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Dr. Joseph  Lorenzo

Vitamin D Supplements and the Risk of Fractures

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Vitamin D is essential for the maintenance of bone health. However, its role in the prevention of osteoporotic fractures has been controversial. Previous published trials have been inconsistent in their results. Now Bischoff-Ferrari et al (1) have performed an extensive meta-analysis of 11 previous double blind, randomized placebo controlled trials of vitamin D supplementation, encompassing 31,022 participants. These involved people 65 years of age or older (predominantly women) in which vitamin D supplementation (with or without calcium) was compared to a control (non-treated) group. Significantly, these authors obtained the primary data from the original studies and estimated the actual amount of vitamin D that each participant consumed. They then divided treated participants into four quartiles depending on the amount of actually consumed vitamin D. The primary end points of the meta-analysis were the risks of hip fracture and nonvertebral fracture. The authors also performed additional tests of their data, including a sensitivity analysis, which excluded additional supplemental doses of vitamin D that were outside those of the study protocol from the calculation of actual intake, and an internal validation analysis, which compared the highest quartile of actual intake of vitamin D with the lowest quartile, regardless of the randomized study-group assignment. For the primary analyses, one analysis for hip fracture and one analysis for nonvertebral fracture was performed in which all quartiles of actual intake of vitamin D were compared to the control group. Because of the potential for false positive results due to multiple testing, a P value of 0.0125 was used to indicate significant differences between the treated and control groups.


An intention-to-treat analysis, which analyzed all participants entering the trial regardless of whether they finished, demonstrated a nonsignificant reduction in the risk of hip fracture with vitamin D supplementation (hazard ratio = 0.90; 95% confidence interval [CI] = 0.80 to 1.01), which did not differ according to assigned treatment dose. However, when the authors performed an actual intake analysis of the quartile treated with the highest dose of vitamin D (792 to 2000 IU/ day, median = 800 IU/day), they found a significant (30%) reduction in the incidence of hip fractures compared to the controls (HR = 0.70, CI = 0.58-0.86). Similarly, the actual intake analysis demonstrated a 14% decrease in nonvertebral fractures (HR = 0.86, CI = 0.76–0.96) in subjects consuming the highest dose of vitamin D compared to the controls. These results were confirmed by both the sensitivity analysis and the internal validation analysis.


The authors also performed a subgroup analysis of 4383 subjects for whom baseline 25 hydroxy-vitamin D measurements were available. This suggested a dose response relationship between the risk of fracture (either at the hip or nonvertebral) and the quartiles of baseline vitamin D. In addition, individuals with vitamin D levels at entry of 61 nmol/liter (~24 ng/mL) or greater had a risk of hip fracture that was reduced by 37% (HR = 0.63; CI = 0.46 to 0.87) and a risk of nonvertebral fracture that was reduced by 31% (HR = 0.69; CI = 0.57 to 0.84). Finally, pooled subgroup analyses of eight trials that used vitamin D combined with calcium indicated that the risk of fracture was reduced only in the group that was treated with the highest actual-intake level of vitamin D. In addition, at the highest actual-intake level of vitamin D, there was the suggestion that calcium supplementation of less than 1000 mg per day was more beneficial in reducing the risk of fracture than calcium supplementation of greater than or equal to 1000 mg per day.


Limitations of this analysis are the lack of follow-up measurements of serum 25 hydroxyvitamin D during treatment to assess the ability of supplements to raise this value or correlate treatment serum 25 hydroxyvitamin D values with fracture risk. In addition, all of the trials that were analyzed lacked a group that treated subjects without calcium but with the highest doses of vitamin D (up to 2000 IU/day). However, the data do demonstrate that supplementation with vitamin D of at least 800 IU per day as recommended by the most recent Institute of Medicine report (2) appear to be beneficial for reducing the risk of osteoporotic fractures. Finally, they argue that values of 25 hydroxyvitamin D of 60 nmol/liter (24 ng/mL) or greater are desirable to prevent fractures.


Joe Lorenzo,

Farmington, CT USA

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