Background: Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acute respiratory infections have yielded mixed results. Individual participant data (IPD) meta-analysis has the potential to identify factors that may explain this heterogeneity. Objectives: To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect. Data sources: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Number (ISRCTN) registry. Study selection: Randomised, double-blind, placebo-controlled trials of supplementation with vitamin D₃ or vitamin D₂ of any duration having incidence of acute respiratory infection as a prespecified efficacy outcome were selected. Study appraisal: Study quality was assessed using the Cochrane Collaboration Risk of Bias tool to assess sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity. Results: We identified 25 eligible RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were obtained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity p < 0.001]. Subgroup analysis revealed that protective effects were seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI 0.72 to 0.91), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI 0.86 to 1.10; p = 0.05). Among those receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in individuals with a baseline 25-hydroxyvitamin D [25(OH)D] concentration of < 25 nmol/l (aOR 0.30, 95% CI 0.17 to 0.53) than in those with a baseline 25(OH)D concentration of ≥ 25 nmol/l (aOR 0.75, 95% CI 0.60 to 0.95; p = 0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI 0.80 to 1.20; p = 0.83). The body of evidence contributing to these analyses was assessed as being of high quality. Limitations: Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately. Conclusions: Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving bolus doses experienced the benefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes. Study registration: This study is registered as PROSPERO CRD42014013953. Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Indirect evidence suggests that optimal vitamin D status is achieved with a serum 25-hydroxyvitamin D [25(OH)D] concentration >75 nmol/L. Objective: We aimed to determine the intake of vitamin D₃ needed to raise serum 25(OH)D to >75 nmol/L. Design: The design was a 6-mo, prospective, randomized, double-blinded, double-dummy, placebo-controlled study of vitamin D₃ supplementation. Serum 25(OH)D was measured by radioimmunoassay. Vitamin D₃ intake was adjusted every 2 mo by use of an algorithm based on serum 25(OH)D concentration. Results: A total of 138 subjects entered the study. After 2 dose adjustments, almost all active subjects attained concentrations of 25(OH)D >75 nmol/L, and no subjects exceeded 220 nmol/L. The mean (±SD) slope at 9 wk [defined as 25(OH)D change/baseline dose] was 0.66 ± 0.35 (nmol/L)/(μg/d) and did not differ statistically between blacks and whites. The mean daily dose was 86 μg (3440 IU). The use of computer simulations to obtain the most participants within the range of 75–220 nmol/L predicted an optimal daily dose of 115 μg/d (4600 IU). No hypercalcemia or hypercalciuria was observed. Conclusions: Determination of the intake required to attain serum 25(OH)D concentrations >75 nmol/L must consider the wide variability in the dose-response curve and basal 25(OH)D concentrations. Projection of the dose-response curves observed in this convenience sample onto the population of the third National Health and Nutrition Examination Survey suggests a dose of 95 μg/d (3800 IU) for those above a 25(OH)D threshold of 55 nmol/L and a dose of 125 μg/d (5000 IU) for those below that threshold.

There is consensus on the optimal calcium intake that should be recommended for reducing postmenopausal bone loss.¹ Although it is recognized that vitamin D is important in calcium economy, optimal vitamin D intake is controversial.² Serum 25-hydroxyvitamin D (25-OHD) is the best indicator of vitamin D status.³ Serum levels lower than 10 ng/mL (25 nmol/L) lead to rickets and osteomalacia, and levels lower than 20 ng/mL (50 nmol/L) may lead to secondary hyperparathyroidism and bone loss.³ Recent studies^2,4,5 of the relationship of serum concentrations of 25-OHD to parathyroid hormone (PTH) have led many investigators to conclude that levels of 25-OHD greater than 32 ng/mL (80 nmol/L) are necessary to prevent a rise in PTH (and bone loss, by inference). It has been estimated that a vitamin D intake as high as 100 μg/d would be needed to attain these levels in light-skinned people residing in northern latitudes.⁶

African Americans have lower serum 25-hydroxyvitamin D concentrations and a lower risk of fragility fractures than do other populations. I review the evidence on factors other than vitamin D that might explain this paradox and the calcium economy in different life stages. Researchers are actively trying to explain this genetically programmed advantage. Factors that could protect African Americans against fracture include their higher peak bone mass, increased obesity rates, greater muscle mass, lower bone turnover rates, and advantageous femur geometry. In addition, bone histomorphometry in young adults shows longer periods of bone formation. Although African Americans fall as frequently as do whites, the direction of their falls and their manner of breaking falls could protect them from fractures. African American girls accrue more calcium than do white girls during adolescence as the result of increased calcium absorption and superior renal calcium conservation. In adulthood, higher parathyroid hormone concentrations do not result in increased bone loss in African Americans because of their skeletal resistance to parathyroid hormone, and their superior renal conservation of calcium persists. These advantages diminish in the elderly, in whom further increases in parathyroid hormone result in increased bone turnover and bone loss. Ultimately, I explain the paradox by multiple factors associated with fracture risk and calcium economy in African Americans. Despite African Americans' reduced risk of osteoporotic fractures, such fractures remain an important public health problem for this population that vitamin D intervention studies have not addressed.

Background: Optimal vitamin D status for the prevention of osteoporosis has been inferred from examinations of the serum 25-hydroxyvitamin D [25(OH)D] concentration below which there is an increase in serum parathyroid hormone (PTH). Objective: The objectives of the study were to ascertain whether a threshold for serum 25(OH)D exists below which serum PTH increases and whether persons with 25(OH)D above this threshold have lower rates of bone loss than do persons with 25(OH)D below the threshold. Design: The relation of serum 25(OH)D to serum PTH was analyzed in 208 African American women studied longitudinally for 3 y. These healthy women in midlife were randomly assigned to receive placebo or 800 IU vitamin D₃/d; after 2 y, the vitamin D₃ supplementation was increased to 2000 IU/d. Both groups received calcium supplements to ensure an adequate calcium intake. A systematic literature review found a wide range of threshold values in part due to varied calcium intake. Results: A Loess plot suggested a breakpoint between 40 and 50 nmol/L for serum 25(OH)D. A line-line model was fitted to the data, and it showed a spline knot at 44 nmol/L. A heuristic approach verified that PTH does not decline as rapidly when the serum concentration of 25(OH)D is >40 nmol/L as when it is <40 nmol/L. We found no significant difference in rates of bone loss between persons with 25(OH)D concentrations above and below 40 nmol/L. Conclusion: Although a threshold for 25(OH)D can be identified, we suggest that it should not be used to recommend optimal vitamin D status.