Search

Objective: We used machine learning to develop and validate a multivariable algorithm allowing the accurate and early prediction of postoperative hypocalcemia risk. Background: Postoperative hypocalcemia is frequent after total thyroidectomy. An early and accurate individualized prediction of the risk of hypocalcemia could guide the selective prescription of calcium supplementation only to patients most likely to present with hypocalcemia after total thyroidectomy. Methods: This retrospective study enrolled all patients undergoing total thyroidectomy in a single referral center between November 2019 and March 2022 (derivation cohort) and April 2022 and September 2022 (validation cohort). The primary study outcome was postoperative hypocalcemia (serum calcium under 80 mg/L). Exposures were multiple clinical and biological variables prospectively collected and analyzed with various machine learning methods to develop and validate a multivariable prediction algorithm. Results: Among 610/118 participants in the derivation/validation cohorts, 100 (16.4%)/26 (22%) presented postoperative hypocalcemia. The most accurate prediction algorithm was obtained with random forest and combined intraoperative parathyroid hormone measurements with 3 clinical variables (age, sex, and body mass index) to calculate a postoperative hypocalcemia risk for each patient. After multiple cross-validation, the area under the receiver operative characteristic curve was 0.902 (0.829--0.970) in the derivation cohort, and 0.928 (95% CI: 0.86; 0.97) in the validation cohort. Postoperative hypocalcemia risk values of 7% (low threshold) and 20% (high threshold) had, respectively, a sensitivity of 92%, a negative likelihood ratio of 0.11, a specificity of 90%, and a positive of 7.6 for the prediction of postoperative hypocalcemia. Conclusions: Using machine learning, we developed and validated a simple multivariable model that allowed the accurate prediction of postoperative hypocalcemia. The resulting algorithm could be used at the point of care to guide clinical management after total thyroidectomy. [ABSTRACT FROM AUTHOR]

Introduction: So far, only 11 PTH mutations have been described as causes of familial isolated hypoparathyroidism (FIH). In this report, we describe a family with FIH but with significant elevation of functionally inactive PTH due to a PTH mutation. We also show a positive therapeutic outcome of recombinant human PTH (teriparatide) therapy in one of the siblings who was not well controlled on large doses of calcitriol and calcium replacement therapy. Case description: The proband is a 34-year-old woman who has a history of chronic severe hypocalcemia (HypoCa) since birth. She and her three brothers (33-year-old male twins, and a 21-year-old male) were diagnosed with pseudohypoparathyroidism type 1b (PHPT 1b) based on the presence of chronic HypoCa (serum Ca 1.6-1.85 mmol/l) since birth associated with significantly elevated plasma PTH levels in the range of 310-564 pg/dl (normal range 10-65) and absence of signs of Albright hereditary osteodystrophy. Molecular studies: WES showed no pathogenic, likely pathogenic or variants of unknown significance in any known calcium-associated genetic disorder but a bi-allelic variant in the PTH itself ((NM_000315.4:c.128G>A, p.Gly43Glu). This was confirmed by Sanger sequencing in the patient and her affected brothers. Management: Because the patient's HypoCa was not controlled on large doses of calcitriol and calcium carbonate, a trial of teriparatide 20 mcg SC daily was started and resulted in normalization of calcium, decline in PTH levels and significant improvement in her general wellbeing. Conclusion: High PTH in the presence of congenital hypocalcemia is not always due to receptor or post-receptor defect and can be due to a biologically inactive mutated PTH. In such cases, treatment with teriparatide may result in stabilization of biochemical profile and improvement in quality of life. [ABSTRACT FROM AUTHOR]

Human parathyroid hormone (1–34) (PTH) exhibits osteoanabolic and osteocatabolic effects, with shorter plasma exposure times favoring bone formation. Subcutaneous injection (SCI) is the conventional delivery route for PTH but faces low delivery efficiency due to limited passive diffusion and the obstruction of the vascular endothelial barrier, leading to prolonged drug exposure times and reduced osteoanabolic effects. In this work, a microcurrent delivery system (MDS) based on multimicrochannel microneedle arrays (MMAs) is proposed, achieving high efficiency and safety for PTH transdermal delivery. The internal microchannels of the MMAs are fabricated using high‐precision 3D printing technology, providing a concentrated and safe electric field that not only accelerates the movement of PTH but also reversibly increases vascular endothelial permeability by regulating the actin cytoskeleton and interendothelial junctions through Ca2+‐dependent cAMP signaling, ultimately promoting PTH absorption and shortening exposure times. The MDS enhances the osteoanabolic effect of PTH in an osteoporosis model by inhibiting osteoclast differentiation on the bone surface compared to SCI. Moreover, histopathological analysis of the skin and organs demonstrated the good safety of PTH delivered by MDS in vivo. In addition to PTH, the MDS shows broad prospects for the high‐efficiency transdermal delivery of macromolecular drugs. [ABSTRACT FROM AUTHOR]

Primary hyperparathyroidism (PHPT) is a common endocrine disease characterized by hypercalcemia due to inappropriately high parathyroid hormone secretion. While in the typical, symptomatic form of the disease diagnosis is set easily and standard management is surgical removal of the hyperfunctioning parathyroid (HP), this may not be the case in more subtle forms of PHPT, such as the asymptomatic and the normocalcemic PHPT. Localization of the HP could also be challenging, especially in small-sized adenomas, ectopic lesions or multiglandular disease. An experienced surgical team is essential to achieve curative parathyroidectomy. In this article, we used illustrative clinical vignettes to dissect the approach to the patient with PHPT, from the diagnosis establishment to the suggested investigation to identify classical and non-classical PHPT features and the methodology to locate the abnormal tissue. Accordingly, we elaborated on appropriate management, both surgical and conservative. [ABSTRACT FROM AUTHOR]

Purpose: The management of primary hyperparathyroidism (PHPT) during pregnancy may be surgical or conservative. This study compared adverse outcomes between surgical and non-surgical treatments. Additionally, the study investigated the correlation between serum calcium values and complication rates. Methods: A systematic review of retrospective studies, case series, and case reports. Biochemical parameters, interventions, and outcomes of each pregnancy were recorded. The study population comprised two groups: the non-surgical and surgical groups. Adverse outcomes were categorized as maternal, obstetric, or neonatal. Results: The surgical and non-surgical groups consisted of 163 and 185 patients, respectively. A positive correlation was observed between the mean maternal gestational calcium value and both maternal and obstetric complication. Neonatal complications were more prevalent in patients treated conservatively across all maternal calcium values (p < 0.001). No significant differences were observed in maternal outcomes and overall obstetric outcomes between the study groups, albeit a higher mean serum calcium value in the surgical group (12.3 mg/dL) compared with the non-surgical group (11.1 mg/dL). Conclusions: Given the significantly lower neonatal adverse outcomes in the surgical group compared to the non-surgical group, along with non-inferior maternal and obstetric outcomes in the surgical group, the overall data of this study suggest that parathyroidectomy is favorable to non-surgical management even in cases of mild hypercalcemia. [ABSTRACT FROM AUTHOR]

Background Hypothesis/Objectives Animals Methods Results Conclusions and Clinical Importance Monitoring serum phosphorus concentrations is crucial in the management of chronic kidney disease in cats. The diurnal variation of serum phosphorus concentration may affect clinical assessment.Characterize the diurnal variation of serum phosphorus concentration in cats and determine the associations between changes in serum phosphorus concentration and several metabolites of phosphorus metabolism.Six apparently healthy, intact male, specific‐pathogen‐free cats were housed in a photoperiod, humidity, and temperature‐controlled facility.Blood sampling was performed hourly for 24 hours to obtain the serum concentrations of phosphorus, ionized calcium, parathyroid hormone, and calcidiol. Results were analyzed using linear mixed‐effect models to determine the significance of diurnal variation and associations between serum phosphorus concentrations and other metabolites over time.Diurnal variation in serum phosphorus concentration was noted with an apex around 11:00 followed by gradually declining concentrations to reach the nadir around 23:00. The serum phosphorus concentration again increased through the early morning on the next day. An approximately 25% difference in serum phosphorus concentration at the apex and the nadir was documented. A non‐linear relationship between the serum concentrations of phosphorus and ionized calcium over time was identified.Diurnal variations of serum phosphorus concentration and associations between the trending of serum phosphorus and ionized calcium concentrations were evident in a group of clinically healthy adult cats housed in a controlled environment. These findings can help in the interpretation of clinical and research data regarding calcium and phosphorus metabolism and kidney health in cats. [ABSTRACT FROM AUTHOR]

