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During pregnancy and lactation, the maternal skeleton provides calcium for fetal/infant growth, resulting in substantial bone loss, which partially recovers after weaning. However, the amount of bone that is lost and the extent of post-weaning recovery are highly variable among different skeletal sites, and, despite persistent alterations in bone structure at some locations, reproductive history does not increase postmenopausal fracture risk. To explain this phenomenon, we hypothesized that the degree of reproductive bone loss/recovery at trabecular sites may vary depending on the extent to which the trabecular compartment is involved in the bone's load-bearing function. Using a rat model, we quantified the proportion of the load carried by the trabeculae, as well as the extent of reproductive bone loss and recovery, at two distinct skeletal sites: the tibia and lumbar vertebra. Both sites underwent significant bone loss during pregnancy and lactation, which was partially recovered post-weaning. However, the extent of the deterioration and the resumption of trabecular load-bearing capacity after weaning varied substantially. Tibial trabecular bone, which bore a low proportion of the total applied load, underwent dramatic and irreversible microstructural deterioration during reproduction. Meanwhile, vertebral trabecular bone bore a greater fraction of the load, underwent minimal deterioration in microarchitecture, and resumed its full load-bearing capacity after weaning. Because pregnancy and lactation are physiological processes, the distinctive responses to these natural events among different skeletal sites may help to elucidate the extent of the trabecular bone's structural versus metabolic functions. [ABSTRACT FROM AUTHOR]

Combined parathyroid hormone (PTH) and bisphosphonate (alendronate--ALN) therapy has recently been shown to increase bone volume fraction and plate-like trabecular structure beyond either monotherapy. To identify the mechanism through which plate-like structure was enhanced, we used in vivo microcomputed tomography (µCT) of the proximal tibia metaphysis and individual trabecular dynamics (ITD) analysis to quantify connectivity repair (incidences of rod connection and plate perforation filling) and deterioration (incidences of rod disconnection and plate perforation). Three-month-old female, intact rats were scanned before and after a 12 day treatment period of vehicle (Veh, n = 5), ALN (n = 6), PTH (n = 6), and combined (PTH+ALN, n - 6) therapy. Additionally, we used computational simulation and finite element (FE) analysis to delineate the contributions of connectivity repair or trabecular thickening to trabecular bone stiffness. Our results showed that the combined therapy group had greater connectivity repair (5.8 ± 0.5% connected rods and 2.0 ± 0.3% filled plates) beyond that of the Veh group, resulting in the greatest net gain in connectivity. For all treatment groups, increases in bone volume due to thickening (5-31%) were far greater than those due to connectivity repair (2-3%). Newly formed bone contributing only to trabecular thickening caused a 10%, 41 %, and 69% increase in stiffness in the ALN, PTH, and PTH+ALN groups, respectively. Moreover, newly formed bone that led to connectivity repair resulted in an additional improvement in stiffness, with the highest in PTH+ALN (by an additional 12%), which was significantly greater than either PTH (5.6%) or ALN (4.5%). An efficiency ratio was calculated as the mean percent increase in stiffness divided by mean percent increase in BV for either thickening or connectivity repair in each treatment. For all treatments, the efficiency ratio of connectivity repair (ALN: 2.9; PTH: 3.4; PTH+ALN: 4.4) was higher than that due to thickening (ALN: 2.0; PTH: 1.7; PTH+ALN: 2.2), suggesting connectivity repair required less new bone formation to induce larger gains in stiffness. We conclude that through rod connection and plate perforation filling PTH+ALN combination therapy improved bone stiffness in a more efficient and effective manner than either monotherapy. [ABSTRACT FROM AUTHOR]

