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Evidence Summary

Other Supporting Document for Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: Preventive Medication

By Leila C. Kahwati, MD, MPH; Rachel Palmieri Weber, PhD; Huiling Pan, BA; Margaret Gourlay, MD, MPH; Erin LeBlanc, MD, MPH; Manny Coker-Schwimmer, MPH; and Meera Viswanathan, PhD

The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.

This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

This article was published in the Journal of the American Medical Association on April 17, 2018.

Abstract

Importance: Osteoporotic fractures result in significant morbidity and mortality.

Objective: To update the evidence for benefits and harms of vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults to inform the US Preventive Services Task Force.

Data Sources: PubMed, EMBASE, Cochrane Library, and trial registries through March 21, 2017; references; and experts. Surveillance continued through February 28, 2018.

Study Selection: English-language randomized clinical trials (RCTs) or observational studies of supplementation with vitamin D, calcium, or both among adult populations; studies of populations that were institutionalized or had known vitamin D deficiency, osteoporosis, or prior fracture were excluded.

Data Extraction and Synthesis: Dual, independent review of titles/abstracts and full-text articles and study quality rating using predefined criteria. Random-effects meta-analysis used when at least 3 similar studies were available.

Main Outcomes and Measures: Incident fracture, mortality, kidney stones, cardiovascular events, and cancer.

Results: Eleven RCTs (N = 51,419) in adults 50 years and older conducted over 2 to 7 years were included. Compared with placebo, supplementation with vitamin D decreased total fracture incidence (1 RCT [n = 2686]; absolute risk difference [ARD], −2.26% [95% CI, −4.53% to 0.00%]) but had no significant association with hip fracture (3 RCTs [n = 5496]; pooled ARD, −0.01% [95% CI, −0.80% to 0.78%]). Supplementation using vitamin D with calcium had no effect on total fracture incidence (1 RCT [n = 36,282]; ARD, −0.35% [95% CI, −1.02% to 0.31%]) or hip fracture incidence (2 RCTs [n = 36,727]; ARD from the larger trial, −0.14% [95% CI, −0.34% to 0.07%]). The evidence for calcium alone was limited, with only 2 studies (n = 339 total) and very imprecise results. Supplementation with vitamin D alone or with calcium had no significant effect on all-cause mortality or incident cardiovascular disease; ARDs ranged from −1.93% to 1.79%, with CIs consistent with no significant differences. Supplementation using vitamin D with calcium was associated with an increased incidence of kidney stones (3 RCTs [n = 39,213]; pooled ARD, 0.33% [95% CI, 0.06% to 0.60%]), but supplementation with calcium alone was not associated with an increased risk (3 RCTs [n = 1259]; pooled ARD, 0.00% [95% CI, −0.87% to 0.87%]). Supplementation with vitamin D and calcium was not associated with an increase in cancer incidence (3 RCTs [n = 39,213]; pooled ARD, −1.48% [95% CI, −3.32% to 0.35%]).

Conclusions and Relevance: Vitamin D supplementation alone or with calcium was not associated with reduced fracture incidence among community-dwelling adults without known vitamin D deficiency, osteoporosis, or prior fracture. Vitamin D with calcium was associated with an increase in the incidence of kidney stones.

Introduction

Osteoporotic fractures occur as a result of bone fragility resulting from bone loss or structural changes.1 Although not all osteoporotic fractures may be directly attributable to deficiencies in vitamin D or calcium, these nutrients are important modifiable factors associated with optimal bone health.2 If effective, supplementation among unselected, community-dwelling populations, which does not rely on knowledge of a person's underlying fracture risk, bone mass, vitamin D status, or diet, could be a more efficient approach for fracture prevention than a preventive approach that requires laboratory testing, imaging, or dietary assessment to determine whether treatment with vitamin D or calcium should be used. At the same time, it is important to understand potential harms of supplementation with these agents.

In 2013, the US Preventive Services Task Force (USPSTF) recommended against daily supplementation of 400 IU or less of vitamin D3 and 1000 mg or less of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women (D recommendation).3 The USPSTF also concluded that there was insufficient evidence to recommend vitamin D with or without calcium supplementation in premenopausal women and in men and at doses greater than 400 IU with or without calcium (at doses greater than 1000 mg) for noninstitutionalized, postmenopausal women. To inform an updated recommendation, the evidence about the benefits and harms of supplemental vitamin D and calcium, alone or in combination, for the primary prevention of fractures in unselected, community-dwelling adult populations relevant to US primary care was reviewed.

Methods

Scope of the Review

Detailed methods are available in the full evidence report at: https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/vitamin-d-calcium-or-combined-supplementation-for-the-primary-prevention-of-fractures-in-adults-preventive-medication. In addition, the full evidence report includes results from sensitivity analyses not reported here. The analytic framework and key questions (KQs) that guided the review are shown in Figure 1.

Data Sources and Searches

PubMed/MEDLINE, EMBASE, and the Cochrane Library were searched for English-language articles. For the evaluation of vitamin D alone or vitamin D combined with calcium, the search built on the prior review for the USPSTF5 and included January 1, 2011, through March 21, 2017. For calcium-alone interventions, which were not considered in the prior review, the search was conducted from inception through March 21, 2017. The search strategies are listed in eMethods 1 in the Supplement. ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform were also searched.

To supplement electronic searches, studies included in relevant existing systematic reviews and reference lists of pertinent articles, and studies suggested by reviewers, were reviewed. Since March 2017, ongoing surveillance through article alerts and targeted searches of journals with high impact factor and journals relevant to the topic was conducted to identify major studies published in the interim that may affect the conclusions or understanding of the evidence and therefore the related USPSTF recommendation. The last surveillance was conducted on February 28, 2018.

Study Selection

Two investigators independently reviewed titles, abstracts, and full-text articles using prespecified inclusion criteria for each KQ, with disagreements about inclusion resolved by discussion. Studies of community-dwelling adults with no known disorders of bone metabolism or vitamin D deficiency were included. Studies were excluded if participant enrollment was based on known high risk of fracture or falls or if more than 20% of participants had a prior history of osteoporotic fractures or prevalent fractures at baseline. Studies with between 20% and 50% of participants with exclusionary medical conditions were used in sensitivity analyses.

Eligible vitamin D interventions included oral or intramuscular vitamin D2 or vitamin D3 at any dosage or frequency. Eligible calcium interventions included oral calcium salt preparations at any dose and frequency. Eligible comparator groups were no treatment, placebo, or lower- or higher-dose vitamin D or calcium regimens.

Studies of vitamin D plus calcium vs calcium alone were considered vitamin D–alone interventions, since the only difference between groups was the vitamin D intervention. Studies were excluded in which the intervention and comparator groups would not allow for evaluation of the independent contribution of vitamin D or calcium to the effect; for example, when these supplements were taken in a multivitamin or used as part of a multicomponent intervention that included other pharmacologic agents or environmental or behavioral interventions.

