Osteoporosis and muscle frailty are important health problems in elderly men and may be partly related to biological androgen activity. This androgen action can be mediated directly through stimulation of the androgen receptor (AR) or indirectly through stimulation of estrogen receptor-alpha (ERalpha) following aromatization of androgens into estrogens. To assess the differential action of AR and ERalpha pathways on bone and body composition, AR-ERalpha double-knockout mice were generated and characterized. AR disruption decreased trabecular bone mass, whereas ERalpha disruption had no additional effect on the AR-dependent trabecular bone loss. In contrast, combined AR and ERalpha inactivation additionally reduced cortical bone and muscle mass compared with either AR or ERalpha disruption alone. ERalpha inactivation--in the presence or absence of AR--increased fat mass. We demonstrate that AR activation is solely responsible for the development and maintenance of male trabecular bone mass. Both AR and ERalpha activation, however, are needed to optimize the acquisition of cortical bone and muscle mass. ERalpha activation alone is sufficient for the regulation of fat mass. Our findings clearly define the relative importance of AR and ERalpha signaling on trabecular and cortical bone mass as well as body composition in male mice.

Although it is well established that males acquire more bone mass than females, the underlying mechanism and timing of this sex difference remain controversial. The aim of this study was to assess the relative contribution of sex steroid versus growth hormoneinsulin-like growth factor 1 (GH-IGF-1) action to pubertal bone mass acquisition longitudinally in pubertal mice. Radial bone expansion peaked during early puberty (3 to 5 weeks of age) in male and female mice, with significantly more expansion in males than in females (þ40%). Concomitantly, in 5 week old male versus female mice, periosteal and endocortical bone formation was higher (þ70%) and lower (À47%), respectively, along with higher serum IGF-1 levels during early puberty in male mice. In female mice, ovariectomy increased radial bone expansion during early puberty as well as the endocortical perimeter. In male mice, orchidectomy reduced radial bone expansion only during late puberty (5 to 8 weeks of age), whereas combined androgen and estrogen deficiency modestly decreased radial bone expansion during early puberty, accompanied by lower IGF-1 levels. GHRKO mice with very low IGF-1 levels, on the other hand, showed limited radial bone expansion and no skeletal dimorphism. From these data we conclude that skeletal sexual dimorphism is established during early puberty and depends primarily on GH-IGF-1 action. In males, androgens and estrogens have stimulatory effects on bone size during late and early puberty, respectively. In females, estrogens limit bone size during early puberty. These longitudinal findings in mice provide strong evidence that skeletal dimorphism is determined by independent and time-specific effects of sex steroids and IGF-1. ß

Mechanical loading is one of the key factors that influence bone mass and the osseointegration of bone-anchored implants. From a clinical point of view, mechanical stimulation may be used to enhance bone strength and implant osseointegration. Among the many loading parameters that influence the response to mechanical loading, the effects of loading frequency and rate have been investigated in many studies. In this paper the most relevant animal studies that have addressed the effect of loading frequency, rate, and vibration on either bone adaptation or implant osseointegration are systematically reviewed. Apparently contradictory results are discussed and interpreted within the context of mechanotransduction and mechanoregulation of bone. A combined experimental and computational approach is suggested to address some of the remaining research questions.

Bone strain is considered one of the factors inducing bone tissue response to loading. Nevertheless, where animal studies can provide detailed data on bone response, they only offer limited information on experimental bone strains. Including micro-CT-based finite element (micro FE) models in the analysis represents a potent methodology for quantifying strains in bone. Therefore, the main objective of this study was to develop and validate specimen-specific micro FE models for the assessment of bone strains in the rat tibia compression model. Eight rat limbs were subjected to axial compression loading; strain at the medio-proximal site of the tibiae was measured by means of strain gauges. Specimen-specific micro FE models were created and analyzed. Repeated measurements on each limb indicated that the effect of limb positioning was small (COV = 6.45 ± 2.27 %). Instead, the difference in the measured strains between the animals was high (54.2%). The computational strains calculated at the strain gauge site highly correlated to the measured strains (R (2) = 0.95). Maximum peak strains calculated at exactly 25% of the tibia length for all specimens were equal to 435.11 ± 77.88 microstrains (COV = 17.19%). In conclusion, we showed that strain gauge measurements are very sensitive to the exact strain gauge location on the bone; hence, the use of strain gauge data only is not recommended for studies that address at identifying reliable relationships between tissue response and local strains. Instead, specimen-specific micro FE models of rat tibiae provide accurate estimates of tissue-level strains.

BackgroundMechanical loading is known to play an important role in bone remodelling. This study aimed to evaluate the effect of high- and low-frequency axial loading, applied directly to the implant, on peri-implant bone healing and implant osseointegration.MethodologyTitanium implants were bilaterally installed in rat tibiae. For every animal, one implant was loaded (test) while the other one was not (control). The test implants were randomly divided into 8 groups according to 4 loading regimes and 2 experimental periods (1 and 4 weeks). The loaded implants were subject to an axial displacement. Within the high- (HF, 40 Hz) or low-frequency (LF, 8 Hz) loading category, the displacements varied 2-fold and were ranked as low- or high-magnitude (LM, HM), respectively. The strain rate amplitudes were kept constant between the two frequency groups. This resulted in the following 4 loading regimes: 1) HF-LM, 40 Hz-8 µm; 2) HF-HM, 40 Hz-16 µm; 3) LF-LM, 8 Hz-41 µm; 4) LF-HM, 8 Hz-82 µm. The tissue samples were processed for resin embedding and subjected to histological and histomorphometrical analyses. Data were analyzed statistically with the significance set at p<0.05.Principal FindingsAfter loading for 4 weeks, HF-LM loading (40 Hz-8 µm) induced more bone-to-implant contact (BIC) at the level of the cortex compared to its unloaded control. No significant effect of the four loading regimes on the peri-implant bone fraction (BF) was found in the 2 experimental periods.ConclusionsThe stimulatory effect of immediate implant loading on bone-to-implant contact was only observed in case of high-frequency (40 Hz) low-magnitude (8 µm) loading. The applied load regimes failed to influence the peri-implant bone mass.