Parathyroid hormone (PTH) increases fibroblast growth factor 23 (FGF23), mediated both by protein kinase A (PKA) and Wnt signaling, and decreases expression of sclerostin, a Wnt antagonist derived from osteocytes. Patients with primary hyperparathyroidism (PHPT) have lower serum sclerostin levels than healthy controls, consistent with the idea of SOST downregulation by PTH. Nevertheless, the relationship between FGF23 and sclerostin in PHPT is still unclear. We examined this issue in a mouse model of PHPT. PHPT mice had increased FGF23 and decreased sclerostin expression in calvaria and in their serum concentrations compared with wild-type (WT) mice. In UMR106 osteoblasts, PTH increased Fgf23 expression and decreased Sost expression, as well as forskolin, a PKA agonist, whereas inhibition of PKA reversed the changes in Fgf23 and Sost expression, stimulated by PTH. Sclerostin treatment had no effect on Fgf23 expression, but when it was added together with PTH, it statistically significantly abrogated the increase in Fgf23 expression. By contrast, there was no statistically significant correlation between serum FGF23 and sclerostin, whereas PTH was positively and negatively correlated with serum FGF23 and sclerostin, respectively. These results indicate that the high level of PTH in PHPT mice leads to increased FGF23 and decreased sclerostin expression in serum and calvaria. A decrease of sclerostin may further augment FGF23 in vitro; however, there was no statistically significant association between circulating FGF23 and sclerostin. It is suggested that the pathogenesis of increased FGF23 expression in PHPT mice may be modified by not only sclerostin, but also other regulatory factors modulated by PTH.

Objective Infection is related to higher rate of hospitalization and subsequent death in patients undergoing hemodialysis. Limited data are available about factors associated with death after hospitalization for infection. Nutritional disorder also known as protein-energy wasting is profoundly associated with poor consequences. Geriatric nutritional risk index (GNRI) is a simple but useful nutritional screening tool to predict mortality. We examined whether GNRI could predict hospitalization for infection and subsequent death. Design and Methods This was a prospective cohort study in hemodialysis patients. The predictor was GNRI. The patients were divided into tertiles of GNRI (T1 to T3), with the highest tertile of T3 as referent. The outcomes of interest were all-cause mortality, hospitalization for infection and subsequent death. Results Of 518 patients, 107 patients died (median follow-up period, 5.0 years; interquartile range 3.6-5.0) and 169 patients experienced new hospitalization for infection (median follow-up period, 4.5 years; interquartile range 3.4-5.0) during the follow-up period from December 2004 to December 2009. A lower GNRI was a significant predictor for all-cause mortality in multivariable Cox models (hazard ratio [HR] 2.9, 95% confidential interval [CI] 1.5-5.5, p < 0.001 for T1 vs. T3). However, GNRI was not associated with hospitalization for infection in multivariable Fine-Gray models with death as a competing risk (subdistributional HR 1.5, 95% CI 1.0-2.3, p = 0.056 for T1 vs. T3). After hospitalization for infection, 38 patients died during subsequent 2.5-year follow-up period. GNRI was a significant predictor of death after hospitalization for infection in multivariable Cox models (HR 2.7, 95% CI 1.3-5.6, p = 0.006 for T1 vs. T2+T3). Conclusions A lower GNRI predicted a higher risk of all-cause mortality but not hospitalization for infection. However, a lower GNRI was significantly associated with a higher risk of mortality after hospitalization for infection. These findings suggest that long-term mortality after hospitalization for infection was predicted by nutritional disorder evaluated by GNRI.

Cognitive impairment and dementia are common in patients with chronic kidney disease, including those undergoing hemodialysis. Since magnesium and phosphate play important roles in brain function and aging, alterations in these and other factors related to bone mineral disorder (MBD) may contribute to low cognitive performance in patients on hemodialysis. This cross-sectional study examined the associations between cognitive function and MBD-related factors among 1207 patients on maintenance hemodialysis. Cognitive function was assessed by the Modified Mini-Mental State examination (3MS). The exposure variables of interest were serum magnesium, phosphate, calcium, calcium–phosphate product, intact parathyroid hormone, fetuin-A, T50 calciprotein crystallization test, use of phosphate binders, use of cinacalcet, and use of vitamin D receptor activators. Multivariable-adjusted linear regression models were used to examine the associations between 3MS and each of the exposure variables independent of 13 potential non-mineral confounders. We found that lower 3MS was associated with lower serum magnesium, lower phosphate, lower calcium–phosphate product, and nonuse of phosphate binders. These results suggest that magnesium and phosphate play potentially protective roles against cognitive impairment in this population.

We determined the bone mineral density (BMD) and the expression of serum bone formation marker (procollagen type I N-terminal propeptide: PINP) and bone resorption marker (C-terminal telopeptide of collagen: CTX) by ELISA to evaluate ovariectomy-induced osteoporosis in ovariectomized (OVX) mice. The intestinal microbiota of the mice was assessed using 16S rRNA gene sequencing. OVX mice exhibited a lower BMD of 87% with higher serum levels of CTX and PINP compared to sham-operated (sham) mice. The cecum microbiome of OVX mice showed lower bacterial diversity than that of sham mice. TNFα mRNA levels in the colon were 1.6 times higher, and zonula occludens-1 mRNA and protein expression were lower in OVX mice than in sham mice, suggesting that ovariectomy induced inflammation and increased intestinal permeability. Next, we used antibiotic treatment followed by fecal microbiota transplantation (FMT) to remodel the gut microbiota in the OVX mice. A decrease in PINP was observed in antibiotic-treated mice, while there was no change in BMD or CTX between mice with and without antibiotic treatment. Oral transplantation of the luminal cecal content of OVX or sham mice to antibiotic-treated mice did not affect the BMD or PINP and CTX expression. Additionally, transplantation of the luminal contents of OVX or sham mice to antibiotic-treated OVX mice had similar effects on BMD, PINP, and CTX. In conclusion, although ovariectomy induces dysbiosis in the colon, the changes in the gut microbiota may only have a minor role in ovariectomy-induced osteoporosis.