To synthesize the benefits of supplementation (KQ1), studies that reported incident fractures or fracture-related morbidity and mortality were included, regardless of whether fracture outcomes were considered the primary reported outcome. To synthesize the harms of supplementation (KQ2), studies that reported on all-cause mortality, symptomatic acute or chronic vitamin D or calcium toxicity, incident kidney stones, incident cancer, and incident cardiovascular disease (including stroke and venous thromboembolism) were included.

Randomized clinical trials (RCTs) were eligible for KQ1 and KQ2; prospective cohort and case-control study designs were also eligible for KQ2. Systematic reviews using study selection criteria similar to this review were also eligible for both KQs. Studies and articles that were not published in English, were not original research, or were conducted in countries other than those categorized as "very high" on the 2015 Human Development Index (as defined by the United Nations Human Development Programme) were excluded.6 Studies reviewed at the full-text stage but excluded, and reasons for their exclusion, are available in the full evidence report.

Data Extraction and Quality Assessment

For each included study, 1 investigator extracted information about design, population, intervention, and outcomes, and a second investigator reviewed for completeness and accuracy. Two independent investigators assessed the quality of each study as good, fair, or poor, using predefined criteria developed by the USPSTF7, 8 and adapted for this topic based on guidance from the Cochrane Collaboration.9 Quality ratings for the individual studies are reported in eTables 2 through 15 in the Supplement.

Data Synthesis and Analysis

Findings were qualitatively synthesized for each KQ in tabular and narrative formats by intervention: vitamin D alone, calcium alone, or vitamin D with calcium. Studies were included in the main analysis if they met all study selection criteria and were fair or good quality; this included studies from the prior review that informed the 2013 USPSTF recommendation that met the study selection criteria for this update. Sensitivity analyses were conducted using RCTs excluded for poor quality and RCTs excluded because of mixed study populations (ie, those with between 20% and 50% of the population having a history of prior fracture).

To determine whether a quantitative synthesis was appropriate, the number of studies and the clinical and methodological heterogeneity present were assessed based on established guidance.10 When at least 3 independent and similar RCTs were available, random-effects models using the inverse-variance weighted method of DerSimonian and Laird was used to estimate pooled effects using Stata version 14 (StataCorp).11 Statistical heterogeneity was assessed using the I2 statistic.12 Because fracture and harm events were rare in many studies, both absolute risk differences (ARDs) and relative risk ratios (RRs) or hazard ratios (HRs) were used for assessing effects.

The strength of evidence for each outcome was assessed based on the Agency for Healthcare Research and Quality Methods Guide for Effectiveness and Comparative Effectiveness Reviews,13 which specifies the assessment of study limitations, directness, consistency, precision, and reporting bias for each intervention comparison and major outcome of interest.

Results

Study selection included reviewing 3131 unique titles and abstracts and assessing 291 full-text articles for eligibility (Figure 2); 11 RCTs (N = 51,419) were eligible. Characteristics of included studies are reported in Table 1. Detailed individual study characteristics and findings of studies are reported in eTables 16 through 18 in the Supplement.

Benefits of Supplementation

Key Question 1. Is there direct evidence for supplementation with vitamin D or calcium alone or vitamin D combined with calcium for the prevention of fractures or reduction in fracture-related morbidity and mortality?

Eight good- or fair-quality RCTs that randomized 47,672 participants examined the effect of supplementation with vitamin D alone,14-18 calcium alone,19, 20 or vitamin D with calcium23, 24 on fracture prevention over 3 to 7 years. No studies reporting outcomes related to fracture-related morbidity or mortality were identified. The rest of this section describes characteristics of included studies, followed by results organized by intervention and then by fracture type.

One RCT (Women's Health Initiative Calcium and Vitamin D [WHI CaD] trial24) enrolled 36,282 women; the other trials enrolled only women (3 RCTs,14, 19, 20 571 total participants) or both women and men (4 RCTs,15-18, 23 10,819 total participants). The vitamin D3 doses used included 300 IU, 400 IU, or 700 IU daily or 100,000 IU every month (after an initial dose of 200,000 IU) or every 4 months. The calcium doses used included daily doses of 1000 mg, 1200 mg, or 1600 mg alone, or 500 mg or 1000 mg daily in combination with vitamin D. The comparator group was a placebo control in all but 1 study.14 Three studies stated that the effect on incident fracture was the study aim15, 16, 24; however, only 1 study (WHI CaD trial) used fractures as the primary end point to determine required sample size.24 Incident fracture outcomes ascertained across studies included total fractures at any site, hip fractures, clinical or morphometric vertebral fractures, nonvertebral fractures, and peripheral fractures (distal radius, humerus, ankle, foot, leg). Three studies reported confirmation of fractures through practitioner verification, medical or hospital record review, radiographic review, or claims.14, 17, 18, 26

Figure 3 summarizes findings from these RCTs. All but 1 study reported statistically nonsignificant differences in fracture incidence between supplementation and placebo groups over 3 to 7 years, with ARDs ranging from −6.99% to 7.26% and RRs ranging from 0.36 to 1.34. Most estimates were imprecise, with confidence intervals spanning a range that would include a clinical benefit or harm.

Four RCTs reported the effect of vitamin D alone compared with placebo15-18 or control group with no placebo14 on fracture incidence. Only 1 reported on total fracture incidence; in this trial, fractures were reported in 119 participants (8.8%) in the vitamin D group and 149 participants (11.1%) in the placebo group over 5 years (unadjusted ARD, −2.26% [95% CI, −4.53% to 0.00%]; unadjusted RR, 0.80 [95% CI, 0.63 to 1.00]; age-adjusted RR, 0.78 [95% CI, 0.61 to 0.99]).16 Three RCTs reported incident hip fracture over 3 to 5 years, and pooled estimates suggest no association (pooled ARD, −0.01% [95% CI, −0.80% to 0.78%]; I2 = 0.0%; pooled RR, 1.08 [95% CI, 0.79 to 1.48]; I2 = 0.0%; 3 RCTs [5496 participants]).

For calcium alone compared with placebo, neither of the 2 eligible studies comparing calcium with placebo reported incident total or hip fracture.19, 20 One reported nonvertebral fractures in 11 participants (9.2%) assigned to receive calcium and 12 participants (10.3%) assigned to receive placebo (ARD, −1.01% [95% CI, −8.58% to 6.56%]; RR, 0.90 [95% CI, 0.41 to 1.96]).20 Both reported nonsignificant effects on morphometric vertebral fractures, but estimates were imprecise.

For vitamin D combined with calcium compared with placebo, the WHI CaD trial reported 2102 fractures (11.6%) in the vitamin D with calcium group and 2158 (11.9%) in the placebo group (ARD, −0.35% [95% CI, −1.02% to 0.31%]; HR, 0.96 [95% CI, 0.91 to 1.02]).24 In that trial, 175 participants (1.0%) in the vitamin D with calcium group had a hip fracture at 7 years, compared with 199 participants (1.1%) in the placebo group (ARD, −0.14% [95% CI, −0.34% to 0.07%]; HR, 0.88 [95% CI, 0.72 to 1.08]).24 The only other eligible trial reporting hip fracture incidence reported 1 hip fracture (in the placebo group) over the duration of study follow-up.23

No studies reported subgroup findings by dose or dosing interval; some studies reported subgroup findings by age, sex, or other participant characteristic, such as menopausal hormone therapy use or baseline use of supplemental vitamin D or calcium. Details of subgroup results are provided in the full evidence report.

