In 1981, R. Edgar Hope-Simpson proposed that a 'seasonal stimulus' intimately associated with solar radiation explained the remarkable seasonality of epidemic influenza. Solar radiation triggers robust seasonal vitamin D production in the skin; vitamin D deficiency is common in the winter, and activated vitamin D, 1,25(OH)2D, a steroid hormone, has profound effects on human immunity. 1,25(OH)2D acts as an immune system modulator, preventing excessive expression of inflammatory cytokines and increasing the 'oxidative burst' potential of macrophages. Perhaps most importantly, it dramatically stimulates the expression of potent anti-microbial peptides, which exist in neutrophils, monocytes, natural killer cells, and in epithelial cells lining the respiratory tract where they play a major role in protecting the lung from infection. Volunteers inoculated with live attenuated influenza virus are more likely to develop fever and serological evidence of an immune response in the winter. Vitamin D deficiency predisposes children to respiratory infections. Ultraviolet radiation (either from artificial sources or from sunlight) reduces the incidence of viral respiratory infections, as does cod liver oil (which contains vitamin D). An interventional study showed that vitamin D reduces the incidence of respiratory infections in children. We conclude that vitamin D, or lack of it, may be Hope-Simpson's 'seasonal stimulus'.

Vitamin D status differs by latitude and race, with residents of the northeastern United States and individuals with more skin pigmentation being at increased risk of deficiency. A PubMed database search yielded 63 observational studies of vitamin D status in relation to cancer risk, including 30 of colon, 13 of breast, 26 of prostate, and 7 of ovarian cancer, and several that assessed the association of vitamin D receptor genotype with cancer risk. The majority of studies found a protective relationship between sufficient vitamin D status and lower risk of cancer. The evidence suggests that efforts to improve vitamin D status, for example by vitamin D supplementation, could reduce cancer incidence and mortality at low cost, with few or no adverse effects.

BackgroundHigher intake of calcium and vitamin D has been associated with a reduced risk of colorectal cancer in epidemiologic studies and polyp recurrence in polyp-prevention trials. However, randomized-trial evidence that calcium with vitamin D supplementation is beneficial in the primary prevention of colorectal cancer is lacking. MethodsWe conducted a randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women from 40 Women's Health Initiative centers: 18,176 women received 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D 3 twice daily (1000 mg of elemental calcium and 400 IU of vitamin D 3 ) and 18,106 received a matching placebo for an average of 7.0 years. The incidence of pathologically confirmed colorectal cancer was the designated secondary outcome. Baseline levels of serum 25-hydroxyvitamin D were assessed in a nested case-control study. ResultsThe incidence of invasive colorectal cancer did not differ significantly between women assigned to calcium plus vitamin D supplementation and those assigned to placebo (168 and 154 cases; hazard ratio, 1.08; 95 percent confidence interval, 0.86 to 1.34; P = 0.51), and the tumor characteristics were similar in the two groups. The frequency of colorectal-cancer screening and abdominal symptoms was similar in the two groups. There were no significant treatment interactions with baseline characteristics. ConclusionsDaily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer among postmenopausal women. The long latency associated with the development of colorectal cancer, along with the seven-year duration of the trial, may have contributed to this null finding. Ongoing follow-up will assess the longer-term effect of this intervention. (ClinicalTrials.gov number, NCT00000611.) Calcium plus Vitamin D and Colorectal-Cancer Risk n engl j med 354;7 www.nejm.org february 16, 2006 * Plus-minus values are means ±SD. SEER denotes Surveillance, Epidemiology, and End Results.† Hazard ratios, 95 percent confidence intervals (CIs), and P values were derived from Cox proportional-hazards analyses stratified according to age, randomized assignment in the Hormone Therapy and Dietary Modification trials, and presence or absence of corresponding prevalent condition. ‡ This category includes the cecum, the ascending colon, the hepatic flexure, and the transverse colon. § This category includes the splenic flexure, the descending colon, and the sigmoid colon. ¶ This category includes cancers of both the rectum and the rectosigmoid junction. ‖ Data were available only for centrally adjudicated cases. ** Information on intestinal polyps and kidney stones is from self-reported data and was not centrally confirmed.

The report by Hyppönen and Power in this issue of the Journal (1) highlights a frustrating and regrettable situation for nutrition researchers. In the early 1970s, the same serum 25-hydroxyvitamin D [25(OH)D] concentrations reported by Hyppönen and Power were thought to be indicative of "healthy" white adults in the United Kingdom (2). However, during those early years after the discovery of 25(OH)D, the adequacy of its serum concentration was based simply on whether the concentration was enough to prevent osteomalacia or rickets. Three decades later, we know that 25(OH)D concentrations relate to many other aspects of health, including fracture risk, bone density, colon cancer, and even tooth attachment (3); we also know that much higher concentrations of 25(OH)D are needed to prevent adverse outcomes. Indeed, in the 1958 British birth cohort, lower 25(OH)D is associated with a higher percentage of hemoglobin A 1C (a measure of long-term glucose concentration), which further emphasizes the need to maintain optimal 25(OH)D concentrations (4).Randomized trials using the currently recommended intakes of 400 IU vitamin D/d have shown no appreciable reduction in fracture risk (3). In contrast, trials using 700 -800 IU vitamin D/d found less fracture incidence, with and without supplemental calcium (3). The reduction in fracture incidence occurs when mean serum 25(OH)D concentrations exceed 72 nmol/L, and this change may result from both improved bone health and reduction in falls due to greater muscle strength (3). Although it is not yet proven through clinical trials, higher intakes may also reduce the incidence of colon and other cancers, and these relations indicate that the desirable 25(OH)D concentration is ͧ75 nmol/L (3). One recent report associates greater 25(OH)D concentrations with lower risk of nursing home admission; the most desirable category of concentration starts at 75 nmol/L (5).Human diets do not provide sufficient vitamin D; if they did, the abovementioned associations between health and serum 25(OH)D concentrations would not be so routinely observed. The vitamin D provided by foods and supplements is overwhelmed by the effect of skin exposure to ultraviolet B light. Geography, season, skin color, and sun-related behavior are the main predictors of vitamin D nutritional status (6 -10). Correction of low 25(OH)D concentrations can happen only if some or all of the following are implemented: the encouragement of safe, moderate exposure of skin to ultraviolet light; appropriate increases in food fortification with vitamin D; and the provision of higher doses of vitamin D in supplements for adults.Evaluation of most relations of health and disease that involve vitamin D leads to the conclusion that a desirable 25(OH)D concentration is ͧ75 nmol/L (30 ng/mL) (3-5). If a concentration of 75 nmol/L is the goal to be achieved by consumption of vitamin D, then why is it so rare for members of the population to accomplish this? One reason is that almost every time the public media report that vitamin D nutri...