Does adiposity status influence femoral cortical strength in rodent models of growth hormone deficiency?

Abstract

Growth hormone (GH)-deficiency is usually associated with elevated adiposity, hyperleptinemia, and increased fracture risk. Since leptin is thought to enhance cortical bone formation, we have investigated the contribution of elevated adiposity and hyperleptinemia on femoral strength in rodent models of GH deficiency. Quantification of the transpubertal development of femoral strength in the moderately GH-deficient/hyperleptinemic Tgr rat and the profoundly GH-deficient/hypoleptinemic dw/dw rat revealed that the mechanical properties of cortical bone in these two models were similarly compromised, a 25-30% reduction in failure load being entirely due to impairment of geometric variables. In contrast, murine models of partial (GH antagonist transgenic) and complete (GH receptor-null) loss of GH signaling and elevated adiposity showed an impairment of femoral cortical strength proportionate to the reduction of GH signaling. To determine whether impaired femoral strength is exacerbated by obesity/hyperleptinemia, femoral strength was assessed in dw/dw rats following two developmental manipulations that elevate abdominal adiposity and circulating leptin, neonatal monosodium glutamate (MSG) treatment, and maintenance on an elevated fat diet. The additional impairment of femoral strength following MSG treatment is likely to have resulted from a reduction in residual activity of the hypothalamo-pituitary-GH-IGF-I axis, but consumption of elevated dietary fat, which did not reduce circulating IGF-I, failed to exacerbate the compromised femoral strength in dw/dw rats. Taken together, our data indicate that the obesity and hyperleptinemia usually associated with GH deficiency do not exert a significant influence over the strength of cortical bone.

The influence of leptin on trabecular architecture and marrow adiposity in GH-deficient rats

“…This difference in trabecular structure between the two models was more pronounced than our measurements of cortical strength (Stevenson et al 2009). When seen in the light of the similar degree of insulin-like growth factor 1 (IGF1) deficiency reported in these models (Davies et al 2007; Fig.…”

“…However, it is clear from the present data that, during the early pubertal period (before 6 weeks of age), this impairment of cortical strength is not matched by impaired trabecular architecture, even in the model of profound GH deficiency. This divergent influence of GH on the regulation of cortical and trabecular bone has also been reported in GH receptor/ binding protein-null mice, which show normal trabecular bone volume (Venken et al 2007) despite a marked reduction in cortical diameter and strength (Stevenson et al 2009). Following the rapid growth phase (from 9 weeks of age), however, the number, shape and connectivity of the femoral trabeculae become progressively impaired in GH-deficient rats.…”

“…Our data indicate that while elevated truncal adiposity and circulating leptin normally seen in GH deficiency make a negligible contribution to the impairment of trabecular structure in long bones, elevating leptin in the marrow compartment may reduce the number of marrow adipocytes and increase osteoblast surface. We have previously reported that cortical strength is significantly compromised in both juvenile and adult GH-deficient rats (Evans et al 2003, Stevenson et al 2009). However, it is clear from the present data that, during the early pubertal period (before 6 weeks of age), this impairment of cortical strength is not matched by impaired trabecular architecture, even in the model of profound GH deficiency.…”

“…However, it is becoming clear that the relationship between the degree of GH deficiency and the impairment of bone strength is not simple. For example, we have shown that the compromised strength of the femoral cortex in the moderately GH-deficient transgenic growth retarded (Tgr) rat is similar to that in the profoundly GH-deficient dwarf (dw/dw) rat (Stevenson et al 2009). This suggests that the impairment of bone strength in GH deficiency may be partially determined by other related variables.…”

“…This difference is potentially significant, since low levels of circulating leptin are associated with prevention of bone loss (Martin et al 2007), and high leptin and extreme obesity are accompanied by decreased bone formation (Martin et al 2007, Núñez et al 2007. However, developmental manipulations to elevate adiposity and circulating leptin in the dw/dw rat failed to affect the biomechanical properties of the femoral cortex (Stevenson et al 2009), suggesting that, in the cortex at least, adiposity is not a determinant of strength. Evidence is now emerging that the actions of leptin in bone are site specific, enhancing the formation of cortical bone (Hamrick et al 2005, Guidobono et al 2006) but inducing bone loss in trabecular structures (Ducy et al 2000, Guidobono et al 2006.…”