Harms of Supplementation

Key Question 2. Is there direct evidence for the harms of supplementation with vitamin D or calcium alone or vitamin D combined with calcium?

Nine RCTs that randomized 51,375 participants reported on the effect of supplementation with vitamin D alone, calcium alone, or vitamin D with calcium on all-cause mortality,14-18, 22, 24, 25 incident kidney stones,20-22, 24, 25, 27, 28 cardiovascular disease,14, 16-18, 22, 24, 29-32 or cancer.14, 16, 21, 24, 28, 29, 33-37 The rest of this section describes study characteristics, followed by results organized by outcome and then by intervention.

Six of the 8 RCTS contributing evidence to KQ1 were also eligible for KQ2.14-18, 20, 24 Three additional RCTs were also identified as eligible for KQ2.21, 22, 25 The evidence is dominated by the WHI CaD trial,24 which enrolled 36,282 women; the others enrolled only women (4 RCTs),14, 20, 21, 25 only men (1 RCT),22 or both women and men (3 RCTs).15-18 The doses and comparators used are similar to what has been described for KQ1. Although all included studies reported on KQ2-specified outcomes, these outcomes were primary end points in only 2 studies.

All-Cause Mortality

Seven RCTs examined the effect of supplementation with vitamin D alone,14-18 calcium alone,22 or vitamin D with calcium24, 25 on all-cause mortality. For vitamin D alone compared with placebo, the pooled ARD was −0.74% (95% CI, −1.80% to 0.32%; I2 = 19.6%; 4 RCTs [10,599 participants]), and the pooled RR was 0.91 (95% CI, 0.82 to 1.01; I2 = 0.0%), suggesting no association. For calcium alone compared with placebo, only 1 study was eligible, and it compared 600-mg or 1200-mg doses with placebo and reported 1 death in each of the placebo and 2 treatment groups.22 For vitamin D combined with calcium, 2 RCTs were eligible. One RCT reported 7 deaths (0.6%) in the vitamin D with calcium group and 9 deaths (0.8%) in the placebo group over 4 years (ARD, −0.19% [95% CI, −0.90% to 0.52%]; RR, 0.77 [95% CI, 0.29 to 2.07]).25 The WHI CaD trial reported 744 deaths (4.1%) in the vitamin D with calcium group over 7 years, compared with 807 deaths (4.5%) in the placebo group (ARD, −0.36% [95% CI, −0.78% to 0.05%]; HR, 0.91 [95% CI, 0.83 to 1.01]).29

Kidney Stones

Five RCTs examined the effect of supplementation with calcium alone20-22 or vitamin D combined with calcium24, 25, 27, 28 on incident kidney stones. No studies evaluating the effects of vitamin D alone on incident kidney stones were identified. Findings are summarized in Figure 4. For calcium alone compared with placebo, the pooled ARD for incident kidney stones over 2 to 4 years was 0.00% (95% CI, −0.88% to 0.87%) and the pooled RR was 0.68 (95% CI, 0.14 to 3.36; I2 = 0.0%; 3 RCTs [1259 participants]), suggesting no association. For vitamin D combined with calcium compared with placebo, a statistically significant association for increase in incidence was found (pooled ARD, 0.33% [95% CI, 0.06% to 0.60%]; pooled RR, 1.18 [95% CI, 1.04 to 1.35]; I2 = 0.0%; 3 RCTs [39,213 participants]).

Cardiovascular Disease

Five RCTs examined the effect of supplementation with vitamin D alone,14, 16-18 calcium alone,22 or vitamin D with calcium24, 29-32 on cardiovascular disease outcomes. For vitamin D alone compared with placebo, 3 RCTs were eligible, and none found significant findings for any outcome. One RCT reported myocardial infarction incidence over 3.3 years in 28 participants (1.1%) in the vitamin D group and 31 participants (1.2%) in the placebo group (ARD, −0.12%, [95% CI, −0.71% to 0.47%]; HR, 0.90 [95% CI, 0.54 to 1.50]).17 Similar, nonsignificant findings were found for stroke, venous thromboembolism, and heart failure outcomes. Another RCT reported incident ischemic heart disease over 5 years in 224 participants (16.7%) assigned to vitamin D vs 233 participants (17.4%) assigned to placebo (ARD, −0.72% [95% CI, −3.56 to 2.12]; age-adjusted RR, 0.94 [95% CI, 0.77 to 1.15]).16 For incident cerebrovascular disease, 105 participants (7.8%) in the vitamin D group vs 101 (7.5%) in the placebo group experienced events (ARD, 0.27% [95% CI, −1.74% to 2.29%]; age-adjusted RR, 1.02 [95% CI, 0.77 to 1.36]). Cardiovascular disease events in the third RCT were rare; 1 woman experienced a myocardial infarction and 1 underwent coronary artery bypass graft surgery in the vitamin D group, and no cardiovascular events were reported in the placebo group.14

For calcium alone compared with placebo, 1 RCT reported no cardiovascular disease events in the placebo group, 1 event in the 600-mg calcium group (ARD, 1.02% [95% CI,−1.75% to 3.80%]; RR, 3.03 [95% CI, 0.12 to 73.49]), and 2 events in the 1200-mg calcium group (ARD, 2.15% [95% CI, −1.38% to 5.68%]; RR, 5.32 [95% CI, 0.26 to 109.35]).22

For vitamin D combined with calcium, the WHI CaD trial reported myocardial infarction in 411 participants (2.3%) in the vitamin D and calcium group compared with 390 participants (2.2%) in the placebo group at 7 years (ARD, 0.11% [95% CI, −0.20% to 0.41%]; HR, 1.03 [95% CI, 0.90 to 1.19]).29 Similar findings for stroke, venous thromboembolism, and hospitalization for heart failure were also reported (stroke: ARD, −0.09% [95% CI, −0.38% to 0.20%] and HR, 0.95 [95% CI, 0.82 to 1.10]; venous thromboembolism: ARD, −0.16% [95% CI, −0.44% to 0.12%] and HR, 0.92 [95% CI, 0.79 to 1.07]; heart failure: ARD, −0.11% [95% CI, −0.40% to 0.18%] and HR, 0.95 [95% CI, 0.82 to 1.09]).31, 32

