Abstract
Purpose of Review
Increasing bone mineral accrual during childhood might delay the onset of osteoporosis. We discuss the scientific evidence for early life approaches to optimising skeletal health.
Recent Findings
There is an ever-growing body of evidence from observational studies suggesting associations between early life exposures, particularly during foetal development, and bone mineral density (BMD). The findings of such studies are often heterogeneous, and for some exposures, for example, maternal smoking and alcohol intake in pregnancy or age at conception, intervention studies are not feasible. The most frequently studied exposures in intervention studies are calcium or vitamin D supplementation in pregnancy, which overall suggest positive effects on offspring childhood BMD.
Summary
Maternal calcium and/or vitamin D supplementation during pregnancy appear to have positive effects on offspring BMD during early childhood, but further long-term follow-up is required to demonstrate persistence of the effect into later life.
Similar content being viewed by others
Introduction
Osteoporosis is a disorder of bone mass and microarchitecture resulting in increased propensity to fracture. Osteoporosis and the associated fragility fractures are an important cause of healthcare use and expenditure. It was estimated that in 2019, 32 million individuals in the European Union plus the United Kingdom (UK) and Switzerland (termed EU27 + 2) were living with osteoporosis. There were estimated to be 4.3 million new fragility fractures during that year, equivalent to 11,705 fractures per day [1]. The total cost of new fragility fractures, existing fractures and pharmacological interventions for osteoporosis in the EU27 + 2 was calculated at €56.9 billion, representing approximately 3.5% of healthcare expenditure in these countries [1]. In addition to pain and disability, fracture is associated with an increased risk of death, and nearly 250,000 deaths in the EU27 + 2 in 2019 were directly attributed to fracture [1]. Importantly, with an ageing population observed in most developed countries, the burden of osteoporosis has and will likely continue to increase unless primary preventative strategies can be implemented. One approach might be to improve skeletal health in early life to improve peak bone mass (PBM) and delay the onset of osteoporosis [2].
Bone Mass Throughout the Lifecourse
Osteoporotic bone typically has both low bone mineral density (BMD) and a deterioration in the microarchitecture of the bone, including cortical thinning and a reduction in trabecular number and thickness. However, the clinical definition of osteoporosis, as defined by the World Health Organisation (WHO), is based solely on a measurement of BMD by dual-energy X-ray absorptiometry (DXA). BMD is compared to data from a reference population of healthy young adult females to generate a standard deviate “T-score”, with a T-score less than − 2 used to define osteoporosis [3]. Certainly, the clinical relevance of a low BMD is demonstrated by lower BMD in both adults [4] and children [5] who fracture.
Skeletal development begins in utero at 8–12 weeks’ gestation but foetal skeletal calcium accretion peaks during the third trimester of pregnancy. Foetal bone mineral accretion is primarily determined by foetal plasma calcium ion (Ca2+) concentration, which is dependent on the active transport of Ca2+ from the maternal to foetal circulation by the placenta [6]. Adaptations to maternal calcitropic hormones and increased intestinal calcium absorption during pregnancy help to facilitate this high foetal calcium demand, yet maternal serum Ca2+ is maintained within the normal adult range. At birth, bone mineral constitutes approximately 2% of an infant’s body weight [7].
During childhood and adolescence, skeletal growth in both length and width due to constant modelling and remodelling results in bone mineral accrual and an increase in bone mass (the composite of bone mineral content and bone size). Puberty is a critical period for bone mineral accrual, during which whole body bone mass roughly doubles. Notably, the rate of gain in bone mass temporally lags behind peak growth velocity by approximately 6 months, resulting in a period of relative under-mineralisation [8]. This coincides with an increased incidence of fracture during adolescence, observed later in boys than girls and coinciding with the later puberty onset in males [9]. Following final height achievement, bone mineral accrual continues into early adulthood. Recent analysis of cross-sectional data collected during 2005–2014 in the National Health and Nutrition Examination Survey (NHANES) in the United States of America (USA) suggested PBM was attained between 20 and 24 years in males and 19 and 20 years in females depending on skeletal site. PBM is typically attained earlier at the femoral neck and total hip than lumbar spine in both sexes, with no difference by ethnicity or body mass index [10]. Thereafter, bone mass decreases, with an acceleration in bone loss after the menopause in women. Mathematical modelling has demonstrated that achieving a 10% higher PBM will delay the onset of osteoporosis by 13 years [2], highlighting the necessity to optimise early life bone mineral accrual to reduce the burden of osteoporosis and fragility fracture.
Modifiable Factors Affecting Bone Health in Childhood and Adolescence
There is evidence of moderate to high tracking (maintenance of the relative position of an individual within the population distribution over time) of BMD through childhood, puberty and into young adulthood [11, 12]. This might partly reflect a genetic tendency as osteoporosis has high heritability and numerous loci associated with BMD have been identified in genome-wide association studies (GWAS) [13]. Thus far, single nucleotide polymorphisms have been identified accounting for up to 20% of the variance in adult BMD [13]; whilst further genetic contribution will undoubtedly be identified in future studies, findings thus far raise the possibility of modifiable lifestyle factors influencing BMD in early and later postnatal life.
Physical activity has beneficial effects on the growing skeleton. In childhood and adolescence, higher levels of physical activity are associated with greater BMC, BMD and measures of bone strength by peripheral quantitative computed tomography in both cross-sectional and longitudinal studies [14,15,16,17]. Vigorous physical activity has however been associated with higher risk of fracture, probably due to confounding by greater exposure to potential fracture-inducing events [14]. Two randomised controlled trials (RCT) have demonstrated positive effects of a high impact jumping intervention in pre-pubertal children on whole body, lumbar spine and hip BMC with some persistence of the effect several years after cessation of the intervention [18, 19]. Furthermore, observational studies have also demonstrated associations between self-reported physical activity in adolescence and young adulthood and BMD in mid- and older adulthood [20,21,22]. For example, Zhang et al., using the Hertfordshire Cohort Study, found self-reported physical activity in women at age 18–29 years was associated with higher total hip BMD at age 72–80 years after adjustment for current activity levels [21], highlighting the importance of promoting physical activity in early life and around PBM to reduce osteoporosis risk.
Consideration of nutritional health is also important to maximise bone mineral accrual. This is of particular importance in preterm infants and those born with low birth weight, who often have had the reduced in utero bone mineral accrual as transplacental calcium transfer is maximum in the third trimester. The lower BMD can persist into later childhood and adulthood in those born preterm [23, 24]. Human breast milk is known to have beneficial effects on the risk of neonatal sepsis and complications of prematurity including necrotising enterocolitis and retinopathy of prematurity [25], and there is some evidence to suggest that there are long-term benefits for bone health [26]. These benefits are similarly observed in term infants in observational studies [27]. Fortification of human milk can also increase BMC in preterm infants [28].
