Increased Serum Parathyroid Hormone Research Articles

Rare genetic disorders that impair parathyroid hormone synthesis, secretion, or bioactivity provide insights into the diagnostic utility of different parathyroid hormone assays.

Parathyroid hormone (PTH) is the major peptide hormone regulator of blood calcium homeostasis. Abnormal PTH levels can be observed in patients with various congenital and acquired disorders, including chronic kidney disease (CKD). This review will focus on rare human diseases caused by PTH mutations that have provided insights into the regulation of PTH synthesis and secretion as well as the diagnostic utility of different PTH assays. Over the past years, numerous diseases affecting calcium and phosphate homeostasis have been defined at the molecular level that are responsible for reduced or increased serum PTH levels. The underlying genetic mutations impair parathyroid gland development, involve the PTH gene itself, or alter function of the calcium-sensing receptor (CaSR) or its downstream signaling partners that contribute to regulation of PTH synthesis or secretion. Mutations in the pre sequence of the mature PTH peptide can, for instance, impair hormone synthesis or intracellular processing, while amino acid substitutions affecting the secreted PTH(1-84) impair PTH receptor (PTH1R) activation, or cause defective cleavage of the pro-sequence and thus secretion of a pro- PTH with much reduced biological activity. Mutations affecting the secreted hormone can alter detection by different PTH assays, thus requiring detailed knowledge of the utilized diagnostic test. Rare diseases affecting PTH synthesis and secretion have offered helpful insights into parathyroid biology and the diagnostic utility of commonly used PTH assays, which may have implications for the interpretation of PTH measurements in more common disorders such as CKD.

Injection of luteinizing hormone or human chorionic gonadotropin increases calcium excretion and serum PTH in males

Animal and human studies have suggested that sex steroids have calciotropic actions, and it has been proposed that follicle-stimulating hormone (FSH) may exert direct effects on bone. Here, we demonstrate the expression of the receptor for Luteinizing hormone (LH) and human choriogonadotropin (hCG), LHCGR, in human kidney tissue, suggesting a potential influence on calcium homeostasis. To investigate the role of LHCGR agonist on calcium homeostasis in vivo, we conducted studies in male mice and human subjects. Male mice were treated with luteinizing hormone (LH), and human extrapolation was achieved by injecting 5000 IU hCG once to healthy men or men with hypergonadotropic or hypogonadotropic hypogonadism. In mice, LH treatment significantly increased urinary calcium excretion and induced a secondary increase in serum parathyroid hormone (PTH). Similarly, hCG treatment in healthy men led to a significant increase in urinary calcium excretion, serum PTH levels, and 1,25 (OH)2D3, while calcitonin, and albumin levels were reduced, possibly to avoid development of persistent hypocalcemia. Still, the rapid initial decline in ionized calcium coincided with a significant prolongation of the cardiac QTc-interval that normalized over time. The observed effects may be attributed to LH/hCG-receptor (LHCGR) activation, considering the presence of LHCGR expression in human kidney tissue, and the increase in sex steroids occurred several hours after the changes in calcium homeostasis. Our translational study shed light on the intricate relationship between gonadotropins, sex hormones and calcium, suggesting that LHCGR may be influencing calcium homeostasis directly or indirectly.

Serum Biochemical Evaluation of Patients with Chronic Renal Failure on Hemodialysis