Cancer

Four RCTs examined the effect of supplementation with vitamin D alone,14, 16, 33 calcium alone,21 or vitamin D with calcium24, 28, 29, 34-37 on incident cancer. For vitamin D alone compared with placebo, 1 RCT reported incident cancer in 188 participants (14%) in the vitamin D group compared with 173 (13%) in the placebo group (ARD, 1.08% [95% CI, −1.50% to 3.66%]; age-adjusted RR, 1.09 [95% CI, 0.86 to 1.36]).16 A second RCT conducted among a younger study population reported a lower overall incidence of cancer: 2 participants (1.8%) in the vitamin D group and 3 participants (2.6%) in the placebo group (ARD, −0.82% [95% CI, −4.63% to 2.99%]; RR, 0.68 [95% CI, 0.12 to 4.02]).33 For calcium alone compared with placebo, 1 RCT reported incident nonskin cancer in 17 women (3.8%) who took calcium compared with 20 (6.9%) who took placebo (ARD, −3.12% [95% CI, −6.56% to 0.31%]; RR, 0.55 [95% CI, 0.29 to 1.03]).21 For vitamin D combined with calcium compared with placebo, pooled estimates found no significant association for total incident cancer (pooled RR, 0.73 [95% CI, 0.49 to 1.10]; I2 = 75.8%; pooled ARD, −1.48% [95% CI, −3.32% to 0.35%]; I2 = 70.9%; 3 RCTs [39,213 participants]). Similar findings were reported for breast cancer (pooled RR, 0.82 [95% CI, 0.56 to 1.19]; I2 = 39.5%) and colon cancer (pooled RR, 1.07 [95% CI, 0.87 to 1.33]; I2 = 0.0%).

Discussion

The evidence reviewed to inform an updated USPSTF recommendation is summarized in Table 2. Among the community-dwelling populations without prior history of fractures or known vitamin D deficiency or osteoporosis, the preponderance of the evidence suggests no decreased fracture risk from supplementation with vitamin D with or without calcium, although the strength of evidence was graded as low. This finding is consistent with the findings of the prior review on behalf of the USPSTF,5 since only 2 new studies evaluating vitamin D supplementation (with or without calcium) were identified. Limited evidence was found in this update to draw conclusions regarding the effect of calcium alone on fracture prevention; calcium-alone interventions were not included in the prior review.

This review included evidence on 4 harms: all-cause mortality, kidney stones, cardiovascular disease, and cancer. The evidence suggests that vitamin D with calcium increases the incidence of kidney stones, and this evidence was graded as moderate. The strength of evidence for no harm for all other interventions and outcomes was graded as either insufficient or low. Cohort and case-control studies of supplementation were eligible for the review of harms, but all were excluded for poor quality because of many methodologic limitations also noted by others.38, 39

Because this review was narrower in scope than other published reviews of vitamin D (with or without calcium), the conclusions may differ from the conclusions drawn from other reviews with a broader scope. As an example, a 2014 Cochrane review evaluated vitamin D and vitamin D analogues for preventing fractures and, similar to this review, found no benefit for vitamin D alone; however, they concluded that vitamin D with calcium may prevent fracture.40 The study populations considered in the Cochrane review included participants with osteoporosis, institutionalized participants, and secondary prevention populations. The fracture benefits overall appear to be largely attributable to benefits among the high-risk populations, with little to no benefit in lower-risk populations (1 fewer hip fracture per 1000 community-dwelling adults per year [95% CI, 0 to 2]). Similar to this review, the Cochrane review concluded that vitamin D with calcium was associated with increased renal disease (defined as renal calculi or insufficiency) but did not adversely affect the risk of death. Bolland and Grey discussed the issue of discordant results from different meta-analyses on the same topic using vitamin D supplementation and fracture as an example.41 In their analysis, differences in trial selection, outcome definitions used, and analytic approaches explain the majority of differences in findings. Across a body of evidence of 25 trials, they found strong statements concluding both benefit and no benefit of supplementation. Thus, it is important to consider the scope of the populations and interventions included when drawing conclusions from the body of evidence in this review to avoid inappropriate comparisons to reviews with a different scope.

Limitations

This review and the body of evidence included in this review has several limitations. For applicability to primary care populations, the review was scoped to focus on community-dwelling populations not known to have vitamin D deficiency, osteoporosis, high risk for falls, or prior history of fracture. As such, this review cannot address the effect of supplementation in higher-risk, selected populations. Several studies did not report the proportion of participants with a history of prior osteoporotic fracture; study authors were contacted to determine whether such data were available, and, in most cases, data were not available. These studies were ultimately included in this review because the reported baseline characteristics were similar to characteristics reported in the studies largely focused on primary prevention. The review was limited to oral or injectable vitamin D and oral calcium preparations that are available as dietary supplements and did not consider vitamin D analogues or formulations typically dispensed with a prescription.

Most studies included in this review were not powered for the fracture or harm outcomes considered; thus, small sample sizes and low event rates resulted in imprecise effect estimates. Some studies, notably the WHI CaD trial, allowed for use of personal calcium and vitamin D supplements during the study, and some have suggested this design feature as an explanation for the nonsignificant intention-to-treat analysis findings reported by the WHI CaD trial.42 Heterogeneity in outcome specification is another limitation of this body of evidence. The anatomical sites contributing to "total fracture" varied across studies and included both traumatic and osteoporotic fractures in most studies. Studies evaluating harms varied in specificity of definition or rigor of harm outcome ascertainment, some relying on self-report to identify cases and others relying on adverse event reporting during study monitoring or on secondary data sources (registries, claims, death certificates). Although some evidence on men exists, the majority of this body of evidence is applicable to postmenopausal, white women. In addition, only a few studies evaluated vitamin D doses higher than 800 IU per day, and the evidence on calcium was limited to doses ranging from 400 mg to 1600 mg per day.

Conclusions

Vitamin D supplementation alone or with calcium was not associated with reduced fracture incidence among community-dwelling adults without known vitamin D deficiency, osteoporosis, or prior fracture. Vitamin D with calcium was associated with an increase in the incidence of kidney stones

Article Information

Source: This article was first published in the Journal of the American Medical Association on April 17, 2018 (JAMA. 2018;319(15):1600-1612).

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr LeBlanc reported that her institution has received grant funding from Merck, Bristol-Meyer Squibb, AstraZeneca, and Amgen for projects on which she was an investigator; however, this work was unrelated to the topic of this manuscript. No other authors reported disclosures.

Funding/Support: This research was funded under contract HHSA-290-2015-00011-I, Task Order 5, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the USPSTF.

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure that the analysis metmethodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

Additional Information: A draft version of the full evidence report underwent external peer review from 4 content experts (Mei Chung, PhD, Tufts University; Joann Manson, MD, Harvard Medical School; Elizabeth Yetley, PhD, Office of Dietary Supplements, National Institutes of Health; and 1 reviewer who wished to remain anonymous) and 5 federal partner reviewers (Centers for Disease Control and Prevention, Indian Health Service, National Heart, Lung, and Blood Institute [2 reviewers], National Institute of Diabetes and Digestive and Kidney Diseases). Comments from reviewers were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.

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14. Komulainen MH, Kröger H, Tuppurainen MT, et al. HRT and vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial. Maturitas. 1998;31(1):45-54.

15. Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM. Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann Intern Med. 1996;124(4):400-6.

16. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ. 2003;326(7387):469.

