Advances in the Endocrine Role of the Skeleton

Excess adiposity in childhood may affect bone development, ultimately leading to bone frailty. Previous reports showing an increased rate of extremity fractures in children with obesity support this fear. On the other hand, there is also evidence suggesting that bone mineral content is higher in obese children than in normal weight peers. Both adipocytes and osteoblasts derive from multipotent mesenchymal stem cells (MSCs) and obesity drives the differentiation of MSCs toward adipocytes at the expense of osteoblast differentiation. Furthermore, adipocytes in bone marrow microenvironment release a number of pro-inflammatory and immunomodulatory molecules that up-regulate formation and activation of osteoclasts, thus favoring bone frailty. On the other hand, body adiposity represents a mechanical load, which is beneficial for bone accrual. In this frame, bone quality, and structure result from the balance of inflammatory and mechanical stimuli. Diet, physical activity and the hormonal milieu at puberty play a pivotal role on this balance. In this review, we will address the question whether the bone of obese children and adolescents is unhealthy in comparison with normal-weight peers and discuss mechanisms underlying the differences in bone quality and structure. We anticipate that many biases and confounders affect the clinical studies conducted so far and preclude us from achieving robust conclusions. Sample-size, lack of adequate controls, heterogeneity of study designs are the major drawbacks of the existing reports. Due to the increased body size of children with obesity, dual energy absorptiometry might overestimate bone mineral density in these individuals. Magnetic resonance imaging, peripheral quantitative CT (pQCT) scanning and high-resolution pQCT are promising techniques for the accurate estimate of bone mineral content in obese children. Moreover, no longitudinal study on the risk of incident osteoporosis in early adulthood of children and adolescents with obesity is available. Finally, we will address emerging dietary issues (i.e., the likely benefits for the bone health of polyunsaturated fatty acids and polyphenols) since an healthy diet (i.e., the Mediterranean diet) with balanced intake of certain nutrients associated with physical activity remain the cornerstones for achieving an adequate bone accrual in young individuals regardless of their adiposity degree.

The multiple endocrine functions of bone other than those related to mineral metabolism, such as regulation of insulin sensitivity, glucose homeostasis, and energy metabolism, have recently been discovered. In vitro and murine studies investigated the impact of several molecules derived from osteoblasts and osteocytes on glucose metabolism. In addition, the effect of glucose on bone cells suggested a mutual cross-talk between bone and glucose homeostasis. In humans, these mechanisms are the pivotal determinant of the skeletal fragility associated with both type 1 and type 2 diabetes. Metabolic abnormalities associated with diabetes, such as increase in adipose tissue, reduction of lean mass, effects of hyperglycemia per se, production of the advanced glycation end products, diabetes-associated chronic kidney disease, and perturbation of the calcium-PTH-vitamin D metabolism, are the main mechanisms involved. Finally, there have been multiple reports of antidiabetic drugs affecting the skeleton, with differences among basic and clinical research data, as well as of anti-osteoporosis medication influencing glucose metabolism. This review focuses on the aspects linking glucose and bone metabolism by offering insight into the most recent evidence in humans.