Additionally, particular importance should be given to the nutritional status of children with chronic medical conditions that impact on nutritional intake or intestinal absorption, and are as such at increased risk of poor bone health. Despite bone mineral containing over 99% of the body’s total calcium, the benefits of calcium supplementation in children and adolescents on BMC and BMD are unclear. Prevention of dietary calcium and vitamin D deficiency are vital to prevent rickets and symptomatic hypocalcaemia. However, whilst observational studies suggest positive associations between calcium intake and BMC or BMD [17], the findings of RCTs have generally been inconclusive and few have demonstrated persistence of a positive effect after discontinuation of supplementation. A recent meta-analysis of RCTs of calcium supplementation in children and young adults up to 35 years of age suggested a small positive effect on BMD at the femoral neck and whole body with a similar direction of effect at the lumbar spine and total hip but with confidence intervals bounding zero. The effect appeared to be stronger in studies that included only individuals over 20 years of age, although the number of studies was small, and some studies were limited to only women [29]. Similarly, observational studies suggest a non-linear relationship between 25-hydroxyvitamin D [25(OH)D] status and BMD or BMC in childhood [30], and this is supported by a meta-analysis of RCTs of vitamin D supplementation, but RCTs suggest that the effect of vitamin D supplementation on BMD in healthy children is small and may only be of benefit to those with biochemically low 25(OH)D levels [31,32,33].
The In Utero Environment and Long-Term Bone Health
There is now increasing recognition that modifiable exposures occurring before birth impact long-term health. In 1986, Barker and colleagues observed a close geographical relationship between infant mortality rates and standardised mortality from cardiovascular disease 65 years later, leading to the “developmental origins of health and disease hypothesis” [34]. Subsequent observations of relationships between birth weight and other non-communicable diseases extended this hypothesis to other clinical outcomes, including skeletal health. Indeed, birthweight is positively associated with bone mass in both young and late adulthood [35]. Whilst birthweight is a proxy for poor intrauterine nutrition, poor intrauterine growth might not result in low birth weight. The importance of in utero growth, as opposed to simply achieved weight at birth, to long-term skeletal health is further supported by data from both the Southampton Women’s Survey (UK) and Generation R (The Netherlands) mother–offspring birth cohort studies, in which measures of foetal growth derived from ultrasound measurements during pregnancy have also shown positive associations with BMD and hip geometry in childhood [36, 37].
Maternal Lifestyle in Pregnancy and Offspring Bone Health
Maternal health and lifestyle factors are important determinants of intrauterine growth, and their associations with offspring skeletal health have been assessed in observational studies. Smoking, for example, is recognised to impact negatively on foetal growth and birth weight due to detrimental effects on placental function. However, the relationship of maternal smoking with offspring bone health is more complex. In both the Princess Anne Hospital cohort and the SWS, maternal smoking was associated with lower neonatal BMC and BMD [38, 39]. Jones et al. similarly found lower BMD at age 8 years in Australian children born to mothers who smoked in pregnancy [40], but this relationship was no longer evident at age 16 years [41]. Some studies have found maternal smoking in pregnancy to be associated with higher BMD in childhood [37, 42]. A recently published meta-analysis suggested that maternal smoking in pregnancy was associated with lower offspring BMD in childhood/adolescence, but that this relationship was no longer evident after adjustment for current weight [43]. Indeed, it is well recognised that maternal smoking in pregnancy is associated with greater childhood obesity, and obese children tend to have higher BMD. The intricate relationships between poor in utero growth in infants of smokers, postnatal catch-up weight gain and coupled with increased risk of other postnatal risk factors for poor bone development may underlie these differing relationships in observational studies. Interestingly, offspring of women who smoked during pregnancy were shown in a large population-based registry study in Sweden to have higher risk of fracture from age 5 years to young adulthood; however, the risk of fracture in siblings with differing in utero smoking exposure was similar, suggesting this risk might be confounded by similar post-natal environmental characteristics [44], although other shared maternal factors during pregnancy (e.g. diet, body composition) may also be relevant.
Alcohol exposure during foetal life appears to have a detrimental effect on bone development. Children with foetal alcohol spectrum disorders (FASD) have lower WBLH BMD in adolescence than controls [45]. This might reflect their shorter stature given the effect of bone size on BMD measurement by DXA, and greater exposure to other drugs of abuse is seen in children with FASD and might also affect bone health [45]. However, animal studies have suggested that even low levels of alcohol exposure are deleterious to bone development independent of the effect on foetal growth [46]. In a large prospective birth cohort study in Finland, moderate maternal alcohol consumption was associated with a more than two-fold increased risk of fracture before 8 years of age [47], but to our knowledge, there are no studies assessing pregnancy alcohol use and offspring BMD.
In developing countries such as the UK, maternal age at conception is advancing [48], which based on the findings of a birth cohort in Sweden might increase the risk of poor long-term offspring bone health. In that study, increasing maternal age was associated with lower total body and lumbar spine areal BMD in young adult males when controlling for several potential confounders [49]. Maternal parity however does not appear to be associated with offspring BMD [39, 49].
Although physical activity is recognised as important for skeletal development postnatally, the influence of maternal physical activity on offspring bone development has been rarely investigated. In a study of offspring of rats exposed to exercise or control during pregnancy, offspring whole body BMD by DXA did not differ, but offspring tibial cortical volumetric BMD was lower in the offspring of exercised dams [50]. Similarly, in the SWS, walking speed in late pregnancy, used as a measure of maternal physical activity, was negatively associated with neonatal BMC and bone area [39]. These findings raise the possibility of competition between the maternal and foetal skeleton for finite mineral resource.
Maternal Body Habitus and Offspring Bone Health
The prevalence of maternal obesity is increasing, and is associated with poorer obstetric health [51, 52]. In the SWS, greater maternal triceps skinfold thickness in pregnancy, used as a surrogate marker of adiposity, was associated with greater neonatal BA and BMC [39]. Similarly, in a cohort study in Japan, children born to underweight mothers had lower WBLH BMC and BA, but similar BMD, at age 10 years. However, it is probable that this was mediated by offspring weight, which may also have shared genetic and environmental origins in mother and child [53]. Indeed, there is likely a non-linear relationship between maternal body habitus and offspring bone development, but there is stronger evidence to support a role for dietary quality and components affecting offspring bone health.
Maternal Nutrition in Pregnancy and Offspring Bone Health
Dietary Quality
Several studies have examined the relationships between maternal overall dietary quality and offspring bone health. In the Princess Anne Hospital Study, 198 women had diet assessed by a food frequency questionnaire at 15 and 32 weeks’ gestation. A dietary score was generated to quantify dietary intake compared to recommendations for a healthy diet. In late pregnancy, a diet characterised by higher intakes of fruit, vegetables, wholemeal bread, rice and pasta, yoghurt and breakfast cereals and lower intakes of chips, roast potatoes, processed meats, sugar, crisps and soft drinks, termed a “prudent diet”, was positively associated with offspring whole body and lumbar spine BMC and aBMD at 9 years of age, including after adjustment for maternal educational achievement, social class, anthropometry and smoking status [54]. Similarly, in over 50,000 mother–offspring pairs in the Danish National Birth Cohort study, a more Western diet in mid-pregnancy, characterised by high intakes of meat, potatoes and white bread but low fruit and vegetable intake, was associated with higher offspring risk of childhood forearm fracture [55]. More recently published work using the SWS and ALSPAC birth cohorts showed maternal consumption of a diet with a high dietary inflammatory index was negatively associated with offspring BA, BMC and aBMD in childhood [56].
