Faculty of Medicine The effect of dosing regimen on outcomes of vitamin D supplementation trials A study of current literature — Anette Uhlving Larsen Master thesis in Medicine (MED-3950) June 2019 Supervisor: Professor Rolf Jorde, Institute of Clinical Medicine Abstract Results from observational studies have indicated associations between vitamin D and extra- skeletal outcomes, including respiratory tract infections (RTI) and all-cause mortality. However, available trial-data have shown inconsistent results. The main objective of this thesis was to investigate whether a beneficial effect of daily supplementation of vitamin D on RTI and all-cause mortality could have been masked by the use of less frequent supplementation intervals. This thesis included data from double-blinded, randomized controlled trials (RCTs) published in the last 10 years. Eligible trials were identified through screening of the reference lists of systematic reviews of meta-analyses (MAs), and of reference lists of MAs on the selected outcomes included in these reviews. Also, additional searches were performed to ensure that also recently published RCTs, not identified in a previous step of the search strategy, were considered for inclusion. The search strategy was designed to promote selection of trials of adequate methodological quality. To be included the record had to be written in English and report results of a double-blinded placebo-controlled RCT with vitamin D supplementation in a human population. Studies including pregnant women or assessing the effect of prenatal supplementation were not included, nor were studies including populations with chronic kidney disease and/or other diseases known to affect the conversion of active metabolites of vitamin D. Titles and abstracts of identified records were screened for eligibility. Eligible full-text articles were retrieved, and key information extracted and summarized in modified PICO-tables. This thesis included a total of 21 RCTs reporting effects of vitamin D supplementation on RTI, and 15 RCTs reporting effects of vitamin D supplementation on all-cause mortality. Comparing the effect of dosing regimen on the pooled relative effect estimates showed a significantly lower odds of RTI with daily supplementation compared to less frequent dosing regimens in children. The same trend was observed in adults, but the difference was non- significant. No significant effects of dosing regimen were observed regarding the all-cause mortality outcome. II Innholdsfortegnelse ABSTRACT ....................................................................................................................................................................... II PREFACE – THE WORK PROCESS ........................................................................................................................ VI 1 INTRODUCTION .................................................................................................................................................... 1 1.1 DISCOVERY ............................................................................................................................................................................. 1 1.2 VITAMIN D PHYSIOLOGY .................................................................................................................................................... 1 1.3 VITAMIN D DEFICIENCY ...................................................................................................................................................... 2 1.4 EXTRA-SKELETAL EFFECTS ................................................................................................................................................ 3 1.5 INTERMITTENT DOSING REGIMENS AND CLINICAL TRIALS ....................................................................................... 3 1.5.1 Respiratory tract infections ............................................................................................................................................. 5 1.5.2 All-cause mortality ............................................................................................................................................................. 6 1.6 THE AIM OF THE THESIS ....................................................................................................................................................... 6 2 METHODS ................................................................................................................................................................ 6 2.1 CRITERIA FOR CONSIDERING STUDIES TO BE INCLUDED IN THIS THESIS .............................................................. 6 2.1.1 Delimitations ......................................................................................................................................................................... 6 2.1.2 Inclusion criteria ................................................................................................................................................................. 7 2.1.3 Exclusion criteria ................................................................................................................................................................ 7 2.2 OUTCOMES .............................................................................................................................................................................. 8 2.2.1 Respiratory tract infections ............................................................................................................................................. 8 2.2.2 All-cause mortality ............................................................................................................................................................. 8 2.3 LITERATURE SEARCH STRATEGY ...................................................................................................................................... 9 2.3.1 Summary ................................................................................................................................................................................. 9 2.3.2 Search for systematic reviews of meta-analyses ..................................................................................................... 9 2.3.3 Screening of identified meta-analyses’ reference lists ......................................................................................... 9 2.3.4 Supplemental search for and screening of recently published randomized controlled trials ............... 9 2.4 DATA COLLECTION ............................................................................................................................................................ 10 2.4.1 Selection of studies .......................................................................................................................................................... 10 2.4.2 Data extraction and synthesis ..................................................................................................................................... 10 2.4.3 Assessment of risk of bias ............................................................................................................................................. 10 2.5 DATA ANALYSIS – MEASURES OF TREATMENT EFFECT ......................................................................................... 11 2.6 ETHICAL ASPECTS .............................................................................................................................................................. 12 3 RESULTS ................................................................................................................................................................ 12 3.1 RESULTS OF THE LITERATURE SEARCH STRATEGY .................................................................................................. 12 3.1.1 Respiratory tract infection ............................................................................................................................................ 13 3.1.2 All-cause mortality .......................................................................................................................................................... 13 3.2 STUDY AND PARTICIPANT CHARACTERISTICS OF ELIGIBLE STUDIES .................................................................. 13 3.2.1 Respiratory tract infection ............................................................................................................................................ 13 3.2.2 All-cause mortality .......................................................................................................................................................... 14 3.3 EXCLUDED STUDIES .......................................................................................................................................................... 15 3.4 RISK OF BIAS IN INCLUDED STUDIES ............................................................................................................................. 15 3.4.1 GRADE assessments ....................................................................................................................................................... 15 3.4.2 Assessment of publication bias ................................................................................................................................... 16 3.5 EFFECT OF INTERVENTIONS ...........................................................................................................................................