17. Scragg R, Stewart AW, Waayer D, et al. Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the vitamin D assessment study: a randomized clinical trial. JAMA Cardiol. 2017;2(6):608-16.

18. Khaw K-T, Stewart AW, Waayer D, et al. Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial. Lancet Diabetes Endocrinol. 2017;5(6):438-447.

19. Recker RR, Hinders S, Davies KM, et al. Correcting calcium nutritional deficiency prevents spine fractures in elderly women. J Bone Miner Res. 1996;11(12):1961-6.

20. Riggs BL, O'Fallon WM, Muhs J, O'Connor MK, Kumar R, Melton LJ 3rd. Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women. J Bone Miner Res. 1998;13(2):168-74.

21. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85(6):1586-1591.

22. Reid IR, Ames R, Mason B, et al. Randomized controlled trial of calcium supplementation in healthy, nonosteoporotic, older men. Arch Intern Med. 2008;168(20):2276-82.

23. Dawson-Hughes B, Harris SS, Krall EA, et al. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med. 1997;337(10):670-6.

24. Jackson RD, LaCroix AZ, Gass M, et al; Women's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354(7):669-683.

25. Lappe J, Watson P, Travers-Gustafson D, et al. Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial. JAMA. 2017;317(12):1234-1243.

26. Li M, Xia WB, Xing XP, et al. Benefit of infusion with ibandronate treatment in children with osteogenesis imperfecta. Chin Med J (Engl). 2011;124(19):3049-3053.

27. Wallace RB, Wactawski-Wende J, O'Sullivan MJ, et al. Urinary tract stone occurrence in the Women's Health Initiative (WHI) randomized clinical trial of calcium and vitamin D supplements. Am J Clin Nutr. 2011;94(1):270-277.

28. Wactawski-Wende J, Kotchen JM, Anderson GL, et al; Women's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med. 2006;354(7):684-696.

29. Prentice RL, Pettinger MB, Jackson RD, et al. Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study. Osteoporos Int. 2013;24(2):567-580.

30. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040.

31. Blondon M, Rodabough RJ, Budrys N, et al. The effect of calcium plus vitamin D supplementation on the risk of venous thromboembolism: from the Women's Health Initiative randomized controlled trial. Thromb Haemost. 2015;113(5):999-1009.

32. Donneyong MM, Hornung CA, Taylor KC, et al. Risk of heart failure among postmenopausal women: a secondary analysis of the randomized trial of vitamin D plus calcium of the Women's Health Initiative. Circ Heart Fail. 2015;8(1):49-56.

33. Komulainen M, Kröger H, Tuppurainen MT, et al. Prevention of femoral and lumbar bone loss with hormone replacement therapy and vitamin D3 in early postmenopausal women: a population-based 5-year randomized trial. J Clin Endocrinol Metab. 1999;84(2):546-552.

34. Jackson RD, LaCroix AZ, Cauley JA, McGowan J. The Women's Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Ann Epidemiol. 2003;13(9 suppl):S98-S106.

35. Tang JY, Fu T, Leblanc E, et al. Calcium plus vitamin D supplementation and the risk of nonmelanoma and melanoma skin cancer: post hoc analyses of the Women's Health Initiative randomized controlled trial. J Clin Oncol. 2011;29(22):3078-3084.

36. Brunner RL, Wactawski-Wende J, Caan BJ, et al. The effect of calcium plus vitamin D on risk for invasive cancer: results of the Women's Health Initiative (WHI) calcium plus vitamin D randomized clinical trial. Nutr Cancer. 2011;63(6):827-841.

37. Bolland MJ, Grey A, Gamble GD, Reid IR. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr. 2011;94(4):1144-1149.

38. Chung M, Tang AM, Fu Z, Wang DD, Newberry SJ. Calcium intake and cardiovascular disease risk: an updated systematic review and meta-analysis. Ann Intern Med. 2016;165(12):856-866.

39. Reid IR, Bristow SM, Bolland MJ. Cardiovascular complications of calcium supplements. J Cell Biochem. 2015;116(4):494-501.

40. Avenell A, Mak JC, O'Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev. 2014;(4):CD000227.

41. Bolland MJ, Grey A. A case study of discordant overlapping meta-analyses: vitamin D supplements and fracture. PLoS One. 2014;9(12):e115934.

42. Finkelstein JS. Calcium plus vitamin D for postmenopausal women—bone appétit? N Engl J Med. 2006;354(7):750-752.

Table 1. Study Characteristics of Randomized Clinical Trials Evaluating the Effect of Vitamin D, Calcium, or Combined Supplementation

Source No. of
Participants
Analyzed
Population No. (%) Age, Mean (SD), y Intervention Control Follow-up, y Study Quality
Women Nonwhite
Vitamin D vs Placebo or Control
Komulainen et al,14 1998
(Finland)
232 Community-dwelling women (52-61 y) between 6 and 24 mo postmenopause recruited from enrollees in the OSTPRE study 232 (100) NR 52.7 (NR) D3 (300 IU) with calcium (93 mg) daily Calcium (93 mg) daily Mean, 4.3 (range, 0-5.9) Fair
Lips et al,15 1996
(The Netherlands)
2578 Adults (≥70 y) recruited from general practitioners or from apartment houses or homes for elderly personsa 1916 (74.3) NR 80.0 (6.0) D3 (400 IU) daily Placebo Median, 3.5 Fair
Trivedi et al,16 2003
(United Kingdom)
2686 Community-dwelling adults (65-85 y) recruited from the British Doctor's Study and general practice registers 649 (24.2) NR 74.7 (4.6) D3 (100,000 IU) every 4 mo Placebo 5 (planned) Fair
ViDA
Scragg et al,17 2017
Khaw et al,18 2017
(New Zealand)
5108 Community-dwelling adults (50-84 y) recruited from general practices 2141 (41.9) 857 (16.8) 65.9 (8.3) D3 (200,000 IU) initial dose followed by 100,000 IU every mo Placebo Median, 3.3 (range, 2.5-4.2) Sun protection; sunscreen
Calcium vs Placebo
Recker et al,19 1996
(United States)
103b Community-dwelling women (≥60 y) who were ambulatory and living independently, recruited from government-sponsored meal sites 103 (100) NR 72.5 (6.7) Calcium (1200 mg) daily Placebo Mean, 4.3 (SD, 1.1) Fair for benefits; poor for harms
Riggs et al,20 1998
(United States)
236 Community-dwelling women (61-70 y) who were postmenopausal for ≥10 y and identified through medical record review 236 (100) 0 66.3 (NR) Calcium (1600 mg) daily Placebo 4 (planned) Fair
Lappe et al,21 2007
(United States
1179c Community-dwelling postmenopausal women (≥55 y) in rural areas, recruited through random-digit dialing 1179 (100) 0 66.7 (7.3) Calcium (1400 mg) daily Placebo 4 (planned) Fair to goodd
Reid et al,22 2008
(New Zealand)
290 Healthy men (≥40 y) recruited through newspaper advertisement 0 NR 56.0 (10) Calcium (600 mg and 1200 mg) daily Placebo 2 (planned) Fair for harms;
poor for benefits
Vitamin D With Calcium vs Placebo
Dawson-Hughes et al,23 1997
(United States)
389 Healthy, community-dwelling adults (≥65 y) recruited through direct mailings and community presentations 213 (54.8) 15 (3.9) Women: 71.5 (4.5)
Men: 70.5 (4.5)
D3 (700 IU) + calcium (500 mg) daily Placebo 3 (planned) Fair
WHI Calcium and Vitamin D Trial
Jackson et al,24 2006
(United States)
36,282 Community-dwelling postmenopausal women (50-79 y) recruited from enrollees in either the WHI Dietary Modification or WHI Hormone Therapy trials 36,282 (100) 6129 (16.9) 62.4 (7.0) D3 (400 IU) + calcium (1000 mg) daily Placebo Mean, 7.0 (SD, 1.4) Fair
Lappe et al,21 2007
(United States
1179c Community-dwelling postmenopausal women (≥55 y) in rural areas, recruited through random-digit dialing 1179 (100) 0 66.7 (7.3) D3 (1000 IU) + calcium (1400 mg) daily Placebo 4 (planned) Fair to goodd
Lappe et al,25 2017
(United States)
2197 Community-dwelling postmenopausal women (≥55 y) recruited through population-based mailings 2197 (100) NR (0.5) 65.0 (NR) D3 (2000 IU) + calcium (1500 mg) daily Placebo 4 (planned) Fair

