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Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study

BMJ 2018; 362 doi: (Published 29 August 2018) Cite this as: BMJ 2018;362:k3225

RE: Vitamin D status and bone health: a possible inverse association

A large body of data from randomized clinical trials and large meta-analyses have shown no clear evidence for a beneficial effect of vitamin D on bone mineral density or fracture risk [1]. Notably, recent studies have demonstrated that high vitamin D levels (above the physiological requirements) can exert a deleterious effects on bone health [2],[3]. Furthermore, it has been shown that high-levels of vitamin D can lead to impaired muscle function [4] and increase the risk of falling [5] - both important fracture risk factors. These findings are in line with previous RCTs showing more falling and increased fracture risk in individuals randomized to high-dose vitamin D [2],[3].

We welcome the additional evidence provided by Sugiyama et al. surrounding the potential mechanism(s) by which vitamin D can have a negative effect on bone heath. Overall, we agree with Sugiyama that the borderline inverse findings in our study [6] might be pertinent, as they convey a message similar to those from the aforementioned studies. Still, in our Mendelian randomization study the 95% confidence intervals of genetically-determined vitamin D levels include the null, reason why these results should be interpreted with caution.

Moreover, in our study we tested the evidence for casual effects of fracture risk across 15 different traits. Therefore, after correcting the significance threshold for multiple testing (alpha = 0.05/15 = 0.003) the borderline significant vitamin D results (P=0.07) are far from significant. In the face of high rates of vitamin D supplementation use [7],[8] our results, combined with those from recent trials, do not support its widespread use in the general population for the prevention of fracture risk. In addition, we agree with the contention that, potential harm from vitamin D over-supplementation should not be disregarded.

[1] Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet 2014;383:146–55. doi:10.1016/S0140-6736(13)61647-5.
[2] Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, et al. Annual High-Dose Oral Vitamin D and Falls and Fractures in Older Women. JAMA 2010;303:1815. doi:10.1001/jama.2010.594.
[3] Smith H, Anderson F, Raphael H, Maslin P, Crozier S, Cooper C. Effect of annual intramuscular vitamin D on fracture risk in elderly men and women a population-based, randomized, double-blind, placebo-controlled trial. Rheumatology 2007;46:1852–7. doi:10.1093/rheumatology/kem240.
[4] Bislev LS, Langagergaard Rødbro L, Rolighed L, Sikjaer T, Rejnmark L. Effects of Vitamin D3 Supplementation on Muscle Strength, Mass, and Physical Performance in Women with Vitamin D Insufficiency: A Randomized Placebo-Controlled Trial. Calcif Tissue Int 2018;103:483–93. doi:10.1007/s00223-018-0443-z.
[5] Smith LM, Gallagher JC, Suiter C. Medium doses of daily vitamin D decrease falls and higher doses of daily vitamin D3 increase falls: A randomized clinical trial. J Steroid Biochem Mol Biol 2017;173:317–22. doi:10.1016/j.jsbmb.2017.03.015.
[6] Trajanoska K, Morris JA, Oei L, Zheng H-F, Evans DM, Kiel DP, et al. Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study. BMJ 2018;362:k3225. doi:10.1136/BMJ.K3225.
[7] Schleicher RL, Sternberg MR, Lacher DA, Sempos CT, Looker AC, Durazo-Arvizu RA, et al. The vitamin D status of the US population from 1988 to 2010 using standardized serum concentrations of 25-hydroxyvitamin D shows recent modest increases. Am J Clin Nutr 2016;104:454–61. doi:10.3945/ajcn.115.127985.
[8] Rooney MR, Harnack L, Michos ED, Ogilvie RP, Sempos CT, Lutsey PL. Trends in Use of High-Dose Vitamin D Supplements Exceeding 1000 or 4000 International Units Daily, 1999-2014. JAMA 2017;317:2448. doi:10.1001/jama.2017.4392.

Competing interests: No competing interests

27 November 2018
Fernando Rivadeneira
Associate Professor
Katerina Trajanoska, John Morris, J Brent Richards
Department of Internal Medicine, Erasmus MC
Dr. Molewaterplein 40 3015 GD Rotterdam, NL