Disentangling the Heterogeneity of Bone Accrual

Bone accrual during childhood and adolescence largely determines the peak (maximal) bone mass achieved approximately in the third decade of human life. This process is essential to assess the risk of fracture throughout life. This thesis aimed to disentangle the multifactorial process of bone accretion in children including fetal exposures influencing early programming of the trait, possible effect of body size and composition during growth in bone status and innate genetic factors affecting bone mineral density at school age. We found that modifiable factors as maternal phosphorous intake, homocysteine concentrations, vitamin B-12 concentration and protein intake partly determine the amount of bone mass of the children at six years, whilst fetal and infant growth, as well as muscle attainment, are strongly correlated with the process of bone accrual. In addition, this dissertation emphasizes in the genetic factors influencing pediatric bone mineral density (BMD). Between 35 -50% of the pediatric BMD variability is explained by genetic polymorphisms. These genetic variants affect bone in a site- and age-specific manner and can as well impact simultaneously other body composition traits. In total, we identified 14 different loci associated with pediatric BMD. It is worth remaking the pivotal role of the 7q31.31 locus, harboring the WNT16 gene, in bone acquisition. The mechanistic biological role of WNT16 in osteoblastogenesis conveys pharmaceutical potential for the treatment of bone loss later in life. Additionally, the results of this thesis are in agreement with the contention that ethnic differences in BMD are partly explained by genetic factors. Children from African background carry a higher number of BMD-increasing variants than children of non-African background. Moreover, we found evidence pointing to natural selection as the engine driving these genetic patterns. In summary, this research provides a first glance to the genetics of bone accrual and highlights the importance of a healthy lifestyle for early life for bone health, which could effectively reduce the risk of osteoporosis later in life.