Objective Previous studies indicate a possible bidirectional stimulatory relationship between parathyroid hormone (PTH) and adrenocortical hormones, but the pattern of adrenocortical secretion in hypoparathyroidism is unknown. We aimed to characterize the adrenocortical secretion in patients with postsurgical hypoparathyroidism, and whether continuous subcutaneous PTH (1-34) infusion alters secretion patterns. Design Crossover interventional study. Methods We recruited 10 patients with postsurgical hypoparathyroidism with very low PTH levels on stable treatment with active vitamin D and calcium. Cortisol, cortisone, and aldosterone levels were measured in microdialysate from subcutaneous tissue over 24 h, before and during continuous subcutaneous PTH (1-34) infusion. Cortisol was also assayed in serum, saliva, and urine, and aldosterone and ACTH in serum and plasma, respectively. Ten patients with primary hyperparathyroidism and 10 healthy volunteers matched for sex and age served as controls. Results Hypoparathyroid patients displayed both ultradian and circadian rhythmicity for tissue cortisol, cortisone, and aldosterone. Tissue aldosterone and cortisone levels were significantly lower in hypoparathyroid patients than in healthy controls, with no difference in tissue cortisol, but a higher cortisol to cortisone ratio. Treatment with PTH (1-34) increased tissue levels of aldosterone, cortisol, and cortisone and reduced the ratio of cortisol to cortisone. Conclusion Adrenocortical hormone levels are reduced in postsurgical hypoparathyroidism, and partly restored by short-term continuous subcutaneous PTH (1-34) therapy. Clinical trial registration number NCT02986607 [ABSTRACT FROM AUTHOR]

Purpose: This aim of this study was to assess the possible association between diurnal oscillations and biochemical markers associated with calcium homeostasis. This included the markers parathyroid hormone (PTH), total calcium, total alkaline phosphatase, phosphate, and 25-hydroxyvitamin D (25-OH-D). By examining the influence of circadian rhythms on these parameters, the study aimed to deepen the understanding of calcium metabolism dynamics and its clinical implications. Patients and methods: Blood samples from 24 Caucasian male volunteers aged 20 to 40 (mean age 26) with normal pulse, blood pressure, and BMI were analyzed for biochemical markers related to calcium homeostasis. Data was obtained from the Bispebjerg study of diurnal variations. Blood samples were collected every three hours over a 24-hour period. Patients were fasting from 22:00 to 09:00. The participants spent 24 h in the hospital ward, receiving regular meals and engaging in low-intensity activities. They experienced 15 h of daylight and 9 h of complete darkness during sleep. Diurnal oscillations were analyzed using cosinor analysis with statistical significance set at p < 0.05. Results: Total calcium, phosphate, and PTH exhibited significant diurnal variations. Total calcium and PTH were inversely synchronized while PTH and phosphate oscillated in synchronization. The three parameters showed relatively large amplitude/reference range ratios from 25.4% to 41.5%. Conclusion: This study found notable fluctuations in total calcium, phosphate, and PTH levels over a 24-hour cycle, while 25-OH-D and total alkaline phosphatase remained consistent. It highlights the importance of considering sampling times for total calcium, PTH, and phosphate in clinical settings. [ABSTRACT FROM AUTHOR]

Objective: There is limited information on population‐specific norms of trabecular‐bone‐score (TBS) and its associated factors. Here, we provide norms of TBS in Asian‐Indians and its relationship with serum 25‐hydroxyvitamin D [25(OH)D] and intact‐parathyroid hormone (iPTH). Participants and Measurements: TBS, bone‐mineral‐density (BMD), and vertebral‐fractures (VFs) were assessed using dual‐energy X‐ray absorptiometry in 923 healthy Asian‐Indians (aged 20–60 years). Serum 25(OH)D, iPTH, T4/TSH,, glycosylated‐haemoglobin (HbA1c) were measured and associations with TBS assessed using multivariable linear regression. Subjects with BMD Z‐score ≤ −2.0 or ≥2.0 at any sites, VFs, TSH > 10.0 or <0.05 µIU/ml, blood‐glucose >11.1 mmol/L or HbA1c > 8.0% were excluded for generating Asian‐Indian norms. Results: TBS norms were generated in 744 healthy Asian‐Indians (M:F,389:385). The cut‐offs generated for 'normal', 'partially‐degraded', and 'degraded' TBS were >1.305, 1.204–1.305 and <1.204, respectively. Mean TBS was lower in females than males (p <.001). There was 75% congruency in TBS categories between Asian‐Indian and existing norms. Specificity (97.8 vs. 77.9%, p <.001) and diagnostic‐accuracy (97.8% vs. 78.4%, p <.001) of TBS to detect osteoporosis were higher with Asian‐Indian norms. The sensitivity of 'partially‐degraded' TBS to diagnose osteopenia was also higher with Asian‐Indian norms. In multivariable regression, gender, body‐mass‐index (BMI), BMD‐L1‐L4, serum PTH, daily dietary‐calorie intake and calcium intake were associated with TBS. Though 25(OH)D inversely correlated with PTH, 25(OH)D was not associated with TBS. Conclusion: This study provides norms for TBS in Asian‐Indians with gender‐specific differences. Increasing age and higher BMI were associated with lower TBS. Associations of TBS with circulating PTH and/or 25(OH)D need confirmation in further studies. [ABSTRACT FROM AUTHOR]

Background The longitudinal changes in hip-bone microstructures and estimated bone strength in dialysis patients, and the impact of chronic kidney disease–mineral and bone disorder (CKD-MBD) biomarkers on these changes, remain insufficiently explored. Methods This retrospective study examined changes in cortical and trabecular bone compartments and estimated bone-strength indices, obtained by using 3D-SHAPER software, in the hip regions of 276 dialysis patients over up to 2.5 years. We used multivariate mixed models to investigate the associations between time-dependent CKD-MBD biomarkers and bone health metrics. Results There was a significant decrease in areal bone mineral density (aBMD), integral volumetric BMD (vBMD), trabecular vBMD, cortical thickness and cortical surface BMD (sBMD). Similar deteriorations were found in estimated bone-strength indices [cross-sectional area (CSA), cross-sectional moment of inertia (CSMI), section modulus (SM) and buckling ratio]. Neither serum calcium nor phosphate levels were significantly associated with changes in three-dimensional parameters or estimated bone-strength indices. In contrast, serum alkaline phosphatase levels showed a significant inverse correlation with aBMD and CSA. The intact-parathyroid hormone (i-PTH) was significantly inversely correlated with aBMD, integral vBMD, trabecular vBMD, cortical thickness, cortical vBMD, CSA, CSMI and SM. When applying the KDIGO criteria as a sensitivity analysis, the higher PTH group had significant negative associations with aBMD, integral vBMD, cortical vBMD, cortical thickness and cortical sBMD. Notably, the lower PTH group showed a positive significant correlation with integral vBMD and trabecular vBMD. Conclusions Elevated PTH, not low PTH, was associated with deterioration of hip-bone microstructures. Better management of PTH levels may play a crucial role in the hip-bone microstructure in dialysis patients. [ABSTRACT FROM AUTHOR]

Managing mineral bone disease (MBD) could reduce cardiovascular risk and improve the survival of dialysis patients. Our study focuses on the impact of calcium bath exposure in dialysis patients by comparing peritoneal dialysis patients (PD, intervention group) and hemodialysis patients (HD, control group). We assessed various factors, including calcium, phosphorus, magnesium, PTH, vitamin D 25-OH, C-terminal telopeptide (CTX), and FGF-23 levels, as well as the calcium bath six hours before the blood sample and the length of daily calcium exposure. We enrolled 40 PD and 31 HD patients with a mean age of 68.7 ± 13.6 years. Our cohort had median PTH and FGF-23 levels of 194 ng/L (Interquartile range [IQR] 130-316) and 1296 pg/mL (IQR 396-2698), respectively. We identified the length of exposure to a 1.25 mmol/L calcium bath, phosphate levels, and CTX as independent predictors of PTH (OR 0.279, p = 0.011; OR 0.277, p = 0.012; OR 0.11, p = 0.01, respectively). In contrast, independent predictors of FGF-23 were phosphate levels (OR 0.48, p < 0.001) and serum calcium levels (OR 0.25, p = 0.015), which were affected by the calcium bath. These findings suggest that managing dialysate calcium baths impacts phosphaturic hormones and could be a critical factor in optimizing CKD-MBD treatment in PD patients, sparking a new avenue of research and potential interventions. [ABSTRACT FROM AUTHOR]