Introduction: Chronic renal failure (CRF) is associated with aberrations in the metabolism of minerals, such as calcium, phosphates, sodium, and potassium and other biochemical parameters. Various studies have identified parathyroid hormone (PTH) as the main regulator of minerals and biochemical parameters homeostasis. This study was conducted to evaluate the biochemical profile in CRF patients on hemodialysis in Aden. Methods: This study is a descriptive, cross sectional study, conducted in Aden Hemodialysis Center for the period Jan.1st to June 30th, 2022. Included 82 patients with CRF on HD. The data collected included demographic with clinical data, and blood samples taken for complete blood count and serum creatinine; urea; sodium; potassium; total calcium, ionized calcium; phosphate; alkaline phosphatase, and parathyroid hormone. Results: More male were found than female patients with CRF (67.1% vs. 32.9% respectively), with a mean age of 48.8 ± 12.6 years. The mean body mass index was (23.3 ± 4.7 kg/m2) and the mean duration of CRF was (4.8 ± 2.9 years). For renal function, the mean serum creatinine, urea, and estimated creatinine clearance were (9.9 mg/dl, 128.6 mg/dl, and 7.1 mL/min per 1.73 m2 respectively). For minerals, the mean serum sodium, potassium, chloride, phosphorus, calcium and ionized calcium were (134.4 mmol/L, 5.04 mmol/L, 104.1 mmol/L, 4.37 mg/dl, 9.4 mg/dl, and 1.12 mmol/L, respectively). The mean Calcium x Phosphorus product was in the recommended range (40.7mg2/dl2). The mean alkaline phosphatase was (286.2 U/L), and the mean parathyroid hormone was (322.7 pg/ml). Secondary hyperparathyroidism (PTH level of ≥130 pg/ml) was detected in (58.5%) of them. Parathormone concentration showed significant positive correlation to alkaline phosphatase (r: 0.640, p:0.001) in patients with CRF on hemodialysis. Conclusion: This study concluded that in patients with CRF on HD, there is an increase level of alkaline phosphatase which is considered as an adjunct marker of high-turnover bone disease associated with disturbed level of calcium and phosphorus that increase serum PTH level.

Fracture Risk Among Living Kidney Donors 25 Years After Donation

Living kidney donors may have an increased risk of fractures due to reductions in kidney mass, lower concentrations of serum 1,25-dihydroxyvitamin D, and secondary increases in serum parathyroid hormone. To compare the overall and site-specific risk of fractures among living kidney donors with strictly matched controls from the general population who would have been eligible to donate a kidney but did not do so. This survey study was conducted between December 1, 2021, and July 31, 2023. A total of 5065 living kidney donors from 3 large transplant centers in Minnesota were invited to complete a survey about their bone health and history of fractures, and 16 156 population-based nondonor controls without a history of comorbidities that would have precluded kidney donation were identified from the Rochester Epidemiology Project and completed the same survey. A total of 2132 living kidney donors and 2014 nondonor controls responded to the survey. Statistical analyses were performed from May to August 2023. Living kidney donation. The rates of overall and site-specific fractures were compared between living kidney donors and controls using standardized incidence ratios (SIRs). At the time of survey, the 2132 living kidney donors had a mean (SD) age of 67.1 (8.9) years and included 1245 women (58.4%), and the 2014 controls had a mean (SD) age of 68.6 (7.9) years and included 1140 women (56.6%). The mean (SD) time between donation or index date and survey date was 24.2 (10.4) years for donors and 27.6 (10.7) years for controls. The overall rate of fractures among living kidney donors was significantly lower than among controls (SIR, 0.89; 95% CI, 0.81-0.97). However, there were significantly more vertebral fractures among living kidney donors than among controls (SIR, 1.42; 95% CI, 1.05-1.83). This survey study found a reduced rate of overall fractures but an excess of vertebral fractures among living kidney donors compared with controls after a mean follow-up of 25 years. Treatment of excess vertebral fractures with dietary supplements such as vitamin D3 may reduce the numbers of vertebral fractures and patient morbidity.

High sodium promotes the secretion and synthesis of PTH through PiT-1-IKKβ pathway in parathyroid gland in vitro.

Parathyroid hormone (PTH) is secreted by the parathyroid glands (PTGs) and is an important hormone regulating mineral metabolism. Previous studies reported that high sodium diet will cause the increase in serum PTH, but the specific mechanism is unknown. Consequently, the present study aims to investigate the effects and mechanisms of high sodium on PTH synthesis and secretion from PTGs. We developed a tissue culture model using normal rat PTGs, discovered that sodium elicited and promoted concentration-dependent and time-dependent PTH secretion. Changes in sodium-associated transporters from PTGs incubated with high sodium were thoroughly examined. Increased expression of sodium-phosphate cotransporter Slc20a1 (also known as PiT-1) was observed. Further tests revealed that PiT-1 activated the NF-κB signaling pathway, resulting in increased IKKβ phosphorylation, IKBα degradation, and increased p65 phosphorylation followed by nuclear entry, which led to increased PTH transcription. Meanwhile, IKKβ phosphorylated SNAP23, promoting exocytosis and eventually led to increased PTH secretion. In conclusion, our findings indicate that PiT-1 plays an important role in the increased secretion and synthesis of PTH directly induced by high sodium under physiological conditions, and may provide a potential therapeutic target for secondary hyperparathyroidism (SHPT).

