Vitamin D supplementation, especially at doses of 700-800 IU/day of cholecalciferol, has been shown to reduce the risk of hip fractures and nonvertebral fractures when combined with calcium intake of at least 500 mg/day. Several meta-analyses found the greatest benefits in individuals with vitamin D levels <50 nmol/L or calcium intake <700 mg/day. While vitamin D alone showed no significant fracture reduction, supplementation that achieved 25(OH)D levels >75 nmol/L or included additional calcium intake was more effective in preventing fractures.

1. Fall prevention with supplemental and active forms of vitamin D

2. Fall prevention with supplemental and active forms of vitamin D
Bischof-Ferrari BMJ 2009;339:b3692

3. Cochrane Database Syst Rev 2010(1):CD005465
Cochrane review 2010

4. Cochrane Database Syst Rev 2010(1):CD005465
Cochrane review 2010
post-hoc subgroup < 50 nmol/l 25(OH)D :
• rate of falls levels (RR 0.57, 95% CI 0.37 to 0.89) in 260
participants, 2 trials

5. J Am Geriatr Soc 2010, 58(7):1299-1310

6. J Am Geriatr Soc 2010, 58(7):1299-1310
fall reduction was significant in several subgroups of individuals:
1.mean age younger than 80
2.additional calcium therapy
3.dose of 800 IU or greater
4.cholecalciferol therapy
no evidence was found of a relation between higher doses of vitamin D or longer duration of
vitamin D therapy and treatment effect

7. Calcium en vitamine D in interventie trials

8. 2005-2010: 7 Meta-analyses vitamine D en fractuurreductie
• Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B: Fracture
prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005,
293(18):2257-2264.
• Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P: Need for additional
calcium to reduce the risk of hip fracture with vitamin d supplementation: evidence from a comparative
metaanalysis of randomized controlled trials. J Clin Endocrinol Metab 2007, 92(4):1415-1423.
• Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A: Use of calcium or calcium in combination with
vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-
analysis. Lancet 2007, 370(9588):657-666.
• Bischoff-Ferrari HA, Willett WC, Wong JB, Stuck AE, Staehelin HB, Orav EJ, Thoma A, Kiel DP,
Henschkowski J: Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-
analysis of randomized controlled trials. Arch Intern Med 2009, 169(6):551-561.
• Avenell A, Gillespie WJ, Gillespie LD, O'Connell D: Vitamin D and vitamin D analogues for preventing
fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev
2009(2):CD000227.
• Bergman GJ, Fan T, McFetridge JT, Sen SS: Efficacy of vitamin D3 supplementation in preventing fractures
in elderly women: a meta-analysis. Curr Med Res Opin 2010, 26(5):1193-1201.
• Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe.
BMJ 2010, 340:b5463
van den Bergh, Curr osteoporos reviews, in press

9. Bischoff-Ferrari. JAMA 2005, 293(18):2257-2264.
Fracture prevention with vitamin D supplementation: a meta-analysis of
randomized controlled trials.
• 5 RCTs for hip fracture (n = 9294)
• 7 RCTs for nonvertebral fracture risk (n = 9820)
• vitamin D 700 to 800 IU/d reduced the relative risk of hip fracture by
26% (3 RCTs with 5572 persons; RR 95% CI 0.61-0.88)
• any nonvertebral fracture by 23% (5 RCTs with 6098 persons; RR
95% CI, 0.68-0.87) versus calcium or placebo in individuals ≥60
years
• No significant benefit was observed for RCTs with 400 IU/d vitamin
D (2 RCTs with 3722 persons)

10. Bischoff-Ferrari. JAMA 2005, 293(18):2257-2264.
Fracture prevention with vitamin D supplementation: a meta-analysis of
randomized controlled trials.
• 5 RCTs for hip fracture (n = 9294)
• 7 RCTs for nonvertebral fracture risk (n = 9820)
• vitamin D 700 to 800 IU/d colecalciferol reduced the relative risk of
hip fracture by 26% (3 RCTs with 5572 persons; RR 95% CI 0.61-
0.88)
• any nonvertebral fracture by 23% (5 RCTs with 6098 persons; RR
95% CI, 0.68-0.87) versus calcium or placebo in individuals ≥60
years
• No significant benefit was observed for RCTs with 400 IU/d vitamin
D (2 RCTs with 3722 persons)
• => 700-800 IU/d vitamin D3

11. Boonen S. J Clin Endocrinol Metab 2007, 92(4):1415-1423.
Need for additional calcium to reduce the risk of hip fracture with vitamin d
supplementation: evidence from a comparative meta-analysis of randomized controlled
trials.
• designed to extend the findings of Bischoff-Ferrari et al. 2005
• A total of 53,260 patients from nine RCTs were included in this
analysis and all RCTs used cholecalciferol with a dose of 700–800
IU/d in six trials and 400 IU/d in the other three trials.
• Calcium (500–1200 mg/d) was given with vitamin D in six RCTs.
• only vitamin D with additional calcium demonstrated a significant
reduction of hip and nonvertebral fractures versus placebo or no
treatment
• It has to be noted that two trials with very low nutritional baseline
calcium intake had an important impact on the results of this meta-
analysis

