In this pre-pubertal, free-living population, fat mass, adjusted for lean mass, was associated positively with bone size but negatively with true volumetric density assessed by pQCT, across the whole fat mass distribution.
We recruited children from a free-living population cohort and used objective measures of body composition and bone size and density. However, there are several limitations to our study. We were only able to study a proportion of the original cohort. However the children who underwent the 6 year assessment did not differ at birth or 1 year old from those who did not. Mothers of children who underwent 6 year assessment were broadly similar to mothers of those children who did not, but were more likely to be of higher social class and less likely to smoke. However, as the analysis is based on internal comparisons it is difficult to envisage how this would have spuriously shown an association between fat mass and bone size and density. The study population included a very small number of non-white Caucasian children and therefore it is uncertain whether our findings may be generalisable across these other ethnic groups. Secondly we used DXA to measure bone mass. This technique is associated with technical limitations in children. Measurement of bone mineral in young children is hampered by their tendency to move and also by their low absolute BMC. However, we used specific paediatric software, and movement artefact was modest and uniform across the cohort; those few children with excessive movement were excluded from the analysis. DXA measures of bone mass have been shown to correlate well with whole body calcium content in ashing studies of piglets[13
]. Finally, we used a number of adjustments in the analyses, for example adjusting fat mass for lean mass. There is a biological rationale for this approach, as described in the methods, but as a result of co-linearity between measurements, it is possible that some analyses were over-adjusted; our conclusions are supported, however, by the results from the unadjusted analyses.
Children who are overweight have approximately a twofold increased risk of forearm fractures compared with controls[15
]. A recent study has shown that among obese children with a history of fracture, lumbar spine bone mineral apparent density was reduced by 2-3SD compared with non-obese children with a history of fracture[16
]. Thus at least part of the increased risk of fracture in obese children may be mediated via reduced bone density rather than other factors such as increased risk of falling. Our findings are in accord with some, but not all, studies of pre-pubertal children using DXA and pQCT. Thus fat mass adjusted for lean mass was positively associated with whole body bone area and bone mineral content in a large cohort in the South of England[2
]. Volumetric density was not reported in this study however. Other studies with DXA have shown children with higher fat mass to have reduced BMC[4
] for their body size. In a cohort of 239 children, aged 3 to 5 years old, percentage fat mass was positively associated with bone size but negatively with volumetric density measured by pQCT at the tibia[8
]. A more recent study from the same group examined cross-sectional and then longitudinal relationships between body composition and pQCT measured bone indices. In this cohort of 370 children, aged 8 to 18 years, body composition was assessed by DXA at baseline and children were followed up with pQCT up to 90 months later[9
]. In contrast to our study, pQCT measurements were obtained at the radius, a non-weight-bearing site, but longitudinally at the 4% site there were negative relationships between percentage fat mass and volumetric density. Interestingly in this study cross-sectional and some longitudinal relationships between fat mass and bone size were also negative, suggesting possible discordant effects of fat mass on upper and lower limbs (perhaps indicating differential importance of endocrine vs mechanical mechanisms on non weight bearing and weight bearing limbs). This study also raises the possibility of differential influences of fat over time on childhood growth.
We observed that the relationships between lean adjusted total fat mass and the DXA indices and trabecular density measured by pQCT appeared stronger in the boys than the girls. There are very few data in the literature pertaining to gender differences in the relationships between body composition and bone measures, particularly in young children. Associations between total fat mass and BMC measured at the lumbar spine, hip and radius appeared stronger in boys than girls in one population based study in children aged 10 to 17 years[17
]. A larger study of 926 children aged 6 to 18 years, found similar relationships between total fat mass and bone mineral content in boys and girls before puberty but only in girls after puberty[18
]. A further study observed opposing influences of age and menache on the fat-bone relationship in female children[9
] , supporting the notion that hormonal factors such as oestrogen might be important here, but clearly further work will be needed to elucidate any potential mechanisms that might underlie these observations.
There are several mechanisms whereby obesity might influence bone size and density: firstly by directly applying a greater load to the skeleton; secondly via an increase in compensatory muscle mass and thirdly via modulation of physiological and biochemical parameters. The first two of these mechanisms would suggest a positive relationship between fat mass and bone and perhaps could explain the positive relationships with bone size, but not the negative associations with volumetric density. Additionally we found that the positive associations between fat mass and bone size and the negative associations between fat mass and volumetric density persisted after adjustment for lean mass, suggesting that the relationships were not mediated by muscle mass.
The emerging evidence that fat is not an inert tissue, but a highly active endocrine organ, yields some additional possible explanations. Adipocytes produce leptin, a peptide hormone involved in the regulation of fat metabolism and appetite through hypothalamic mechanisms[19
]. Recent work in animals has suggested that the primary effect of leptin on bone formation is negative via hypothalamic action on the sympathetic nervous system[20
]. How this relates to mechanisms in humans is as yet unclear. Conversely leptin may push mesenchymal stem cells towards differentiation to osteoblasts rather than adipocytes[21
] and leptin receptors have been found on osteoblasts, chondrocytes and bone marrow stromal cells[23
]. Thus it is possible that leptin may explain some of the relationship between fat mass and bone, both positive and negative. Adiponectin is another hormone released by adipocytes; in contrast to leptin it is negatively related to overall fat mass. Adiponectin is associated with increased insulin sensitivity and improved glucose tolerance. A recent study from a large UK cohort related adiponectin, measured at 9.9 years, cross-sectionally to bone indices measured by DXA, and longitudinally to those measured by pQCT at 15.5 years[24
]. The direct relationships between fat mass and volumetric density were not reported but total fat mass was negatively related to adiponectin concentration, which in turn negatively predicted volumetric density at 15.5 years. It seems unlikely, therefore, that adiponectin could explain negative relationships between fat mass and volumetric bone density. Insulin has been shown to have positive effects on bone in animal studies[25
], with insulin resistance (and higher levels of insulin, as might be found in obesity) associated with increased BMD[26
] and reduced fracture risk in humans[29
]. Finally, recent work has suggested a role for peroxisome proliferator-activated receptors (PPARs) in the regulation of bone mass; reduced osteoblast function[30
], increased osteoclastogenesis[32
] and altered adipocyte/ osteoblast differentiation[33
] have been demonstrated in animal studies; thiazolidinedione drugs, which activate PPAR-gamma, have been shown to increase fracture risk[34
]. Subtypes of these nuclear receptors also have a role in regulating insulin sensitivity and lipid metabolism[35
], and thus are likely to relate to obesity, but there are currently insufficient data to allow detailed conclusions regarding any bone-related role in humans to be made.
In summary we have demonstrated that increased lean-adjusted fat mass is related to increased bone size but decreased volumetric bone density at the tibia. These results suggest that there is a negative relationship between total fat mass and volumetric density of the tibia across the distribution of fat mass, independent of lean mass. Given the importance of peak bone mass for future fracture risk, obesity in childhood could be a major target for public health interventions aimed at optimising bone health.