Final Research Plan
Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: Preventive Medication
June 23, 2016
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
The final Research Plan will be used to guide a systematic review of the evidence by researchers at an Evidence-based Practice Center. The resulting Evidence Review will form the basis of the USPSTF Recommendation Statement on this topic.
The draft Research Plan was available for comment from March 31 to April 27, 2016 at 8:00 p.m., ET.
† Measures of whole body calcium status do not exist; thus, the indirect evidence pathway for calcium cannot be evaluated.
Abbreviation: KQ = key question.
This figure is the analytic framework depicting the two key questions and the research approach that will guide the evidence review outlined in this research plan. In general, the figure illustrates the overarching question of whether supplementation with vitamin D or calcium alone or vitamin D combined with calcium leads to improved fracture and fracture-related morbidity and mortality health outcomes (key question 1). The framework starts on the left with the population of interest, generally healthy persons with no known disorders. Moving from left to right, the figure depicts the harms that may result from supplementation with vitamin D or calcium alone or vitamin D combined with calcium. Supplementation with vitamin D alone or combined with calcium may affect vitamin D status. Vitamin D status, an intermediate outcome, may be associated with fractures and fracture-related morbidity and mortality.
- Does supplementation with vitamin D or calcium alone or vitamin D combined with calcium prevent fractures or reduce fracture-related morbidity and mortality? Do the benefits of supplementation vary by:
- Dose or dosing interval?
- Fracture type?
- Subpopulation (including, but not limited to: age, sex, or race/ethnicity)?
- Are there harms of supplementation with vitamin D or calcium alone or vitamin D combined with calcium? Do the harms of supplementation vary by:
- Dose or dosing interval?
- Subpopulation (including, but not limited to: age, sex, or race/ethnicity)?
Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.
- What are the effects of vitamin D supplementation alone or combined with calcium on change in vitamin D status?
- What is the association between vitamin D status and fracture outcomes?
The Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the Evidence Review. Criteria are overarching as well as specific to each of the key questions (KQs).
Included | Excluded | |
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Population |
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Intervention/ exposure |
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Comparison | Placebo, no treatment, or lower- or higher-dose vitamin D or calcium regimens | Intervention and comparison arms that do not allow for evaluation of the independent contribution of vitamin D or calcium, either alone or combined (e.g., studies assessing a multicomponent intervention that includes vitamin D as one of several components compared to no intervention would not be eligible unless the comparison arm included all of the other intervention components except vitamin D) |
Outcomes | KQ 1: Total primary fractures at any site other than face, skull, finger, toe, and heel; total primary major osteoporotic fracture, defined as fracture of the hip; vertebral (clinical), proximal humerus, distal radius, and morphometric vertebral fractures; fracture-related morbidity and mortality
KQ 2: All-cause mortality, symptomatic acute or chronic vitamin D or calcium toxicity, incident symptomatic nephrolithiasis, incident cancer (other than nonmelanoma skin cancer), incident cardiovascular disease (myocardial infarction, stroke, peripheral artery disease), and other harms reported as being definitely or probably related to study intervention |
KQ 1: Recurrent osteoporotic fracture (i.e., preventing a second fracture in patients known to have a previous osteoporotic fracture); bone mineral density changes; other intermediate measures of bone or muscle strength or quality
KQ 2: Asymptomatic outcomes (soft-tissue calcification, nephrocalcinosis, artery calcification, hypercalcemia, hypercalciuria) |
Timing | KQ 1: Intervention duration of ≥1 month
KQ 2: Any duration |
KQ 1: Intervention duration of <1 month
KQ 2: No exclusions |
Setting |
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Study design | KQ 1: Randomized, controlled trials; systematic reviews that use study selection criteria similar to this review*
KQ 2: Randomized, controlled trials; systematic reviews that use study selection criteria similar to this review; prospective cohort or case-control studies, if they:
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Study designs not listed as specifically included (e.g., case reports, case series, studies without a comparison group) |
Other |
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Study quality | Good- and fair-quality studies | Poor-quality studies |
* Only the most recent systematic review update will be included if there are multiple systematic reviews from the same group of investigators using the same review process. For situations where there are several systematic reviews on the same topic with similar conclusions and the same set of primary studies, the systematic review with either the latest cutoff date for the end of the literature search or the most included primary studies will be selected.
The draft Research Plan was posted for public comment on the USPSTF Web site from March 31 to April 27, 2016. The USPSTF received several comments about broadening the scope of the included populations, interventions, and outcomes considered, such as focusing on vitamin D–deficient populations and populations with osteoporosis or at high risk for falls. However, the focus of the evidence review is to understand the benefits and harms of vitamin D and calcium supplementation in persons who are not already identified as needing treatment for a given condition. Screening for vitamin D deficiency, screening for osteoporosis, and providing interventions to prevent falls are addressed in other USPSTF recommendations. In response to comments, the USPSTF revised the key question regarding harms to remove indication of an assumption of harms with vitamin D or calcium supplementation.