Calciotropic Hormones Research Articles

Frequent Unrecognized Vertebral Fractures Associated with Increased Body Fat Mass in Children and Adolescents with Duchenne Muscular Dystrophy.

Patients with Duchenne muscular dystrophy (DMD) have an increased risk of vertebral fractures (VFs). Ethnic variations may partly contribute to the fracture risk. This study aimed to demonstrate the VFs and body fat mass in Asian patients with DMD. Demographic data and DMD-related parameters of the enrolled patients were collected. Lateral thoracolumbar spine radiographs were performed for VF assessment. Genant classification was applied for VF severity grading (mild, moderate and severe). Body composition analysis using dual-energy X-ray absorptiometry was performed. Serum calcium, phosphate, intact parathyroid hormone and 25-hydroxyvitamin D concentrations were determined. There were 25 children and adolescents with DMD enrolled. Median (IQR) age was 12.9 (9.6, 19.3) years. Nine patients (36%) had VFs with a total of 31 sites of VFs (mild, N=10; moderate, N=3 and severe, N=18). These VFs had never been recognized prior to this study. Comparing with the non-VF group, the VF group received a significantly greater cumulative prednisolone equivalent dose (1,258 (948, 1,664) vs. 291 (17, 823) mg/kg, p=0.003). Body fat mass, represented by fat mass index and body fat percentage Z-scores was greater in the VF group [2.46 (2.21, 2.51) vs. 1.63 (0.36, 2.07), p=0.011 and 4.4 (3.1, 5.5) vs. 1.8 (0.6, 3.5), p=0.008, respectively]. No differences in serum calciotropic hormones and vitamin D status were demonstrated between patients with and without VFs. VFs were frequent in patients with DMD. Patients with VFs had greater cumulative glucocorticoid dose and body fat mass than those without VFs.

Modeling calcium and magnesium balance: Regulation by calciotropic hormones and adaptations under varying dietary intake

Magnesium (Mg2+) is crucial for several cellular and physiological processes and is tightly regulated due to health risks associated with imbalances. Mg2+, calcium (Ca2+), parathyroid hormone, and vitamin D3 are tightly coupled, ensuring proper bone metabolism and intestinal and renal absorption of Mg2+ and Ca2+. While several Ca2+ homeostasis models exist, no computational model has been developed to study Mg2+ homeostasis. We developed a computational model of Mg2+ homeostasis in male rats, integrating it with an existing Ca2+ homeostasis model, to understand the interconnected physiological processes regulating their homeostasis. We then analyzed adaptations in these interconnected processes under (1) dietary Mg2+ deficiency, (2) low/high dietary Ca2+ with Mg2+ deficiency, and (3) vitamin D3 deficiency. Model simulations predicted severe hypomagnesemia and mild hypocalcemia with significant dietary Mg2+ deficiency. Low dietary Ca2+ improved, while high dietary Ca2+ worsened Mg2+ deficiency. Finally, vitamin D3 deficiency caused severe hypocalcemia, with minimal impact on Mg2+ homeostasis.

Biology of bone mineralization and ectopic calcifications: the same actors for different plays

Bone has several crucial functions. It is essential for locomotion and allows our body to stand erect against gravity. A mismatch between the mechanical stresses applied to it and its mechanical resistance leads to fractures. Bone also has numerous endocrine functions. It acts as a reservoir for minerals such as calcium and phosphorus, making it the target of calciotropic hormones that mobilize these minerals, particularly calcium, according to the body's needs. Additionally, bone secretes hormones, notably fibroblast growth factor 23 (FGF23), which regulates urinary excretion of phosphate and the bioavailability of active vitamin D. Bone mineralization is the process that facilitates the organized deposition of minerals in the bone matrix, providing rigidity and appropriate mechanical resistance. This process is compromised in genetically related bone mineralization disorders, such as those causing hypophosphatemia or hypophosphatasia. Conversely, calcification can be pathological, affecting soft tissues like the blood vessels, as seen in generalized arterial calcification of infancy (GACI) or arterial calcification due to CD73 deficiency (ACDC). The aim of this article is to first present the composition and structure of the mineralized bone matrix, to review the current understanding of the molecular mechanisms of mineralization, and finally to discuss the conditions associated with ectopic calcification and the underlying mechanisms.