12. Boonen S. J Clin Endocrinol Metab 2007, 92(4):1415-1423.
Need for additional calcium to reduce the risk of hip fracture with vitamin d
supplementation: evidence from a comparative meta-analysis of randomized controlled
trials.
• designed to extend the findings of Bischoff-Ferrari et al. 2005
• A total of 53,260 patients from nine RCTs were included in this
analysis and all RCTs used cholecalciferol with a dose of 700–800
IU/d in six trials and 400 IU/d in the other three trials.
• Calcium (500–1200 mg/d) was given with vitamin D in six RCTs.
• only vitamin D with additional calcium demonstrated a significant
reduction of hip and nonvertebral fractures versus placebo or no
treatment
• It has to be noted that two trials with very low nutritional baseline
calcium intake had an important impact on the results of this meta-
analysis
• => + calcium, low nutritional intake

13. Tang. Lancet 2007, 370(9588):657-666.
Use of calcium or calcium in combination with vitamin D supplementation to
prevent fractures and bone loss in people aged 50 years and older: a meta-
analysis.
• 17 trials met 63.897 personen: (RR 0.88; CI 0.83-0.95, p=0.0004)
• 1000 mg per dag calcium monotherapie in 6 van de 9 trials: RR 0.90 (CI 0.80-1.00)
• 7 van de 8 trials met calcium in combinatie met vitamin D:RR 0.87 (0.77-0.97),
waarin beide analyse niet significant van elkaar verschilden.
• 25(OH)D3 <25 nmol/l: met calcium en vitamine D-suppletie een grotere
risicoreductie dan met calcium monotherapie (RR 0.86 vs. 0.94; p=0.06)
• Dit effect verdween bij een afkappunt voor serum 25(OH)D van 50 nmol/l
• Het effect was groter bij mensen met een lage calciuminname via de voeding (<700
mg/dag) en bij calciumdoseringen van 1200 mg

14. Tang. Lancet 2007, 370(9588):657-666.
Use of calcium or calcium in combination with vitamin D supplementation to
prevent fractures and bone loss in people aged 50 years and older: a meta-
analysis.
• 17 trials met 63.897 patienten individuen: (RR 0.88; CI 0.83-0.95, p=0.0004)
• 1000 mg per dag calcium monotherapie in 6 van de 9 trials: RR 0.90 (CI 0.80-1.00)
• 7 van de 8 trials met calcium in combinatie met vitamin D:RR 0.87 (0.77-0.97),
waarin beide analyse niet significant van elkaar verschilden.
• 25(OH)D3 <25 nmol/l: met calcium en vitamine D-suppletie een grotere
risicoreductie dan met calcium monotherapie (RR 0.86 vs. 0.94; p=0.06)
• Dit effect verdween bij een afkappunt voor serum 25(OH)D van 50 nmol/l
• Het effect was groter bij mensen met een lage calciuminname via de voeding (<700
mg/dag) en bij calciumdoseringen van 1200 mg
• => combinatie van calcium en vitamine D bij lage calciuminname en bij
25(OH)D<50 nmol/l)

15. Bischoff-Ferrari. Arch Intern Med 2009, 169(6):551-561
Prevention of nonvertebral fractures with oral vitamin D and dose dependency:
a meta-analysis of randomized controlled trials.
• 12 RCTs for nonvertebral fractures (two with ergocalciferol, ten with
cholecalciferol, n=42.279 > 65 yr)
• 8 RCTs for hip fractures (n=40 886)
• The anti fracture efficacy of vitamin D increased significantly with
higher received dose or higher achieved 25-hydroxyvitamin D levels
(> 75nmol/l) for any nonvertebral fractures and for hip fractures
• No fracture reduction for a dose of 400 IU/d or less, 482 to 770 IU/d
of supplemental vitamin D reduced nonvertebral fractures by 20%
and hip fractures by 18%.
• better fracture reduction with cholecalciferol compared with
ergocalciferol, whereas additional calcium did not further improve
antifracture efficacy

16. Bischoff-Ferrari. Arch Intern Med 2009, 169(6):551-561
Prevention of nonvertebral fractures with oral vitamin D and dose dependency:
a meta-analysis of randomized controlled trials.
• 12 RCTs for nonvertebral fractures (two with ergocalciferol, ten with
cholecalciferol, n=42.279 > 65 yr)
• 8 RCTs for hip fractures (n=40 886)
• The anti fracture efficacy of vitamin D increased significantly with
higher received dose or higher achieved 25-hydroxyvitamin D levels
(> 75nmol/l) for any nonvertebral fractures and for hip fractures
• No fracture reduction for a dose of 400 IU/d or less, 482 to 770 IU/d
of supplemental vitamin D reduced nonvertebral fractures by 20%
and hip fractures by 18%.
• better fracture reduction with cholecalciferol compared with
ergocalciferol, whereas additional calcium did not further improve
antifracture efficacy
• => higher dose or higher 25(OH)D levels (> 75nmol/l)

