Towards a Consensus on Vitamin D Supplementation and Bone Health

Abstract

In a 3-year randomized controlled trial (RCT) that investigated the effects of daily high-dose vitamin D supplements (mean 3490 IU/day) on areal bone mineral density (aBMD) in the hip, lumbar spine, radius, and total body among elderly healthy black American women with a baseline mean of 55 nmol/L of serum 25-hydroxyvitamin D (25[OH]D), Aloia and colleagues (1) demonstrated that higher levels of serum 25(OH)D targeted above 75 nmol/L (mean 108, 114, and 117 nmol/L at 12, 24, and 36 months, respectively) in the active group had no clinically meaningful impact on aBMD in any region analyzed compared with the placebo group (mean 48, 49, and 51 nmol/L at 12, 24, and 36 months, respectively). Notably, this marked evidence fully agrees with findings from other RCTs of high-dose vitamin D, for instance, among older overweight adults with weekly supplementation (2) and healthy children and pregnant women with daily supplementation. (3,4) In contrast, many observational studies have reported a significant positive association between serum 25(OH)D levels and aBMD. The discrepancy is a timely and important issue that should be resolved to achieve a consensus on vitamin D supplements and skeletal health.In a recent 1-year RCT among aged white and black women with serum 25(OH)D below 50 nmol/L recruited from the general population, there were no effects of increasing daily vitamin D doses ranging from 400 to 4800 IU/day on aBMD in the hip, lumbar spine, and total body, whereas a significant positive linear correlation was observed between serum 25(OH)D levels at 12 months and change in aBMD in the lumbar spine. (5) Consistent with a meta-analysis of RCTs that showed a significantly inferior effect of higher-dose vitamin D supplementation on aBMD in the lumbar spine compared with lower-dose vitamin D supplementation, (6) Mendelian randomization analyses have found a possible inverse relation of vitamin D status with skeletal health. (7) Consequently, the possibility of a causal positive association between serum 25(OH)D levels and aBMD would be almost ruled out by these two key analyses to assess causality, (6,7) though the indirect effects (8) of high-dose vitamin D supplements in RCTs could be detected in the hip or tibia. (9-11) Accordingly, the positive linear correlation between serum 25(OH)D levels at 12 months and change in aBMD in the lumbar spine (5) can be interpreted as a result of the involvement of individual life and health status including physical activity outdoors (12) because the wide variability in serum 25(OH)D levels after supplementation with vitamin D (5) suggests that serum 25(OH)D levels at 12 months resulted not only from vitamin D supplements, but also from other factors such as vitamin D synthesis in the skin following sunlight exposure.In conclusion, I would like to emphasize that understanding the noncausal positive association between serum 25(OH)D levels and skeletal health in observational studies is essential to building a consensus that the recommended dietary allowance for vitamin D by the ...

Effects of High-Dose Vitamin D Supplementation on Bone Fragility

“…Nevertheless, I fully agree with the authors (1,2) that high-dose vitamin D supplementation (≥4000 IU per day) is not recommended for skeletal health among generally healthy older adults with adequate vitamin D status; (3) the recommended dietary allowance and the upper-level intake for vitamin D by the Institute of Medicine have been 800 and 4000 IU per day (600 and 4000 IU per day at 70 years old or younger), respectively. (1,2,10)…”