The IOM Committee’s work extended from March 2009 to November 2010, including eight in-person meetings in Washington, D.C., an open public workshop, two open sessions to receive input from other scientists, and the maintenance of a public web site for stakeholder input. The Committee conducted an extensive and comprehensive review of the existing evidence on calcium and vitamin D in relation to diverse health outcomes. Two key systematic reviews used by the Committee included reports conducted by the Agency for Healthcare Research and Quality (AHRQ) in 2007 (3
) and 2009 (4
), providing evidence-based reviews of the research on calcium and vitamin D in relation to both skeletal and extraskeletal chronic disease outcomes. The Committee conducted its own literature review in addition to consideration of the AHRQ reports.
The Committee, using a risk assessment framework, considered a wide range of chronic disease and other indicators to assess nutrient adequacy for calcium and vitamin D. Indicators that were considered and reviewed in detail in the report included: bone and skeletal health (including bone mineral content and density, fracture risk, and rickets/osteomalacia), calcium absorption and balance, measures such as serum 25-hydroxyvitamin D (25OHD) and PTH, cancer and site-specific neoplasms, cardiovascular disease, hypertension, diabetes, metabolic syndrome, falls and physical performance, autoimmune disorders, infectious diseases, neuropsychological functioning (including autism, cognition, and depression), and disorders of pregnancy.
After careful consideration of the evidence, the Committee concluded that bone health was the only outcome that satisfied criteria for use as an “indicator” whereby causality was established and the available evidence on dose-response was sufficient to support its use for DRI development. In addition, serum 25OHD levels were considered to be the most useful marker of vitamin D exposure, incorporating endogenous synthesis from solar exposure, dietary intake from foods, fortified products, and/or supplements, and other factors. For cancer, cardiovascular disease, diabetes, falls, physical performance, autoimmune disorders, and other extraskeletal chronic disease outcomes, the evidence was deemed to be inconsistent, inconclusive as to causality, and insufficient to serve as a basis for DRI development. Importantly, randomized trial evidence was sparse, and few clinical trials of calcium and/or vitamin D had been done with these extraskeletal outcomes as the primary prespecified outcomes. The AHRQ systematic review of 2009 (4
) had also concluded that the evidence for an association between these nutrients and extraskeletal outcomes was inconsistent and inconclusive.
Key challenges included the strong interrelationship between calcium and vitamin D and the difficulty separating their effects in many studies, the small number of relevant randomized clinical trials allowing for assessment of dose-response relationships, the complexity that vitamin D is obtained not only from diet but also synthesized endogenously, and the potential for confounding in observational studies. Although measures of 25OHD were considered to be a useful marker of exposure, the Committee was cognizant of its limitations as a biomarker of effect. Correlation does not prove causation in observational studies, underscoring the need for caution in interpretation of study findings. Specific factors relevant to vitamin D are sources of potential confounding, such as obesity (due to sequestration in adipose tissue), physical activity (correlated with time outdoors and solar exposure), race/skin pigmentation, and nutritional status including supplementation practices. Reverse causation bias is also a threat to study validity if poor health curtails outdoor activities and sunlight exposure or adversely affects diet. These potential biases must be carefully considered in the interpretation of observational studies. In this regard, it should be noted that many micronutrient interventions that seemed promising in observational studies (e.g.
β-carotene, vitamins C and E, folic acid, and selenium) did not withstand rigorous testing in clinical trials, and many even suggested hazards with high levels of supplementation (5