Draft Research Plan

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

March 31, 2016

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

Abbreviation: KQ = key question.

Text Description.

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.

  1. 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:
    1. Dose or dosing interval?
    2. Fracture type?
    3. Subpopulation (including, but not limited to: age, sex, or race/ethnicity)?
  2. What are the harms associated with supplementation with vitamin D or calcium alone or vitamin D combined with calcium? Do the harms of supplementation vary by:
    1. Dose or dosing interval?
    2. 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.

  1. What are the effects of vitamin D supplementation alone or combined with calcium on change in vitamin D status?
  2. What is the association between vitamin D status and fracture outcomes?

The proposed 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
Population
  • Community-dwelling adult populations with no known disorders related to bone metabolism
  • Mixed populations will be included if no more than 20% of the study population has any of the excluded conditions
  • Age <18 years
  • Studies for which patient eligibility is determined by testing for vitamin D deficiency or bone measurement testing, with selection based on vitamin D or bone density level
  • Studies with inclusion criteria designed to assemble a population with a specific condition or a group of closely related conditions; for example, studies in populations that:
    • Have known osteoporosis, are taking antiresorptive agents, or have a prior history of osteoporotic fractures
    • Have long-term use of systemic corticosteroids or other medications associated with osteoporosis (e.g., aromatase inhibitors, androgen deprivation therapy, antiretrovirals)
    • Have a history of falls or are considered at “high risk” for falls
    • Have a medical condition associated with vitamin D deficiency (e.g., hyperparathyroidism, rickets, calcium or phosphorus metabolism disorders, malabsorptive disorders, celiac disease, cystic fibrosis, short gut syndrome, cholestatic liver disease, hepatic failure, cirrhosis, chronic kidney disease, scleroderma, lupus, dermatomyositis)
    • Have a bone disorder (e.g., osteogenesis imperfecta, osteopetrosis, osteitis deformans)
    • Have cancer or history of cancer (excluding nonmelanoma skin cancer)
    • Have known coronary artery disease
    • Have nephrolithiasis or nephrocalcinosis
    • Are pregnant or lactating
Intervention/ exposure
  • Vitamin D alone
  • Calcium alone
  • Vitamin D combined with calcium
  • Types of vitamin D considered: vitamin D2 (ergocalciferol) and D3 (cholecalciferol)
  • Types of calcium considered: calcium carbonate, calcium phosphate, calcium citrate, and calcium malate
  • Dosage: any, including daily or annual (vitamin D only) supplementation, as long as it is considered long term (≥1 month or equivalent)
  • Short-term use (<1 month daily use or equivalent)
  • Vitamin D preparations or metabolites not designed as supplements (e.g., calcitriol, alphacalcitriol, calcifediol)
  • Synthetic vitamin D analogs (specifically doxercalciferol, paricalcitol, falecalcitriol, oxacalcitriol, alfacalcidol)
  • Multivitamin supplements that include vitamin D or calcium, unless the independent effects of vitamin D, calcium, or both can be evaluated
  • Foods or beverages fortified with vitamin D, calcium, or both
  • Vitamin D obtained through natural or artificial ultraviolet light exposure
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: Duration of intervention of ≥1 month

KQ 2: Any timing

 KQ 1: Duration of intervention of <1 month

KQ 2: No exclusions
Setting
  • Community and primary care–relevant settings; assisted and independent living facilities
  • Studies conducted in countries categorized as “very high” on the Human Development Index (as defined by the United Nations Development Programme)
  • Skilled nursing facilities; postacute care  and rehabilitation facilities
  • Studies conducted in countries not categorized as “very high” on the Human Development Index (as defined by the United Nations Development Programme)
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:

  • Were designed specifically to evaluate the use of vitamin D or calcium supplements
  • Adequately measured and controlled for nonsupplemental sources of vitamin D or calcium
 Study designs not listed as specifically included (e.g., case reports, case series, studies without a comparison group)
Other
  • English language
  • Original research
  • Languages other than English
  • Narrative reviews
  • Editorials
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.