Puberty is a crucial period for rapid changes in bone mineral, size, geometry, and microarchitecture. The mechanostat theory postulates that increased mechanical loading will affect bone phenotype and strength during development and in later life. Individuals with cystic fibrosis(CF) have an increased risk of developing osteoporosis and fragility fractures in young adulthood, which may be caused by poor growth. The aim was to investigate whether sex and disease status modified the relationship between: 1) puberty and bone, and 2) muscle and bone. This would contribute to the understanding of how sex(malesvs.females) and disease group(CFvs.controls) alters the relationship between bone and muscle in children and adolescents as they transition through puberty and who, on a population level, differ in the prevalence of osteoporosis and risk of fracture in later life. This observational study used novel imaging and muscle assessment techniques to measure bone and muscle parameters in White Caucasian children and adolescents, aged 8 to 16 years, living in the UK, with children with CF(n=65) and controls(n=151). Anthropometry and pubertal status were assessed. Dual energy x-ray absorptiometry, peripheral quantitative computed tomography(pQCT), high-resolution pQCT, and jumping mechanography were used to measure bone and muscle outcomes. ANCOVA with Scheffé post hoc and multiple linear regression tests were performed. Data were adjusted according to the research aims and included covariates; sex, disease group, pubertal stage, age, quadratic age, height, weight, maximum force(Fmax), and maximum power(Pmax). Data are presented as beta-coefficient(%) and p-value, with the significance level set to p<0.05. In height adjusted analyses, among healthy participants, females had smaller bones and lower bone density compared to males. With pubertal maturation, females had lower apparent gains in the distal and proximal total area(Tt.ArandCSA), distal cortical porosity(Ct.Po) and proximal bone strength(SSI) but higher apparent gains in distal and proximal cortical bone density(Ct.BMD,Ct.TMD,vBMD). Females had consistently lower distal total area(total CSA) and density(totalvBMD), distal trabecular density(BV/TV) and number(Tb.N), and proximal cortical area(CSA) compared to males, across all stages of puberty. With increasing muscle force(Fmax), females had higher apparent gains in total body less head bone mineral(TBLH BMC) and bone area(BA), distal total and trabecular density(totalandtrabvBMD) compared to males. In contrast, with increasing muscle power (Pmax), females had higher apparent gains in distal total and cortical densities(D100,Ct.BMDandCt.TMD), and distal trabecular thickness(Tb.Th), and proximal cortical density(corticalvBMD) but lower apparent gains in distal cortical porosity(Ct.Po) and trabecular number(Tb.N) compared to males. In height adjusted analyses, participants with CF had smaller bones and lower bone density compared to controls. With increasing pubertal maturation, participants with CF had lower apparent gains in total body less head bone mineral and bone area, and in distal trabecular density, cortical porosity, and trabecular thickness compared to controls. Participants with CF had consistently lower distal total and cortical area, distal total and trabecular densities and proximal bone strength compared to controls, across all stages of puberty. With increasing muscle force, participants with CF had lower apparent gains in total body less head bone mineral and bone area, distal total density, trabecular density, and trabecular number. In contrast, with increasing muscle