Since these were endocrine outpatients, we had expected their general perception of wellbeing to be less than that of the general population. Since older persons with 25(OH)D <50 nmol/L risk losing muscle strength  and development of musculoskeletal pain [22, 23], there was reason to consider non-osteoporosis-related responses to vitamin D in patients with such low 25(OH)D levels. From an ethical perspective, patients who are selected because of low 25(OH)D levels should receive at least a meaningful amount of vitamin D [34, 35]. We provided at least the vitamin D AI for the oldest age group, 15 mcg (600 IU)/day, because some of our patients were older than 70 years, and because age does not affect the 25(OH)D response to a dose of vitamin D [8, 36].
The greatest biochemical responses to the vitamin D occurred after six months of supplementation. During follow-up, there was no clear plateau in 25(OH)D (Figure 2). Lack of a plateau may reflect season, because the final samples for 25(OH)D in the figure were taken through the summer and autumn, when 25(OH)D levels should be higher than in winter. Differences between the first and the third box of each cluster in Figure 2 reflect the effects of the intervention, not the season, because these samples had been collected about one year apart. Future studies of vitamin D supplementation should take into account that it may take a year to reach stable 25(OH)D levels. Although previous work (including our own) has implied that plateau levels of 25(OH)D can occur within five months [5, 37], the impression of a plateau reflects the time pattern of sampling; i.e. samples taken at short time intervals can give a false impression of a plateau.
Higher levels of 25(OH)D generally correlate with lower concentrations of PTH [1, 8]. The present data confirm that both doses produced a significant suppression of PTH. The box-plots in Figure 2 suggest a somewhat greater PTH suppression with the higher dose of vitamin D, and we attribute the lack of a statistical difference in PTH between the dose groups to the relatively small sample sizes in this study. In our cross-sectional study of 1741 such patients we observed steady decreases in PTH as 25(OH)D increased . There was no evidence of a change in plasma ionized calcium as a result of this relatively long-term use of vitamin D at a relatively high dose of 100 mcg (4000 IU)/day. We should point out that this dose is not high in the physiologic context, because it approximates what healthy men acquire daily, if they work outdoors . The present data extend the time-frame for follow-up beyond what has been reported previously, and our focus was on patients who did require additional vitamin D; this contrasts with earlier studies of 100 mcg (4000 IU)/day that involved healthy volunteers, where most were already sufficient in vitamin D [5, 7].
Lansdowne and Provost reported that 10 or 20 mcg (400 or 800 IU)/day of vitamin D, given for 5 days improved the mood of healthy Australian students during winter . Their protocol provided a total of 100 mcg (4000 IU) vitamin D or less, which could not have produced a detectable change in 25(OH)D concentrations. The results we obtained in Study 1 indicated that the 100 mcg (4000 IU)/day dose of vitamin D resulted in fewer affirmative responses to questions that were mainly related to depression. However, since statistical significance was one-tailed – which we did regard as valid because the effect was in the direction hypothesized beforehand – we wanted to confirm the greater efficacy of the higher dose. The next winter, the protocol was refined (Study 2) to include a more stringent recruitment, requiring lower summer 25(OH)D concentrations (<51 nmol/L) and additional questions relating to wellbeing .
In Study 2, both dose groups exhibited highly statistically significant improvement in wellbeing between December 2002 and February 2003. The only patients who did not improve during the second winter were those who had been maintained on the higher dose of vitamin D for the 12 months leading up to December 2002, and whose wellbeing score had already improved during Study 1. Overall, both studies presented here were consistent with the expectation that higher vitamin D nutrition improves sense of wellbeing. The relatively greater improvement during Study 2 compared to Study 1 could be explained to the lower initial 25(OH)D concentrations of Study 2. The eventual wellbeing response of low-dose patients from Study 1 may reflect a cumulative effect of their vitamin D intake. Since there was no placebo group used in this study, we cannot rule out other reasons for improvement. Questionnaire portions of this research were carried out entirely through the mail, with randomized blinded doses, and minimal direct contact between personnel and the participants; thus, it is not likely that investigator bias played a role. The winter was more severe during Study 2, so we doubt that weather would have explained the improved wellbeing reported during Study 2.
In retrospect, the SF-36 questionnaire, which is acceptable to the FDA as a measure of health outcome, would have been better to assess wellbeing . Nonetheless, simple screening tools like ours do correlate with, and perform about as well as more complex, well-validated questionnaires . Therefore, it as unlikely that a different questionnaire would have affected the sorts of changes we observed, or the conclusions about wellbeing in relation to vitamin D.