Evaluation of T helper17 as skeletal homeostasis factor in peripheral blood mononuclear cells and T helper cells of end-stage renal disease cases with impaired parathyroid hormone.

Chronic renal failure is mainly connected with high and low parathyroid hormone (PTH) levels and immunological impairments. The present study aimed to evaluate T helper 17 (Th17) cells as a crucial modulator of the immune system and skeletal homeostasis in hemodialysis patients with impaired intact PTH (iPTH). In this research, blood samples were taken from ESRD patients with high (> 300 pg/mL), normal (150-300 pg/mL), and low (< 150 pg/mL) serum intact parathyroid hormone (iPTH( levels (n = 30 in each group). The frequency of Th17 (CD4+ IL17+) cells was evaluated by flow cytometry in each group. The expression levels of Th17 cell-related master transcription factors, cytokines in peripheral blood mononuclear cells (PBMC), and Th cells, and the level of the mentioned cytokines were determined in the supernatant of PBMCs. The number of Th17 cells remarkably increased in subjects with high iPTH against low and normal iPTH. Also, RORɣt and STAT3 levels were significantly higher in high iPTH ESRD patients than in other groups in the expression of mRNA and protein levels. These findings are confirmed by evaluating the IL-17 and IL-23 in the supernatant of cultured PBMCs and isolated Th cells. Our findings indicated that increased serum PTH levels in hemodialysis cases may be involved in increasing the differentiation of CD4 + cells to Th17 cells in PBMC.

Occult Renal Calcifications in Patients with Normocalcemic Primary Hyperparathyroidism and Their Association with the Parathyroid Hormone-Vitamin D Axis.

Normocalcemic primary hyperparathyroidism (NPHPT) is characterized by elevated serum levels of parathyroid hormone (PTH) with persistently normal serum calcium concentrations after excluding secondary causes of hyperparathyroidism. Urolithiasis and/or nephrocalcinosis may occur in hypercalcemic PHPT, but little is known about these complications in NPHPT. Objectives. To identify occult urolithiasis and nephrocalcinosis in asymptomatic patients with NPHPT and evaluate biochemical markers as risk predictors for the development of renal calcification (RC). Methods. Cross-sectional analysis of 34 patients with no history of urolithiasis and/or nephrocalcinosis. The diagnosis of NPHPT was as follows: elevated serum PTH (reference range: 15–65 pg/mL), normal albumin-corrected serum calcium, normal urinary calcium excretion, serum 25(OH)D >30 ng/mL, eGFR (CKD-EPI) > 60 mL/min/1.73 m2, without intestinal disease, and not on medications such as thiazide diuretics, lithium, bisphosphonates, or denosumab. Patients were categorized according to the presence or absence of RC identified by renal imaging. Their clinical and biochemical characteristics were then compared. Results. The patients had a mean age of 67.97 ± 10.45 years, predominantly postmenopausal women (88.2%); serum PTH, 119.67 ± 64.44 pg/mL; 25(OH)D, 39.00 ± 8.88 ng/dL; 1.25(OH))2D, 74.53 ± 26.37 pg/mL; corrected serum calcium, 9.34 ± 0.62 mg/dL; and 24-hour urinary calcium, 134.87 ± 79.68 mg/day. RC was identified in 26.5% of the patients. There was no difference in anthropometric and clinical parameters, renal function, 25(OH)D, and urinary pH in patients with or without RC. Patients with RC had higher PTH values (176.22 vs. 99.32 pg/mL, P = 0.001), 1.25(OH) 2D (96.83 vs. 62.36 pg/mL, P = 0.005), and 24-hour urinary calcium (181.9 vs. 117.94 mg/day, P = 0.037). Conclusion. Occult renal calcifications are common in NPHPT and are associated with increased serum PTH, 1.25(OH))2D, and 24 h urinary calcium.

Molecular Mechanisms of Parathyroid Disorders in Chronic Kidney Disease.

Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that induces morbidity and mortality in patients. How CKD stimulates the parathyroid to increase parathyroid hormone (PTH) secretion, gene expression and cell proliferation remains an open question. In experimental SHP, the increased PTH gene expression is post-transcriptional and mediated by PTH mRNA–protein interactions that promote PTH mRNA stability. These interactions are orchestrated by the isomerase Pin1. Pin1 participates in conformational change-based regulation of target proteins, including mRNA-binding proteins. In SHP, Pin1 isomerase activity is decreased, and thus, the Pin1 target and PTH mRNA destabilizing protein KSRP fails to bind PTH mRNA, increasing PTH mRNA stability and levels. An additional level of post-transcriptional regulation is mediated by microRNA (miRNA). Mice with parathyroid-specific knockout of Dicer, which facilitates the final step in miRNA maturation, lack parathyroid miRNAs but have normal PTH and calcium levels. Surprisingly, these mice fail to increase serum PTH in response to hypocalcemia or uremia, indicating a role for miRNAs in parathyroid stimulation. SHP often leads to parathyroid hyperplasia. Reduced expressions of parathyroid regulating receptors, activation of transforming growth factor α-epidermal growth factor receptor, cyclooxygenase 2-prostaglandin E2 and mTOR signaling all contribute to the enhanced parathyroid cell proliferation. Inhibition of mTOR by rapamycin prevents and corrects the increased parathyroid cell proliferation of SHP. This review summarizes the current knowledge on the mechanisms that stimulate the parathyroid cell at multiple levels in SHP.

Analysis of the cause and management of persistent laboratory abnormalities occurring after the surgical treatment of primary hyperparathyroidism.

PurposeThe surgical success rate for primary hyperparathyroidism (PHPT) is currently 95%–98%. However, 3%–24% of patients show persistently elevated (Pe) parathyroid hormone (PTH) levels after parathyroidectomy (PTX). This single-center retrospective study aimed to compare the outcomes of patients with normal PTH and PePTH levels after successful PTX and to identify the factors associated with PePTH.MethodsThe normal group, defined as patients with normal serum calcium and PTH levels immediately after PTX, was compared with the PePTH group (patients with normal or low serum calcium and increased serum PTH levels up to 6 months postoperatively) to determine the causes of disease in the PePTH group.ResultsThere were no significant differences in age, sex, or preoperative estimated glomerular filtration rate between the normal PTH group (333 of 364, 91.5%) and the PePTH group (31 of 364, 8.5%). However, there were significant differences in preoperative 25-hydroxyvitamin D (17.9 and 11.8 ng/mL, respectively; P = 0.003) and PTH levels (125.5 and 212.4 pg/mL, respectively; P < 0.001) between the 2 groups. Among the 31 cases of the PePTH group, 18 were attributed to vitamin D deficiency.ConclusionPreoperative vitamin D deficiency is a predictive factor for PePTH. Therefore, preoperative administration of vitamin D supplements may reduce the probability of postoperative disease persistence. Patients with temporary laboratory abnormalities within 6 months after successful PTX should be monitored, and appropriate vitamin D and calcium supplementation may reduce the effort and cost of various examinations or reoperations.

Simultaneous primary hyperparathyroidism and multiple myeloma in a dog with hypercalcaemia

AbstractA 14‐year‐old male castrated Pomeranian was found to be hypercalcaemic and hyperglobulinaemic during investigation of anorexia and haematochezia. Ionised hypercalcaemia, increased serum parathyroid hormone concentration, normophosphatemia and a parathyroid nodule found on cervical ultrasound examination were diagnostic for primary hyperparathyroidism (PHPT). Thoracic radiographs revealed ovoid lytic lesions in multiple bones. To investigate the hyperglobulinaemia, serum electrophoresis and immunoglobulin (Ig) quantification were performed, revealing an IgA biclonal gammopathy. Bone marrow cytopathology confirmed multiple myeloma (MM). Following bilateral parathyroidectomy, the dog's hypercalcaemia resolved, and pulse‐dose chemotherapy with prednisone and melphalan was initiated to treat MM. To the authors' knowledge, this is a unique case report of simultaneous PHPT and MM in the veterinary literature, diseases that are rarely reported concurrently in humans. This case highlights the need to thoroughly investigate multiple problems when they are not explained by a single diagnosis.

Vitamin D and parathyroid hormone status in community-dwelling elderly patients with mild-to-moderate kidney impairment.

