High-dose Vitamin D Reduces Fracture Risk

Abstract & Commentary

By Jeffrey T. Jensen, MD, MPH , Leon Speroff, Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: A reanalysis of 11 double-blind, randomized, controlled trials demonstrated that high-dose vitamin D supplementation (> 800 IU daily) was somewhat favorable in the prevention of hip fracture and any nonvertebral fracture in persons 65 years of age or older.

Source: Bischoff-Ferrari HA, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med 2012;367:40-49.

Results of primary studies on and meta-analyses of the effects of vitamin D therapy on fracture risk have failed to conclusively demonstrate benefit. To help clarify this relationship, the authors conducted a reanalysis of recent randomized controlled trials. They obtained participant-level data from 11 double-blind, randomized, controlled trials of oral vitamin D supplementation (daily, weekly, or every 4 months), with or without calcium, as compared with placebo or calcium alone in persons 65 years of age or older and pooled the data to examine the primary endpoints of hip and any nonvertebral fractures incidence according to Cox regression analyses, and adjusted these outcomes for age group, gender, type of dwelling, and study. Their primary aim was to compare data from quartiles of actual intake of vitamin D (including treatment adherence and supplement use outside the study protocol). The analysis group included 31,022 persons (mean age, 76 years; 91% women) with 1111 incident hip fractures and 3770 nonvertebral fractures. Overall, participants who received vitamin D had clinically unimportant reductions in fracture: A nonsignificant 10% reduction in the risk of hip fracture (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.80 to 1.01) and a statistically significant 7% reduction in the risk of nonvertebral fracture (HR, 0.93; 95% CI, 0.87 to 0.99). However, when risk was analyzed by quartiles of actual intake, a 30% reduction in the risk of hip fracture (HR, 0.70; 95% CI, 0.58 to 0.86) and a 14% reduction in the risk of any nonvertebral fracture (HR, 0.86; 95% CI, 0.76 to 0.96) was seen at the highest vitamin D intake level (median, 800 IU daily; range, 792 to 2000), and the benefits at this level of intake were consistent across subgroups such as age, type of dwelling, baseline 25-hydroxyvitamin D level, and additional calcium intake.


The risk of fracture in women accelerates after menopause. Although reduction in fracture risk is well established with estrogen therapy, some women have contraindications to estrogen use, and others prefer not to use it. However, in the absence of estrogen, accelerated bone turnover occurs in early menopause. With this turnover, serum levels of calcium are high and calcium excretion is increased. With all of the pressure moving calcium away from bone, it is not surprising that the role of calcium supplementation is somewhat controversial. I think of it like throwing a 5-pound bag of salt into the ocean. More substantively, among women in the placebo group of the Early Postmenopausal Interventional Cohort study (a clinical trial of alendronate) whose total calcium intake was > 1333 mg/d (the highest tertile of total calcium intake), a decline in bone mineral density of almost 2% was observed, and this was similar to declines observed in the lower two tertiles of total calcium intake.1 So calcium supplementation alone is insufficient to prevent bone demineralization.

Vitamin D deficiency is common, and at menopause the effect of inadequate nutrition and low exposure to sunlight is amplified by an age-related decrease in the ability of tissues to convert the major circulating form of vitamin D (25-hydroxyvitamin D) to the active form of vitamin D (1,25 dihydroxyvitamin D).2 Active vitamin D binds with high affinity to the nuclear vitamin D receptor (VDR) to orchestrate biologic effects in the intestine, bone, skin/hair follicle, and other VDR-containing tissues.3 Adequate vitamin D replacement appears to be more important than calcium replacement. Unfortunately, the available literature on vitamin D and bone health has been inconsistent.

The paper by Bischoff-Ferrari and colleagues helps to unravel some of the mystery surrounding the vitamin D literature. The technique of reanalysis is much more powerful than simple meta-analysis, as the primary original data are analyzed as a new study, rather than simply combining outcomes to improve statistical power. Since the majority of subjects were women, this applies to our practice.

The most important contribution of this paper is the clear documentation of a dose response. Compliant subjects receiving the higher dose of 800 IU/day had a 30% reduction in hip fracture. Unfortunately, few of the studies included information about actual vitamin D levels. Although giving more vitamin D to someone with already adequate levels will not improve outcomes, it probably makes sense to either replace at the higher levels (1500-2000 IU/day) recommended by the endocrine society or to follow serum levels (to maintain 25-hydroxyvitamin D > 30 ng/mL). To restore very low levels of vitamin D, prescription strength vitamin D3 should be provided (50,000 IU once weekly for 6 months) followed by standard replacement.


  1. Hosking DJ, et al. Evidence that increased calcium intake does not prevent early postmenopausal bone loss. Clin Ther 1998;20:933-944.
  2. DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group. Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 2010;340:b5463.
  3. Jurutka PW, et al. Vitamin D receptor: Key roles in bone mineral pathophysiology, molecular mechanism of action, and novel nutritional ligands. J Bone Miner Res 2007;22(Suppl 2):V2-10.