Individual Dietary Components
Many studies have been undertaken to establish the roles of individual dietary components in bone health. Care must be taken in the interpretation of these due to potential inaccuracies in establishing true intakes from food frequency questionnaires; blood biomarkers of dietary components may be more reliable. There is also greater potential for intervention studies to establish causality for single micronutrients than overall dietary quality in determining offspring BMD.
Calcium
Unsurprisingly, considering the importance of calcium to bone mineral accrual, the role of maternal calcium intake in pregnancy on offspring bone health has received much attention. A recent meta-analysis with literature searches performed in September 2020 identified six RCTs of calcium supplementation in pregnancy with assessment of offspring bone health [57]; a small effect of calcium supplementation on whole body BMD in the neonatal period was noted; however, a long-lasting effect could not be established from the available studies.
Polyunsaturated Fatty Acids (PUFA)
Data from animal models suggest that PUFA, derived from fish oils, have a role in bone metabolism [58, 59]. In the SWS, maternal plasma n-3 PUFA at 34 weeks’ gestation was positively associated with offspring WBLH and LS BMC and BMD at 4 years of age [60]. In one recently published RCT, fish-oil supplementation during pregnancy increased offspring WBLH BMC but not BMD at age 6 years. BMI, fat mass and lean mass were also higher in the fish-oil supplemented offspring suggesting a general growth stimulating effect rather than specific to bone [61].
Iron
Fibroblast growth factor-23 (FGF23) regulates body phosphate homeostasis, primarily by increasing phosphaturia, and is also involved in vitamin D regulation. Maternal iron deficiency is associated with increased expression of FGF23 and has therefore been postulated to have implications for the developing skeleton. Antenatal iron supplementation has recently been shown to reduce maternal and neonatal FGF23 [62], but a direct effect on bone health has not yet been examined.
Vitamin A
Vitamin A comprises a group of fat-soluble essential nutrients that have roles in vision, immune function, growth and cell division and differentiation. In older adults, the different forms of dietary vitamin A have opposing associations with fracture risk [63]: high intakes of retinol, primarily from animal sources, are associated with high fracture risk, whereas β-carotene intake, primarily from plant sources, is negatively associated with fracture risk. Similarly, in the SWS birth cohort, maternal serum retinol in late pregnancy was negatively associated with offspring neonatal whole body BMC and BA, but not BMD, whereas maternal serum β-carotene concentration was positively associated with BMC and BA but again not BMD [64]. Comparably, in a much smaller mother–offspring study in Norway, maternal serum retinol in pregnancy was not associated with offspring whole body or LS BMD at age 26 years [65]. Overall, these findings lend support to dietary recommendations to limit retinol intake during pregnancy due to the known teratogenic effects, and suggest possible beneficial effects of carotenoids on offspring bone health should be investigated.
Folate
Folate supplementation during pregnancy is strongly advised to prevent neural tube defects. Observational studies assessing the relationships between maternal folate intake and offspring BMD are conflicting [66,67,68], but dose-comparator intervention studies on this outcome are lacking.
Maternal Vitamin D Status in Pregnancy and Offspring Bone Health
Vitamin D is primarily obtained from the action of sunlight on the skin rather than through dietary sources. However, vitamin D deficiency is highly prevalent in pregnant women [69] and can be improved with supplementation and/or food fortification practices [70]. Considering this and the importance of 25(OH)D in maternal calcium absorption, the effect of maternal vitamin D supplementation on offspring BMD has received scientific interest. Observational studies assessing the associations between maternal 25(OH)D status and offspring BMD have reported inconsistent findings, but variation in gestation at 25(OH)D assessment, age at follow-up, cohort demographics and geographical location of the study limit comparison between studies (Table 1) [71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89].
There have been numerous RCTs that have assessed the effect of pregnancy vitamin D supplementation on neonatal anthropometry and/or calcium status [90]. Our own meta-analysis of these studies suggested a small positive effect on birth weight and neonatal serum calcium. There are, however, fewer studies that have examined the effect of pregnancy vitamin D supplementation on offspring musculoskeletal parameters; to date, there are 2 published trials assessing neonatal BMD [91, 92] and four trials with assessment of BMD in early childhood [93,94,95,96]. The largest published RCT is the MAVIDOS study, which was conducted in three centres in the UK and randomised women with a baseline 25(OH)D of 25–100 nmol/l to either 1000 IU/day cholecalciferol or placebo from 14 to 17 weeks’ gestation until delivery [97]. Supplementation increased maternal serum 25(OH)D, although achieved 25(OH)D in late pregnancy was also influenced by maternal BMI, baseline 25(OH)D and genetic variation within the vitamin D metabolism pathway [98,99,100]. DXA data were obtained for 665 infants within 2 weeks of birth [91] and 452 children at 4 years of age [93]. Across the whole trial population, no effect of vitamin D supplementation on neonatal bone mass was observed, but an interaction with season of birth was noted such that BMD was higher in winter-born infants of supplemented mothers compared to the placebo group [91]. However, at age 4 years, a significant effect of vitamin D supplementation on offspring BMD was noted across the whole cohort [93] (Fig. 1), equating to approximately 0.17 SD difference between the two groups. If this effect is sustained into adulthood, it would be expected to reduce fracture risk. WBLH lean mass was also increased in the cholecalciferol group, consistent with earlier findings from the SWS which showed a positive association between late pregnancy 25(OH)D and offspring grip strength [101].
The effect of 1000 IU/day cholecalciferol supplementation from 14 to 17 weeks’ gestation until delivery on offspring whole body less head bone mineralisation at 4 years of age. Reproduced with permission from Curtis et al. JBMR + 2022. BMC, bone mineral content; aBMD, areal bone mineral density; scBMD, size corrected bone mineral content
A positive effect of pregnancy vitamin D supplementation was also found in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010), in which women were randomised to either 2400 IU/day or 400 IU/day cholecalciferol from 24 weeks’ gestation. In that study, differences in WBLH BMC and aBMD at 6 years of age of 0.15 and 0.2 SD, respectively, were identified, thus of comparable magnitude to the differences observed in MAVIDOS [94]. However, no differences in WBLH BMC or aBMD were identified at age 3 years. In contrast, O’Callaghan et al. found no differences in WBLH BMD or BMC at 4 years of age in offspring of children born to mothers randomised to either 4200 IU/week, 16,800 IU/week or 28,000 IU/week cholecalciferol in Bangladesh [95]. The differences in study findings likely reflect methodological differences, including timing of commencing vitamin D supplementation, dosing, daily versus weekly supplementation and the geographical location and population in which the study was performed. This highlights the need to consider generalisability of a study population. Nonetheless, taken together, these studies do suggest a possible benefit of pregnancy vitamin D supplementation for offspring bone health, but further follow-up of these cohorts is needed to demonstrate persistence into adolescence and adulthood.