Evidence on vitamin D and parathyroid hormone (PTH) status in patients with early kidney impairment is limited. We aimed to determine the associations among kidney function, vitamin D, and PTH status in community-dwelling elderly patients with mild-to-moderate kidney impairment. Community-dwelling elderly patients were enrolled in this Institutional Review Board approved cross-sectional study. The eligibility criteria were as follows: age > 60years, no recent hospitalization within the past 12months, no conditions that affect vitamin D status including vitamin D supplementation, and eGFR > 30mL/min/1.73m2. Serum 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) levels were assessed. A total of 226 patients were enrolled. Data were expressed as mean ± SD. The mean serum 25(OH)D was 26.61 ± 10.44ng/mL and the mean serum PTH was 50.67 ± 22.67pg/mL. The prevalence of vitamin D deficiency [25(OH)D < 20ng/mL] and secondary hyperparathyroidism [PTH > 65pg/mL] were 25.3% and 18.1%, respectively. Patients with eGFR 30- < 60mL/min/1.73m2 had significantly higher prevalence of 25(OH)D < 20ng/mL (33.7% versus 19.4%, p < 0.05) than patients with eGFR ≥ 60mL/min/1.73m2. Multiple regression analysis showed independent negative association of serum PTH level with eGFR (mL/min/1.73m2, β: - 0.261, 95% CI [- 0.408, - 0.114]) and serum 25(OH)D (ng/mL, β: - 0.499, 95% CI [- 0.775, - 0.223], adjusted for possible confounders). The prevalence of vitamin D deficiency was higher in patients with eGFR 30 - < 60mL/min/1.73m2 than those with eGFR ≥ 60mL/min/1.73m2. Both decreased serum 25(OH)D levels and decreased eGFR were independently associated with increased serum PTH levels among these patients.

Effects of normal and low calcium and phosphorus levels and 25-hydroxycholecalciferol supplementation on performance, serum antioxidant status, meat quality, and bone properties of broilers.

To determine the effects of normal and low dietary calcium (Ca) and phosphorus (P) levels and 25-hydroxycholecalciferol (25-OH-D3) supplementation on performance, serum antioxidant status, meat quality, and bone properties of broilers, 224 1-day-old Arbor Acre male broilers were used in this study. Broilers were allotted randomly to 1 of 4 treatments in a 2 × 2 factorial arrangement that included normal or low Ca and P diet with or without 69 μg/kg 25-OH-D3. The trial consists of a starter phase from day 1 to 21 and a grower phase from day 22 to 42. Dietary 25-OH-D3 supplementation increased (P < 0.05) average daily weight gain from day 22 to 42 and decreased feed conversation ratio from day 22 to 42 and day 0 to 42. On day 21, 25-OH-D3 increased serum concentrations of total antioxidant capacity (T-AOC), catalase (CAT), and glutathione peroxidase in broilers fed low Ca and P diet (Interaction, P < 0.05). 25-hydroxycholecalciferol significantly decreased serum malondialdehyde concentration. Dietary Ca and P deficiencies significantly decreased serum Ca and P concentrations and increased serum parathyroid hormone (PTH) concentration, and serum Ca and 25-OH-D3 concentrations were significantly increased by 25-OH-D3 supplementation. On day 42, serum T-AOC and CAT concentrations were decreased by dietary Ca and P deficiencies without 25-OH-D3 (Interaction, P < 0.05) and unaffected by dietary Ca and P deficiencies with 25-OH-D3. Dietary Ca and P deficiencies significantly decreased Ca, P, and alkaline phosphatase concentrations and increased PTH concentration in serum. Dietary 25-OH-D3 increased (P < 0.05) serum Ca and 25-OH-D3 concentrations and decreased (P < 0.05) serum tartrate-resistant acid phosphatase concentration. The interaction between CaP level and 25-OH-D3 was observed (P < 0.05) for tibial Ca content and femoral bone density. 25-hydroxycholecalciferol significantly increased tibial breaking strength. These data indicated that 25-OH-D3 supplementation at 69 μg/kg increased growth performance in some periods, enhanced serum antioxidant capacity, and improved bone mineralization and breaking strength of broilers.

Parathyroid Cell Proliferation in Secondary Hyperparathyroidism of Chronic Kidney Disease.

Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that correlates with morbidity and mortality in uremic patients. It is characterized by high serum parathyroid hormone (PTH) levels and impaired bone and mineral metabolism. The main mechanisms underlying SHP are increased PTH biosynthesis and secretion as well as increased glandular mass. The mechanisms leading to parathyroid cell proliferation in SHP are not fully understood. Reduced expressions of the receptors for calcium and vitamin D contribute to the disinhibition of parathyroid cell proliferation. Activation of transforming growth factor-α-epidermal growth factor receptor (TGF-α-EGFR), nuclear factor kappa B (NF-kB), and cyclooxygenase 2- prostaglandin E2 (Cox2-PGE2) signaling all correlate with parathyroid cell proliferation, underlining their roles in the development of SHP. In addition, the mammalian target of rapamycin (mTOR) pathway is activated in parathyroid glands of experimental SHP rats. Inhibition of mTOR by rapamycin prevents and corrects the increased parathyroid cell proliferation of SHP. Mice with parathyroid-specific deletion of all miRNAs have a muted increase in serum PTH and fail to increase parathyroid cell proliferation when challenged by CKD, suggesting that miRNA is also necessary for the development of SHP. This review summarizes the current knowledge on the mechanisms of parathyroid cell proliferation in SHP.

Moderators of the Association Between Serum Parathyroid Hormone and Metabolic Syndrome in Participants with Elevated Parathyroid Hormone: NHANES 2003-2006.

This cross-sectional study extracted data of 392 NHANES participants with elevated serum parathyroid hormone (PTH) concentrations from 2 cycles of the US National Health and Nutrition Examination Survey (NHANES) 2003-2006 and evaluated the association between serum (PTH) concentration and metabolic syndrome (MetS) to identify dietary and lifestyle factors that may modify that association. The primary outcome was MetS severity scores. Results of univariate linear regression analyses revealed that serum PTH concentrations correlated positively and significantly with MetS severity scores (β=0.399, p=0.030). After adjusting for gender, age, race, and alcohol consumption, results of multivariate analysis revealed that increased serum PTH concentration correlated significantly with higher MetS severity scores (β=0.413, p=0.045) in participants with moderate physical activity over the past 30 days. Serum PTH concentration also correlated significantly with higher MetS severity scores in participants with serum 25-hydroxyvitamin D deficiency (β=0.456 and p=0.014), those without vitamin D supplementation (β=0.524, p=0.028) and with higher protein intake (β=0.586 and p=0.030). In conclusion, increased serum PTH concentration is associated with higher MetS severity scores in participants with elevated serum PTH at baseline. The association between PTH concentration and MetS severity is moderated by participants' physical activity levels, status of serum vitamin D, vitamin D supplementation, and daily protein intake.

Serum PTH is not a good marker for defining a threshold for vitamin D deficiency.

ObjectiveIn addition to its skeletal effects, vitamin D may also be important for health in general. It is uncertain what level of serum 25-hydroxyvitamin D (25(OH)D), marker of vitamin D status, is sufficient for these effects. With decreasing serum 25(OH)D levels there is an increase in serum PTH. The point at which this occurs has been considered as a threshold for vitamin D sufficiency. The thresholds found have varied widely and have mainly been based on observational studies. However, to truly establish a threshold for vitamin D effects, this has to be based on randomized controlled trials (RCTs).MethodsThe study included 2803 subjects from a general health survey, the Tromsø study, and pooled individual person data from five vitamin D intervention studies (n = 1544). Serum parathyroid hormone (PTH) and change in PTH after vitamin D supplementation were related to serum 25(OH)D levels in steps of 25 nmol/L (<24, 25–49, 50–74, 75–99, and >99 nmol/L).ResultsIn the Tromsø study, in the females there was a gradual decrease in serum PTH with increasing serum 25(OH)D with no apparent plateau, whereas in the males the decrease in PTH in subjects with serum 25(OH)D >74 nmol/l was marginal. In pooled RCTs, there was a significant reduction in serum PTH by vitamin D supplementation regardless of baseline serum 25(OH)D level.ConclusionsThe use of the serum PTH–25(OH)D relation from observational studies to determine a threshold for vitamin D sufficiency is highly questionable.

Post-transcriptional mechanisms regulating parathyroid hormone gene expression in secondary hyperparathyroidism.

