Vitamin D for older adults : Determinants of status, supplementation strategies and its role in muscle function

Vitamin D has been identified as an important factor in healthy aging and is receiving growing attention in clinical research. Vitamin D is a fat-soluble molecule, which is synthesized by hepatic and renal or extra-renal hydroxylation into the active hormone 1,25-dihydroxyvitamin D (1,25(OH)2D). The main function of this metabolite is to regulate calcium and phosphorus homeostasis and to support bone mineralization. In the circulation, the 25-hydroxyvitamin D metabolite (25(OH)D) is most stable and thus, considered the best marker of vitamin D status. A serum 25(OH)D concentration <30-50 nmol/L is considered deficient. Given the increased risk of deficiency and the potential beneficial effect of supplementation on musculoskeletal health, older adults present a specific target group for vitamin D interventions. However, the optimal serum 25(OH)D concentration is a matter of ongoing debate as randomized trials show conflicting results. With the research presented in this thesis, we aimed to gain insight in the prevalence and main determinants of a low vitamin D status, to investigate strategies to prevent or reverse vitamin D deficiency, and to study the effect of vitamin D supplementation on muscle strength and physical performance in Dutch older adults. In chapter 2, we examined the prevalence and the main determinants of a low vitamin D status in a large population of community-dwelling older adults (n=2857). Vitamin D deficiency was highly prevalent, with serum 25(OH)D concentrations <50 nmol/L in 45%, and <30 nmol/L in 14% of the population. When exploring the main determinants of serum 25(OH)D status, significant associations were observed with age, BMI, dietary intake, sun exposure behavior, and genetic polymorphisms encoding for enzymes in the vitamin D pathway. Combined, these factors explained 35% of the variation in serum 25(OH)D concentrations. To explore potential strategies that prevent vitamin D deficiency, we investigated the contribution of dietary vitamin D intake and specific food groups to serum 25(OH)D concentration in chapter 3. Daily vitamin D intake from dietary sources showed a median (25-75th percentile) intake of 4.0 (3.0-5.4) µg/day (n=595) and only 12-20% of older adults reported to take vitamin D supplements. These findings are in sharp contrast with the current nutrient guidelines and show that the vast majority of older adults do not meet the reference intakes for vitamin D. Nevertheless, significant associations were observed between the highest tertile of dietary vitamin D intake and serum 25(OH)D concentration, suggesting that regular intake of foods rich in vitamin D can support the prevention of modest insufficiency. For the majority of older adults, supplementation is required to ensure sufficient serum 25(OH)D concentrations throughout the year. Currently, supplementation with vitamin D3 is the most common strategy. However, alternative treatment regimens exist that require further investigation. In chapter 4, we report on a dose-response trial (n=59) that investigated the efficacy of calcifediol (5, 10 or 15 µg/d) as a supplementation strategy. Compared to vitamin D3, calcifediol is more hydrophilic, does not require hepatic hydroxylation, and binds with higher affinity to its binding proteins. In our study, we observed that calcifediol was safe and well tolerated in the supplemented doses over the entire study period of 6-months. We concluded that a dose of 10 µg/day resulted in sustained serum 25(OH)D concentrations between 75-100 nmol/L. Furthermore, calcifediol had a ~3 times higher potency when compared to vitamin D3, in increasing serum 25(OH)D concentrations. All in all, calcifediol may offer a valuable supplementation regimen to rapidly correct deficiency. Vitamin D presents an important endocrine regulator in the musculoskeletal health of older adults. Besides its role in bone health, low serum 25(OH)D concentrations have been linked to impaired physical performance and increased risk of falling. The active metabolite 1,25-dihydroxyvitamin D is suggested to act upon a wide variety of cells throughout the body, including muscle cells. Although the exact mechanisms by which vitamin D acts on muscle are unclear, several indirect or direct regulatory pathways have been described, including effects of 1,25-dihyroxyvitamin D through intracellular calcium and phosphate homeostasis, or via activation of transcription factors when binding to the vitamin D receptor in muscle cells. In chapter 5 we observed significant associations between low serum 25(OH)D concentrations, physical performance and frailty in community-dwelling older adults (n=494-756). However, randomized trials are needed to define the causality of the observed associations. A previous pilot study indicated plausible beneficial effects of calcifediol over vitamin D3 on performance and strength. As such, we aimed to further explore the potential role of calcifediol or vitamin D3 on muscle function in chapter 6. We performed a placebo-controlled trial in pre-frail and frail, vitamin D deficient older adults, supplementing either 10 µg/d calcifediol or 20 µg/d vitamin D3, compared to placebo over a 6-month period (n=78). Again, calcifediol induced a faster and higher increase in serum 25(OH)D status when compared to vitamin D3. However, we observed no effect of either supplementation regimen on lower extremity strength or physical performance. Current literature suggests positive effects on strength and balance when supplementing with vitamin D, however, results are inconsistent. Meta-analyses of randomized trials indicate that the beneficial effects of vitamin D supplementation might be more pronounced in vulnerable populations with more severe vitamin D deficiencies. All in all, the high prevalence of vitamin D deficiency is alarming. Promoting adequate vitamin D status is important considering the beneficial effects on bone health. In the last decade, research has come a long way in exploring the role of vitamin D in muscle function. However, the evidence base remains uncertain and further research on the optimal vitamin D status for older adults is needed to guide clinical practice. Until then, focus should be placed on prevention and identification of deficiency.