Diets containing inorganic phosphate additives are unbalanced with respect to calcium and these diets have been linked to the development of altered bone metabolism. Using 2 randomized cross-over studies in healthy humans, we (1) characterized the hormonal and urinary response to 2 meals with the same reported phosphorus amount (562–572 mg), where one was manufactured with inorganic phosphate additives and a comparatively lower Ca:P molar ratio (0.26 vs 0.48), and (2) assessed how acute homeostatic mechanisms adapt following 5-d exposure to recommended dietary phosphorus amount (~700 mg P/d) compared to a diet enriched with inorganic phosphate additives (~1100 mg P/d). Participants were then challenged with 500 mg of oral phosphorus in the form of inorganic phosphate after an overnight fast following each diet condition. Measurements included serum calcium, phosphate, PTH, and fibroblast growth factor 23 , vitamin D metabolites, and urine calcium and phosphate excretion. Following the meal containing inorganic phosphate additives with a low Ca:P ratio, serum phosphate was higher and more phosphate was excreted in the urine compared to the low additive meal. Although the Ca:P and calcium content was lower in the high additive meal, the same amount of calcium was excreted into the urine. Subsequently, increasing only dietary phosphate through additives resulted in lower 24-h excretion of calcium. The oral phosphate challenge promoted urinary calcium excretion, despite no consumption of calcium, which was attenuated when pre-acclimated to a high phosphate diet. These data suggest that ingestion of inorganic phosphate promotes calcium excretion, but homeostatic mechanisms may exist to reduce calcium excretion that are responsive to dietary intake of phosphate. Future studies are required to evaluate potential implication of diets enriched with inorganic phosphate additives on bone health. Lay Summary: Excessive dietary phosphorus has been linked to the development of bone and vascular disorders. Further, highly bioavailable inorganic phosphate additives, which are unregulated, have been estimated to comprise approximately 50% of an individual's consumed dietary phosphorus. Using 2 randomized cross-over studies in young healthy participants, we assessed (1) the hormonal and urinary response to 2 meals with the same reported phosphate amount, but one manufactured with inorganic phosphate additives, and (2) how acute homeostatic mechanisms adapt following 5-d of a diet supplemented with inorganic phosphate additives. The results suggest that ingestion of meals containing phosphate additives promotes excess calcium excretion, but homeostatic mechanisms in young healthy adults are sufficient to reduce calcium excretion in response to a 5-d dietary intake of these phosphate additives. These findings indicate an important role of inorganic phosphate additives on acute and chronic calcium homeostasis that will need to be carefully explored for potential implications on bone and/or vascular outcomes. Together these findings also indicate the critical importance of bioavailability of phosphate and the balance with calcium in dietary management. Graphical Abstract [ABSTRACT FROM AUTHOR]

Although clinical guidelines recommend measuring total plasma 25-hydroxyvitamin D (25[OH]D) to assess vitamin D (VitD) status, this index does not account for 3-fold inter-individual variation in VitD binding protein (VDBP) level. We present 3 individuals with total plasma 25(OH)D levels of 10.8 to 12.3 ng/mL (27-30.7 nmol/L). Because Endocrine Society guidelines define VitD deficiency as 25(OH)D = 20 ng/mL (50 nmol/L), all 3 would be judged to be VitD deficient. VitD3 supplementation increased 25(OH)D to the range of 31.7 to 33.8 ng/mL (79.1-84.4 nmol/L). Patient #1 exhibited secondary hyperparathyroidism; VitD3 supplementation decreased parathyroid hormone (PTH) by 34% without a clinically significant change in PTH levels in the other 2 individuals. Thus, 25(OH)D level did not distinguish between the 1 patient who had secondary hyperparathyroidism and the 2 who did not. We therefore inquired whether VitD metabolite ratios (which are VDBP-independent) might distinguish among these 3 individuals. Of all the assessed ratios, the 1,25(OH)2D/24,25(OH)2D ratio was the most informative, which had a value of 102 pg/ng in the individual with secondary hyperparathyroidism but lower values (41 and 20 pg/ng) in the other 2 individuals. These cases illustrate the value of the 1,25(OH)2D/24,25(OH)2D ratio to provide clinically relevant information about VitD status. [ABSTRACT FROM AUTHOR]

Sclerostin (SOST) is produced by osteocytes and is known as a negative regulator of bone homeostasis. Parathyroid hormone (PTH) regulates calcium, phosphate as well as vitamin D metabolism, and is a strong inhibitor of SOST synthesis in vitro and in vivo. PTH has two methionine amino acids (positions 8 and 18) which can be oxidized. PTH oxidized at Met18 (Met18(ox)-PTH) continues to be bioactive, whereas PTH oxidized at Met8 (Met8(ox)-PTH) or PTH oxidized at Met8 and Met18 (Met8, Met18(di-ox)-PTH) has minor bioactivity. How non-oxidized PTH (n-oxPTH) and oxidized forms of PTH act on sclerostin synthesis is unknown. The effects of n-oxPTH and oxidized forms of PTH on SOST gene expression were evaluated in UMR106 osteoblast-like cells. Moreover, we analyzed the relationship of SOST with n-oxPTH and all forms of oxPTH in 516 stable kidney transplant recipients using an assay system that can distinguish in clinical samples between n-oxPTH and the sum of all oxidized PTH forms (Met8(ox)-PTH, Met18(ox)-PTH, and Met8, Met18(di-ox)-PTH). We found that both n-oxPTH and Met18(ox)-PTH at doses of 1, 3, 20, and 30 nmol/L significantly inhibit SOST gene expression in vitro, whereas Met8(ox)-PTH and Met8, Met18(di-ox)-PTH only have a weak inhibitory effect on SOST gene expression. In the clinical cohort, multivariate linear regression showed that only n-oxPTH, but not intact PTH (iPTH) nor oxPTH, is independently associated with circulating SOST after adjusting for known confounding factors. In conclusion, only bioactive PTH forms such as n-oxPTH and Met18(ox)-PTH, inhibit SOST synthesis. [ABSTRACT FROM AUTHOR]

Background/Objectives: The general condition of implantology patients is crucial when considering the long- and short-term survival of dental implants. The aim of the research was to evaluate the correlation between the new corticalization index (CI) and patients' condition, and its impact on marginal bone loss (MBL) leading to implant failure, using only radiographic (RTG) images on a pixel level. Method: Bone near the dental implant neck was examined, and texture features were analyzed. Statistical analysis includes analysis of simple regression where the correlation coefficient (CC) and R2 were calculated. Detected relationships were assumed to be statistically significant when p < 0.05. Statgraphics Centurion version 18.1.12 (Stat Point Technologies, Warrenton, VA, USA) was used to conduct the statistical analyses. Results: The research revealed a correlation between MBL after 3 months and BMI, PTH, TSH, Ca2+ level in blood serum, phosphates in blood serum, and vitamin D. A correlation was also observed between CI and PTH, Ca2+ level in blood serum, vitamin D, LDL, HDL, and triglycerides on the day of surgery. After 3 months of the observation period, CI was correlated with PTH, TSH, Ca2+ level in blood serum, and triglycerides. Conclusion: The results of the research confirm that the general condition of patients corresponds with CI and MBL. A patient's general condition has an impact on bone metabolism around dental implants. Implant insertion should be considered if the general condition of the patient is not stable. However, CI has not yet been fully investigated. Further studies are necessary to check and categorize the impact of corticalization on marginal bone loss near dental implants. [ABSTRACT FROM AUTHOR]

PurposeThe current primary hyperparathyroidism (PHPT) presents as a mild disease. We explored skeletal phenotypes in postmenopausal women affected by PHPT, focusing on fracture prevalence.MethodsPHPT women were retrospectively evaluated at four Italian centers for osteoporosis management (two centers in Milan, n = 244; Cuneo, n = 128; Pisa, n = 131). Data collected from clinical records were analyzed by hierarchical clusterization.ResultsConsidering the whole PHPT series [n = 503, aged 67.0 (61.0–74.0) years], 90% had low bone mineral density (BMD) and approximately 30% reported at least one fracture. Vertebral fractures were associated with older age and lower hypophosphatemia, while women with appendicular fractures were younger with less severe hypophosphatemia. Fractures were predicted by lumbar T-score. By using a clustering approach, we identified four different skeletal phenotypes (cluster, C): C1 (n = 53) and C2 (n = 172) included women with lumbar and femur neck osteopenia, with low prevalence of fractures (11.3%). Osteoporotic PHPT women were grouped into C3 (n = 142) and C4 (n = 136); all women in C4 experienced fractures, were older, and were more frequently affected with cardiovascular diseases. In contrast, women included in C3 never experienced fractures and had a lower body mass index (BMI), though they were characterized by severe reduction in BMD at both lumbar and femur sites. Ionized and total calcium, phosphate, 25hydroxyvitamin D levels, kidney function, and stone prevalence (range, 26.4%–29.0%) were similar among clusters C1, C2, and C4, while unfractured women in C3 showed slightly higher ionized hypercalcemia, lower hypophosphatemia, and higher hypercalciuria with a trend to more frequently develop kidney stones (38.7%) than women in the remaining clusters.ConclusionsSkeletal involvement in women with PHPT presented heterogeneous phenotypes with different prevalence of fractures. Fractures were not related to PHPT severity, suggesting that other factors besides PHPT, such as age, BMI, and lumbar and femur BMD, should be considered in the evaluation of bone involvement in postmenopausal women with PHPT.

