Purpose:

To review the evidence on the benefits and harms of supplementation with vitamin D, calcium, and vitamin D with calcium, for the primary prevention of fractures in unselected, community-dwelling adults without known osteoporosis or vitamin D deficiency.

Data Sources:

PubMed, Embase, the Cochrane Library, and trial registries through March 21, 2017; bibliographies from retrieved articles; suggestions from experts; surveillance of the literature through December 31, 2017.

Study Selection:

Two investigators independently selected English-language studies using a priori criteria. We selected randomized, controlled trials (RCTs) that evaluated supplemental vitamin D, calcium, or vitamin D with calcium at any dose and that reported incident fractures or harms (i.e., all-cause mortality, kidney stones, cardiovascular disease, and cancer). Prospective cohort and case-control study designs were also eligible for inclusion for harms. We excluded studies assessing treatment of vitamin D deficiency or osteoporosis and studies conducted in developing countries or with a majority of participants with prevalent or prior fractures or in institutionalized settings. Sensitivity analyses evaluated the contribution of studies with 20 to 50 percent of participants with prevalent or prior fracture and poor-quality trials.

Data Extraction:

One investigator extracted data and a second checked accuracy. Two reviewers independently rated quality using predefined criteria.

Data Synthesis:

We included a total of 11 RCTs (51,419 participants). Eight RCTs assessed the benefit of supplementation on incident fracture and nine assessed the harms. Doses of vitamin D and calcium ranged from 300 international units (IU) per day to 100,000 IU every 1 to 4 months for vitamin D, and from 600 to 1,600 mg per day for calcium.

Compared with placebo, supplementation with vitamin D for 3.5 to 5 years minimally decreased total fracture incidence, but findings were imprecise (1 RCT, 2,686 men and women; absolute risk difference [ARD], -2.26% (95% CI, -4.53% to 0.00%; relative risk [RR], 0.78 [95% CI, 0.61 to 0.99]) and it had no statistically significant effect on hip fracture (3 RCTs, 5,496 men and women; pooled ARD, -0.01% [95% CI, -0.80%, to 0.78%; I²=0%]; pooled RR, 1.08 [95% CI, 0.79 to 1.48; I²=0%]). Supplementation using vitamin D with calcium for 3 to 7 years had no statistically significant effect on total fracture incidence (1 RCT, 36,282 women; ARD, -0.35% [95% CI, -1.02% to 0.31%]; hazard ratio [HR], 0.96 [95% CI, 0.91 to 1.02]) or hip fracture incidence (2 RCTs, 36,727 men and women; ARD from the much larger trial, -0.14% [95% CI, 0.34% to 0.07%]; HR, 0.88 [95% CI, 0.72 to 1.08]). The evidence for calcium alone was limited to 2 RCTs (339 women) reporting on incident morphometric vertebral fractures; one trial also reported nonvertebral fractures (236 women; ARD, -1.01% [95% CI, -8.58% to 6.56%]; RR, 0.90 [95% CI, 0.41 to 1.96]).

Compared with placebo, supplementation with vitamin D alone or with calcium had no effect on all-cause mortality or incident cardiovascular disease; the ARDs for these harms ranged from 1.93% to 1.79%, with confidence intervals that spanned the null effect. The evidence for calcium alone also suggested no increased incidence, but was limited to one study for each harm.

Supplementation with calcium alone for 2 to 4 years did not increase the incidence of kidney stones (3 RCTs, 1,259 participants; pooled ARD, 0.00% [95% CI, -0.88% to 0.87%; I²=0%]; pooled RR, 0.68 [95% CI, 0.14 to 3.36]). Vitamin D with calcium for 4 to 7 years increased the incidence of kidney stones (pooled ARD 0.33% [95% CI, 0.06% to 0.60%]; pooled RR, 1.18 [95% CI, 1.04 to 1.35]; I²=0%; 3 RCTs; 39,213 participants). The evidence for the impact of supplementation with vitamin D or calcium alone on cancer incidence was inconsistent and imprecise; supplementation using vitamin D with calcium did not increase cancer incidence (pooled ARD -1.48% [95% CI, -3.32% to 0.35%]; I²=70.9%; 3 RCTs, 39,213 participants).

Limitations:

This body of evidence was limited by imprecise effect estimates largely because studies were not powered to assess fracture or other outcomes of interest. Other limitations include heterogeneity in outcome specification and ascertainment and the lack of fair- or good-quality trials that assess the impact of supplementation with calcium alone. The evidence is applicable to postmenopausal women; evidence for some fracture and harm outcomes is also applicable to men.

Conclusions:

In unselected, community-dwelling populations without known osteoporosis or vitamin D deficiency, the evidence does not support a finding of fewer fractures with vitamin D supplementation alone or with calcium; the evidence for supplementation with calcium alone is limited. The evidence suggests that supplementation with vitamin D alone does not increase all-cause mortality or cardiovascular events, but the evidence is limited for other harms. The evidence suggests that supplementation with calcium alone does not increase the incidence of kidney stones, but the evidence is limited for other harms. The evidence suggests that vitamin D with calcium does not increase all-cause mortality, cardiovascular events, or cancer incidence, but it is associated with an increase in the incidence of kidney stones.