Abbreviations: D3, vitamin D3 (cholecalciferol); NR, not reported; OSTPRE, Osteoporosis Risk Factor and Prevention Study; ViDA, Vitamin D Assessment; WHI,Women’s Health Initiative.
a Participants recruited from practitioners lived independently; participants recruited from apartments or homes for elderly persons received some care (but less than they would receive in a nursing home, per study report).
b Only data for the subgroup (n = 103) of participants without prevalent vertebral fracture at baseline were included in this review.
c Includes 3 study groups: placebo (n = 288), calcium alone (n = 445), and vitamin D with calcium (n = 446).
d Study quality rated as good for cancer outcomes and fair for kidney stone outcomes.

Table 2. Summary of Evidence for Supplementation With Vitamin D, Calcium, or Both on Primary Prevention of Fracture and Harms

Intervention No. of Studies
(Participants
Analyzed)
Summary of Findings Consistency
and Precision
Reporting Bias Body of Evidence Limitations Applicability Overall Quality, No. of RCTs EPC Assessment
of Strength of Evidence
KQ1: Benefits Related to Prevention of Fractures
Vitamin D alone 4 RCTs (n = 10,606) Over 3.3 to 5 y: total fracture (1 RCT, n = 2686): ARD, −2.26% (95% CI, −4.53% to 0.00%); RR, 0.78 (95% CI, 0.61 to 0.99)a
Hip fracture (3 RCTs, n = 5496; I2 = 0.0%): pooled ARD, −0.01% (95% CI, −0.80% to 0.78%); pooled RR, 1.08 (95% CI, 0.79 to 1.48)
Nonvertebral fracture (2 RCTs, n = 5340): smaller study (n = 232): ARD, −3.45% (95% CI, −11.55% to 4.66%); RR, 0.64 (95% CI, 0.29 to 1.42); larger study (n = 5108): ARD, 0.77% (95% CI, −0.51% to 2.04%); adjusted HR, 1.19 (95% CI, 0.94 to 1.50)
Clinical vertebral fracture (1 RCT, n = 2686): ARD, −0.75% (95% CI, −1.73% to 0.23%); RR, 0.63 (95% CI, 0.35 to 1.14)
Consistent, imprecise Undetected Studies not powered for fracture outcomes; variability in populations and outcome specification and ascertainment; not enough studies to evaluate the influence of dose, route, or frequency on incidence Three of the 4 studies included men; studies conducted outside of United States but likely applicable to US settings; doses include 300 IU/d and 400 IU/d, 100,000 IU every 4 mo, and 100,000 IU every mo (after an initial 200,000-IU loading dose) Fair: 3
Good: 1
Low for no benefit
Calcium alone 2 RCTs (n = 339) Over 4 y: nonvertebral fracture (1 RCT, n = 236): ARD, −1.01% (95% CI, −8.58% to 6.56%); RR, 0.90 (95% CI, 0.41 to 1.96)
Morphometric vertebral fracture (2 RCTs, n = 339): ARDs, 7.26% (95% CI, −9.84% to 24.36%) and −0.97% (95% CI, −7.57% to 5.63%); RRs, 1.34 (95% CI, 0.68 to 2.64) and 0.87 (95% CI, 0.35 to 2.19)
Inconsistent, imprecise Detectedb Studies not powered for fracture outcomes; limited fracture outcomes reported; not enough studies to evaluate the influence of dose, route, or frequency on incidence Postmenopausal women in United States; doses included 1200 mg/d and 600 mg/d Fair Insufficient
Vitamin D with calcium 2 RCTs (n = 36,671) Over 3 to 7 y: total fracture (1 RCT, n = 36,282): ARD, −0.35% (95% CI, −1.02% to 0.31%); HR, 0.96 (95% CI, 0.91 to 1.02)
Hip fracture (2 RCTs, n = 36,671): from larger trialc: ARD, −0.14% (95% CI, −0.34% to 0.07%); HR, 0.88 (95% CI, 0.72 to 1.08)
Nonvertebral fractures (1 RCT, n = 389): ARD, −6.99% (95% CI, −12.71% to −1.27%); RR, 0.46 (95% CI, 0.23 to 0.90)
Clinical vertebral fracture (1 RCT, n = 36,282): ARD, −0.09% (95% CI, −0.30% to 0.12%); HR, 0.90 (95% CI, 0.74 to 1.10)
Inconsistent, imprecise Detectedb Not enough studies to evaluate the influence of dose, route, or frequency on incidence; participants allowed to take personal vitamin D and calcium supplements during the trial in the larger of the 2 trials Postmenopausal women in United States; the smaller of the 2 trials included men; vitamin D doses were 400 IU/d and 700 IU/d; calcium doses were 500 mg/d and 1000 mg/d Fair Low for no benefitd
KQ2: All-Cause Mortality
Vitamin D alone 4 RCTs (n = 10,599) Over 3.3 to 5 y: pooled ARD, −0.74% (95% CI, −1.80% to 0.32%); I2 = 19.6%; pooled RR, 0.91 (95% CI, 0.82 to 1.01); I2 = 0.0% Consistent, imprecise Undetected Studies not powered to assess all-cause mortality Older men and postmenopausal women in non-US countries, although likely applicable to United States; doses were 300 IU/d and 400 IU/d and 100,000 IU every mo or 4 mo Fair: 3
Good: 1
Low for no harm
Calcium alone 1 RCT (n = 290) Over 2 y: ARD, 0.01% (95% CI, −2.29% to 2.32%); RR, 1.01 (95% CI, 0.09 to 11.06) Unknown consistency (single study), very imprecisee Undetected Study not powered to assess all-cause mortality; no reporting of how mortality ascertained Predominantly white men (≥40 y) in New Zealand, although likely applicable to United States; doses included 600 mg/d and 1200 mg/d Fair Insufficient
Vitamin D with calcium 2 RCTs (n = 38,479) Over 4 y (smaller trial, n = 2303): ARD, −0.19% (95% CI, −0.90% to 0.52%); RR, 0.77 (95% CI, 0.29 to 2.07)
