Fat mass and bone development

Several studies suggest there is a positive relationship between fat mass and bone mineral density (BMD) in adults, particularly in postmenopausal women [1]. Whether a similar association exists in children, implying that fat mass helps the development as well as maintenance of bone, is more controversial. In a cross sectional study, we previously reported that fat mass is positively related to total body bone mass independently of lean mass and height in 3082 boys and girls at a mean age of 9.9 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) [2]. In this investigation, an equivalent relationship was observed between fat mass and bone size, which is closely related to bone mass, suggesting that a relationship between fat mass and bone mass that we found largely reflected an influence on skeletal growth. On the contrary, Janicka et al. found no association between fat mass and bone size at the spine and femur in 300 boys and girls between 13–21 years of age [3]. A possible explanation for these apparently discrepant findings lies in differences in the power of the two studies to estimate potentially complex inter-relationship between bone size, body size, fat mass and lean mass. One method of exploring causal pathways in epidemiological studies is to use a mendelian randomization approach, whereby an instrumental variable related to the exposure of interest, but independent of confounders, is used as a proxy exposure measure. The subsequent observation from ALSPAC that genetic polymorphisms within the two obesity genes, FTO and MC4R, showed similar relationships with bone mass compared with measured fat mass, provides evidence that a causal relationship exists between fat mass and bone mass accrual in childhood [4].

Controversy surrounding a protective effect of fat mass on bone development in childhood has also been stoked by findings that as well as reduced BMD, increased body weight is a risk factor for fractures in childhood, including the risk of repeated fractures [5,6]. However, rather than indicating an adverse effect of fat mass on skeletal development, an alternative explanation for this association is that fracture risk is increased in those children where the underlying relationship between fat mass and bone development is deficient, possibly reflecting a failure of skeletal growth to keep pace with that in height and weight. Consistent with this interpretation, in a prospective study of fractures in ALSPAC, whereas a weak inverse association was observed between BMD and fracture risk, a stronger association was seen between fracture risk and bone size relative to body size [7].

In terms of how fat mass influences skeletal development, a recent study in ALSPAC based on tibial peripheral quantitative computerized tomographic (pQCT) scans obtained in over 4000 children at age 15 years, suggested that fat mass acts to increase cortical bone area by two distinct mechanisms, namely stimulation of outwards growth at the periosteal surface, and suppression of expansion at the inner endosteal surface [8]. The latter action appeared to be more marked in girls compared with boys. To the extent that these components of skeletal structure acquired towards the end of childhood track throughout life, these findings suggest that low fat mass in childhood and adolescence represents a modifiable risk factor for postmenopausal osteoporosis. As such, there is strong justification for research intended to clarify the biological basis for these relationships, and to develop strategies for combating the potentially harmful effects of reduced fat mass, particularly in adolescent girls and their risk of osteoporosis in later life.

In terms of the biological basis for the influence of fat mass on bone development, one possible explanation is that this simply represents a mechanical effect as a consequence of excess weight, for which evidence is currently conflicting. In the ALSPAC study based on analysis of total body dual energy x-ray scans in children, there was no evidence that fat mass is preferentially related to bone mass at weight-bearing sites [2], as also reported in adults [1], which goes against a purely mechanical effect. On the other hand, in a previous pQCT study of around 1000 18-year-old men, fat mass was found to be positively related to cortical bone size as measured at the tibia but not the radius, suggesting a preferential influence of fat mass at weight-bearing sites [9].

To the extent that systemic factors may be involved in mediating the relationship between fat mass and bone mass, a variety of pathways have been suggested to play a role, including pancreatic β cell-derived hormones, adipocyte-derived hormones and a CNS-sympathetic relay involving leptin [1]. Arguably, the most plausible mechanism is that involving endocrine changes associated with insulin resistance, several of which might be expected to lead to gains in fat mass. Insulin and IGF-1, which are both increased in insulin-resistant states, are both known to exert trophic effects on bone. For example, as well as stimulating longitudinal growth, IGF-1 enhances periosteal expansion in animal models [10], which could conceivably contribute to the positive relationship observed between fat mass and cross-sectional area in the children described above. A role of insulin resistance could also involve the adipocyte-derived factor adiponectin, which is inversely related to measures of insulin resistance [11], fat mass [12] and BMD [13]. However, against such a role of adiponectin, though adiponectin appears to be inversely related to measures of bone mass in ALSPAC, this association is largely independent of fat mass [Tobias J et al., Unpublished Data].