Bone atrophy and its related fragility fractures are frequent, late side effects of radiotherapy in cancer survivors and have a detrimental impact on their quality of life. In another study, we showed that parathyroid hormone 1-34 and anti-sclerostin antibody attenuates radiation-induced bone damage by accelerating DNA repair in osteoblasts. DNA damage responses are partially regulated by the ubiquitin proteasome pathway. In the current study, we examined whether proteasome inhibitors have similar bone-protective effects against radiation damage. MG132 treatment greatly reduced radiation-induced apoptosis in cultured osteoblastic cells. This survival effect was owing to accelerated DNA repair as revealed by γH2AX foci and comet assays and to the up-regulation of Ku70 and DNA-dependent protein kinase, catalytic subunit, essential DNA repair proteins in the nonhomologous end-joining pathway. Administration of bortezomib (Bzb) reversed the loss of trabecular bone structure and strength in mice at 4 wk after focal radiation. Histomorphometry revealed that Bzb significantly increased the number of osteoblasts and activity in the irradiated area and suppressed the number and activity of osteoclasts, regardless of irradiation. Two weeks of Bzb treatment accelerated DNA repair in bone-lining osteoblasts and thus promoted their survival. Meanwhile, it also inhibited bone marrow adiposity. Taken together, we demonstrate a novel role of proteasome inhibitors in treating radiation-induced osteoporosis. [ABSTRACT FROM AUTHOR]

Bone atrophy and its related fragility fractures are frequent, late side effects of radiotherapy in cancer survivors and have a detrimental impact on their quality of life. In another study, we showed that parathyroid hormone 1-34 and anti-sclerostin antibody attenuates radiation-induced bone damage by accelerating DNA repair in osteoblasts. DNA damage responses are partially regulated by the ubiquitin proteasome pathway. In the current study, we examined whether proteasome inhibitors have similar bone-protective effects against radiation damage. MG132 treatment greatly reduced radiation-induced apoptosis in cultured osteoblastic cells. This survival effect was owing to accelerated DNA repair as revealed by γH2AX foci and comet assays and to the up-regulation of Ku70 and DNA-dependent protein kinase, catalytic subunit, essential DNA repair proteins in the nonhomologous end-joining pathway. Administration of bortezomib (Bzb) reversed the loss of trabecular bone structure and strength in mice at 4 wk after focal radiation. Histomorphometry revealed that Bzb significantly increased the number of osteoblasts and activity in the irradiated area and suppressed the number and activity of osteoclasts, regardless of irradiation. Two weeks of Bzb treatment accelerated DNA repair in bone-lining osteoblasts and thus promoted their survival. Meanwhile, it also inhibited bone marrow adiposity. Taken together, we demonstrate a novel role of proteasome inhibitors in treating radiation-induced osteoporosis. [ABSTRACT FROM AUTHOR]

Background: a rat model of supraspinatus overuse has suggested mechanisms governing tendon degeneration; however, delineating which changes are pathologic or simply physiologic adaptations to increased loading remains a question. The objective of this study was to develop and characterize a rat exercise model that induces systemic and local shoulder adaptations without mechanical injury to the supraspinatus tendon. Methods: exercise rats completed a treadmill training protocol for 12 weeks. Body, fat pad, and heart weights were determined. Supraspinatus tendon collagen content, cross-sectional area, and mechanical properties were measured. Supraspinatus muscle cross-sectional area, weight, and the expression of mitochondrial oxidative phosphorylation (OXPHOS) proteins were measured. Humeri were analyzed with μCT and mechanically tested. Results: exercise decreased fat pad mass. Supraspinatus muscle hypertrophied and had increased OXPHOS proteins. Humerus trabecular bone had increased anisotropic orientation, and cortical bone showed increased bone and tissue mineral density. Importantly, the supraspinatus tendon did not have diminished mechanical properties, indicating that this protocol was not injurious to the tendon. Conclusion: this study establishes the first rat exercise protocol that induces adaptations in the shoulder. Future research can use this as a comparison model to study how the supraspinatus tendon adapts to loading and undergoes degeneration with overuse. [ABSTRACT FROM AUTHOR]