Over 7 y (larger trial, n = 36,282): ARD, −0.36% (95% CI, −0.78% to 0.05%); HR, 0.91 (95% CI, 0.83 to 1.01)
Consistent, imprecise Undetected Studies not powered to assess all-cause mortality; participants allowed to take personal vitamin D and calcium supplements in larger trial Postmenopausal women in United States; vitamin D dose 400 IU/d or 2000 IU/d; calcium dose 1000 mg/d to1500 mg/d Fair Low for no harm
KQ2: Incident Kidney Stones
Vitamin D alone 0 (NA) NA NA NA NA NA NA Insufficient
Calcium alone 3 RCTs (n = 1259) Over 2 to 4 y: pooled ARD, 0.00% (95% CI, −0.88% to 0.87%); I2 = 0.0%; pooled RR, 0.68 (95% CI, 0.14 to 3.36); I2 = 0.0% Consistent, imprecise Undetected Studies not powered to assess incident kidney stones; limited information on outcome specification and ascertainment Postmenopausal women in United States and New Zealand; doses ranging from 600 mg/d to 1600 mg/d Fair Low for no harm
Vitamin D with calcium 3 RCTs (n = 39,213) Pooled ARD, 0.33% (95% CI, 0.06% to 0.60%); I2 = 0.0%; pooled RR, 1.18 (95% CI, 1.04 to 1.35); I2 = 0.0% Consistent, precise (primarily considering the larger 2 trials)f Undetected Studies not powered to assess incident kidney stones; participants allowed to take personal vitamin D and calcium supplements during largest trial Postmenopausal women in United States; vitamin D dose 400 IU/d, 1000 IU/d, and 2000 IU/d; calcium dose 1000 mg/d and 1400 to 1500 mg/d Fair Moderate for harm
KQ2: Incident Cardiovascular Disease
Vitamin D alone 3 RCTs (n = 8021) Over 3.3 to 5 y in the 2 larger trials (n = 2686 and n = 5108)g: myocardial infarction: ARD, −0.72% (95% CI, −3.56% to 2.12%); RR, 0.94 (95% CI, 0.77 to 1.15) and ARD, −0.12% (95% CI, −0.71% to 0.47%); HR, 0.90 (95% CI, 0.54 to 1.50)
Cerebrovascular disease/stroke: ARD, 0.27% (95% CI, −1.74% to 2.29%); RR, 1.02 (95% CI, 0.77 to 1.36) and ARD, −0.04% (95% CI, −0.60% to 0.51%); HR, 0.95 (95% CI, 0.55 to 1.62)
Consistent, imprecise Undetected Only 1 study powered for cardiovascular disease events; varying control event rates suggest heterogeneity in populations, outcome specifications, and ascertainment methods Postmenopausal women and men in United States, United Kingdom, and New Zealand; doses included 300 IU/d and 100,000 IU every 1 to 4 mo Fair: 2
Good: 1
Low for no harm
Calcium alone 1 RCT (n = 290) Over 2 y: myocardial infarction: 600-mg dose: ARD, 1.02% (95% CI, −1.75% to 3.80%); RR, 3.03 (95% CI, 0.12 to 73.49)
1200-mg dose: ARD, 2.15% (95% CI, −1.38% to 5.68%); RR, 5.32 (95% CI, 0.26 to 109.35)
Unknown consistency (single study), very impreciseh Undetected Study not powered for cardiovascular disease events. Predominantly white men (≥40 y) in New Zealand, although likely applicable to United States; doses included 600 mg/d and 1200 mg/d Fair Insufficient
Vitamin D with calcium 1 RCT (n = 36,282) Over 7 y: myocardial infarction: ARD, 0.11% (95% CI, −0.20% to 0.41%); HR, 1.03 (95% CI, 0.90 to 1.19)
Stroke: ARD, −0.09% (95% CI, −0.38% to 0.20%); HR, 0.95 (95% CI, 0.82 to 1.10)
Venous thromboembolism: ARD, −0.16% (95% CI, −0.44% to 0.12%); HR, 0.92 (95% CI, 0.79 to 1.07)
Heart failure hospitalization: ARD, −0.11% (95% CI, −0.40% to 0.18%); HR, 0.95 (95% CI, 0.82 to 1.09)
Unknown consistency (single study), precise Undetected Study not powered for cardiovascular disease events; participants allowed to take personal vitamin D and calcium supplements during the trial in the larger of the 2 trials Postmenopausal women in United States; vitamin D dose 400 IU/d; calcium dose 1000 mg/d Fair Low for no harm
KQ2: Incident Cancer
Vitamin D alone 2 RCTs (n = 2918) Over 5 y: any incident cancer: ARDs, 1.08% (95% CI, −1.50% to 3.66%) and −0.82% (95% CI, −4.63% to 2.99%); RRs, 1.09 (95% CI, 0.86 to 1.36) and 0.68 (95% CI, 0.12 to 4.02 Inconsistent, imprecise Undetected Studies not powered for cancer outcomes; no validation of self-reported cancers Older men and postmenopausal women; doses included 300 IU/d and 100,000 IU every 4 mo Fair Insufficient
Calcium alone 1 RCT (n = 733) Over 4 y: any incident nonskin cancer: ARD, −3.12% (95% CI, −6.56% to 0.31%); RR, 0.55 (95% CI, 0.29 to 1.03) Unknown consistency (single study), imprecise Undetected Study not powered for cancer outcomes Postmenopausal women in the United States without a recent history of cancer; dose 1400 to 1500 mg/d Good Insufficient
Vitamin D with calcium 3 RCTs (n = 39,213) Over 4 to 7 y: total (nonskin cancer): pooled ARD, −1.48% (95% CI, −3.32% to 0.35%); I2 = 70.9%; pooled RR, 0.73 (95% CI, 0.49 to 1.10); I2 = 75.8% Inconsistent, precise (primarily considering the largest of the trials) Undetected Largest study not powered for cancer outcomes; participants allowed to take personal vitamin D and calcium supplements during the trials Postmenopausal women in United States; vitamin D dose 400 IU/d, 1000 IU/d, 2000 IU/d; calcium dose 1000 mg/d, 1400 to 1500 mg/d Fair: 2
Good: 1
Low for no harm