In terms of the public health implications of the role of fat mass in bone development, such a relationship raises concerns that reductions in fat mass during childhood and adolescence might affect skeletal development, particularly in girls, with adverse consequences for the risk of postmenopausal osteoporosis in later life. Although this seems a reasonable implication to draw from experimental findings reported to date, the latter have largely comprised observational studies, and evidence from longitudinal investigations that substantial changes in weight have important consequences for bone development is lacking. However, one intriguing example is provided by a report of long-term survivors of childhood leukemia. In the latter group, long-term deficits in trabecular bone mass are well recognized, presumably owing to a combination of effects of the disease and its treatment on bone remodeling in the marrow compartment. However, this group does not appear to be at increased risk of fractures since periosteal circumference of the radius was found to be increased as assessed by pQCT [14]. Although the reason for this increase is unclear, a possible explanation is that this results from the relatively high fat mass commonly observed following successful treatment of childhood leukemia, resulting from a combination of glucocorticoid therapy and reduced physical activity. To the extent that changes in fat mass in childhood influence bone development, this would also have parallels in early postmenopausal women, in whom weight loss following the menopause and a combination of calorie restriction and mild exercise was found to accelerate postmenopausal bone loss [15].

In terms of combating potential adverse consequences of reduced fat mass in childhood and adolescence in terms of skeletal health, there are clearly pressures to reduce fat mass in this age group. This arises not only from social pressures and concerns over body image, particularly in girls, but also from the wider health benefits in view of the increased risk of a range of chronic disorders associated with obesity, such as Type 2 diabetes and cardiovascular disease. These health benefits of reduced obesity have led to numerous public health campaigns intended to reduce obesity in childhood by encouraging children to make appropriate modifications to their diet, and take more exercise such as walking.

Theoretically, reducing obesity by increasing energy expenditure from greater participation in weight-bearing physical activities might have less of an adverse impact on skeletal development than dieting alone, in light of the positive relationship between physical activity and bone mass described in many studies, and the strong association between muscle mass and bone mass. Consistent with this possibility, in the ALSPAC cohort, increased participation in moderate or vigorous physical activity was found to have a positive influence on bone size, which compensated for a negative influence of similar magnitude as a consequence of reduced fat mass [16]. However, bone strain (i.e., deformation relative to bone length) influences bone remodeling activity in proportion to its rate and magnitude, and is directly related to the strength of applied force [17]. Therefore, whereas reductions in fat mass achieved through weight-bearing exercise may be less deleterious to skeletal development compared with reductions achieved by calorie restriction alone, this may only apply to physical activity above a critical threshold. Exercise interventions in children that have been effective in increasing BMD, involving vigorous weight-bearing activities, such as jumping, provide an example of the type of activity likely to be successful in this regard [18]. However, since these activities are only transitory, they are in themselves unlikely to achieve significant weight loss and are therefore best considered as complementary to other activity-based weight-loss programs rather than as a stand-alone intervention.

In conclusion, there is emerging evidence that fat mass represents a positive influence on bone development, particularly in girls, although the biological mechanisms that mediate this effect are currently unclear. In light of this relationship between fat and bone development, current health policies intended to combat childhood obesity might have the unwanted consequence of increasing the risk of osteoporotic fracture in later life, which is in itself a major cause of morbidity and mortality in the elderly. Of the different strategies for achieving weight reduction, increased physical activity may well be less deleterious for skeletal development compared with dieting, particularly if this includes more intense physical activity associated with levels of strain likely to influence bone remodeling activity. Further research is needed to help understand the relationships between physical activity, weight loss and bone development in more detail, and to produce public health policies aimed at optimizing physical activity levels and weight restriction in childhood without adversely affecting skeletal development and the risk of osteoporosis in later life.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.