Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe

Abstract

Objectives: To identify participants' characteristics that influence the anti-fracture efficacy of vitamin D or vitamin D plus calcium with respect to any fracture, hip fracture, and clinical vertebral fracture and to assess the influence of dosing regimens and co-administration of calcium.

Design: Individual patient data analysis using pooled data from randomised trials.

Data sources: Seven major randomised trials of vitamin D with calcium or vitamin D alone, yielding a total of 68 517 participants (mean age 69.9 years, range 47-107 years, 14.7% men).

Study selection: Studies included were randomised studies with at least one intervention arm in which vitamin D was given, fracture as an outcome, and at least 1000 participants.

Data synthesis: Logistic regression analysis was used to identify significant interaction terms, followed by Cox's proportional hazards models incorporating age, sex, fracture history, and hormone therapy and bisphosphonate use.

Results: Trials using vitamin D with calcium showed a reduced overall risk of fracture (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99, P=0.025) and hip fracture (all studies: 0.84, 0.70 to 1.01, P=0.07; studies using 10 microg of vitamin D given with calcium: 0.74, 0.60 to 0.91, P=0.005). For vitamin D alone in daily doses of 10 microg or 20 microg, no significant effects were found. No interaction was found between fracture history and treatment response, nor any interaction with age, sex, or hormone replacement therapy.

Conclusion: This individual patient data analysis indicates that vitamin D given alone in doses of 10-20 microg is not effective in preventing fractures. By contrast, calcium and vitamin D given together reduce hip fractures and total fractures, and probably vertebral fractures, irrespective of age, sex, or previous fractures.

Fig 1 Flow chart of analysis. RCT=randomised controlled trial

Fig 2 Interaction tests on logistic regression base model, 36 months intention to treat scenario. Each panel shows summary of 10 separate interaction analyses, testing statistical significance of each treatment by covariate interaction term added to base model. Coefficients differing significantly from 1.0 indicate presence of interaction (non-proportional hazards) between covariate and treatment; coefficients below 1.0 indicate greater treatment response (lower risk of fracture), and coefficients above 1.0 indicate smaller treatment response (higher risk of fracture). HRT=hormone replacement therapy

Fig 3 Cumulative fracture incidence for vitamin D (darker lines) and controls (lighter lines). Vitamin D and calcium studies and vitamin D studies are shown separately. Inset shows treatment effect and 95% confidence intervals. CaD=calcium and vitamin D; D=vitamin D

Fig 4 Cumulative hip fracture incidence for vitamin D (darker lines) and controls (lighter lines). Vitamin D and calcium studies and vitamin D studies are shown separately. Inset shows treatment effect and 95% confidence intervals. CaD=calcium and vitamin D; D=vitamin D

Fig 5 Sensitivity analysis: influence of removing individual studies from analysis. CaD=calcium and vitamin D trials; D=vitamin D trials; w/o=without