IntroductionSo far, only 11 PTH mutations have been described as causes of familial isolated hypoparathyroidism (FIH). In this report, we describe a family with FIH but with significant elevation of functionally inactive PTH due to a PTH mutation. We also show a positive therapeutic outcome of recombinant human PTH (teriparatide) therapy in one of the siblings who was not well controlled on large doses of calcitriol and calcium replacement therapy.Case descriptionThe proband is a 34-year-old woman who has a history of chronic severe hypocalcemia (HypoCa) since birth. She and her three brothers (33-year-old male twins, and a 21-year-old male) were diagnosed with pseudohypoparathyroidism type 1b (PHPT 1b) based on the presence of chronic HypoCa (serum Ca 1.6-1.85 mmol/l) since birth associated with significantly elevated plasma PTH levels in the range of 310-564 pg/dl (normal range 10-65) and absence of signs of Albright hereditary osteodystrophy.Molecular studiesWES showed no pathogenic, likely pathogenic or variants of unknown significance in any known calcium-associated genetic disorder but a bi-allelic variant in the PTH itself ((NM_000315.4:c.128G>A, p.Gly43Glu). This was confirmed by Sanger sequencing in the patient and her affected brothers.ManagementBecause the patient’s HypoCa was not controlled on large doses of calcitriol and calcium carbonate, a trial of teriparatide 20 mcg SC daily was started and resulted in normalization of calcium, decline in PTH levels and significant improvement in her general wellbeing.ConclusionHigh PTH in the presence of congenital hypocalcemia is not always due to receptor or post-receptor defect and can be due to a biologically inactive mutated PTH. In such cases, treatment with teriparatide may result in stabilization of biochemical profile and improvement in quality of life.

IntroductionOver 6.8 million fractures occur annually in the US, with 10% experiencing delayed- or non-union. Anabolic therapeutics like PTH analogs stimulate fracture repair, and small molecule salt inducible kinase (SIK) inhibitors mimic PTH action. This study tests whether the SIK inhibitor YKL-05-099 accelerates fracture callus osteogenesis.Methods126 female mice underwent femoral shaft pinning and midshaft fracture, receiving daily injections of PBS, YKL-05-099, or PTH. Callus tissues were analyzed via RT-qPCR, histology, single-cell RNA-seq, and μCT imaging. Biomechanical testing evaluated tissue rigidity. A hydrogel-based delivery system for PTH and siRNAs targeting SIK2/SIK3 was developed and tested.ResultsYKL-05-099 and PTH-treated mice showed higher mineralized callus volume fraction and improved structural rigidity. RNA-seq indicated YKL-05-099 increased osteoblast subsets and reduced chondrocyte precursors. Hydrogel-released siRNAs maintained target knockdown, accelerating callus mineralization.DiscussionYKL-05-099 enhances fracture repair, supporting selective SIK inhibitors’ development for clinical use. Hydrogel-based siRNA delivery offers targeted localized treatment at fracture sites.

Studies on associations between biomarkers of vitamin D metabolism and fracture risk have focused predominantly on White or elderly populations and may not be generalizable to relatively healthy multiethnic populations. We tested associations of total 25-hydroxyvitamin D (25[OH]D), the ratio of 24,25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 (vitamin D metabolite ratio, VDMR), parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF-23) concentrations measured in serum with risk of hip and vertebral fractures in the Multi-Ethnic Study of Atherosclerosis (MESA). Serum 25-hydroxyvitamin D2 and D3 and 24,25-dihydroxyvitamin D3 were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The study cohort of 6466 participants was without clinically apparent cardiovascular disease and was 39% White, 27% Black, 22% Hispanic, and 12% Chinese. The mean age was 62 years, and 53% were female. There were 128 hip and vertebral fractures over a mean follow-up of 14.2 years. 25(OH)D, the VDMR, PTH, and FGF-23 were not significantly associated with fracture risk after adjustment for demographics, diabetes, smoking, systolic blood pressure, body mass index, medication use, albuminuria, and estimated glomerular filtration rate. Principal component analysis did not suggest differences in linear combinations of 25(OH)D, the VDMR, PTH, and FGF-23 between participants who experienced fractures and those who did not. We did not observe significant interaction between race and ethnicity and any biomarker of vitamin D metabolism on fracture risk. In conclusion, none of the four serum biomarkers of vitamin D metabolism investigated showed a significant association with fracture risk in relatively healthy multiethnic populations. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Spinal cord injury (SCI) is currently a highly disabling disease, which poses serious harm to patients and their families. Due to the fact that primary SCI is caused by direct external force, current research on SCI mainly focuses on the treatment and prevention of secondary SCI. Oxidative stress is one of the important pathogenic mechanisms of SCI, and intervention of oxidative stress may be a potential treatment option for SCI. Teriparatide is a drug that regulates bone metabolism, and recent studies have found that it has the ability to counteract oxidative stress and is closely related to SCI. This article summarizes the main pathological mechanisms of oxidative stress in SCI, as well as the relationship between them with teriparatide, and explores the therapeutic potential of teriparatide in SCI. [ABSTRACT FROM AUTHOR]

Background: Recognizing the parathyroid gland and distinguishing the parathyroid from thyroid lesions in fine needle aspiration (FNA) is challenging. This study aimed to identify cytomorphologic features suggestive of parathyroid origin and to assess the utility of cytopathology in conjunction with ancillary tests in the identification of parathyroid glands. Materials and methods: Ultrasound (US) guided FNA of parathyroid gland and lesions in 81 patients were reviewed concerning clinical history and correlated to histopathologic findings in available cases. FNA smears were evaluated for cellularity, architectural patterns, cellular and nuclear features, and background of the smears. In 78 cases, FNA was supplemented by a measurement of parathormone (PTH) levels in the needle washout fluid (FNA‐PTH assay) and/or GATA3/PTH/chromogranin‐A immunostainings. Results: Sixty‐four cases were diagnosed cytologically as parathyroid lesions in conjunction with FNA‐PTH assay and/or immunocytochemical examinations. In an additional nine cases, a diagnosis of parathyroid lesions was rendered after repeated FNA with FNA‐PTH assay. The histolopathologic diagnosis of surgically excised cases (n = 75) included parathyroid adenoma (60 cases), atypical parathyroid adenoma (4 cases), parathyroid hyperplasia (10 cases), and parathyroid carcinoma (1 case). Major cytological findings of parathyroid tissue included high cellularity, scattered naked nuclei, cribriform and three‐dimensional clusters, stippled chromatin, and oxyphilic cytoplasm while papillary pattern or colloid‐like material was identified in three cases respectively. No nuclear grooves or inclusions were seen in any case. Conclusions: High cellularity scattered naked nuclei, cribriform and three‐dimensional patterns, stippled chromatin and oxyphilic cytoplasm are cytomorphologic features that favour parathyroid origin. A combination of these features with FNA‐PTH assay and/or GATA3, PTH, and chromogranin‐A immunostainings on cytologic specimens aid in the identification of parathyroid glands and the distinguishing of parathyroid from thyroid lesions. [ABSTRACT FROM AUTHOR]

Although parathyroid hormone (PTH) is best known for its role as a regulator of skeletal remodelling and calcium homeostasis, more recent evidence supports a role for it in energy metabolism and other non-classical targets. In this report, we summarize evidence for an effect of PTH on adipocytes. This review is based upon all peer-reviewed papers, published in the English language with PubMed as the primary search engine. Recent preclinical studies have documented an effect of PTH to stimulate lipolysis in both adipocytes and liver cells and to cause browning of adipocytes. PTH also reduces bone marrow adiposity and hepatic steatosis. Although clinical studies are limited, disease models of PTH excess and PTH deficiency lend support to these preclinical findings. This review supports the concept of PTH as a polyfunctional hormone that influences energy metabolism as well as bone metabolism. [ABSTRACT FROM AUTHOR]

