The purpose of the present study was to determine if bone mass of prepubertal overweight children with pre-diabetes is lower compared to prepubertal overweight children with normal glucose levels. We found that total body BMC was 4% lower in overweight children with pre-diabetes than those without pre-diabetes, after taking into account sex, race, height, and weight or fat-free soft tissue mass. This finding suggests that abnormal glucose regulation may have a negative effect on the growing skeleton prior to puberty.
To our knowledge, this is the first study to examine bone mass in prepubertal overweight children by pre-diabetes status. The notion that pre-diabetes may be associated with reduced bone mass in children was introduced by Afghani el al(18)
in a cohort of Hispanic-American youth, ranging in pubertal development from Tanner I to V. They found total body BMC (unadjusted and adjusted for age, pubertal stage, and FFST mass) to be lower in those with impaired glucose tolerance compared to a normal-glucose group; however, these differences did not reach statistical significance. The same investigators determined relations in their impaired glucose tolerance group and found that total body BMC was significantly and inversely associated with markers of insulin resistance, as determined by OGTT.(18)
In another study that included obese Brazilian adolescents (Tanner Stage V), total body BMC was negatively related to HOMA-IR.(34)
In our study, inverse associations were found not only with markers of insulin resistance but also with C-reactive protein in the overweight kids with pre-diabetes. C-reactive protein is recognized marker of a systemic inflammation associated with cardiovascular risk, but its role in bone metabolism is unclear. Evidence suggests, however, that increased inflammation may reduce osteoblast differentiation as demonstrated in vitro.(35,36)
Collectively, our data along with the two aforementioned pediatric studies may provide preliminary insight for the link between childhood obesity and skeletal fractures; however, the causal order of these cross-sectional associations cannot be determined. Further investigations are warranted that will require prospective study design and sufficient representation of children and adolescents at all stages of growth and development.
Although type 1 diabetes is known to have negative effects on bone metabolism,(37,38)
it was not until recently that type 2 diabetes was considered a potential risk for skeletal fractures.(39,40)
The low bone mass typically associated with type 1 diabetes is thought to contribute to the greater number of skeletal fractures observed in type 1 diabetes patients than in controls.(41,42)
Type 2 diabetes patients, on the other hand, are generally characterized with high BMC and aBMD,(41,43)
although reduced bone size and structure, assessed by 3-dimensional bone imaging, has recently been reported in type 2 diabetic adult men.(44)
This finding, along with animal work,(16)
suggests that increased bone fragility in type 2 diabetes
may not be discerned as much from bone mass as other aspects of skeletal strength such as bone size and structure. Although we did not measure structural parameters of bone strength by 3-dimensional bone imaging, our comparison of total body bone area between groups seems to indicate a smaller bone size in those with pre-diabetes. The mechanism for potential negative effects of impaired glucose metabolism on bone is unknown; however, some hypotheses include increased calcium excretion,(45)
alterations in vitamin D metabolism,(46)
increased concentrations of advanced glycation end-products in collagen,(47)
and increased inflammation.(35)
It is possible that obesity in children promotes both low bone mass accrual and risk for diabetes through events that are mechanistically associated. Recent studies conducted in mice have uncovered the presence of a unique “bone-fat-pancreas” axis that regulates energy homeostasis, coordinates energy partitioning between bone and adipose tissue, and impacts insulin sensitivity.(48,49)
According to Lee et al.,(48)
only the uncarboxylated form of OCN has the capacity to induce insulin secretion and the expression of genes encoding adiponectin and insulin, and ultimately improving glucose metabolism. In contrast, carboxylated OCN was found to have none of these effects. The same researchers further revealed that the adipocyte-derived hormone leptin inhibits bone formation via sympathetic activation.(49)
Decreased bone formation in turn depresses insulin sensitivity and secretion via decreased production of uncarboxylated OCN. In this study, uncarboxlated OCN was significantly lower in the pre-diabetes group compared to the normal-glucose group; however, including uncarboxylated osteocalcin as a covariate in our analyses did not change any of our bone outcomes between groups (data not shown). Given that few human studies exist on the effect of uncarboxylated and carboxylated OCN on the “bone-fat-pancreas” axis, further work in this area is warranted, particularly since it is unclear which form of OCN (carboxylated or uncarboxylated) is associated with metabolism.(50–52)
