Calcium and Vitamin D Supplementation for Fracture Prevention in Postmenopausal Women

1. Vitamin D or Calcium and Prevention of Fracture Tuan V. Nguyen Garvan Institute of Medical Research Sydney, Australia

2. Calcium plus Vitamin D Supplementation and the Risk of Fractures ABSTRACT Background The efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal. Methods We recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental calciumas calcium carbonate with 400 IUof vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers. Results Hip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels. ConclusionsAmong healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611 NEJM 2006; 354:669-683February 16, 2006

3. Treatment vs Prevention

4. How many fractures can we prevent by treatment? 1000 Low risk 800 Hi risk 200 Prevalence of high risk individuals No Fx 8 NoFx 792 No Fx 4 NoFx 196 Incidence of fx Efficacy: RR = 0.50 Prevent 2 fx

5. How many fractures can be prevented in a population-wide prevention ? Population mean = 0.78 (SD = 0.12). Shift the whole population to 1SD higher  population mean = 0.90 (SD = 0.12). Number of fx can be reduced by 30%

6. Calcium, vitamin D and bone • 99% of total body calcium is in bones and teeth • Calcium absorption ? • Regulation of calcium absorption: Vitamin D

7. Dietary calcium intakes

8. Prevalence of vitamin D deficiency Nursing home residents: 76% (1) Younger adults: 23 – 43% (2) Veiled women: 80% (3) • Nowson C, MacInnis R, Stein M, et al. (2000) • Lethonen-Veromaa M, Mottonen T, Irjala K, et al. (1999) • Grover S, Morley R. (2001)

9. Calcium and vitamin D as preventive means • Inexpensive • Relatively safe • Effectiveness?

10. Past studies on vitamin D: any fracture

11. Past studies on vitamin D: hip fracture

12. Women’s Health Initiative Study 36,282 women Ca+VitD: 18,176 Placebo: 18,106 7 years of follow-up 16,936 alive 352 withdrawals 144 LFU 744 deaths 16,815 alive 332 withdrawals 152 LFU 807 deaths

13. Some baseline characteristics

14. Changes in BMD Mean change in BMD after 9 years of follow-up: Total hip: Ca+VitD = 0% Placebo: -1% Total spine: Ca+VitD = 3% Placebo: 3% Whole body: Ca+VitD = 3% Placebo: 3%

15. WHI primary results: fracture ITT analysis “Compliant” analysis

16. Sub-group analyses for hip fracture

17. Sub-group analyses for hip fracture

18. Safety

19. Issue of external validity

20. Bayesian updating

21. Why updating? • A single study can never resolve a scientific issue • Traditional inference is counterintuitive • We don’t want to know Pr(data | effect) • We want to know Pr(effect | data)

22. Bayesian approach Disease diagnosis Prior probability of disease Test result Posterior prob. of disease = x Scientific inference Prior probability of effect New data Posterior prob. of effect = x

23. Past studies on vitamin D: any fracture

24. Bayesian updating of data

25. Probability of efficacy

26. Conclusions • WHI data: difficult to interpret • Accumulative data: evidence of modest effect of Ca or vit D on hip fx