Background Calcimimetics are widely used in hemodialysis patients and influence serum calcium levels. Although the Kidney Disease: Improving Global Outcomes guidelines argued that low calcium levels induced by calcimimetics may be harmless, large observational studies investigating the association between hypocalcemia and mortality are scarce. We investigated the association between serum calcium levels and cardiovascular mortality in calcimimetics users using the nationwide Japanese registry for dialysis patients. Methods In this 9-year prospective cohort study, the baseline data were collected at the end of 2009. We enrolled patients on maintenance hemodialysis or hemodiafiltration. We employed three models (baseline, time-dependent and time-averaged) to conduct Cox proportional hazard regression analyses. Results Cinacalcet was prescribed to 12.7% (N  = 22 853) at baseline. The median observation period was 98 (interquartile range 40–108) months and 108 (interquartile range 59–108) months in the whole cohort (N  = 180 136) and in cinacalcet users, respectively. Three-quarters of survivors at the end of 2019 had continued calcimimetic therapy for 10 years, corresponding to a mean annual dropout rate of 2.9%. Hypocalcemia was not associated with cardiovascular mortality in the baseline or time-averaged model. In the time-dependent model, however, the lowest calcium decile (corrected calcium <8.4 mg/dL) was significantly associated with higher cardiovascular mortality than the reference (corrected calcium 8.7–8.9 mg/dL) in both cinacalcet users and all patients [hazard ratio (95% confidence interval) 1.32 (1.00, 1.75) and 1.15 (1.05, 1.26), respectively]. Hypocalcemia was especially associated with sudden death and death due to hemorrhagic stroke, heart failure and ischemic heart disease. Higher rate of fatal and non-fatal cardiovascular events was observed in hypocalcemic patients regardless of cinacalcet usage. Conclusions Our findings suggest that transient hypocalcemia was associated with an increased risk of cardiovascular death independent of cinacalcet usage. We should pay attention to hypocalcemia transiently induced by cinacalcet. [ABSTRACT FROM AUTHOR]

Over the last years non-alcoholic fatty liver disease (NAFLD) has grown into the most common chronic liver disease globally, affecting 17-38% of the general population and 50-75% of patients with obesity and/or type 2 diabetes mellitus (T2DM). NAFLD encompasses a spectrum of chronic liver diseases, ranging from simple steatosis (non-alcoholic fatty liver, NAFL) and non-alcoholic steatohepatitis (NASH; or metabolic dysfunction-associated steatohepatitis, MASH) to fibrosis and cirrhosis with liver failure or/and hepatocellular carcinoma. Due to its increasing prevalence and associated morbidity and mortality, the disease-related and broader socioeconomic burden of NAFLD is substantial. Of note, currently there is no globally approved pharmacotherapy for NAFLD. Similar to NAFLD, osteoporosis constitutes also a silent disease, until an osteoporotic fracture occurs, which poses a markedly significant disease and socioeconomic burden. Increasing emerging data have recently highlighted links between NAFLD and osteoporosis, linking the pathogenesis of NAFLD with the process of bone remodeling. However, clinical studies are still limited demonstrating this associative relationship, while more evidence is needed towards discovering potential causative links. Since these two chronic diseases frequently co-exist, there are data suggesting that anti-osteoporosis treatments may affect NAFLD progression by impacting on its pathogenetic mechanisms. In the present review, we present on overview of the current understanding of the liver-bone cross talk and summarize the experimental and clinical evidence correlating NAFLD and osteoporosis, focusing on the possible effects of antiosteoporotic drugs on NAFLD. [ABSTRACT FROM AUTHOR]

Parathyroid hormone (PTH) plays a pivotal role in maintaining calcium homeostasis, largely by modulating bone remodeling processes. Its effects on bone are notably dependent on the duration and frequency of exposure. Specifically, PTH can initiate both bone formation and resorption, with the outcome being influenced by the manner of PTH administration: continuous or intermittent. In continuous administration, PTH tends to promote bone resorption, possibly by regulating certain genes within bone cells. Conversely, intermittent exposure generally favors bone formation, possibly through transient gene activation. PTH's role extends to various aspects of bone cell activity. It directly influences skeletal stem cells, osteoblastic lineage cells, osteocytes, and T cells, playing a critical role in bone generation. Simultaneously, it indirectly affects osteoclast precursor cells and osteoclasts, and has a direct impact on T cells, contributing to its role in bone resorption. Despite these insights, the intricate mechanisms through which PTH acts within the bone marrow niche are not entirely understood. This article reviews the dual roles of PTH—catabolic and anabolic—on bone cells, highlighting the cellular and molecular pathways involved in these processes. The complex interplay of these factors in bone remodeling underscores the need for further investigation to fully comprehend PTH's multifaceted influence on bone health. [ABSTRACT FROM AUTHOR]

Abstract Introduction Chronic kidney disease-mineral and bone disorder (CKD-MBD) is characterized by bone abnormalities, vascular calcification, and some other complications. Although there are diagnostic criteria for CKD-MBD, in situations when conducting target feature examining are unavailable, there is a need to investigate and discover alternative biochemical criteria that are easy to obtain. Moreover, studying the correlations between the newly discovered biomarkers and the existing ones may provide insights into the underlying molecular mechanisms of CKD-MBD. Methods We collected a cohort of 116 individuals, consisting of three subtypes of CKD-MBD: calcium abnormality, phosphorus abnormality, and PTH abnormality. To identify the best biomarker panel for discrimination, we conducted six machine learning prediction methods and employed a sequential forward feature selection approach for each subtype. Additionally, we collected a separate prospective cohort of 114 samples to validate the discriminative power of the trained prediction models. Results Using machine learning under cross validation setting, the feature selection method selected a concise biomarker panel for each CKD-MBD subtype as well as for the general one. Using the consensus of these features, best area under ROC curve reached up to 0.95 for the training dataset and 0.74 for the perspective dataset, respectively. Discussion/Conclusion For the first time, we utilized machine learning methods to analyze biochemical criteria associated with CKD-MBD. Our aim was to identify alternative biomarkers that could serve not only as early detection indicators for CKD-MBD, but also as potential candidates for studying the underlying molecular mechanisms of the condition.

Introduction: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is characterized by bone abnormalities, vascular calcification, and some other complications. Although there are diagnostic criteria for CKD-MBD, in situations when conducting target feature examining are unavailable, there is a need to investigate and discover alternative biochemical criteria that are easy to obtain. Moreover, studying the correlations between the newly discovered biomarkers and the existing ones may provide insights into the underlying molecular mechanisms of CKD-MBD. Methods: We collected a cohort of 116 individuals, consisting of three subtypes of CKD-MBD: calcium abnormality, phosphorus abnormality, and PTH abnormality. To identify the best biomarker panel for discrimination, we conducted six machine learning prediction methods and employed a sequential forward feature selection approach for each subtype. Additionally, we collected a separate prospective cohort of 114 samples to validate the discriminative power of the trained prediction models. Results: Using machine learning under cross validation setting, the feature selection method selected a concise biomarker panel for each CKD-MBD subtype as well as for the general one. Using the consensus of these features, best area under ROC curve reached up to 0.95 for the training dataset and 0.74 for the perspective dataset, respectively. Discussion/Conclusion: For the first time, we utilized machine learning methods to analyze biochemical criteria associated with CKD-MBD. Our aim was to identify alternative biomarkers that could serve not only as early detection indicators for CKD-MBD, but also as potential candidates for studying the underlying molecular mechanisms of the condition. [ABSTRACT FROM AUTHOR]

Background: Hypoparathyroidism (HypoPT) is characterized by hypocalcemia and undetectable/inappropriately low PTH. Post-surgical HypoPT (PS-HypoPT) is the most common cause. Patients with PS-HypoPT present neuropsychological symptoms, probably due to the PTH deprivation in the central nervous system (CNS). However, these mechanisms are still not elucidated. The aim of this study was to evaluate the effects of PTH deprivation on CNS in an animal model of PS-HypoPT via a cognitive/behavioral assessment approach. Methods: A surgical rat model of PS-HypoPT was obtained and treated with calcium to maintain normocalcemia. Twenty PS-HypoPT rats and twenty sham-operated controls (Crl) underwent behavioral testing in a Morris Water Maze (MWM), Open Field (OF), and Elevated Plus Maze (EPM). Results: In the MWM, PTx rats showed a higher Escape Latency Time compared to Crl rats (p < 0.05); we observed a statistically significant improvement in the performance (day 1 to 8 p < 0.001), which was less pronounced in PTx group. In the OF test, the time and distance spent in the zone of interest were significantly lower in the PTx group compared with the Crl (p < 0.01 and p < 0.01). In the EPM experiment, the time spent in the close arm was significantly higher in the PTx group compared with the Crl (p < 0.01). Conclusions: This animal model of PS-HypoPT shows an impairment in spatial memory, which improved after training, and a marked anxiety-like behavior, resembling the condition of patients with PS-HypoPT. Further studies are needed to elucidate mechanisms. [ABSTRACT FROM AUTHOR]