One of the key findings in this study was that the influence of adiposity on bone mass may depend on the manner in which it accumulates. A limitation of previous pediatric investigations of fat-bone relationships, which were inconclusive, was that most did not investigate the separate influence of total and central adiposity on bone. Because obesity-related metabolic abnormalities are more strongly related to central rather than total adiposity may be another potential explanation for the large body of conflicting data.(53)
To date, three pediatric studies have investigated relations between central adiposity and bone.(54–56)
In these reports, central adiposity was negatively associated with bone mass in Caucasian, African-American, and Hispanic-American children and adolescents(54,55)
and with bone structure in late-adolescent white females.(56)
Although these studies reported relations between central adiposity and bone, they did not discuss(54,55)
their findings between total adiposity and bone. In our study, we found that both total and central adiposity have significant but opposing relations with bone mass. Whereas total fat mass had a positive association with total body bone mass, the central adiposity measurements (VAT and SAAT) had negative relations with total bone mass. In our regression analyses, however, it was VAT and SAAT, rather than total fat mass, that were independent predictors of bone mass. Taken together, it seems that increased central body adiposity, which is more clinically relevant for metabolic abnormalities than increased total body adiposity, could play an adverse role in bone health.
Modifiable factors such as physical activity and diet not only play an important role in obesity and pre-diabetes progression but also impact skeletal development. Thus, it is possible that differences in bone mass found between groups could be attributed to dissimilarities in physical activity and diet. In this study, no significant differences were found between groups for the number of days of moderate and vigorous physical activity; however, we did not collect information on the types of activities performed by the participants. Therefore, it is uncertain the degree to which participants engaged in high-impact physical activities. Certain types of activities with high-impact loading (e.g., artistic gymnastics) have been documented as having a greater positive effect on bone mineral accrual than low-impact loading (e.g., swimming), particularly during growth.(57)
With regard to dietary intake, the groups reported no significant differences in energy, macronutrient and micronutrient intakes. However, it is important to note that the mean self-reported calcium and vitamin D intakes in both groups were considerably lower than the recommended adequate intakes of 1300 mg/day and 5 μg/day, respectively. Given the limitations of childhood dietary recall, it would be preferable to measure calcium absorption/excretion and circulating concentrations of vitamin D. Since obese individuals with impaired glucose metabolism tend to have increased calcium excretion and lower levels of circulating vitamin D,(58)
calcium and vitamin D could be mediating factors in the relations between adiposity, bone, and glucose-insulin metabolism.
Strengths of this study were the comprehensive suite of glucose metabolism parameters collected using robust methodology and the assessment of centralized adiposity by MRI. Furthermore, we minimized the degree of variability in factors known to influence bone, such as body size and maturational status, by comparing two groups of overweight children in Tanner stage I of puberty. A limitation in our study was that we utilized only DXA-derived bone measurements of the total body. Although DXA-derived regional bone measurement would have provided additional information, we recognize the limitations of using DXA in children.(25)
Three-dimensional imaging techniques such as peripheral quantitative computed tomography would afford more definitive information on volumetric BMD and bone geometry and the effect of adiposity and pre-diabetes on the individual cortical and trabecular compartments. Nevertheless, our study findings with total body BMC cannot be disregarded because it is considered one of the preferred bone measurements for the assessment of bone status in youth (reproducibility, low radiation, and lack of areal density-related errors);(25)
and more importantly, total body BMC has been shown to be a good predictor of fracture risk.(59)
Another important limitation to note is that our small sample size did not allow separate analysis of data by males and females or by whites and blacks. Some studies have reported sex and race differences of not only skeletal development but also of fat accumulation and glucose metabolism.(19,20,54,60)
Although determining the effects of pre-diabetes on bone mass by sex and race was not the objective of this study, future work in the area is warranted.
Our study in prepubertal overweight children provides further insight into the fat-bone relationship by taking into account abnormal glucose regulation and associated biochemical parameters. Specifically, our data suggest that pre-diabetic overweight children may be at risk for poor skeletal development. It also appears that central, rather than total adiposity, may be detrimental to bone health.