Early life factors and the development of peak bone mass

\\({Background:}\\) Osteoporosis and osteoporotic fractures are major public health problems. Optimizing peak bone mass (PBM) is critical to the prevention of osteoporosis in later life. The role of genetic components and environmental factors in the PBM remains uncertain. There are only few prospective studies followed from infancy through to adult life. Moreover, bone outcomes in previous studies are limited to areal bone mineral density (BMD), which is only one factor contributing to bone strength. Therefore, this thesis aimed to evaluate the magnitude of genetic contributions to PBM and the association of early-life exposures with bone development from birth to young adulthood when PBM is achieved. \\({Methods:}\\) We performed a 25-year follow-up from our original birth cohort in Tasmanian Infant Health Survey (TIHS) in 1988 and 1989. The pregnant mothers were invited in our original study and then both mothers and offspring were followed when offspring were aged 8, 16 and 25 years. Outcomes measured were offspring's areal BMD at the spine, hip, and total body by dual-energy x-ray absorptiometry (DXA) at each follow-up and trabecular and cortical bone measures at the distal radius and tibia by high-resolution peripheral quantitative computed tomography (HRpQCT) at age 25 years. Early life exposures included breastfeeding, maternal smoking and birth weight obtained from the child's medical record and postnatal questionnaires. Serum 25-hydroxyvitamin D (25OHD) concentrations were measured and fractures were self-reported and confirmed by radiographs at each follow-up. Other factors measured were anthropometrics, lean mass (LM), and fat mass (FM) (by DXA), inhaled corticosteroids (ICS) usage, sports participation, and fitness (by physical work capacity (PWC\\(_{170}\\))). Multivariable linear regressions were used to analyse the associations of the exposures with all bone measures. \\({Results:}\\) There were 201 participants followed up from birth to age 25 years. We found: 1) Genetic factors have an important role in the development of bone microarchitecture in young adulthood measured by HRpQCT with heritability estimates ranging from 24% to 74% within mother-offspring pairs; this heritability was strongly shared for the radius and tibia and varied by sex; 2) Areal BMD tracks strongly from childhood to young adulthood (correlation coefficients: males, 0.59 to 0.65; females, 0.70 to 0.82) and this is largely independent of linear growth; increasing LM in both sexes, more fitness and sports participation in males from age 8 to 25 years had positive associations with BMD at age 25 years; 3) For early life exposures: breastfeeding was beneficially ( standardised coefficient =- 0.78 to 0.88) and maternal smoking was detrimentally (standardised coefficient = -0.38 to 0.41) associated with volumetric BMD and bone microarchitecture in young adulthood; associations of birth weight with these bone measures did not persist after adjustment for weight gain since birth; 4) Serum 25OHD concentrations at age 16 significantly associated with BMD and bone microarchitecture at age 25 (standardised coefficient = -0.17 to 0.18). However, serum 25OHD at age 8 had no association with any bone measures and serum 25OHD at age 25 was only associated with hip BMD (standardised coefficient = 0.18); 5) Pre-pubertal fractures were significantly associated with a smaller increase in areal BMD from age 8 to 25 compared to participants with no fractures and were negatively associated with volumetric BMD and microarchitecture measures at age 25 years (coefficient = -27.59 to 2.60). However, pubertal fractures had no association with any bone measures and postpubertal fractures only with a lower Trabecular number (coefficient = -0.22). \\({Conclusions:}\\) These findings suggest that both genetic and environmental factors play an important role in the development of PBM and improvement of microarchitecture in young adulthood. Strategies like encouraging breastfeeding and avoiding maternal smoking, improving LM, fitness and sport participation, optimising vitamin D status particularly during adolescence and preventing fractures in the pre-pubertal years may help optimise bone development and thereby reduce the risk of osteoporotic fracture in later life.