Parathyroid hormone (PTH) regulates serum calcium levels and bone strength. Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that correlates with morbidity and mortality. In experimental SHP, the increased PTH gene expression is due to increased PTH mRNA stability and is mediated by protein-PTH mRNA interactions. Adenosine-uridine-rich binding factor 1 (AUF1) stabilizes and K-homology splicing regulatory protein (KSRP) destabilizes PTH mRNA. The peptidyl-prolyl cis/trans isomerase Pin1 acts on target proteins, including mRNA-binding proteins. Pin1 leads to KSRP dephosphorylation, but in SHP, parathyroid Pin1 activity is decreased and phosphorylated KSRP fails to bind PTH mRNA, leading to increased PTH mRNA stability and levels. A further level of post-transcriptional regulation occurs through microRNA (miRNA). Dicer mediates the final step of miRNA maturation. Parathyroid-specific Dicer knockout mice that lack miRNAs in the parathyroid develop normally. Surprisingly, these mice fail to increase serum PTH in response to both hypocalcemia and CKD, indicating that parathyroid Dicer and miRNAs are essential for stimulation of the parathyroid. Human and rodent parathyroids share similar miRNA profiles that are altered in hyperparathyroidism. The evolutionary conservation of abundant miRNAs and their regulation in hyperparathyroidism indicate their significance in parathyroid physiology and pathophysiology. let-7 and miR-148 antagonism modifies PTH secretion invivo and invitro, suggesting roles for specific miRNAs in parathyroid function.This review summarizes the current knowledge on the post-transcriptional mechanisms of PTH gene expression in SHP and the central contribution of miRNAs to the high serum PTH levels of both primary hyperparathyroidism and SHP.

C-terminal telopeptide of type I collagen, osteocalcin, alkaline phosphatase, and parathyroid hormone in healthy and hospitalized foals

Hypocalcemia is a common finding in critically ill equine patients. Parathyroid hormone (PTH) helps to maintain calcium homeostasis in hypocalcemic patients by promoting renal calcium reabsorption and bone resorption. Increased serum PTH concentrations have been reported in critically ill people and animals, including horses and foals. It is unknown whether increased secretion of PTH is associated with markers of bone turnover in hospitalized foals. The goals of this study were to measure markers of bone resorption (C-terminal telopeptide of type I collagen [CTX-I]) and bone formation (osteocalcin [OCN]; alkaline phosphatase [ALP]) and to determine their association with PTH concentrations, disease severity, and mortality in hospitalized foals. This prospective, multicenter, cross-sectional study was conducted on 75 newborn foals ≤3 d old divided into hospitalized (n = 65; 41 septic; 24 sick nonseptic) and healthy (n = 10) groups. Blood samples were collected on admission to measure serum CTX-I, OCN, and PTH concentrations and ALP activity. Data were analyzed by nonparametric methods and univariate logistic regression. Serum CTX-I and PTH concentrations were significantly higher, whereas OCN concentrations were lower, in septic compared with healthy foals (P < 0.05). Serum ALP activity was not different between groups; however, it was lower in hospitalized and septic foals with low OCN concentrations (P < 0.05). In hospitalized foals, PTH concentrations were positively correlated with CTX-I concentrations and inversely associated with ALP activity (P < 0.05). High CTX-I and low OCN concentrations were associated with disease severity (P < 0.05). Hospitalized nonsurviving foals had significantly lower OCN concentrations compared with survivors (P < 0.05), but CTX-I concentrations were not associated with survival. Hospitalized foals with PTH concentrations >12.4 pmol/L were more likely to die (OR = 1.5; 95% CI = 1.1–4.16; P < 0.05). Elevated PTH and CTX-I together with reduced OCN concentrations and ALP activity in sick foals indicates that bone resorption is increased during critical illness, which may be a compensatory mechanism to correct hypocalcemia or reflect a response to systemic inflammation and metabolic imbalances. Bone resorption could negatively impact skeletal development in the growing foal. Low OCN and high PTH concentrations were predictors of nonsurvival in hospitalized foals.

Pasteurized Akkermansia muciniphila protects from fat mass gain but not from bone loss.

Probiotic bacteria can protect from ovariectomy (ovx)-induced bone loss in mice. Akkermansia muciniphila is considered to have probiotic potential due to its beneficial effect on obesity and insulin resistance. The purpose of the present study was to determine if treatment with pasteurized Akkermansia muciniphila (pAkk) could prevent ovx-induced bone loss. Mice were treated with vehicle or pAkk for 4 wk, starting 3 days before ovx or sham surgery. Treatment with pAkk reduced fat mass accumulation confirming earlier findings. However, treatment with pAkk decreased trabecular and cortical bone mass in femur and vertebra of gonadal intact mice and did not protect from ovx-induced bone loss. Treatment with pAkk increased serum parathyroid hormone (PTH) levels and increased expression of the calcium transporter Trpv5 in kidney suggesting increased reabsorption of calcium in the kidneys. Serum amyloid A 3 (SAA3) can suppress bone formation and mediate the effects of PTH on bone resorption and bone loss in mice and treatment with pAkk increased serum levels of SAA3 and gene expression of Saa3 in colon. Moreover, regulatory T cells can be protective of bone and pAkk-treated mice had decreased number of regulatory T cells in mesenteric lymph nodes and bone marrow. In conclusion, treatment with pAkk protected from ovx-induced fat mass gain but not from bone loss and reduced bone mass in gonadal intact mice. Our findings with pAkk differ from some probiotics that have been shown to protect bone mass, demonstrating that not all prebiotic and probiotic factors have the same effect on bone.