Comparative effects of vitamin D supplementation on serum calciotropic hormone profile, in orthodox nuns with hypovitaminosis d in different regions of greece, versus intermittent fasting and western diet in lay women

Comparative effects of vitamin D supplementation on serum calciotropic hormone profile, in orthodox nuns with hypovitaminosis d in different regions of greece, versus intermittent fasting and western diet in lay women

Autosomal dominant hypercalciuric hypocalcaemia: the calcium-sensing receptor in renal calcium homeostasis and the impact of renal transplantation.

Calcium-sensing receptors (CaSRs) are G protein-coupled receptors that help maintain Ca2+ concentrations, modulating calciotropic hormone release (parathyroid hormone (PTH), calcitonin and 1,25-dihydroxyvitamin D) by direct actions in the kidneys, gastrointestinal tract and bone. Variability in population calcium levels has been attributed to single nucleotide polymorphisms in CaSR genes, and several conditions affecting calcium and phosphate homeostasis have been attributed to gain- or loss-of-function mutations. An example is autosomal dominant hypercalciuric hypocalcaemia, because of a missense mutation at codon 128 of chromosome 3, as reported in our specific case and her family. As a consequence of treating symptomatic hypocalcaemia as a child, this female subject slowly developed progressive end-stage kidney failure because of nephrocalcinosis and nephrolithiasis. After kidney transplantation, she remains asymptomatic, with decreased vitamin D and elemental calcium requirements, stable fluid and electrolyte homeostasis during intercurrent illnesses and has normalised urinary calcium and phosphate excretion, reducing the likelihood of hypercalciuria-induced graft impairment. We review the actions of the CaSR, its role in regulating renal Ca2+ homeostasis along with the impact of a proven gain-of-function mutation in the CaSR gene resulting in autosomal dominant hypercalciuric hypocalcaemia before and after kidney transplantation.

Periparturient Mineral Metabolism: Implications to Health and Productivity.

Mineral metabolism, in particular Ca, and to a lesser extent phosphorus (P) and magnesium (Mg), is altered with the onset of lactation because of extensive irreversible loss to synthesize colostrum and milk. The transient reduction in the concentration of Ca in blood, particularly when it lasts days, increases the risk of mineral-related disorders such as hypocalcemia and, to a lesser extent, hypophosphatemia. Although the incidence of clinical hypocalcemia can be reduced by prepartum dietary interventions, subclinical hypocalcemia remains prevalent, affecting up to 60% of the dairy cows in the first 3 d postpartum. More importantly, strong associations exist between hypocalcemia and increased susceptibility to other peripartum diseases and impaired reproductive performance. Mechanistic experiments have demonstrated the role of Ca on innate immune response in dairy cows, which presumably predisposes them to other diseases. Hypocalcemia is not related to inadequate Ca intake as prepartum diets marginal to deficient in Ca reduce the risk of the disease. Therefore, the understanding of how Ca homeostasis is regulated, in particular how calciotropic hormones such as parathyroid hormone and 1,25-dihydroxyvitamin D3, affect blood Ca concentrations, gastrointestinal Ca absorption, bone remodeling, and renal excretion of Ca become critical to develop novel strategies to prevent mineral imbalances either by nutritional or pharmacological interventions. A common method to reduce the risk of hypocalcemia is the manipulation of the prepartum dietary cation-anion difference. Feeding acidogenic diets not only improves Ca homeostasis and reduces hypocalcemia, but also reduces the risk of uterine diseases and improves productive performance. Feeding diets that induce a negative Ca balance in the last weeks of gestation also reduce the risk of clinical hypocalcemia, and recent work shows that the incorporation of mineral sequestering agents, presumably by reducing the absorption of P and Ca prepartum, increases blood Ca at calving, although benefits to production and health remain to be shown. Alternative strategies to minimize subclinical hypocalcemia with the use of vitamin D metabolites either fed prepartum or as a pharmacological agent administered immediately after calving have shown promising results in reducing hypocalcemia and altering immune cell function, which might prove efficacious to prevent diseases in early lactation. This review summarizes the current understanding of Ca homeostasis around parturition, the limited knowledge of the exact mechanisms for gastrointestinal Ca absorption in bovine, the implications of hypocalcemia on the health of dairy cows, and discusses the methods to minimize the risk of hypocalcemia and their impacts on productive performance and health in dairy cows.