Skeletal fragility and high fracture rates are common in CKD. A key component of bone loss in CKD with secondary hyperparathyroidism is high bone turnover and cortical bone deterioration through both cortical porosity and cortical thinning. We hypothesized that RANKL drives high bone resorption within cortical bone leading to the development of cortical porosity in CKD (study 1) and that systemic inhibition of RANKL would mitigate the skeletal phenotype of CKD (study 2). In study 1, we assessed the skeletal properties of male and female Dmp1-cre RANKLfl/fl (cKO) and control genotype (Ranklfl/fl ; Con) mice after 10 wk of adenine-induced CKD (AD; 0.2% dietary adenine). All AD mice regardless of sex or genotype had elevated blood urea nitrogen and high PTH. Con AD mice in both sexes had cortical porosity and lower cortical thickness as well as high osteoclast-covered trabecular surfaces and higher bone formation rate. cKO mice had preserved cortical bone microarchitecture despite high circulating PTH as well as no CKD-induced increases in osteoclasts. In study 2, male mice with established AD CKD were either given a single injection of an anti-RANKL antibody (5 mg/kg) 8 wk post-induction of CKD or subjected to 3×/wk dosing with risedronate (1.2 μg/kg) for 4 wk. Anti-RANKL treatment significantly reduced bone formation rate as well as osteoclast surfaces at both trabecular and cortical pore surfaces; risedronate treatment had little effect on these bone parameters. In conclusion, these studies demonstrate that bone-specific RANKL is critical for the development of high bone formation/high osteoclasts and cortical bone loss in CKD with high PTH. Additionally, systemic anti-RANKL ligand therapy in established CKD may help prevent the propagation of cortical bone loss via suppression of bone turnover. [ABSTRACT FROM AUTHOR]

We have studied the role of the intestine, kidney, and several hormones when adapting to changes in dietary P concentration. Normal and parathyroidectomized (PTX) rats were fed pH-matched diets containing 0.1%, 0.6%, and 1.2% P concentrations. 32Pi uptake was determined in the jejunum and kidney cortex brush border membrane vesicles. Several hormone and ion concentrations were determined in the blood and urine of rats. Both jejunum and kidney cortex Pi transport was regulated with 5 d of chronic feeding of P diets in normal rats. Acute adaptation was determined by switching foods on day 6, which was only clearly observed in the kidney cortex of normal rats, with more statistical variability in the jejunum. However, no paradoxical increase of Pi uptake in the jejunum was reproduced after the acute switch to the 1.2% P diet. Pi uptake in the jejunum was parathyroid hormone (PTH)-independent, but in the kidney, the chronic adaptation was reduced, and no acute dietary adaptations were observed. The NaPi2a protein was more abundant in the PTX than the sham kidneys, but contrary to the modest or absent changes in Pi uptake adaptation, the transporter was similarly regulated by dietary P, as in the sham rats. PTH and fibroblast growth factor 23 (FGF23) were the only hormones regulated by all diet changes, even in fasting animals, which exhibited regulated Pi transport despite similar phosphatemia. Evidence of Pi appetite effects was also observed. In brief, our results show new characteristics of Pi adaptations, including a lack of correlation between Pi transport, NaPi2a expression, and PTH/FGF23 concentrations. Graphical Abstract [ABSTRACT FROM AUTHOR]

Several human disorders are caused by genetic or epigenetic changes involving the GNAS locus on chromosome 20q13.3 that encodes the alpha-subunit of the stimulatory G protein (Gsa) and several splice variants thereof. Thus, pseudohypoparathyroidism type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal GNAS exons 1-13 resulting in characteristic abnormalities referred to as Albright's hereditary osteodystrophy (AHO) that are associated with resistance to several agonist ligands, particularly to parathyroid hormone (PTH), thereby leading to hypocalcemia and hyperphosphatemia. GNAS mutations involving the paternal Gsa exons also cause most of these AHO features, but without evidence for hormonal resistance, hence the term pseudopseudohypoparathyroidism (PPHP). Autosomal dominant pseudohypoparathyroidism type Ib (PHP1B) due to maternal GNAS or STX16 mutations (deletions, duplications, insertions, and inversions) is associated with epigenetic changes at one or several differentially methylated regions (DMRs) within GNAS. Unlike the inactivating Gsa mutations that cause PHP1A and PPHP, hormonal resistance is caused in all PHP1B variants by impaired Gsa expression due to loss of methylation at GNAS exon A/B, which can be associated in some familial cases with epigenetic changes at the other maternal GNAS DMRs. The genetic defect(s) responsible for sporadic PHP1B, the most frequent variant of this disorder, remain(s) unknown for the majority of patients. However, characteristic epigenetic GNAS changes can be readily detected that include a gain of methylation at the neuroendocrine secretory protein (NESP) DMR. Multiple genetic or epigenetic GNAS abnormalities can thus impair Gsa function or expression, consequently leading to inadequate cAMP-dependent signaling events downstream of various Gsa-coupled receptors. [ABSTRACT FROM AUTHOR]

Background: The etiopathogenesis of autoimmune diseases is multifactorial, including hormonal factors. Remission of autoimmunity has been observed following treatment for concomitant hyperparathyroidism. Additionally, patients with autoimmune diseases have shown increased expression of parathyroid hormone receptor (PTH1R) and altered distribution of B cells subsets. Hence, this study aims to evaluate potential mechanisms and in vitro effects of PTH stimulation on B lymphocytes. Methods: Using the human B-cell line Ramos (RA.1), various biological effects were evaluated with and without parathyroid hormone (PTH) stimulation at varying concentrations. Flow cytometry was employed to evaluate the phenotype of B lymphocytes based on IgD and CD38 expression, apoptosis induction via Annexin V and proliferation using CFSE. IgM production was quantified through ELISA, and Western blot analysis was performed to assess syk protein phosphorylation as an indicator of cell activation. Results: Ramos cells (RA.1) evidenced a statistically significant change in the phenotype under human PTH stimulation, demonstrating an increased proportion of germinal centre cells (Bm3-Bm4) when stimulated with high concentrations of PTH. Conclusions: The in vitro effects of PTH in B cells subsets align with previous findings of an altered phenotype in B lymphocytes expressing PTH1R among autoimmune disease patients, suggesting a potential role of this hormone in the pathophysiology of autoimmune diseases. However, further studies are necessary to elucidate the mechanisms by which PTH generates observed effects in B lymphocytes and to determine if PTH plays a role in autoimmunity.

Osteoblast adherence to bone surfaces is important for remodeling bone tissue. This study demonstrates that deficiency of TG-interacting factor 1 (Tgif1) in osteoblasts results in altered cell morphology, reduced adherence to collagen type I-coated surfaces, and impaired migration capacity. Tgif1 is essential for osteoblasts to adapt a regular cell morphology and to efficiently adhere and migrate on collagen type I-rich matrices in vitro. Furthermore, Tgif1 acts as a transcriptional repressor of p21-activated kinase 3 (Pak3), an important regulator of focal adhesion formation and osteoblast spreading. Absence of Tgif1 leads to increased Pak3 expression, which impairs osteoblast spreading. Additionally, Tgif1 is implicated in osteoblast recruitment and activation of bone surfaces in the context of bone regeneration and in response to parathyroid hormone 1–34 (PTH 1–34) treatment in vivo in mice. These findings provide important novel insights in the regulation of the cytoskeletal architecture of osteoblasts.

Phosphate homeostasis, mediated by dietary intake, renal absorption, and bone deposition, is incompletely understood because of the uncharacterized roles of numerous implicated protein factors. Here, we identified a novel role for one such element, regulator of G protein signaling 14 (RGS14), suggested by genome-wide association studies to associate with dysregulated Pi levels. We show that human RGS14 possesses a carboxy-terminal PDZ ligand required for sodium phosphate cotransporter 2a (NPT2A) and sodium hydrogen exchanger regulatory factor-1 (NHERF1)-mediated renal Pi transport. In addition, we found using isotope uptake measurements combined with bioluminescence resonance energy transfer assays, siRNA knockdown, pull-down and overlay assays, and molecular modeling that secreted proteins parathyroid hormone (PTH) and fibroblast growth factor 23 inhibited Pi uptake by inducing dissociation of the NPT2A-NHERF1 complex. PTH failed to affect Pi transport in cells expressing RGS14, suggesting that it suppresses hormone-sensitive but not basal Pi uptake. Interestingly, RGS14 did not affect PTH-directed G protein activation or cAMP formation, implying a postreceptor site of action. Further pull-down experiments and direct binding assays indicated that NPT2A and RGS14 bind distinct PDZ domains on NHERF1. We showed that RGS14 expression in human renal proximal tubule epithelial cells blocked the effects of PTH and fibroblast growth factor 23 and stabilized the NPT2A-NHERF1 complex. In contrast, RGS14 genetic variants bearing mutations in the PDZ ligand disrupted RGS14 binding to NHERF1 and subsequent PTH-sensitive Pi transport. In conclusion, these findings identify RGS14 as a novel regulator of hormone-sensitive Pi transport. The results suggest that changes in RGS14 function or abundance may contribute to the hormone resistance and hyperphosphatemia observed in kidney diseases.

