Mechanistic determinants of musculoskeletal health throughout childhood: findings from the Southampton Women’s Survey and the MAVIDOS trial

Poor intrauterine and childhood growth have been linked with the risk of osteoporosis in later life, a relationship mediated through a variety of interacting factors. The aim of this work was to use epidemiological methods to contribute to our understanding of the mechanisms early in life which relate to offspring musculoskeletal development, focusing on epigenetic change, vitamin D and alterations in maternal bone turnover. These were investigated through a large prospective mother-offspring cohort, the Southampton Women’s Survey (SWS) and a unique randomised, double-blind, placebo-controlled trial of vitamin D supplementation in pregnancy (MAVIDOS). In the SWS, DNA methylation at a locus linked to ageing and cell cycle regulation (CDKN2A) has been shown to be associated with childhood bone mass. Higher levels of methylation in umbilical cord of specific CpG dinucleotides within the CDKN2A gene locus were associated with lower total whole body minus head bone area, BMC and areal BMD at 4 and 6 years [a 10% increase in methylation was associated with a decrease in BMC of 4-9 g at age 4 years, p ≤ 0.001, n = 538]. Then, building on previous observations in the SWS, methylation at another locus, linked to vitamin D signalling (RXRA), was altered by maternal vitamin D supplementation, and associated with neonatal bone mass, in the MAVIDOS trial. For example, mean difference in % methylation between the supplemented and placebo groups at one CpG site, CpG 5 [-1.98% (95%CI: -3.65 to - 0.32), p = 0.02, n = 447]. In the same trial, the relationship between maternal vitamin D supplementation and a urinary marker of maternal bone resorption was studied (C-terminal telopeptide of type 1 collagen, CTX). Median CTX increased in both placebo and cholecalciferol supplemented groups, but the increase from early to late pregnancy was greater in the placebo group [111% (IQR 47, 211%) n = 188] than ii the cholecalciferol supplemented group [89% (IQR 23, 83%) n = 184; p difference = 0.02]. Higher maternal CTX was associated with lower DXA measures of bone mass at the total hip and lumbar spine in the early postpartum period. In MAVIDOS, maternal pregnancy cholecalciferol supplementation (vs placebo) led to greater offspring neonatal bone indices in winter births only. However, on reassessment at age 4 years, it was found to be associated with greater offspring measures of whole body (less head) bone mineral density [0.18 SD, 95% CI 0.00, 0.35] and lean mass [0.17 SD, 95% CI 0.00, 0.34], regardless of season of birth. These findings inform our understanding of the early life mechanisms related to maternal vitamin D status, epigenetic marks, maternal bone health and offspring musculoskeletal development and may guide future public health interventions aimed at preventing osteoporotic fractures and sarcopenia.