Mechanisms
The mechanisms underlying the observed associations between the early environment and future bone health are not fully understood. Animal models allow for more marked dietary restrictions than is typically observed in human studies, and can be used to identify potential mechanisms for the observations. For example, rats fed a protein-deficient diet in pregnant have offspring with fewer ossification centres and alterations to the growth plate [102], and in ewes fed a calorie-restricted diet, mesenchymal stem cell activity was reduced [103].
In humans, there may be a direct effect of individual nutrients or overall nutrition (directly or indirectly due to an effect on placental function, e.g. smoking) on bone mineralisation. Maternal 25(OH)D supplementation for example increases umbilical cord calcium concentration [90], and thus, it could be postulated that this increases calcium availability for skeletal mineralisation. However, interestingly, the winter effect of vitamin D supplementation on neonatal BMD at birth [91], but with a positive effect at age 4 years, regardless of season [93], in MAVIDOS, and similar observations at ages 3 and 6 years in COPSAC2010 [94], suggests an evolving effect of vitamin D supplementation on BMD over childhood. This would support an epigenetic mechanism underlying this relationship. Epigenetics is the study of the interaction between the environment and gene expression. Genes can be differentially expressed in different cells and tissues according to function and need, and in experimental studies, alterations to offspring phenotype and gene expression can occur in response to environmental cues and maternal diet [104]. DNA methylation and histone modification are two types of epigenetic mechanisms. These are stable heritable changes that influence gene transcription without changing the DNA sequence, and can be influenced by the in utero environment, such as maternal smoking [105] and, in the MAVIDOS trial, pregnancy vitamin D supplementation [106]. Differences in the level of DNA methylation have been associated with childhood bone mass [107, 108], with methylation at the retinoid-X-receptor-a (RXRA) gene in perinatal tissue implicated as a potential link between maternal 25-hydroxyvitamin D status, vitamin D supplementation and offspring bone mass in both observational and intervention settings [106, 107].
Conclusions
Optimisation of bone mineral accrual during early life is likely to reduce the risk and delay the onset of osteoporosis in later life. Approaches to this include during childhood, such as physical activity and nutrition, and during in utero development. Recently, pregnancy vitamin D supplementation has been demonstrated to have promising beneficial effects on offspring BMD in early childhood in two large randomised controlled trials in the UK [91, 93] and Denmark [94], and a meta-analysis has suggested a small effect of calcium supplementation in pregnancy on neonatal BMD [57]. Ongoing follow-up of these children is required to show persistence of this effect into later life, and further epigenetic and metabolic studies might help to elucidate the underlying mechanisms of this effect.
References
Kanis JA, Norton N, Harvey NC, Jacobson T, Johansson H, Lorentzon M, et al. SCOPE 2021: a new scorecard for osteoporosis in Europe. Arch Osteoporos. 2021;16(1):82. https://doi.org/10.1007/s11657-020-00871-9.
Hernandez CJ, Beaupre GS, Carter DR. A theoretical analysis of the relative influences of peak BMD, age-related bone loss and menopause on the development of osteoporosis. Osteoporos Int. 2003;14(10):843–7.
Consensus development conference. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med. 1993;94(6):646–50.
Curtis EM, Harvey NC, D’Angelo S, Cooper CS, Ward KA, Taylor P, et al. Bone mineral content and areal density, but not bone area, predict an incident fracture risk: a comparative study in a UK prospective cohort. Arch Osteoporos. 2016;11(1):39. https://doi.org/10.1007/s11657-016-0293-0.
Clark EM, Ness AR, Tobias JH. Bone fragility contributes to the risk of fracture in children, even after moderate and severe trauma. J Bone Miner Res. 2008;23(2):173–9. https://doi.org/10.1359/jbmr.071010.
Forestier F, Daffos F, Rainaut M, Bruneau M, Trivin F. Blood chemistry of normal human fetuses at midtrimester of pregnancy. Pediatr Res. 1987;21(6):579–83.
Koo WW, Walters J, Bush AJ, Chesney RW, Carlson SE. Dual-energy X-ray absorptiometry studies of bone mineral status in newborn infants. J Bone Miner Res. 1996;11(7):997–102. https://doi.org/10.1002/jbmr.5650110717.
Kirmani S, Christen D, van Lenthe GH, Fischer PR, Bouxsein ML, McCready LK, et al. Bone structure at the distal radius during adolescent growth. J Bone Miner Res. 2009;24(6):1033–42. https://doi.org/10.1359/jbmr.081255.
Moon RJ, Harvey NC, Curtis EM, de Vries F, van Staa T, Cooper C. Ethnic and geographic variations in the epidemiology of childhood fractures in the United Kingdom. Bone. 2016;85:9–14. https://doi.org/10.1016/j.bone.2016.01.015.
Xue S, Kemal O, Lu M, Lix LM, Leslie WD, Yang S. Age at attainment of peak bone mineral density and its associated factors: the National Health and Nutrition Examination Survey 2005–2014. Bone. 2020;131:115163 https://doi.org/10.1016/j.bone.2019.115163.
Yang Y, Wu F, Winzenberg T, Jones G. Tracking of areal bone mineral density from age eight to young adulthood and factors associated with deviation from tracking: a 17-year prospective cohort study. J Bone Miner Res. 2018;33(5):832–9. https://doi.org/10.1002/jbmr.3361.
Foley S, Quinn S, Jones G. Tracking of bone mass from childhood to adolescence and factors that predict deviation from tracking. Bone. 2009;44(5):752–7. https://doi.org/10.1016/j.bone.2008.11.009.
Morris JA, Kemp JP, Youlten SE, Laurent L, Logan JG, Chai RC, et al. An atlas of genetic influences on osteoporosis in humans and mice. Nat Genet. 2019;51(2):258–66. https://doi.org/10.1038/s41588-018-0302-x.
Clark EM, Ness AR, Tobias JH. Vigorous physical activity increases fracture risk in children irrespective of bone mass: a prospective study of the independent risk factors for fractures in healthy children. J Bone Miner Res. 2008;23(7):1012–22. https://doi.org/10.1359/jbmr.080303.
Gabel L, Macdonald HM, Nettlefold L, McKay HA. Physical activity, sedentary time, and bone strength from childhood to early adulthood: a mixed longitudinal HR-pQCT study. J Bone Miner Res. 2017. https://doi.org/10.1002/jbmr.3115.
Janz KF, Letuchy EM, Burns TL, Eichenberger Gilmore JM, Torner JC, Levy SM. Objectively measured physical activity trajectories predict adolescent bone strength: Iowa Bone Development Study. Br J Sports Med. 2014;48(13):1032–6. https://doi.org/10.1136/bjsports-2014-093574.
Harvey NC, Cole ZA, Crozier SR, Kim M, Ntani G, Goodfellow L, et al. Physical activity, calcium intake and childhood bone mineral: a population-based cross-sectional study. Osteoporos Int. 2012;23(1):121–30. https://doi.org/10.1007/s00198-011-1641-y.
