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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

Vitamin D status and bone health: a possible inverse association

Mendelian randomisation analysis of relatively healthy community-dwelling individuals indicates a possible inverse relation of vitamin D status with bone health such as fracture risk (odds ratio per standard deviation decrease=0.84, 95% confidence interval 0.70 to 1.02, P=0.07) (1) as well as skeletal fragility depending on bone quality and quantity measured by quantitative ultrasound of the most weight-bearing heel (odds ratio per standard deviation increase=-0.03, 95% confidence interval -0.05 to -0.01, P=0.02) (2). This is a highly valuable approach and, therefore, although not discussed by the authors, these borderline significant findings seem to be important (3).

Of note, several lines of clinical evidence have suggested an inverse association between vitamin D status and skeletal health (4-6). Mechanical strain-related stimulus during habitual physical activity, the primary determinant of bone strength, can indirectly affect the skeleton; similarly to lower physical activity, for example, higher vitamin D-induced bone material stiffness would normally result in lower mechanical strain-related stimuli, though the impact of this mechanism should be limited in older adults compared to prepubertal children with lower bone mineralization and higher response to skeletal strain.

Consequently, the aforementioned possible inverse association supports a recent caution that high-dose vitamin D supplementation cannot be recommended for skeletal health if there is no malabsorption (7).

(1) Trajanoska K, Morris JA, Oei L, et al. Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study. BMJ 2018;362:k3225.
(2) Larsson SC, Melhus H, Michaëlsson K. Circulating serum 25-hydroxyvitamin D levels and bone mineral density: mendelian randomization study. J Bone Miner Res 2018;33:840-4.
(3) Liao JM, Stack CB, Goodman S. Annals understanding clinical research: interpreting results with large p values. Ann Intern Med 2018; doi:10.7326/M18-2003
(4) Sugiyama T. Gestational vitamin D and childhood bone health. Lancet Diabetes Endocrinol 2017;5:417-8.
(5) Sugiyama T. Adaptation of bone to mechanical strain. JAMA Pediatr 2018;172:196.
(6) Sugiyama T. Vitamin D and skeletal health during growth: the functional muscle-bone unit. Am J Clin Nutr 2018; doi:10.1093/ajcn/nqy155
(7) Reid IR. High-dose vitamin D: without benefit but not without risk. J Intern Med 2018; doi:10.1111/joim.12836

Competing interests: No competing interests

26 September 2018
Toshihiro Sugiyama
Assistant Professor
Department of Orthopaedic Surgery, Saitama Medical University
Saitama 350-0495, Japan