Aldosterone controls sodium balance by regulating an epithelial sodium channel (ENaC)-mediated sodium transport along the aldosterone-sensitive distal nephron, which expresses both mineralocorticoid (MR) and glucocorticoid receptors (GR). Mineralocorticoid specificity is ensured by 11␤-hydroxysteroid dehydrogenase type 2, which metabolizes cortisol or corticosterone into inactive metabolites that are unable to bind MR and/or GR. The fractional occupancy of MR and GR by aldosterone mediating the sodium transport response in the aldosterone-sensitive distal nephron cannot be studied in vivo. For answering this question, a novel mouse cortical collecting duct cell line (mCCD cl1 ), which expresses significant levels of MR and GR and a robust aldosterone sodium transport response, was used. Aldosterone elicited a biphasic response: Low doses (K 1/2 ‫؍‬ approximately 0.5 nM) induced a transient and early increase of sodium transport (peaking at 3 h), whereas high doses (K 1/2 ‫؍‬ approximately 90 nM) entailed an approximately threefold larger, long-lasting response. At 3 h, the corticosterone doseresponse curve was shifted to the right compared with that of aldosterone by more than two log concentrations, an effect that was fully reverted in the presence of the 11␤-hydroxysteroid dehydrogenase type 2 inhibitor carbenoxolone. Low doses of dexamethasone (0.1 to 1 nM) failed to induce an early response, but high doses elicited a long-lasting response (K 1/2 ‫؍‬ approximately 8 nM), similar to that observed for high aldosterone concentrations. Equilibrium binding assays showed that both aldosterone and corticosterone bind to a high-affinity, low-capacity site, whereas dexamethasone binds to one site. Within the physiologic range of aldosterone concentrations, sodium transport is predicted to be controlled by MR occupancy during circadian cycles and by MR and GR occupancy during salt restriction or acute stress.

Studies are urgently needed to determine 1) the pathophysiological processes involved, 2) the clinical profile of patients at risk for RAVFs, and 3) the management and/or treatment regimens after denosumab discontinuation. Health authorities, physicians, and patients must be aware of this RAVF risk. Denosumab injections must be scrupulously done every 6 months but not indefinitely.

Insulin and insulin-like growth factor 1 (IGF-1) may play a role in the regulation of sodium balance by increasing basal and aldosterone-stimulated transepithelial sodium transport in the aldosterone-sensitive distal nephron (ASDN). As insulin and IGF-1 are capable of binding to each other's receptor with a 50- to 100-fold lower affinity than to their cognate receptor, it is not clear which receptor mediates its respective sodium transport response in the ASDN. The aim of the present study was to characterize the IGF-1 regulation of Na(+) transport in the mCCD(cl1) cell line, a highly differentiated cell line which responds to physiological concentrations (K(1/2)=0.3 nM) of aldosterone. IGF-1 increased basal transepithelial Na(+) transport with a K(1/2) of 0.41+/-0.07 nM. Insulin dose-response curve was displaced to the right 50-fold, as compared to that of IGF-1 (K(1/2)=20.0+/-3.0 nM), indicating that it acts through the IGF type 1 receptor (IGF-1R). Co-stimulation with IGF-1 (0.3 nM) (or 30 nM insulin) and aldosterone (0.3 nM), either simultaneously or by pretreating the cells for 5 h with aldosterone, induced an additive response. The phosphatidylinositol-3' kinase (PI3-K) inhibitor LY294002 completely blocked IGF-1 and aldosterone induced and co-induced currents. As assessed by Western blotting, protein levels of the serum-, and glucocorticoid-induced kinase (Sgk1) were directly and proportionally related to the current induced by either or both IGF-1 and aldosterone, effects also blocked by the PI3-K inhibitor LY294002. IGF-1 could play an important physiological role in regulating basal sodium transport via the PI3-K/Sgk1 pathway in ASDN.

Regional soft tissue may have a noise effect on trabecular bone score (TBS) and eventually alter its estimate. The current TBS software (TBS iNsight®) is based on an algorithm accounting for body mass index (BMI) (TBSv3.03). We aimed to explore the updated TBS algorithm that accounts for soft tissue thickness (TBSv4.0). This study was embedded in the OsteoLaus cohort of women in Lausanne, Switzerland. Hip and lumbar spine (LS) dual‐energy X‐ray absorptiometry (DXA) scans were performed using Discovery A System (Hologic). The incident major osteoporotic fractures (MOFs) were assessed from vertebral fracture assessments using Genant's method (vertebral MOF) or questionnaires (nonvertebral MOF). We assessed the correlations of bone mineral density (BMD) or TBS with body composition parameters; MOF prediction ability of both versions of TBS; and the differences between Fracture Risk Assessment Tool (FRAX) adjusted for TBSv3.03 or TBSv4.0. In total, 1362 women with mean ± SD age 64.4 ± 7.5 years and mean ± SD BMI 25.9 ± 4.5 kg/m2 were followed for 4.4 years and 132 experienced an MOF. All the anthropometric measurements of our interest were positively correlated with LS, femoral neck, or hip BMD and TBSv4.0; whereas with TBSv3.03 their correlations were negative. In the models adjusted for age, soft tissue thickness, osteoporotic treatment, and LS‐BMD, for each SD decline in TBSv3.03, there was a 43% (OR 1.43; 95% CI, 1.12 to 1.83) increase in the odds of having MOF; whereas for each SD decline in TBSv4.0, there was a 54% (OR 1.54; 95% CI, 1.18 to 2.00) increase in the odds of having an MOF. Both FRAXs were very strongly correlated and the mild differences were present in the already high‐risk women for MOF. This study shows that TBSv4.0 overcomes the debatable residual negative correlation of the current TBS with body size and composition parameters, postulating itself as free from the previously acknowledged technical limitation of TBS. © 2019 American Society for Bone and Mineral Research.

TBS is not affected by DD. While BMD increases after 62.5 years, TBS continues to decline. For lumbar spine evaluation, in view of its independence from DD, TBS should play a leading role in the diagnosis in complement to BMD.