Gunter K, Baxter-Jones AD, Mirwald RL, Almstedt H, Fuchs RK, Durski S, et al. Impact exercise increases BMC during growth: an 8-year longitudinal study. J Bone Miner Res. 2008;23(7):986–93. https://doi.org/10.1359/jbmr.071201.
Gunter K, Baxter-Jones AD, Mirwald RL, Almstedt H, Fuller A, Durski S, et al. Jump starting skeletal health: a 4-year longitudinal study assessing the effects of jumping on skeletal development in pre and circum pubertal children. Bone. 2008;42(4):710–8. https://doi.org/10.1016/j.bone.2008.01.002.
Rideout CA, McKay HA, Barr SI. Self-reported lifetime physical activity and areal bone mineral density in healthy postmenopausal women: the importance of teenage activity. Calcif Tissue Int. 2006;79(4):214–22. https://doi.org/10.1007/s00223-006-0058-7.
Zhang J, Parsons C, Fuggle N, Ward KA, Cooper C, Dennison E. Is regular weight-bearing physical activity throughout the lifecourse associated with better bone health in late adulthood? Calcif Tissue Int. 2022;111(3):279–87. https://doi.org/10.1007/s00223-022-00995-9.
Bielemann RM, Domingues MR, Horta BL, Gigante DP. Physical activity from adolescence to young adulthood and bone mineral density in young adults from the 1982 Pelotas (Brazil) Birth Cohort. Prev Med. 2014;62:201–7. https://doi.org/10.1016/j.ypmed.2014.02.014.
Xie LF, Alos N, Cloutier A, Béland C, Dubois J, Nuyt AM, et al. The long-term impact of very preterm birth on adult bone mineral density. Bone Rep. 2019;10:100189 https://doi.org/10.1016/j.bonr.2018.100189.
Balasuriya CND, Evensen KAI, Mosti MP, Brubakk AM, Jacobsen GW, Indredavik MS, et al. Peak bone mass and bone microarchitecture in adults born with low birth weight preterm or at term: a cohort study. J Clin Endocrinol Metab. 2017;102(7):2491–500. https://doi.org/10.1210/jc.2016-3827.
Menon G, Williams TC. Human milk for preterm infants: why, what, when and how? Archives of Disease in Childhood - Fetal and Neonatal Edition. 2013;98(6):F559–62. https://doi.org/10.1136/archdischild-2012-303582.
Fewtrell MS. Does early nutrition program later bone health in preterm infants? Am J Clin Nutr. 2011;94:S1870–3. https://doi.org/10.3945/ajcn.110.000844.
Carter SA, Parsons CM, Robinson SM, Harvey NC, Ward KA, Cooper C, et al. Infant milk feeding and bone health in later life: findings from the Hertfordshire cohort study. Osteoporos Int. 2020;31(4):709–14. https://doi.org/10.1007/s00198-020-05296-1.
Einloft PR, Garcia PC, Piva JP, Schneider R, Fiori HH, Fiori RM. Supplemented vs unsupplemented human milk on bone mineralization in very low birth weight preterm infants: a randomized clinical trial. Osteoporos Int. 2015;26(9):2265–71. https://doi.org/10.1007/s00198-015-3144-8.
Liu Y, Le S, Liu Y, Jiang H, Ruan B, Huang Y, et al. The effect of calcium supplementation in people under 35 years old: a systematic review and meta-analysis of randomized controlled trials. Elife. 2022;11:e79002. https://doi.org/10.7554/eLife.79002.
Moon RJ, Harvey NC, Davies JH, Cooper C. Vitamin D and skeletal health in infancy and childhood. Osteoporos Int. 2014;25(12):2673–84. https://doi.org/10.1007/s00198-014-2783-5.
Winzenberg TM, Powell S, Shaw KA, Jones G. Vitamin D supplementation for improving bone mineral density in children. Cochrane Database Syst Rev 2010(10):CD006944 https://doi.org/10.1002/14651858.CD006944.pub2.
Stounbjerg NG, Thams L, Hansen M, Larnkjær A, Clerico JW, Cashman KD, et al. Effects of vitamin D and high dairy protein intake on bone mineralization and linear growth in 6- to 8-year-old children: the D-pro randomized trial. Am J Clin Nutr. 2021;114(6):1971–85. https://doi.org/10.1093/ajcn/nqab286.
Gallo S, Hazell T, Vanstone CA, Agellon S, Jones G, L’Abbé M, et al. Vitamin D supplementation in breastfed infants from Montréal, Canada: 25-hydroxyvitamin D and bone health effects from a follow-up study at 3 years of age. Osteoporos Int. 2016;27(8):2459–66. https://doi.org/10.1007/s00198-016-3549-z.
Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet. 1986;1(8489):1077–81.
Baird J, Kurshid MA, Kim M, Harvey N, Dennison E, Cooper C. Does birthweight predict bone mass in adulthood? A systematic review and meta-analysis. Osteoporos Int. 2011;22(5):1323–34. https://doi.org/10.1007/s00198-010-1344-9.
Harvey NC, Cole ZA, Crozier SR, Ntani G, Mahon PA, Robinson SM, et al. Fetal and infant growth predict hip geometry at 6 y old: findings from the Southampton Women’s Survey. Pediatr Res. 2013;74(4):450–6. https://doi.org/10.1038/pr.2013.119.
Heppe DH, Medina-Gomez C, de Jongste JC, Raat H, Steegers EA, Hofman A, et al. Fetal and childhood growth patterns associated with bone mass in school-age children: the Generation R Study. J Bone Miner Res. 2014;29(12):2584–93. https://doi.org/10.1002/jbmr.2299.
Godfrey K, Walker-Bone K, Robinson S, Taylor P, Shore S, Wheeler T, et al. Neonatal bone mass: influence of parental birthweight, maternal smoking, body composition, and activity during pregnancy. J Bone Miner Res. 2001;16(9):1694–703. https://doi.org/10.1359/jbmr.2001.16.9.1694.
Harvey NC, Javaid MK, Arden NK, Poole JR, Crozier SR, Robinson SM, et al. Maternal predictors of neonatal bone size and geometry: the Southampton Women’s Survey. J Dev Orig Health Dis. 2010;1(1):35–41. https://doi.org/10.1017/s2040174409990055.
Jones G, Riley M, Dwyer T. Maternal smoking during pregnancy, growth, and bone mass in prepubertal children. J Bone Miner Res. 1999;14(1):146–51. https://doi.org/10.1359/jbmr.1999.14.1.146.
Jones G, Hynes KL, Dwyer T. The association between breastfeeding, maternal smoking in utero, and birth weight with bone mass and fractures in adolescents: a 16-year longitudinal study. Osteoporos Int. 2013;24(5):1605–11. https://doi.org/10.1007/s00198-012-2207-3.