Abstract Background The high impact of vitamin D on brain development and its relationship with inflammatory markers in the clinical course of psychiatric disorders have compelled researchers to investigate the potential association between vitamin D levels, C-reactive protein (CRP) levels, and the incidence of mental disorders. In the present study, we aimed to compare the serum levels of vitamin D and its related markers, including calcium, phosphorus, and parathyroid hormone (PTH), along with CRP, in 3 groups of patients with acute psychotic episodes, including schizophrenia, bipolar disorder, and methamphetamine-induced psychosis, with a standard control group of the Iranian population. Methods This descriptive cross-sectional study was conducted at a psychiatric hospital in Tehran, Iran, and involved a total of 185 subjects. The subjects included four groups: acute phase of schizophrenia (n = 49), acute manic episodes of bipolar disorder (n = 43), methamphetamine-induced psychotic disorder (n = 46), and control group (n = 47). Among 138 patients in acute psychotic episodes, 33 patients were in their first episode of psychosis, while 105 patients were in acute exacerbation of their chronic psychotic disorders. The Brief Psychiatric Rating Scale (BPRS) was measured by an expert attending psychiatrist for all patients. Then, serum levels of calcium, phosphorus, parathormone, vitamin D, and CRP were assessed in all study groups. Results Among our 185 study subjects, it was observed that individuals with higher education levels and those who were married had a lower prevalence of mental disorders. In all patient groups, the serum levels of CRP were significantly higher, and PTH levels were significantly lower than in the control group (p

Abstract Background Minerals play vital roles in physiologic processes. Calcium, phosphorus and magnesium are common minerals. Secretion, absorption and homeostasis of these minerals are affected by associations between the active vitamin D and parathyroid hormone (PTH). Objective The aim of this study was to assess concentrations of vitamin D, PTH and minerals, such as calcium, phosphorus and magnesium in horse sera, as well as associations of these values with lameness in horses. In the references, the reasons for lameness can be deficiency and imbalance of minerals, and clinical observations also confirm this and there is still not enough information regarding the relationship between mineral imbalance and lameness of horses. The prominent forms of lameness include navicular syndrome, back pain, splints, ring bone, side bone, non‐infectious arthritis and bucked shins. Deficiency and inadequacy of calcium, phosphorous and magnesium have been regarded as predisposing and aggravating factors of the aforementioned diseases. Materials and methods This cross‐sectional study was carried out on 60 horses, including 30 lame and 30 healthy adult horses, summer to fall 2021. Levels of calcium, phosphorus, magnesium, vitamin D and PTH were assessed in sera using automatic analyser, atomic absorption spectroscopy and commercially available kits. Results The average level of calcium was higher healthy horses than lame horses in the two seasons (p

Recent studies have suggested that 25-hydroxyvitamin D (25(OH)D) may be a poor biomarker of bone health, in part because measured levels incorporate both protein-bound and free vitamin D. The ratio of its catabolic product (24,25-dihydroxyvitamin D [24,25(OH)2 D]) to 25(OH)D (the vitamin D metabolite ratio [VMR]) may provide more information on sufficient vitamin D stores and is not influenced by vitamin D-binding protein concentrations. We evaluated whether the VMR or 25(OH)D are more strongly associated with bone loss and fracture risk in older adults. We performed a retrospective cohort study of 786 community-dwelling adults aged 70 to 79 years who participated in the Health Aging and Body Composition study. Our primary outcomes were annual changes in bone density and incident fracture. The mean age of these participants was 75 ± 3 years, 49% were female, 42% were Black, and 23% had an estimated glomerular filtration rate (eGFR)

Managing mineral bone disease (MBD) could reduce cardiovascular risk and improve the survival of dialysis patients. Our study focuses on the impact of calcium bath exposure in dialysis patients by comparing peritoneal dialysis patients (PD, intervention group) and hemodialysis patients (HD, control group). We assessed various factors, including calcium, phosphorus, magnesium, PTH, vitamin D 25-OH, C-terminal telopeptide (CTX), and FGF-23 levels, as well as the calcium bath six hours before the blood sample and the length of daily calcium exposure. We enrolled 40 PD and 31 HD patients with a mean age of 68.7 ± 13.6 years. Our cohort had median PTH and FGF-23 levels of 194 ng/L (Interquartile range [IQR] 130-316) and 1296 pg/mL (IQR 396-2698), respectively. We identified the length of exposure to a 1.25 mmol/L calcium bath, phosphate levels, and CTX as independent predictors of PTH (OR 0.279, p = 0.011; OR 0.277, p = 0.012; OR 0.11, p = 0.01, respectively). In contrast, independent predictors of FGF-23 were phosphate levels (OR 0.48, p < 0.001) and serum calcium levels (OR 0.25, p = 0.015), which were affected by the calcium bath. These findings suggest that managing dialysate calcium baths impacts phosphaturic hormones and could be a critical factor in optimizing CKD-MBD treatment in PD patients, sparking a new avenue of research and potential interventions.

BackgroundDespite the association of physical activity with improved cardiovascular outcomes and the association of high coronary artery calcification (CAC) scores with poor prognosis, elite endurance athletes have increased CAC. Yet, they nevertheless have better cardiovascular survival. We hypothesized that exercise may transform vascular calcium deposits to a more stable morphology.MethodsTo test this, hyperlipidemic mice (Apoe-/-) with baseline aortic calcification were separated into 2 groups (n = 9/group) with control mice allowed to move ad-lib while the exercise group underwent a progressive treadmill regimen for 9 weeks. All mice underwent blood collections and in vivo 18F-NaF μPET/μCT imaging both at the start and end of the exercise regimen. At euthanasia, aortic root specimens were obtained for histomorphometry.ResultsResults showed that, while aortic calcification progressed similarly in both groups based on µCT, the fold change in 18F-NaF density was significantly less in the exercise group. Histomorphometric analysis of the aortic root calcium deposits showed that the exercised mice had a lower mineral surface area index than the control group. The exercise regimen also raised serum PTH levels twofold.ConclusionThese findings suggest that weeks-long progressive exercise alters the microarchitecture of atherosclerotic calcium deposits by reducing mineral surface growth, potentially favoring plaque stability.

Abstract Background As an invasive technique, selective venous sampling (SVS) is considered a useful method to identify a lesion’s location to increase the success rate of secondary surgery in patients with primary hyperparathyroidism (pHPT) caused by ectopic parathyroid adenomas. Case presentation We present a case of post-surgical persistent hypercalcemia and elevated parathyroid hormone (PTH) levels in a 44-year-old woman with previously undetected parathyroid adenoma. An SVS was then performed for further localization of the adenoma, as other non-invasive methods showed negative results. After SVS, an ectopic adenoma was suspected in the sheath of the left carotid artery, previously considered as a schwannoma, and was pathologically confirmed after the second operation. Postoperatively, the patient’s symptoms disappeared and serum levels of PTH and calcium normalized. Conclusions SVS can provide precise diagnosis and accurate positioning before re-operation in patients with pHPT.