Paradoxical Response of Parathyroid Hormone to Vitamin D–Calcium Supplementation in Indian Children

To investigate the effect of oral vitamin D-calcium supplementation on serum intact parathyroid hormone (PTH), calcium, phosphorous, and alkaline phosphatase (ALK-P) concentrations in children with habitually low calcium intakes. In this follow-up study to a randomized controlled trial that aimed to assess the effect of vitamin D-calcium supplementation on immunity, data related to dietary intake, anthropometry, and biochemistry [serum 25(OH)D and bone profile] were collected from 178 children-79 in the vitamin D group and 99 in the non-vitamin D group. Dietary calcium to phosphorus intake ratio was 0.4:1. Baseline serum 25(OH)D concentration was 58.2±10.9nmol/L; 66% children were vitamin D sufficient and none deficient. After supplementation, vitamin Dgroup, compared with the non-vitamin D group, had significantly (P<.05) greater 25(OH)D (83.9±30.1nmol/L vs 58.3±15.7nmol/L), significantly greater PTH (6.7±3.6 pmol/L vs 5.5±3.2 pmol/L), and positive correlation (rs=0.24) between serum 25(OH)D and PTH (vs negative correlation [rs=-0.1] in non-vitamin D group). Mean concentrations of serum bone measures in the vitamin D group were calcium (2.2±0.1mmol/L), phosphorus (1.7±0.2mmol/L), and ALK-P (178.7±40.7 IU/L). At follow-up, 1-year post-supplementation, in the vitamin D group, PTH concentrations continued to remain high (but not significantly different from levels at 6months), with low normal serum calcium, high normal phosphate, and ALK-P in reference range. In children who are vitamin D sufficient but with habitually low dietary calcium intake, vitamin D-calcium supplementation paradoxically and significantly increased serum PTH concentrations with no apparent effect on other bone biochemistry. Chronic low dietary calcium to phosphorus ratio is likely to have caused this paradoxical response.

Increased Serum Parathyroid Hormone, Osteocalcin and Alkaline Phosphatase Are Associated with a Long-Term Adverse Cardiovascular Outcome after Coronary Artery Bypass Graft Surgery.

Despite the fact that an association of osteopoenia/osteoporosis with elevated risk of coronary artery calcification (CAC) and coronary atherosclerosis (CA) is well-established, it remains unclear whether bone turnover markers can be employed in long-term prognostication of such patients. Here we measured serum calcium, phosphate, calcitonin, parathyroid hormone (PTH), osteoprotegerin, osteocalcin, osteopontin, alkaline phosphatase and its bone isoenzyme, subsequently correlating them with an adverse cardiovascular outcome after 3 years of follow-up. The extent of brachiocephalic artery stenosis, CA, or CAC, as well as prevalence of osteopoenia/osteoporosis before the coronary artery bypass graft (CABG) surgery, did not differ between outcome groups, suggesting that subtle molecular mechanisms might be involved in determining the outcome rather than clinical or subclinical disease. After stepwise logistic regression, serum osteocalcin > 26.8 ng/mL and PTH > 49.1 pg/mL were independent predictors of an adverse outcome. Serum ionised calcium correlated with multivessel coronary artery disease; moreover, patients with severe CA (SYNTAX score > 21) had higher serum ionised calcium than those with mild CA. Likewise, serum alkaline phosphatase was associated with severe CA and CAC (Agatston score > 400). In conclusion, serum PTH, osteocalcin, and alkaline phosphatase are associated with an adverse cardiovascular outcome 3 years after CABG surgery regardless of osteopoenia/osteoporosis, coronary/peripheral atherosclerosis, and CAC.