Macdonald-Wallis C, Tobias JH, Davey Smith G, Lawlor DA. Parental smoking during pregnancy and offspring bone mass at age 10 years: findings from a prospective birth cohort. Osteoporos Int. 2011;22(6):1809–19. https://doi.org/10.1007/s00198-010-1415-y.
BaradaranMahdavi S, Daniali SS, Farajzadegan Z, Bahreynian M, Riahi R, Kelishadi R. Association between maternal smoking and child bone mineral density: a systematic review and meta-analysis. Environ Sci Pollut Res. 2020;27(19):23538–49. https://doi.org/10.1007/s11356-020-08740-1.
Brand JS, Hiyoshi A, Cao Y, Lawlor DA, Cnattingius S, Montgomery S. Maternal smoking during pregnancy and fractures in offspring: national register based sibling comparison study. BMJ. 2020;368:l7057 https://doi.org/10.1136/bmj.l7057.
Young SL, Gallo LA, Brookes DSK, Hayes N, Maloney M, Liddle K, et al. Altered bone and body composition in children and adolescents with confirmed prenatal alcohol exposure. Bone. 2022;164:116510 https://doi.org/10.1016/j.bone.2022.116510.
Simpson ME, Duggal S, Keiver K. Prenatal ethanol exposure has differential effects on fetal growth and skeletal ossification. Bone. 2005;36(3):521–32. https://doi.org/10.1016/j.bone.2004.11.011.
Parviainen R, Auvinen J, Serlo W, Järvelin MR, Sinikumpu JJ. Maternal alcohol consumption during pregnancy associates with bone fractures in early childhood. A birth-cohort study of 6718 participants. Bone. 2020;137:115462 https://doi.org/10.1016/j.bone.2020.115462.
Office for National Statistics. Conceptions in England and Wales: 2020. Available: https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/conceptionandfertilityrates/bulletins/conceptionstatistics/2020. Accessed 2022.
Rudang R, Mellstrom D, Clark E, Ohlsson C, Lorentzon M. Advancing maternal age is associated with lower bone mineral density in young adult male offspring. Osteoporos Int. 2012;23(2):475–82. https://doi.org/10.1007/s00198-011-1558-5.
Rosa BV, Blair HT, Vickers MH, Dittmer KE, Morel PC, Knight CG, et al. Moderate exercise during pregnancy in Wistar rats alters bone and body composition of the adult offspring in a sex-dependent manner. PLoS One. 2013;8(12):e82378. https://doi.org/10.1371/journal.pone.0082378.
Daly M, Kipping RR, Tinner LE, Sanders J, White JW. Preconception exposures and adverse pregnancy, birth and postpartum outcomes: umbrella review of systematic reviews. Paediatr Perinat Epidemiol. 2022;36(2):288–99. https://doi.org/10.1111/ppe.12855.
Lu GC, Rouse DJ, DuBard M, Cliver S, Kimberlin D, Hauth JC. The effect of the increasing prevalence of maternal obesity on perinatal morbidity. Am J Obstet Gynecol. 2001;185(4):845–9. https://doi.org/10.1067/mob.2001.117351.
Fujita Y, Kouda K, Ohara K, Nakamura H, Iki M. Maternal pre-pregnancy underweight is associated with underweight and low bone mass in school-aged children. J Bone Miner Metab. 2020;38(6):878–84. https://doi.org/10.1007/s00774-020-01121-1.
Cole ZA, Gale CR, Javaid MK, Robinson SM, Law C, Boucher BJ, et al. Maternal dietary patterns during pregnancy and childhood bone mass: a longitudinal study. J Bone Miner Res. 2009;24(4):663–8. https://doi.org/10.1359/jbmr.081212.
Petersen SB, Rasmussen MA, Olsen SF, Vestergaard P, Molgaard C, Halldorsson TI, et al. Maternal dietary patterns during pregnancy in relation to offspring forearm fractures: prospective study from the Danish National Birth Cohort. Nutrients. 2015;7(4):2382–400. https://doi.org/10.3390/nu7042382.
Woolford SJ, D’Angelo S, Mancano G, Curtis EM, Ashai S, Shivappa N, et al. Associations between late pregnancy dietary inflammatory index (DII) and offspring bone mass: a meta-analysis of the Southampton Women’s Survey (SWS) and the Avon Longitudinal Study of Parents and Children (ALSPAC). Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2022;37(8):1511–9. https://doi.org/10.1002/jbmr.4623.
Tihtonen K, Korhonen P, Isojärvi J, Ojala R, Ashorn U, Ashorn P, et al. Calcium supplementation during pregnancy and maternal and offspring bone health: a systematic review and meta-analysis. Ann N Y Acad Sci. 2022;1509(1):23–36. https://doi.org/10.1111/nyas.14705.
Tompkins YH, Chen C, Sweeney KM, Kim M, Voy BH, Wilson JL, et al. The effects of maternal fish oil supplementation rich in n-3 PUFA on offspring-broiler growth performance, body composition and bone microstructure. PLoS One. 2022;17(8):e0273025. https://doi.org/10.1371/journal.pone.0273025.
Poulsen RC, Moughan PJ, Kruger MC. Long-chain polyunsaturated fatty acids and the regulation of bone metabolism. Exp Biol Med (Maywood). 2007;232(10):1275–88. https://doi.org/10.3181/0704-mr-100.
Harvey N, Dhanwal D, Robinson S, Kim M, Inskip H, Godfrey K, et al. Does maternal long chain polyunsaturated fatty acid status in pregnancy influence the bone health of children? The Southampton Women’s Survey Osteoporos Int. 2012;23(9):2359–67. https://doi.org/10.1007/s00198-011-1860-2.
Vinding RK, Stokholm J, Sevelsted A, Sejersen T, Chawes BL, Bønnelykke K, et al. Effect of fish oil supplementation in pregnancy on bone, lean, and fat mass at six years: randomised clinical trial. BMJ. 2018;362:k3312-k https://doi.org/10.1136/bmj.k3312.
Braithwaite VS, Mwangi MN, Jones KS, Demir AY, Prentice A, Prentice AM, et al. Antenatal iron supplementation, FGF23, and bone metabolism in Kenyan women and their offspring: secondary analysis of a randomized controlled trial. Am J Clin Nutr. 2021;113(5):1104–14. https://doi.org/10.1093/ajcn/nqaa417.
Wu AM, Huang CQ, Lin ZK, Tian NF, Ni WF, Wang XY, et al. The relationship between vitamin a and risk of fracture: meta-analysis of prospective studies. J Bone Miner Res. 2014;29(9):2032–9. https://doi.org/10.1002/jbmr.2237.
Handel MN, Moon RJ, Titcombe P, Abrahamsen B, Heitmann BL, Calder PC, et al. Maternal serum retinol and beta-carotene concentrations and neonatal bone mineralization: results from the Southampton Women’s Survey cohort. Am J Clin Nutr. 2016;104(4):1183–8. https://doi.org/10.3945/ajcn.116.130146.