As in 2011, when the Spanish Society of Nephrology (SEN) published the Spanish adaptation to the Kidney Disease: Improving Global Outcomes (KDIGO) universal Guideline on Chronic Kidney Disease–Mineral and Bone Disorder (CKD–MBD), this document contains an update and an adaptation of the 2017 KDIGO guidelines to our setting. In this field, as in many other areas of nephrology, it has been impossible to irrefutably answer many questions, which remain pending. However, there is no doubt that the close relationship between the CKD–MBD/cardiovascular disease/morbidity and mortality complex and new randomised clinical trials in some areas and the development of new drugs have yielded significant advances in this field and created the need for this update. We would therefore highlight the slight divergences that we propose in the ideal objectives for biochemical abnormalities in the CKD–MBD complex compared to the KDIGO suggestions (for example, in relation to parathyroid hormone or phosphate), the role of native vitamin D and analogues in the control of secondary hyperparathyroidism and the contribution of new phosphate binders and calcimimetics. Attention should also be drawn to the adoption of important new developments in the diagnosis of bone abnormalities in patients with kidney disease and to the need to be more proactive in treating them. In any event, the current speed at which innovations are taking place, while perhaps slower than we might like, globally drives the need for more frequent updates (for example, through Nefrología al día). Resumen: Al igual a como ocurrió en el año 2011, cuando la Sociedad Española de Nefrología (SEN) publicó la adaptación española a las guías universales Kidney Disease Initiative Global Outcomes (KDIGO) sobre alteraciones del metabolismo óseo-mineral en la enfermedad renal crónica (CKD–MBD), este documento contiene una actualización y adaptación a nuestro medio de las guías KDIGO del 2017. En este campo, al igual que en muchos otros nefrológicos, no se ha podido contestar irrefutablemente muchas cuestiones pendientes aún. Sin embargo, no hay duda acerca de la estrecha relación entre el complejo CKD–MBD/patología cardiovascular/morbimortalidad, nuevos ensayos clínicos aleatorizados en algunas áreas o la aparición de nuevos fármacos han proporcionado notables avances en este campo y crearon la necesidad de dicha actualización. Así, destacamos las discretas divergencias que ofrecemos en los objetivos ideales de las alteraciones bioquímicas del complejo CKD–MBD respecto a las sugerencias de las KDIGO (en relación, por ejemplo, con la hormona paratiroidea o fosfato), el papel de la vitamina D nativa y análogos en el control del hiperparatiroidismo secundario, así como la contribución de nuevos captores de fosfato y calcimiméticos. Asimismo, es de destacar la adopción de importantes novedades en el diagnóstico de las alteraciones óseas del paciente renal y la necesidad de tomar actitudes más proactivas en su tratamiento. En cualquier caso, la velocidad a la que acaecen novedades actualmente, aunque menor de la que sería deseable, sí impulsan globalmente la necesidad de actualizaciones con menor demora (por ejemplo, a través de Nefrología al día).

Background: Rickets occurs in infants and children (aged 2 months to 3 years), compromising their skeletal development and damaging nervous, hematopoietic, immune, and other system functions. This study aimed to explore the significance of CD38 in rickets. Methods: The microarray dataset GSE22523 was analyzed to obtain differentially expressed genes in rickets patients. A total of 36 rickets patients and healthy controls were recruited for the study, and their blood samples were collected, followed by detecting mRNA levels of CD38 using quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, the significance of CD38 in rickets patients was analyzed by receiver operating characteristic (ROC) analysis, while the correlation between CD38 and 25-hydroxy-vitamin D (25OHD)/parathyroid hormone (PTH) was analyzed with Pearson's correlation. Results: Results showed that CD38 mRNA levels and PTH contents were significantly increased in the rickets patients while 25OHD contents were decreased. Correlation analysis indicated that CD38 was positively correlated with PTH and negatively correlated with 25OHD in both serum and plasma samples of rickets patients. Moreover, ROC analysis showed that serum CD38 was 0.9005 (95 % CI: 0.8313–0.9696), and the AUCs of plasma CD38 was 0.7215 (95 % CI: 0.6031–0.8398) in differentiating rickets patients from healthy persons, advocating serum CD38 had better diagnostic value. Conclusion: CD38 mRNA levels were upregulated in rickets patients and closely correlated with PTH and 25OHD contents, indicating CD38 might be a diagnostic marker of rickets patients. Further research on the diagnostic utility of CD38 is necessary for the diagnosis and treatment of ricketsin rickets in the future.

Larger animal models with a well-developed Haversian system, as observed in humans, are ideal to analyze cortical bone remodeling in pharmacological studies of anti-osteoporosis drugs, although they have some limitations in controlling individual variability in size, weight, age, and number. This study aimed to morphometrically analyze cortical bone remodeling focusing on Haversian canals in dogs using four regimens of TPTD with daily and weekly administrations at lower and higher weekly doses (4.9 μg/kg/week and 19.8 μg/kg/week, respectively) for 9 months. A micro-computed tomography-based analysis showed no significant differences among regimen groups. By establishing artificial intelligence (AI)-driven morphometric analyses and geographical information system (GIS)-based spatial mapping of Haversian canals that does not require confocal microscopy but is possible with more commonly used wide field microscopes, we successfully observed significant morphometric distinctions among regimens applied even in dogs. Our analytical results suggested that the daily higher regimen specifically increased the number of eroded pores creating spaces between existing canals, thus stimulating cortical bone remodeling.

We have previously reported that the cortical bone thinning seen in mice lacking the Wnt signaling antagonist Sfrp4 is due in part to impaired periosteal apposition. The periosteum contains cells which function as a reservoir of stem cells and contribute to cortical bone expansion, homeostasis, and repair. However, the local or paracrine factors that govern stem cells within the periosteal niche remain elusive. Cathepsin K (Ctsk), together with additional stem cell surface markers, marks a subset of periosteal stem cells (PSCs) which possess self-renewal ability and inducible multipotency. Sfrp4 is expressed in periosteal Ctsk-lineage cells, and Sfrp4 global deletion decreases the pool of PSCs, impairs their clonal multipotency for differentiation into osteoblasts and chondrocytes and formation of bone organoids. Bulk RNA sequencing analysis of Ctsk-lineage PSCs demonstrated that Sfrp4 deletion down-regulates signaling pathways associated with skeletal development, positive regulation of bone mineralization, and wound healing. Supporting these findings, Sfrp4 deletion hampers the periosteal response to bone injury and impairs Ctsk-lineage periosteal cell recruitment. Ctsk-lineage PSCs express the PTH receptor and PTH treatment increases the % of PSCs, a response not seen in the absence of Sfrp4. Importantly, in the absence of Sfrp4, PTH-dependent increase in cortical thickness and periosteal bone formation is markedly impaired. Thus, this study provides insights into the regulation of a specific population of periosteal cells by a secreted local factor, and shows a central role for Sfrp4 in the regulation of Ctsk-lineage periosteal stem cell differentiation and function. [ABSTRACT FROM AUTHOR]

The parathyroid gland plays an essential role in mineral and bone metabolism. Cultivation of physiological human parathyroid cells has yet to be established and the method by which parathyroid cells differentiate from pluripotent stem cells remains uncertain. Therefore, it has been hard to clarify the mechanisms underlying the onset of parathyroid disorders, such as hyperparathyroidism. In this study, we developed a new method of parathyroid cell differentiation from human induced pluripotent stem (iPS) cells. Parathyroid cell differentiation occurred in accordance with embryologic development. Differentiated cells, which expressed the parathyroid hormone, adopted unique cell aggregation similar to the parathyroid gland. In addition, these differentiated cells were identified as calcium-sensing receptor (CaSR)/epithelial cell adhesion molecule (EpCAM) double-positive cells. Interestingly, stimulation with transforming growth factor-α (TGF-α), which is considered a causative molecule of parathyroid hyperplasia, increased the CaSR/EpCAM double-positive cells, but this effect was suppressed by erlotinib, which is an epidermal growth factor receptor (EGFR) inhibitor. These results suggest that TGF-α/EGFR signaling promotes parathyroid cell differentiation from iPS cells in a similar manner to parathyroid hyperplasia. [ABSTRACT FROM AUTHOR]

Background Diabetic patients on haemodialysis have a higher risk of mortality than non-diabetic patients. The aim of this COSMOS (Current management of secondary hyperparathyroidism: a multicentre observational study) analysis was to assess whether bone and mineral laboratory values [calcium, phosphorus and parathyroid hormone (PTH)] contribute to this risk. Methods COSMOS is a multicentre, open-cohort, 3-year prospective study, which includes 6797 patients from 227 randomly selected dialysis centres in 20 European countries. The association between mortality and calcium, phosphate or PTH was assessed using Cox proportional hazard regression models using both penalized splines smoothing and categorization according to KDIGO guidelines. The effect modification of the association between the relative risk of mortality and serum calcium, phosphate or PTH by diabetes was assessed. Results There was a statistically significant effect modification of the association between the relative risk of mortality and serum PTH by diabetes (P  = .011). The slope of the curve of the association between increasing values of PTH and relative risk of mortality was steeper for diabetic compared with non-diabetic patients, mainly for high levels of PTH. In addition, high serum PTH (>9 times the normal values) was significantly associated with a higher relative risk of mortality in diabetic patients but not in non-diabetic patients [1.53 (95% confidence interval 1.07–2.19) and 1.17 (95% confidence interval 0.91–1.52)]. No significant effect modification of the association between the relative risk of mortality and serum calcium or phosphate by diabetes was found (P  = .2 and P  = .059, respectively). Conclusion The results show a different association of PTH with the relative risk of mortality in diabetic and non-diabetic patients. These findings could have relevant implications for the diagnosis and treatment of chronic kidney disease–mineral and bone disorders. [ABSTRACT FROM AUTHOR]