Morphological Determinants of Femoral Strength in Growth Hormone-Deficient Transgenic Growth-Retarded (Tgr) Rats

Abstract

The extent to which childhood GHD affects adult fracture risk is unclear. We measured femoral strength in adult transgenic growth-retarded rats as a model of GHD. Long-term, moderate GHD was accompanied by endocrine and morphometric changes consistent with a significant reduction in femoral strength.Introduction: Childhood growth hormone deficiency (GHD) is associated with osteopenia, but little is known about its effects on subsequent adult bone strength and fracture risk. Materials and Methods:We have therefore measured femoral strength (failure load measured by three-point bending) in a new model of moderate GHD, the transgenic growth-retarded (Tgr) rat at 15, 22-23, and 52 weeks of age, and have quantified potential morphological and endocrine determinants of bone strength. Results: Skeletal growth retardation in Tgr rats was accompanied by a sustained reduction in the anterior-posterior diameter of the femoral cortex, whereas mid-diaphyseal cortical wall thicknesses were largely unaltered. Total femoral strength was significantly impaired in Tgr rats (p Ͻ 0.01), and this impairment was more pronounced in males than females. Compromised bone strength in Tgr rats could not be accounted for by the reduction in mechanical load (body weight) and was not caused by impairment of the material properties of the calcified tissue (ultimate tensile stress), despite marked reductions in femoral mineral density (areal bone mineral density; p Ͻ 0.001). Microcomputerized tomographical analysis revealed significant modification of the architecture of trabecular bone in Tgr rats, with reductions in the number and thickness of trabeculae (p Ͻ 0.05) and in the degree of anisotropy (p Ͻ 0.01). The marked reduction in plasma insulin-like growth factor-1 in Tgr rats was accompanied by the development of high circulating leptin levels (p Ͻ 0.01). Conclusion: These results show that the changes in endocrinology and bone morphology associated with long-term moderate GHD in Tgr rats are accompanied by changes consistent with a significant reduction in the threshold for femoral fracture.

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

“…This obese phenotype, which is observed in childhood onset GH deficiency (Growth Hormone Research Society 2000, Raine et al 2006), is also present in the Tgr rat (Evans et al 2003, Davies et al 2007), but we have shown that the more profoundly GH-deficient dw/dw rat is surprisingly lean and hypoleptinaemic (Davies et al 2007). 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.…”

“…SD rats used in study 3 were purchased from Charles River (Margate, UK) and maintained under the same conditions in the School of Biosciences, Cardiff University. Rats were permitted ad libitum access to food and water, standard chow animals used in these studies was calculated from our previously published endocrine and metabolic studies (Evans et al 2003, Thompson et al 2004, Davies et al 2007) using the Lenth's Power and Sample Size software (Lenth RV (2006) Java Applets for Power and Sample Size (Computer software), retrieved 20/02/2003 from http://www.stat.uiowa.edu/wrlenth/Power), with the power set at O75% and assuming S.D.s of 32 and 36% for two-group t-test and one-way ANOVA four-group comparisons respectively. Study 1: transpubertal development of trabecular organisation in Tgr and dw/dw rats Groups of non-fasting 3-, 6-, 9-and 52-week-old male wt, Tgr and dw/dw rats (nZ3-6) from the Cardiff colonies were weighed, anaesthetised with halothane and killed by decapitation.…”

“…Figure 1 Diagrammatic representation of the GH and adiposity status of the rat models of GH deficiency used in the present study. Scaled silhouettes (with adiposity in grey) show relative body length and adiposity (based upon % body weight of retroperitoneal fat) with circulating GH, IGF1 and leptin as normalised to their wt (AS) controls (Charlton et al 1988, Legraverend et al 1992, Flavell et al 1996, Wells et al 1997, Evans et al 2003, Davies et al 2007). …”

“…In the Tgr rat, expression of human GH in the arcuate GH releasing hormone neurones produces moderate GH deficiency (Flavell et al 1996, Wells et al 1997, accompanied by obesity and hyperleptinaemia ( Fig. 1; Evans et al 2003, Davies et al 2007. In contrast, an unknown spontaneous mutation in the dw/dw rat leads to profound GH deficiency (Charlton et al 1988, Legraverend et al 1992) and a similar degree of growth retardation, accompanied by leanness and hypoleptinaemia ( Fig.…”

Introduction of a new interlocked intramedullary nailing device for stabilization of critically sized femoral defects in the rat: A combined biomechanical and animal experimental study

“…2,3 Thus, scientific effort focuses on the analysis of bony healing processes in large defects and on possibilities to reduce the healing time using a variety of techniques (e.g., growth factors and stem cells). [4][5][6][7][8] A major drawback of experimental studies is the lack of stable intramedullary fracture fixation, especially in small animals. 9,10 Single K-wire stabilization is widely used for fracture care in small animals.…”