in progress

Final Research Plan

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

April 06, 2023

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.

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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. The figure illustrates the overarching question of whether supplementation with vitamin D alone, calcium alone, or vitamin D in combination with calcium leads to improved fracture, fall, and related morbidity and mortality outcomes (key question 1). The framework starts on the left with the population of interest, generally persons with no known nutritional deficiencies or disorders related to bone metabolism. Moving from left to right, the figure depicts the harms that may result from supplementation using vitamin D alone, calcium alone, or vitamin D in combination with calcium (key question 2). Supplementation with vitamin D alone or in combination with calcium may impact vitamin D status. Vitamin D status, an intermediate outcome, may be associated with the health outcome: fractures, falls, and related morbidity and mortality.

* Measures of whole-body calcium status do not exist; thus, the indirect evidence pathway for calcium cannot be evaluated.
Abbreviation: KQ=key question.

  1. Does supplementation with vitamin D, calcium, or both prevent fractures and falls or reduce fracture- and fall-related morbidity and mortality?
  2. What are the harms of supplementation with vitamin D, calcium, or both?

To the extent that it is reported in the studies, we will describe the population and intervention characteristics of the included studies. Based on available data, we will explore variation in effectiveness and harms of supplementation by age, sex, race, and ethnicity. To explore variation by subpopulation, we will rely on the approach developed for U.S. Preventive Services Task Force (USPSTF) reviews described by Whitlock et al,1 which involves identifying and assessing credibility of within-study subgroup analyses and examining between-study variability (with quantitative assessment if appropriate). We will also explore variation in effectiveness and harms by dosage and duration of supplementation where data are available by stratifying results based on dosage groupings derived from the empiric evidence available.

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 report. Criteria are overarching as well as specific to each of the Key Questions.

Category Include Exclude
Population Community-dwelling adults with no known disorders related to vitamin D, calcium, or bone metabolism.

Mixed populations will be included if no more than 20% of the study population has any of the excluded conditions.

 Children or adolescents age 18 years or younger; pregnant or lactating persons; studies for which patient eligibility is determined by testing to identify vitamin D deficiency or bone measurement testing, with selection based on low vitamin D or bone density level; and studies with inclusion criteria designed to assemble populations with a specific condition or a group of closely related conditions, such as those with:
  • Osteoporosis, or those who take antiresorptive agents, have a prior history of osteoporotic fractures, or have long-term use of systemic corticosteroids or other medications associated with osteoporosis (e.g., aromatase inhibitors, androgen deprivation therapy, or antiretroviral therapy)
  • Medical conditions 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, or dermatomyositis)
  • Bone disorders (e.g., osteogenesis imperfecta, osteopetrosis, or osteitis deformans)
  • Nephrolithiasis or nephrocalcinosis
Setting Community and primary care–relevant settings, including assisted and independent living facilities. Inpatient, skilled nursing facilities; postacute care and rehabilitation facilities.
Interventions
  • Vitamin D2 or D3; any dose given orally or intramuscularly at any frequency.
  • Calcium; any dose given orally at any frequency.
  • Vitamin D and calcium in combination.
 Short-term supplementation use (less than 1 month); vitamin D preparations or metabolites designed for treatment not supplementation (e.g., calcitriol or calcifediol); synthetic vitamin D analogs (i.e., doxercalciferol, paricalcitol, falecalcitriol, oxacalcitriol, or 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; and vitamin D obtained through natural or artificial ultraviolet light exposure.
Comparators Placebo or no treatment. Alternative dosages of vitamin D, calcium, or both.

Intervention and comparison arms that do not allow for the evaluation of the independent contribution of vitamin D, calcium, or both (e.g., studies assessing a multicomponent intervention that includes vitamin D as one of several components compared with no intervention would not be eligible unless the comparison arm included all of the other intervention components except vitamin D).
Outcomes KQ 1:
  • Incident fractures, including all-cause, all-fragility, fall-related, major osteoporotic fractures, hip, and clinical vertebral; fracture-related morbidity and mortality.
  • Incident falls, including all-cause, low-trauma, and injurious falls (i.e., requiring hospitalization or ED visit), and fall-related morbidity and mortality.
  • All-cause mortality
  • Disability as measured by instrumental activities of daily life
  • Quality of life as measured by validated instruments; hospitalization for fall-related injuries; ED visits for fall-related injuries; and institutionalization
KQ 2: Symptomatic acute or chronic vitamin D or calcium toxicity, incident symptomatic nephrolithiasis, and serious adverse events.		 KQ 1: Morphometric vertebral fractures; BMD; laboratory or functional measures of bone or muscle strength or quality; fall efficacy measures; and basic activities of daily living.

KQ 2: Incident cancer or cardiovascular disease or events; asymptomatic renal outcomes (soft-tissue calcification, nephrocalcinosis, artery calcification, hypercalcemia, hypercalciuria); and nonserious adverse events.
Study design KQ 1: RCTs, controlled clinical trials.

KQ 2: RCTs; prospective cohort studies with contemporaneous comparison groups with a primary study aim to evaluate the use of vitamin D or calcium supplementation.

 Study designs not listed as specifically included (e.g., case reports, case series, case-control studies, or studies without a comparison group). Recent systematic reviews will not be included but will be handsearched to ensure that no relevant studies have been missed.
Timing KQ 1: Intervention duration of 1 month or longer.

KQ 2: Any duration.

 KQ 1: Intervention duration of less than 1 month.

KQ 2: No exclusions.
Language Full-text articles published in English. Full-text articles not published in English.
Quality Fair or good quality according to design-specific criteria. Poor quality according to design-specific criteria.

Abbreviations: BMD=bone mineral density; ED=emergency department; KQ=key question; RCT=randomized, controlled trial.

The draft Research Plan was posted for public comment on the UPSTF website from January 12, 2023, to February 8, 2023. In response to comments, the USPSTF added specificity to the fall outcomes eligible for inclusion, removed population exclusions based on cancer or cardiovascular disease, and clarified eligibility of studies enrolling mixed populations that include some persons with excludable conditions.

Reviewers suggested the addition of intermediate health outcomes such as bone mineral density, muscle function, and laboratory measures of calcium, among others; these outcomes are not eligible for inclusion for consistency with the scope of prior reviews for the USPSTF on this topic. Reviewers also suggested that incident cancer and cardiovascular events should be eligible outcomes; these are not included in this update because these outcomes are comprehensively addressed in the recent related review for the USPSTF on vitamin, mineral, and multivitamin supplementation to prevent cardiovascular disease and cancer. Finally, reviewers suggested that studies of persons with low vitamin D levels or known deficiency should be eligible; this population remains excluded for consistency with the prior USPSTF reviews on this topic and because treatment of vitamin D deficiency is addressed in the related review for the USPSTF on screening for vitamin D deficiency in adults.

1. Whitlock EP, Eder M, Thompson JH, et al. An approach to addressing subpopulation considerations in systematic reviews: the experience of reviewers supporting the U.S. Preventive Services Task Force. Syst Rev. 2017;6(1):41.