The initial search yielded 491 references. Forty-five guidelines were selected for full text review and 24 guidelines were finally included in our analysis (Figure 1). Nine (38%) guidelines were from the USA or Canada, seven (29%) from Europe, four (16%) from Asia, two (8%) from Australia and New Zealand, and two (8%) from international organizations. By type of society: fourteen (56%) guidelines were developed by scientific societies, two (8%) by international governmental organizations, and nine (36%) by national governmental organizations.
Thirteen (54%) guidelines targeted general adult population, ten (42%) addressed older populations (≥ 50 years old), and one (4%) targeted pregnant women. Regarding vitamin D screening, eight (33%) guidelines recommended vitamin D screening to individuals with risk factors (e.g. dark skin or low sun exposure) (Table 1 and Table 2).
Nine (38%) guidelines recommended in favor of some form of supplementation of vitamin D at some stage in life, seven (29%) suggested it, and eight (33%) did not recommend or recommended against supplementation. By population, eleven (46%) guidelines recommended or suggested supplementation for the general population, eight (33%) recommended supplementation for pediatric population, six (25%) recommended or suggested supplementation in pregnant women, and twenty-three (96%) recommended it for the elderly and institutionalized patients. The daily intake recommended varied from 400 International Units (IU) to 4000 IU (SD 621.33), the mode being 800 IU. (Table 1 and Table 2 and Supplementary Table 1).
With respect to vitamin D obtention, six guidelines (25%) highlighted the importance of sun exposure to achieve enough vitamin D levels. Twenty guidelines (83%) recommended supplementation as the favored method to obtain adequate vitamin D levels, two (8%) recommended sun exposure, and two guidelines (8%) did not provide a specific method. Five guidelines (21%) recommended vitamin D fortification strategies, either mandatory or voluntary. Regarding vitamin D screening, eight (33%) guidelines recommended vitamin D screening for individuals with risk factors.
In the subdomains of AGREE II evaluated (Figure 2 and Supplementary Table 1), the mean score was 40.1% for Rigor of Development (range 10.4%-90.9%; Standard Deviation (SD): 23.5%), 34.5% for Applicability (range 12.5%-77.1%; SD: 18.1%), and 39.6% for Editorial Independence (range 8.3%-80.6%; SD: 19.8%). Six (25%) guidelines reached a score over 50% for Rigor of Development, Applicability, and Editorial Independence domains. The ICC was 0.954 (CI95% 0.887-0.980) for Rigor of Development, 0.91 (CI95% 0.815-0.96) for Applicability and 0.854 (CI95% 0.682-0.938) for Editorial Independence. See Supplementary File 2 for the detailed score of the guidelines included.
Regarding conflicts of interest (COI) reporting, 19 out of 24 (79%) guidelines reported an explicit process to manage them, in two (8%) the process was unclear and four (17%) did not report any related information. Twenty three out of 24 (96%) reported affiliations, whereas 2 (8%) did not. In 19 out of 24 (79%) reported financial ties, two (8%) did not reported them clearly and four (17%) did not report them at all. Intellectual COI were reported in seven out of 24 guidelines (29%), with 18 (75%) not providing any information. Regarding institutional financial ties five guidelines (21%) reported them, thirteen (54%) did not provide any information, and seven (29%) were unclear. When examining if the institution potentially played an advocatory role favoring intervention, we detected this in five cases (21%), eight (33%) being unclear. Overall, we considered 15 out of 24 guidelines (63%) to have potential COIs (Table 3).
The guidelines that do not recommend vitamin D supplementation (compared with those that suggested or recommended it) scored significantly higher in the Rigor of Development domain (64% recommending against vs 29% suggesting, and 27% recommending for; p=0.002), Applicability (52% vs 26% and 25%; p=0.003) and Editorial Independence (61% vs 35% and 24%; p=0.001) respectively. A post-hoc analysis showed no significant differences between the “suggest” and “recommend” categories.
Guidelines that provided recommendations in favor of vitamin D supplementation were associated with conflicts of interest, either detected or declared (likelihood ratio p=0.018). In the logistic regression model, Rigor of Development and Applicability were independent predictors of recommending vitamin D supplementation; the higher the score, the less likely supplementation was recommended Odds Ratio (OR) 1.11; CI95% 1.02-1.19 and OR 1.15; CI95% 1.03-1.28 respectively. With respect to vitamin D screening, we found a significant association between recommending screening and lower AGREE II scores for Rigor of Development, Applicability and Editorial Independence (50% vs 24% p=0.002; 41% vs 24% p=0.007; 46% vs 31% p=0.05).
Finally, guidelines that declared no conflicts of interest, and guidelines in which no conflicts of interest were detected scored significantly higher in “Rigor of Development”, “Applicability” and “Editorial independence” domains, compared to those guidelines that did not, or for which conflicts of interest were detected (54% vs 32% p=0.033; 48% vs 27% p=0.022, and; 51% vs 33% p=0.024).We did not find any other associations with respect to the rest of predefined variables.