 3: 253-258
Calcium supplements
+ Citric acid
Elemental calcium
Calcium carbonate
Calcium citrate
1000 mg
2500 mg
4750 mg
500 mg (max single dose)
1250 mg
2375 mg
Max per tablet
1250 mg
950 mg
Cheaper
Requires stomach acid for
absorption
Readily absorbed with and
without stomach acid
Less GI side effects (?)
Pill burden
Nephrolithiasis
Bauer. NEJM 2013; 369: 1537-1543
Calcium screening UZ Leuven, 1998
Ca inname obv zuivelanamnese: anno 1998 (n=1280)
Calcium screeningstool UZ Leuven, 2014
Calcium screening UZ Leuven, 2014
Calciuminname obv tool: anno 2014 (n=163)
40
Dieet
35
Frequentie
30
25
20
15
10
5
0
180 360 540 720 900 1080 1260 1440 1620 1800 1980 2160 2340 2520 2700 2880 3060
mg Calcium
Calcium screening UZ Leuven, 2014
Calciuminname obv tool: anno 2014 (n=163)
30
Dieet+CA-supplementen
25
Frequentie
20
15
10
5
0
180 360 540 720 900 1080 1260 1440 1620 1800 1980 2160 2340 2520 2700 2880 3060
mg Calcium
Calcium screening UZ Leuven, 2014
Overzicht
•
•
•
•
•
•
Inleiding
Botmetabolisme
Fractuurpreventie met calcium en vitamine D
Calcium: hoeveel en voor wie?
Vitamine D: hoeveel en voor wie?
Besluit
Vitamin D
Major source – sunlight
Minor source – dietary intake
Ergocalciferol: Vitamin D2 (mushrooms)
Cholecalciferol: Vitamin D3 (fish, eggs,…)
Vitamin D supplements
Vitamin D3 > Vitamin D2
↓ in elderly, dark skin, veils
cave: skin cancer concern
Measurement of serum 25OHD
•
Need for reliable analytical assays
100%
90%
80%
70%
optimaal > 30 ng/ml
60%
normaal 20-30 ng/ml
50%
insufficiënt 10-20 ng/ml
40%
deficiënt < 10 ng/ml
30%
20%
10%
0%
LC-MS
RIA
iSys
Modular
Liaison
UZ Leuven
Dietary reference intake for vitamin D
Recommended dietary
allowance (IU/day)
Upper level intake (IU/day)
1-3 years
600
2500
4-8 years
600
3000
9-13 years
600
4000
14-18 years
600
4000
19-30 years
600
4000
31-50 years
600
4000
51-70 years ♂
51-70 years ♀
600
600
4000
4000
> 70 years
800
4000
= needed to achieve ‘optimal’ serum 25OHD level
IOM Report 2011
Target serum 25-hydroxyvitamin D
• Optimal bone health
o
≥ 20 ng/ml (50 nmol/l)  ≥ 30 ng/ml (75 nmol/l)
o
Risk of very high dose supplementation
48 ng/ml (120 nmol/l)
500.000 IU vit D3 po
1x per year
Incidence Rate Ratio for vit D3 p-value
Estimate (95% CI)
Fractures
1.26 (1.00-1.59)
0.047
Falls
1.15 (1.02-1.30)
0.03
- within 3 months
1.31 (1.12-1.54)
0.001
- after 3 months
1.13 (0.99-1.29)
0.08
36 ng/ml (90 nmol/l)
Ross. JCEM 2011; 96: 53-58; Holick. JCEM 2011; 96: 1911-1930; Bouillon. JCEM 2013; 98: E1283-1304; Sanders. JAMA 2010; 303: 1815-1822
Target serum 25-hydroxyvitamin D
• Extraskeletal health benefits?
o
Observational trials
•
•
o
low 25OHD ~ colorectal and breast cancer, mortality, autoimmune disease and CV diseases
> 40-50 ng/ml (100-125 nmol/l) ~ pancreatic cancer, mortality
Need for RCTs to establish optimal intake
Bouillon. JCEM 2013; 98: E1283-1304; Body. Osteopors Int 2012; 23: S1-S23; Sempos. JCEM 2013; 98: 3001-3009
Overzicht
•
•
•
•
•
•
Inleiding
Botmetabolisme
Fractuurpreventie met calcium en vitamine D
Calcium: hoeveel en voor wie?
Vitamine D: hoeveel en voor wie?
Besluit
Besluit
• Calcium and vitamine D reduce fracture risk by about 20%
• Calcium
o
1000 – 1200 mg per day
o
Dietary +/- supplemental intake
• Vitamin D
o
600 – 800 IU per day
o
~ serum 25OHD ≥ 20 ng/ml
Calcium en vitamine D:
hoeveel en voor iedereen?
Evelien Gielen, MD PhD
Centrum voor Metabole Botziekten, UZ Leuven
Afdeling Gerontologie en Geriatrie, UZ Leuven