Abbreviations: ARD, absolute risk difference; EPC, Evidence-based Practice Center; HR, hazard ratio; KQ, key question; NA, not applicable; RCT, randomized clinical trial; RR, relative risk ratio.
a Adjusted estimate reported by the study; unadjusted estimate based on raw data in article was 0.80 (95% CI, 0.63 to 1.00).
b One RCT was identified that was registered with a primary study aim of evaluating the effect of calcium alone and vitamin D with calcium supplementation on fracture incidence. According to the study’s corresponding author, alendronate became available during the study and about 20% of the study population started it; the trial found no significant differences with respect to fracture incidence, and findings were not published (Joan Lappe, written communication, December 22, 2016).
c Only 1 hip fracture (in control group) occurred in the smaller of the 2 trials.23
d Although findings between trials were inconsistent, the larger trial (Women’s Health Initiative Calcium and Vitamin D trial) was primarily relied on to derive the strength of evidence assessment.
e Reflects effect estimates of the 600-mg or 1200-mg calcium dose compared with placebo. This trial is considered very imprecise because the outcome was very rare; only 1 participant in each active study group died.
f The smaller trial (n = 734) was considered very imprecise because the outcome was very rare; only 1 participant in each study group had kidney stones.21
g The smallest trial (n = 232) reported 1 myocardial infarction and 1 coronary artery bypass graft surgery in treatment group; no events in control group.14
h This trial is considered very imprecise because the outcome was rare; no participants in the control group had any events, 1 participant in the 600-mg group had an event, and 2 participants in the 1200-mg group had an event.22

Figure 1. Analytic Framework: Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Adults

The framework begins on the left with the population of interest: generally healthy persons with no known disorders. To the right is an overarching arrow for the framework representing KQ1. It begins with the interventions of supplementation with vitamin D, alone or with calcium, on the left and ends with a box on the far right that represents the final health outcomes, fractures and fracture-related morbidity and mortality. A second horizontal arrow leads straight from the population of interest to the center of the framework, representing vitamin D status, and continues as a dotted arrow to the aforementioned final health outcomes box. A footnote at the bottom of the figure reads "measures of whole body calcium status do not exist; thus, the indirect evidence pathway for calcium cannot be evaluated." From the arrow leading to intermediate outcomes, a third squiggly arrow descends to an oval circle with the text "Harms" to illustrate the focus of KQ2.

Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate to interventions and outcomes. A dashed line is used to reflect the natural progression of disease between an intermediate outcome and a health outcome. Further details are available from the USPSTF procedure manual.4

a Measures of whole-body calcium status do not exist; thus, the indirect evidence pathway for calcium cannot be evaluated.

Figure 2. Literature Search Flow Diagram

Figure 2 is a preferred reporting of systematic review and meta-analysis (PRISMA) tree that summarizes the search and selection of articles. There were 16 studies identified from prior USPSTF reviews, 3,187 new references identified through database searching, and 64 additional citations identified through reference lists and other sources. After duplicates were removed, the title and abstracts of 3,131 references were screened for potential inclusion. Of these, 2,840 were excluded and 291 were deemed appropriate for full-text review to determine eligibility. After full-text review, 265 records were excluded: 29 were nonoriginal research, 41 for ineligible intervention or exposure, 55 for ineligible population, 1 for ineligible setting, 45 for ineligible outcome, 18 for ineligible study design, 3 for ineligible comparator, 2 for ineligible timing, 1 for ineligible country or region, 6 were study protocols with no outcomes, 29 were systematic reviews used to identify relevant studies, and 35 were excluded for poor overall study quality. Of the 55 records excluded for ineligible population, 5 trials (in 7 publications) with a study population that included 20% to 50% of participants with prior or prevalent fractures were used in sensitivity analyses. The 35 records excluded for poor quality included 8 trials (in 9 publications) and 22 cohort or case-control studies (in 26 publications). Of these, 7 poor-quality trials were used in sensitivity analyses. The 11 good- or fair-quality trials (from 26 publications) not excluded for the aforementioned reasons are included in this review. Among them, 8 trials (from 13 publications) are used in the main analysis for KQ1. An additional 10 trials (in 13 publications) were used in the sensitivity analysis for KQ1: 4 were excluded from the main analyses because of ineligible population, 5 because of poor quality, and 1 because of both ineligible population and poor quality. Nine good- or fair-quality trials (from 22 publications) are used in the main analysis for KQ2. An additional 11 trials (in 15 publications) were used in the sensitivity analysis for KQ2: 4 were excluded from the main analyses because of ineligible population, 6 because of poor quality, and 1 because of both ineligible population and poor quality.

 

KQ indicates key question; RCT, randomized clinical trial; USPSTF, US Preventive Services Task Force.

a Five RCTs (in 7 articles) that were excluded for ineligible study population were used in sensitivity analyses (the study populations in these studies included between 20% and 50% of participants with prior or prevalent fracture).
b Eight RCTs (in 9 articles) and 22 cohort or case-control studies (in 26 articles) were excluded for poor quality. Seven of the poor-quality RCTs were used in the sensitivity analyses.
c Ten RCTs (in 13 articles) were used in sensitivity analyses for KQ1; 4 were excluded from the main analyses because of ineligible population, 5 were excluded because of poor quality, and 1 was excluded for both ineligible population and poor quality.
d Eleven RCTs (in 15 articles) were used in sensitivity analyses for KQ2; 4 were excluded from the main analyses because of ineligible population, 6 were excluded because of poor quality, and 1 was excluded for both ineligible population and poor quality.

Figure 3. Comparison of Incident Fracture in Randomized Trials Comparing Vitamin D, Calcium, or Both With Placebo or Control

Figure 3 displays a forest plot of the relative risks of developing various types of incident fractures after receiving vitamin D, calcium, or combined supplementation compared with placebo or control. All but one study reported statistically nonsignificant differences in fracture incidence between supplementation and placebo groups over 3 to 7 years, with absolute risk differences ranging from −6.99% to 7.26% and relative risks ranging from 0.36 to 1.34. Most estimates were imprecise, with confidence intervals spanning a range that would include a clinical benefit or harm.

Placebo alone was the comparator for all studies except Komulainen et al,14 for which calcium was the comparator (See Table 1). ViDA indicates Vitamin D Assessment; WHI, Women’s Health Initiative.

a Calculated based on raw data provided in study; the authors reported an age-adjusted RR of 0.78 (95% CI, 0.61-0.99).

Figure 4. Comparison of Incident Kidney Stones in Randomized Trials Comparing Calcium or Both Vitamin D and Calcium With Placebo

Figure 4 displays a forest plot of the risk difference of developing incident kidney stones following calcium or combined calcium and vitamin D supplementation compared with placebo. For calcium alone compared with placebo, the pooled absolute risk difference for incident kidney stones over 2 to 4 years was 0.00% and the pooled relative risk was 0.68, suggesting no association. For vitamin D combined with calcium compared with placebo, a statistically significant association for increase in incidence was found.

WHI indicates Women’s Health Initiative.

Current as of: April 2018

Internet Citation: Evidence Summary: Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: Preventive Medication. U.S. Preventive Services Task Force. April 2018.
https://www.uspreventiveservicestaskforce.org/Page/Document/evidence-summary/vitamin-d-calcium-or-combined-supplementation-for-the-primary-prevention-of-fractures-in-adults-preventive-medication

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