Childhood obesity, bone development, and cardiometabolic risk factors

Abstract

Osteoporosis and obesity are both major public health concerns. It has long been considered that these are distinct disorders rarely found in the same individual; however, emerging evidence supports an important interaction between adipose tissue and the skeleton. Whereas overweight per se may augment bone strength, animal studies suggest that the metabolic impairment that accompanies obesity is detrimental to bone. Obesity during childhood, a critical time for bone development, likely has profound and lasting effects on bone strength and fracture risk. This notion has received little attention in children and results are mixed, with studies reporting that bone strength development is enhanced or impaired by obesity. Whether obesity is a risk factor for osteoporosis or childhood bone health, in general, remains an important clinical question. Here, we will focus on clarifying the controversial relationships between childhood obesity and bone strength development, and provide insights into potential mechanisms that may regulate the effect of excess adiposity on bone.

Keywords: Bone; Children; Fat; Inflammation; Insulin resistance; Obesity.

Published by Elsevier Ireland Ltd.

Figures

Fig. 1

Interrelationships between fat accumulation, bone formation, and bone resorption. Mechanisms involving fat and bone are intricate by nature, since both adipocytes and osteoblasts originate from mesenchymal stem cells in bone marrow. Osteoclasts originate from monocyte/macrophage precursors of hematopoietic stem cells. Adipocytes and macrophages can secrete several cytokines such as TNF-α, IL-1β, and IL-6, which are capable of stimulating osteoclast activity and bone resorption via regulation of the RANKL/RANK/OPG pathway. OPG, a decoy receptor secreted by preosteoblasts, acts as a decoy receptor to RANKL, and therefore inhibits osteoclast activation and bone re-sorption. TNF-α: tumor necrosis factor-α; IL-1β: interleukin-1β; IL-6: interleukin-6.

Fig. 2

Mean (±SE) total body bone mineral content (BMC), bone area, and areal bone mineral density (aBMD) in overweight adolescents with no cardiometabolic risk factors (CMR) (healthy group, n = 55), overweight adolescents with one CMR (1 CMR group, n = 46), and overweight adolescents with two or more CMR (≥2 CMR group, n = 42). a Overall P-value on the basis of analysis of covariance, adjusted for age, sex, race, height and fat-free soft tissue mass. bP < 0.05, significantly different from healthy group (least squares difference adjustment for multiple comparisons). (From J Pediatr, Vol. 158, N.K. Pollock et al., Adolescent obesity, bone mass, and cardiometabolic risk factors, pp. 727–734. Copyright 2011, with permission from Elsevier.)

Fig. 3

Possible pathways leading to suboptimal bone strength due to uncontrolled high glucose levels in conditions of insulin resistance and type 2 diabetes mellitus. The mechanism for how impaired glucose metabolism leads to suboptimal bone strength is still elusive. However, some hypotheses include decreased osteoblast function (i.e., decreasing Runx2, osteocalcin and osteonectin expressions and suppressing osteoblast proliferation), increased osteoclast function (i.e., inducing production of TNF-α, MCSF and RANKL, all of which are osteoblast-derived activators of osteoclast proliferation and differentiation), increased osteocyte function (i.e., increasing sclerostin expression), excessive nonenzymatic glycation (i.e., increasing AGE in the organic bone matrix and suppressing osteoblast differentiation), and alterations in vitamin D endocrine function (i.e., low circulating levels of vitamin D, thereby stimulating production of PTH and reducing calcium absorption). Runx2: Runt-related transcription factor; TNF-α: tumor necrosis factor-α; MCSF: macrophage-colony stimulating factor; RANKL: receptor activator of nuclear factor-κB ligand; PPAR-γ: peroxisomal proliferator-activated receptor gamma; ap2: adipocyte fatty acid binding protein; AGE: advanced glycosylation end-products; PTH: parathyroid hormone.

Fig. 4

Relationships between total body bone mineral content (BMC) and total and central adiposity in overweight adolescents. A, Fat mass versus total body BMC; B, visceral adipose tissue (VAT) versus total body BMC; and C, subcutaneous abdominal adipose tissue (SAAT) versus total body BMC. Relationships are adjusted for age, sex, race, height and fat-free soft tissue mass. N = 143. (From J Pediatr, Vol. 158, N.K. Pollock et al., Adolescent obesity, bone mass, and cardiometabolic risk factors, pp. 727–734. Copyright 2011, with permission from Elsevier.)