Calcium en vitamine D: hoeveel en voor iedereen?

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



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



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



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 (%)


38.9%

0.74 (0.60‐0.91))


0.2%

0.36 (0.02‐8.78)

Chapuy et al. 2002

6.5%

0.62 (0.36‐1.07))


2.8%

0.71 (0.31‐1.64)


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


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


(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)


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


Favors Placebo


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)


0.46 (0.23‐0.90)


1.08 (0.61‐1.91)


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



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 (%)


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


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


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



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



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

Calcium en vitamine D: hoeveel en voor iedereen?

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