17. Bischoff-Ferrari. Arch Intern Med 2009, 169(6):551-

18. Avenell - Cochrane Database Syst Rev 2009(2):CD000227
Vitamin D and vitamin D analogues for preventing fractures associated with
involutional and post-menopausal osteoporosis.
• Vitamin D alone appeared unlikely to be effective in preventing:
• hip fracture (9 trials, 24,749 participants, RR 1.15 (0.99 -1.33)
• vertebral fracture (5 trials, 9138 participants, RR 0.90 (0.42-1.92)
• any new fracture (10 trials, 25,016 participants, RR 1.01 (0.93-1.09)
• Vitamin D with calcium reduced hip fractures (eight trials, 46,658
participants, RR 0.84, 95% CI 0.73 to 0.96)

19. Avenell - Cochrane Database Syst Rev 2009(2):CD000227
Vitamin D and vitamin D analogues for preventing fractures associated with
involutional and post-menopausal osteoporosis.
• Vitamin D alone appeared unlikely to be effective in preventing:
• hip fracture (9 trials, 24,749 participants, RR 1.15 (0.99 -1.33)
• vertebral fracture (5 trials, 9138 participants, RR 0.90 (0.42-1.92)
• any new fracture (10 trials, 25,016 participants, RR 1.01 (0.93-1.09)
• Vitamin D with calcium reduced hip fractures (eight trials, 46,658
participants, RR 0.84, 95% CI 0.73 to 0.96)
• => vitamin D + calcium

20. DIPART group. BMJ 2010, 340:b5463
Patient level pooled analysis of 68 500 patients from seven major vitamin D
fracture trials in US and Europe.
• 7 RCT of vitamin D with calcium or vitamin D alone
• 68.517 participants, mean 69.9 years
• vitamin D with calcium – overall RR 0.92, (0.86-0.99, p=0.025)
• hip fracture – RR 0.84 (0.70-1.01, P=0.07)
• vitamin D given alone in doses of 400-800 IU per day was not
effective in preventing fractures

21. DIPART group. BMJ 2010, 340:b5463
Patient level pooled analysis of 68 500 patients from seven major vitamin D
fracture trials in US and Europe.
• 7 RCT of vitamin D with calcium or vitamin D alone
• 68.517 participants, mean 69.9 years
• vitamin D with calcium – overall RR 0.92, (0.86-0.99, p=0.025)
• hip fracture – RR 0.84 (0.70-1.01, P=0.07)
• vitamin D given alone in doses of 400-800 IU per day was not
effective in preventing fractures
• => vitamin D + calcium

22. Tang et al. Lancet 2007; 370: 657–66

23. Dietary intake – hip#
Bischoff , Am J Clin Nutr 2007;86:1780 –90

24. Intervention calcium vs placebo on NV# and hip#
Bischoff , Am J Clin Nutr 2007;86:1780 –90

25. Bolland et al. meta-analyse, BMJ 2010.39440.525752.BE
• 11 RCTs met bijna 12.000 deelnemers, leeftijd 72 jaar, 83% vrouw
• serum 25 OH-D 65 nmol/l
• calcium supplementen ≥ 500 mg per dag vs placebo gedurende 4 jaar
zonder vitamine D.
• RR myocardinfarct: 1.27 (CI 1.01 tot 1.59, P=0.038)
• Het risico op herseninfarct, mortaliteit en het samengestelde eindpunt van
myocardinfarct, CVA en mortaliteit was niet significant verhoogd

26. • 11 RCTs met bijna 12.000 deelnemers, leeftijd 72 jaar, 83% vrouw
• serum 25 OH-D 65 nmol/l
• calcium supplementen ≥ 500 mg per dag vs placebo gedurende 4 jaar
zonder vitamine D.
• RR myocardinfarct: 1.27 (CI 1.01 tot 1.59, P=0.038)
• Het risico op herseninfarct, mortaliteit en het samengestelde eindpunt van
myocardinfarct, CVA en mortaliteit was niet significant verhoogd
• Analyse van 5 van de 11 trials met daarin ruim 8.000 patiënten, met data op
patiënt niveau: alleen een verhoogd risico gevonden bij dieetinname van
805 mg/dag; RR 1.85, (CI 1.28 - 2.67)
• Calcium supplement ≥ 1000 mg per dag behoudens 108 patiënten uit 1 trial
die 600 mg/dag gebruikten
Bolland et al. meta-analyse, BMJ 2010.39440.525752.BE

27. 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

28. Calcium en vitamine D-suppletie: discussiepunten
- Vitamine D: dosering of spiegel
- Dagelijks of bolus
- Advies op basis van fractuurreductie bij interventie vs
placebo (en niet in combinatie met anti-osteoporose
therapie)
- Calcium:
- corrigeer vitamine D
- suppletie op basis van voedingsanamanese
- 500 mg is veelal voldoende