Balasuriya CND, Larose TL, Mosti MP, Evensen KAI, Jacobsen GW, Thorsby PM, et al. Maternal serum retinol, 25(OH)D and 1,25(OH)2D concentrations during pregnancy and peak bone mass and trabecular bone score in adult offspring at 26-year follow-up. PloS one. 2019;14(9):e0222712-e. https://doi.org/10.1371/journal.pone.0222712.
Ganpule A, Yajnik CS, Fall CH, Rao S, Fisher DJ, Kanade A, et al. Bone mass in Indian children–relationships to maternal nutritional status and diet during pregnancy: the Pune Maternal Nutrition Study. J Clin Endocrinol Metab. 2006;91(8):2994–3001.
Tobias JH, Steer CD, Emmett PM, Tonkin RJ, Cooper C, Ness AR. Bone mass in childhood is related to maternal diet in pregnancy. Osteoporos Int. 2005;16(12):1731–41. https://doi.org/10.1007/s00198-005-1912-6.
Percival MA, Pasco JA, Hosking SM, Williams LJ, Holloway-Kew KL, Wark JD, et al. Maternal vitamin D and offspring fracture risk: the Vitamin D in Pregnancy study. Arch Osteoporos. 2021;16(1):159. https://doi.org/10.1007/s11657-021-01023-3.
Saraf R, Morton SMB, Camargo CA Jr, Grant CC. Global summary of maternal and newborn vitamin D status - a systematic review. Matern Child Nutr. 2016;12(4):647–68. https://doi.org/10.1111/mcn.12210.
Itkonen ST, Andersen R, Björk AK, BrugårdKonde Å, Eneroth H, Erkkola M, et al. Vitamin D status and current policies to achieve adequate vitamin D intake in the Nordic countries. Scand J Public Health. 2021;49(6):616–27. https://doi.org/10.1177/1403494819896878.
Nørgaard SM, Dalgård C, Heidemann MS, Schou AJ, Christesen HT. Bone mineral density at age 7 years does not associate with adherence to vitamin D supplementation guidelines in infancy or vitamin D status in pregnancy and childhood: an Odense Child Cohort study. Br J Nutr. 2021;126(10):1466–77. https://doi.org/10.1017/s0007114521000301.
Moon RJ, Harvey NC, Davies JH, Cooper C. Vitamin D and bone development. Osteoporos Int. 2015;26(4):1449–51. https://doi.org/10.1007/s00198-014-2976-y.
Javaid MK, Crozier SR, Harvey NC, Gale CR, Dennison EM, Boucher BJ, et al. Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet. 2006;367(9504):36–43. https://doi.org/10.1016/s0140-6736(06)67922-1.
Namgung R, Tsang RC, Lee C, Han DG, Ho ML, Sierra RI. Low total body bone mineral content and high bone resorption in Korean winter-born versus summer-born newborn infants. J Pediatr. 1998;132(3 Pt 1):421–5. https://doi.org/10.1016/S0022-3476(98)70013-7.
Garcia AH, Erler NS, Jaddoe VWV, Tiemeier H, van den Hooven EH, Franco OH, et al. 25-hydroxyvitamin D concentrations during fetal life and bone health in children aged 6 years: a population-based prospective cohort study. Lancet Diabetes Endocrinol. 2017;5(5):367–76. https://doi.org/10.1016/s2213-8587(17)30064-5.
Lawlor DA, Wills AK, Fraser A, Sayers A, Fraser WD, Tobias JH. Association of maternal vitamin D status during pregnancy with bone-mineral content in offspring: a prospective cohort study. Lancet. 2013;381(9884):2176–83.
Zhu K, Whitehouse AJ, Hart P, Kusel M, Mountain J, Lye S, et al. Maternal vitamin D status during pregnancy and bone mass in offspring at 20 years of age: a prospective cohort study. J Bone Miner Res. 2014;29(5):1088–95. https://doi.org/10.1002/jbmr.2138.
Hyde NK, Brennan-Olsen SL, Mohebbi M, Wark JD, Hosking SM, Pasco JA. Maternal vitamin D in pregnancy and offspring bone measures in childhood: the Vitamin D in Pregnancy study. Bone. 2019;124:126–31. https://doi.org/10.1016/j.bone.2019.04.013.
Hyde NK, Brennan-Olsen SL, Wark JD, Hosking SM, Holloway KL, Pasco JA. Maternal vitamin D and offspring trabecular bone score. Osteoporos Int. 2017;28(12):3407–14. https://doi.org/10.1007/s00198-017-4208-8.
Hyde NK, Brennan-Olsen SL, Wark JD, Hosking SM, Pasco JA. Gestational vitamin D and offspring bone measures: is the association independent of maternal bone quality? Calcif Tissue Int. 2021;108(2):188–95. https://doi.org/10.1007/s00223-020-00762-8.
Viljakainen HT, Korhonen T, Hytinantti T, Laitinen EK, Andersson S, Makitie O, et al. Maternal vitamin D status affects bone growth in early childhood–a prospective cohort study. Osteoporos Int. 2011;22(3):883–91. https://doi.org/10.1007/s00198-010-1499-4.
Viljakainen HT, Saarnio E, Hytinantti T, Miettinen M, Surcel H, Makitie O, et al. Maternal vitamin D status determines bone variables in the newborn. J Clin Endocrinol Metab. 2010;95(4):1749–57. https://doi.org/10.1210/jc.2009-1391.
Velkavrh M, Paro-Panjan D, Benedik E, Mis NF, Godnov U, Salamon AS. The influence of maternal levels of vitamin D and adiponectin on anthropometrical measures and bone health in offspring. Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2019;40(3):91–8. https://doi.org/10.2478/prilozi-2020-0008.
Levkovitz O, Lagerev E, Bauer-Rusak S, Litmanovitz I, Grinblatt E, Sirota GL, et al. Vitamin D levels in pregnant women do not affect neonatal bone strength. Children (Basel). 2022;9(6) https://doi.org/10.3390/children9060883.
Liao XP, Zhang WL, Yan CH, Zhou XJ, Wang P, Sun JH, et al. Reduced tibial speed of sound in Chinese infants at birth compared with Caucasian peers: the effects of race, gender, and vitamin D on fetal bone development. Osteoporos Int. 2010;21(12):2003–11. https://doi.org/10.1007/s00198-009-1158-9.
Boghossian NS, Koo W, Liu A, Mumford SL, Tsai MY, Yeung EH. Longitudinal measures of maternal vitamin D and neonatal body composition. Eur J Clin Nutr. 2019;73(3):424–31. https://doi.org/10.1038/s41430-018-0212-0.
Weiler H, Fitzpatrick-Wong S, Veitch R, Kovacs H, Schellenberg J, McCloy U, et al. Vitamin D deficiency and whole-body and femur bone mass relative to weight in healthy newborns. CMAJ. 2005;172(6):757–61. https://doi.org/10.1503/cmaj.1040508.
Dror DK, King JC, Fung EB, Van Loan MD, Gertz ER, Allen LH. Evidence of associations between feto-maternal vitamin D status, cord parathyroid hormone and bone-specific alkaline phosphatase, and newborn whole body bone mineral content. Nutrients. 2012;4(2):68–77. https://doi.org/10.3390/nu4020068.
