Animal studies

Complementary to in vitro investigations, studies in animals can address questions concerning bone tissue related to systemic withdrawal and re-administration of aromatizable and non-aromatizable androgens, especially in regard to bone histo-morphometry, where study designs are not feasible in humans.

The simplest approach to assess sex steroid effects in male animals is orchiec-tomy. The majority of such trials has been performed in rats, in which androgen

Fig. 7.1 Role of testosterone (T) in bone metabolism. The nature of exerted influence is indicated by plus (positive) or minus (negative) signs on the arrows. Abbreviations: OB: osteoblast, OC: osteoclast, OPG: osteoprotegerin, RANKL: receptor activator of nuclear kappaB-ligand, IL-6: interleukin 6, Vit. D: vitamin D, mech. strain: mechanical strain, PTH: parathyroid hormone. The broken lines symbolize putative non-genomic action.

Fig. 7.1 Role of testosterone (T) in bone metabolism. The nature of exerted influence is indicated by plus (positive) or minus (negative) signs on the arrows. Abbreviations: OB: osteoblast, OC: osteoclast, OPG: osteoprotegerin, RANKL: receptor activator of nuclear kappaB-ligand, IL-6: interleukin 6, Vit. D: vitamin D, mech. strain: mechanical strain, PTH: parathyroid hormone. The broken lines symbolize putative non-genomic action.

effects depend both on age and the type of bone examined. In younger male rats, orchiectomy results in reduction of calcium content of long bones and increment of tibial osteoclasts (Saville 1969; Schoutens etal. 1984). Neither the cross-sectional bone area, nor its medullary or cortical compartment is altered by castration of young rats, but the periosteal cortical bone formation rate is reduced (Gunness and Orwoll 1995; Turner et al. 1989). In trabecular bone, osteoclast density increases after orchiectomy, resulting in loss of bone tissue. (Gunness and Orwoll 1995; Turner et al. 1989; Wakley et al. 1991). Corresponding effects were also seen in young orchiectomized beagle dogs: The mean trabecular thickness and the fraction of labeled osteoid surface decreased significantly three months after orchidec-tomy, but other histomorphometric parameters were unchanged. In the period 7-12 months after orchidectomy, bone volume, mean trabecular thickness, and the fraction of labeled trabecular surface decreased significantly compared with the pre-orchidectomy values (Fukuda and Jida 2000).

In older rats, orchiectomy results in reduction of the calcium content in femur and tibia, which is due to a loss of cortical thickness without affecting of bone density (Vanderschueren et al. 1992; Verhas et al. 1982). Nevertheless, trabecular bone mass is reduced in these animals (Vanderschueren et al. 1992; Wink and Felts 1980). Such was also seen in the cancellous bone area of the proximal tibia of castrated male rats (Erben et al. 2000). The effect was related to an increase of tissue turnover facilitated by invasion of osteoclasts to the trabecular surface. All these effects on the skeleton of rats can be prevented by administration of aromatizable or non-aromatizable androgens (Vanderschueren et al. 1992). This was also observed in orchiectomized, testosterone-substituted estrogen-receptor-a knock-out mice (Vandenput etal. 2001) or castrated, androgen-supplemented and estrogen-receptor blocked rats (Vandenput et al. 2002), suggesting an androgen-receptor mediated effect. There are indications that the modulating influence of androgens on apoptosis of bone-morphogenetic cells is, at least partially and in mice, non-genomic (Kousteni et al. 2002). In contrast, there exists a significant influence of the CAG repeat polymorphism of the androgen receptor gene, which is associated with the transcriptional activity of androgen target genes, on bone density and bone turnover in humans (see Chapters 2 and 3).

In androgen-receptor knock-out (ARKO) mice, bone density of both femur and tibia was reduced in comparison to wild-type (WT) litter-mates. In a controlled model using orchiectomy in both ARKO and WT mice, bone density could be fully restored by testosterone substitution in the WT mice. A significant increment of bone density during testosterone substitution was also seen in the orchiectomized ARKO mice, but this was still markedly blunted in comparison to WT mice. This suggests a partial effect of aromatization mediated by the estrogen receptor and, simultaneously, that for full restoration of bone tissue, the androgen receptor is necessary. When the non-aromatizable androgen dihydrotestosterone was given to orchiectomized ARKO and WT mice, no effect on bone tissue was seen in the knockout animals, while the WT mice exhibited a significant increment of bone density; the latter effect was, nevertheless, blunted in comparison to effects of aromatizable testosterone in orchiectomized WT mice, again suggesting the crucial role of both the androgen and estrogen receptor and, hence, both sex steroids, for complete beneficial effects on bone metabolism (Kawano etal. 2003) (also see 7.2.5).

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