Association Between Single Gene Polymorphisms and Bone Biomarkers and Response to Calcium and Vitamin D Supplementation in Young Adults Undergoing Military Training

Abstract

Initial military training (IMT) is associated with increased stress fracture risk. In prior studies, supplemental calcium (Ca) and vitamin D provided daily throughout IMT reduced stress fracture incidence, suppressed parathyroid hormone (PTH), and improved measures of bone health compared with placebo. Data were analyzed from a randomized, double-blind, placebo-controlled trial to determine whether single-nucleotide polymorphisms (SNPs) in Ca and vitamin D-related genes were associated with circulating biomarkers of bone metabolism in young adults entering IMT, and whether responses to Ca and vitamin D supplementation were modulated by genotype. Associations between SNPs, including vitamin D receptor (VDR), vitamin D binding protein (DBP), and 1-alpha-hydroxylase (CYP27B1), and circulating biomarkers were measured in fasting blood samples from volunteers (n = 748) starting IMT. Volunteers were block randomized by race and sex to receive Ca (2000 mg) and vitamin D (1000 IU) or placebo daily throughout Army or Air Force IMT (7 to 9 weeks). Total Ca and vitamin D intakes were calculated as the sum of supplemental intake based on intervention compliance and dietary intake. Relationships between SNPs, Ca, and vitamin D intake tertile and change in biomarkers were evaluated in trial completers (n = 391). At baseline, the minor allele of a DBP SNP (rs7041) was positively associated with both 25OHD (B = 4.46, p = 1.97E-10) and 1,25(OH) D (B = 9.63, p < 0.001). Combined genetic risk score (GRS) for this SNP and a second SNP in the VDR gene (rs1544410) was inversely associated with baseline 25OHD (r = -0.28, p < 0.001) and response to Ca and vitamin D intake differed by GRS (p < 0.05). In addition, presence of the minor allele of a second VDR SNP (rs2228570) was associated with lower P1NP (B = -4.83, p = 0.04) and osteocalcin (B = -0.59, p = 0.03). These data suggest that VDR and DBP SNPs are associated with 25OHD status and bone turnover and those with the highest GRS require the greatest vitamin D intake to improve 25OHD during IMT. © 2016 American Society for Bone and Mineral Research.

Skeletal responses to an all-female unassisted Antarctic traverse

“…Hughes et al [15] recently observed an increase in trabecular vBMD (2%) and reduction in cortical vBMD (−0.3%) at the tibial metaphysis for women undergoing basic military training. An increase in trabecular vBMD is recognised as an early adaptation to mechanical loading [15,[36][37][38][39], whereas a reduction in cortical vBMD could be due to the unmineralised nature of new bone [10,15]. Basic military training is characterised by large increases in physical [40][41][42] and locomotor activity [40,43], and therefore the mechanical loading for the tibia is considered to be high [15,38,44,45].…”

DKK1 Induced by 1,25D3 Is Required for the Mineralization of Osteoblasts

“…Vitamin D deficiency is characterized by bone loss, increased risk of fractures, and bone mineralization defects, which may lead to bone-related diseases such as osteoporosis, osteopenia, and osteomalacia [1][2][3][4]. Moreover, genetic variants of vitamin D3-related genes are associated with abnormal bone turnover and metabolism of bone diseases [5][6][7][8]. Vitamin D3 supplements are essential treatments for the prevention of bone loss, which underlies the mechanisms for decreasing bone resorption by osteoclasts and increasing bone formation by osteoblasts [9].…”

Low serum 25-hydroxyvitamin D status in the pathogenesis of stress fractures in military personnel: An evidenced link to support injury risk management

“…The absence of a protective effect with a greater increase in vitamin D status between weeks 1 and 15 in f-containing genotypes may represent an inability to respond fully to increasing vitamin D concentrations due to a less efficient VDR. This is supported by evidence from US Army recruits undergoing initial military training who displayed lower concentrations of bone formation markers in response to training with f-containing genotypes [30]. Additionally, the f-containing genotypes are known to be associated with reduced transcription of VDR-responsive genes [26] and it may be that relatively more vitamin D is required to undertake the bone remodelling that training requires.…”

“…The single nucleotide polymorphism FokI produces structural differences in the VDR [25] with functional consequences: the f allele is associated with reduced transcription of VDR-responsive genes compared with FF individuals [26]. The impact of this functional difference has been widely studied in relation to bone mineral density and osteoporosis [27][28][29], and the f allele or ff genotype is associated with lower concentrations of bone formation markers in US Army recruits [30].…”

“….90-3.49) § for age/height/weight/VO2/alcohol/smoking/activity/seasonality. P values refer to the interaction term.with those who stress fractured in the latter half of training (weeks[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. At the midpoint of training (week 15) controls had a higher mean 25OHD concentration than those who went on to fracture 'late' (77.71 vs. 62.76 nmol/L, p = 0.01), having increased significantly from their baseline vitamin D concentration (72.6 vs. 61.8 nmol/L, p = 0.014).…”