Prentice A, Jarjou LM, Goldberg GR, Bennett J, Cole TJ, Schoenmakers I. Maternal plasma 25-hydroxyvitamin D concentration and birthweight, growth and bone mineral accretion of Gambian infants. Acta Paediatr. 2009;98(8):1360–2. https://doi.org/10.1111/j.1651-2227.2009.01352.x.
Green HD, D’Angelo S, Cooper C, Harvey NC, Moon RJ. P300: vitamin D supplementation during pregnancy increases offspring birth weight and calcium status: a systematic review and meta-analysis World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (WCO-IOF-ESCEO 2022). Aging Clin Exp Res. 2022;34(Suppl 1):35–474. https://doi.org/10.1007/s40520-022-02147-3.
Cooper C, Harvey NC, Bishop NJ, Kennedy S, Papageorghiou AT, Schoenmakers I, et al. Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial. Lancet Diabetes Endocrinol. 2016;4(5):393–402. https://doi.org/10.1016/s2213-8587(16)00044-9.
Vaziri F, Dabbaghmanesh MH, Samsami A, Nasiri S, Shirazi PT. Vitamin D supplementation during pregnancy on infant anthropometric measurements and bone mass of mother-infant pairs: a randomized placebo clinical trial. Early Hum Dev. 2016;103:61–8. https://doi.org/10.1016/j.earlhumdev.2016.07.011.
Curtis EM, Moon RJ, D’Angelo S, Crozier SR, Bishop NJ, Gopal-Kothandapani JS, et al. Pregnancy vitamin D supplementation and childhood bone mass at age 4 years: findings from the Maternal Vitamin D Osteoporosis Study (MAVIDOS) Randomized Controlled Trial. JBMR Plus. 2022;6(7):e10651. https://doi.org/10.1002/jbm4.10651.
Brustad N, Garland J, Thorsen J, Sevelsted A, Krakauer M, Vinding RK, et al. Effect of high-dose vs standard-dose vitamin D supplementation in pregnancy on bone mineralization in offspring until age 6 years: a prespecified secondary analysis of a double-blinded, randomized clinical trial. JAMA Pediatr. 2020;174(5):419–27. https://doi.org/10.1001/jamapediatrics.2019.6083.
O’Callaghan KM, Shanta SS, Fariha F, Harrington J, Mahmud AA, Emdin AL, et al. Effect of maternal prenatal and postpartum vitamin D supplementation on offspring bone mass and muscle strength in early childhood: follow-up of a randomized controlled trial. Am J Clin Nutr. 2022;115(3):770–80. https://doi.org/10.1093/ajcn/nqab396.
Sahoo SK, Katam KK, Das V, Agarwal A, Bhatia V. Maternal vitamin D supplementation in pregnancy and offspring outcomes: a double-blind randomized placebo-controlled trial. J Bone Miner Metab. 2017;35(4):464–71. https://doi.org/10.1007/s00774-016-0777-4.
Harvey NC, Javaid K, Bishop N, Kennedy S, Papageorghiou AT, Fraser R, et al. MAVIDOS Maternal Vitamin D Osteoporosis Study: study protocol for a randomized controlled trial. The MAVIDOS Study Group Trials. 2012;13:13. https://doi.org/10.1186/1745-6215-13-13.
Moon RJ, Harvey NC, Cooper C, D’Angelo S, Curtis EM, Crozier SR, et al. Response to antenatal cholecalciferol supplementation is associated with common vitamin D-related genetic variants. J Clin Endocrinol Metab. 2017;102(8):2941–9. https://doi.org/10.1210/jc.2017-00682.
Moon RJ, Harvey NC, Cooper C, D’Angelo S, Crozier SR, Inskip HM, et al. Determinants of the maternal 25-hydroxyvitamin D response to vitamin D supplementation during pregnancy. J Clin Endocrinol Metab. 2016;101(12):5012–20. https://doi.org/10.1210/jc.2016-2869.
Moon RJ, Cooke LDF, D’Angelo S, Curtis EM, Titcombe P, Davies JH, et al. Maternal and fetal genetic variation in vitamin D metabolism and umbilical cord blood 25-hydroxyvitamin D. J Clin Endocrinol Metab. 2022. https://doi.org/10.1210/clinem/dgac263.
Harvey NC, Moon RJ, Sayer AA, Ntani G, Davies JH, Javaid MK, et al. Maternal antenatal vitamin D status and offspring muscle development: findings from the Southampton Women’s Survey. J Clin Endocrinol Metab. 2014;99(1):330–7. https://doi.org/10.1210/jc.2013-3241.
Mehta G, Roach HI, Langley-Evans S, Taylor P, Reading I, Oreffo RO, et al. Intrauterine exposure to a maternal low protein diet reduces adult bone mass and alters growth plate morphology in rats. Calcif Tissue Int. 2002;71(6):493–8. https://doi.org/10.1007/s00223-001-2104-9.
Pillai SM, Sereda NH, Hoffman ML, Valley EV, Crenshaw TD, Park YK, et al. Effects of poor maternal nutrition during gestation on bone development and mesenchymal stem cell activity in offspring. PLoS One. 2016;11(12):e0168382. https://doi.org/10.1371/journal.pone.0168382.
Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr. 2005;135(6):1382–6.
Murphy SK, Adigun A, Huang Z, Overcash F, Wang F, Jirtle RL, et al. Gender-specific methylation differences in relation to prenatal exposure to cigarette smoke. Gene. 2012;494(1):36–43. https://doi.org/10.1016/j.gene.2011.11.062.
Curtis EM, Krstic N, Cook E, D’Angelo S, Crozier SR, Moon RJ, et al. Gestational Vitamin D Supplementation Leads to Reduced Perinatal RXRA DNA Methylation: results From the MAVIDOS Trial. J Bone Miner Res. 2019;34(2):231–40. https://doi.org/10.1002/jbmr.3603.
Harvey NC, Sheppard A, Godfrey KM, McLean C, Garratt E, Ntani G, et al. Childhood bone mineral content is associated with methylation status of the RXRA promoter at birth. J Bone Miner Res. 2014;29(3):600–7. https://doi.org/10.1002/jbmr.2056.
Harvey NC, Lillycrop KA, Garratt E, Sheppard A, McLean C, Burdge G, et al. Evaluation of methylation status of the eNOS promoter at birth in relation to childhood bone mineral content. Calcif Tissue Int. 2012;90(2):120–7. https://doi.org/10.1007/s00223-011-9554-5.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
RJM has received travel bursaries from Kyowa Kirin unrelated to this work. NCH reports personal fees, consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Shire, UCB, Kyowa Kirin, Consilient Healthcare and Internis Pharma, outside the submitted work.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Moon, R.J., Citeroni, N.L., Aihie, R.R. et al. Early Life Programming of Skeletal Health. Curr Osteoporos Rep 21, 433–446 (2023). https://doi.org/10.1007/s11914-023-00800-y
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11914-023-00800-y