Alteration in the gut microbiome is associated with changes in bone metabolism after laparoscopic sleeve gastrectomy.

Laparoscopic sleeve gastrectomy (LSG), the most common bariatric surgical procedure, leads to durable weight loss and improves obesity-related comorbidities. However, it induces abnormalities in bone metabolism. One unexplored potential contributor is the gut microbiome, which influences bone metabolism and is altered after surgery. We characterized the relationship between the gut microbiome and skeletal health in severe obesity and after LSG. In a prospective cohort study, 23 adults with severe obesity underwent skeletal health assessment and stool collection preoperatively and 6mo after LSG. Gut microbial diversity and composition were characterized using 16S rRNA gene sequencing, and fecal concentrations of short-chain fatty acids (SCFA) were measured with LC-MS/MS. Spearman's correlations and PERMANOVA analyses were applied to assess relationships between the gut microbiome and bone health measures including serum bone turnover markers (C-terminal telopeptide of type 1 collagen [CTx] and procollagen type 1N-terminal propeptide [P1NP]), areal BMD, intestinal calcium absorption, and calciotropic hormones. Six months after LSG, CTx and P1NP increased (by median 188% and 61%, P< .01) and femoral neck BMD decreased (mean -3.3%, P< .01). Concurrently, there was a decrease in relative abundance of the phylum Firmicutes. Although there were no change in overall microbial diversity or fecal SCFA concentrations after LSG, those with greater within-subject change in gut community microbial composition (β-diversity) postoperatively had greater increases in P1NP level (ρ= 0.48, P= .02) and greater bone loss at the femoral neck (ρ= -0.43, P= .04). In addition, within-participant shifts in microbial richness/evenness (α-diversity) were associated with changes in IGF-1 levels (ρ= 0.56, P< .01). The lower the postoperative fecal butyrate concentration, the lower the IGF-1 level (ρ= 0.43, P= .04). Meanwhile, the larger the decrease in butyrate concentration, the higher the postoperative CTx (ρ= -0.43, P= .04). These findings suggest that LSG-induced gut microbiome alteration may influence skeletal outcomes postoperatively, and microbial influences on butyrate formation and IGF-1 are possible mechanisms.

Neuropilin 2 in osteoblasts regulates trabecular bone mass in male mice.

Neuropilin 2 (NRP2) mediates the effects of class 3 semaphorins and vascular endothelial growth factor and is implicated in axonal guidance and angiogenesis. Moreover, NRP2 expression is suggested to be involved in the regulation of bone homeostasis. Indeed, osteoblasts and osteoclasts express NRP2 and male and female global Nrp2 knockout mice have a reduced bone mass accompanied by reduced osteoblast and increased osteoclast counts. We first examined the in vitro effect of the calciotropic hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on Nrp2 transcription in osteoblasts. We next generated mice with a conditional deletion of Nrp2 in the osteoblast cell lineage under control of the paired related homeobox 1 promoter and mice with a conditional Nrp2 knockdown in osteoclasts under control of the Lysozyme promoter. Mice were examined under basal conditions or after treatment with either the bone anabolic vitamin D3 analog WY 1048 or with 1,25(OH)2D3. We show that Nrp2 expression is induced by 1,25(OH)2D3 in osteoblasts and is associated with enrichment of the vitamin D receptor in an intronic region of the Nrp2 gene. In male mice, conditional deletion of Nrp2 in osteoblast precursors and mature osteoblasts recapitulated the bone phenotype of global Nrp2 knockout mice, with a reduced cortical cross-sectional tissue area and lower trabecular bone content. However, female mice with reduced osteoblastic Nrp2 expression display a reduced cross-sectional tissue area but have a normal trabecular bone mass. Treatment with the vitamin D3 analog WY 1048 (0.4 μg/kg/d, 14 days, ip) resulted in a similar increase in bone mass in both genotypes and genders. Deleting Nrp2 from the osteoclast lineage did not result in a bone phenotype, even though in vitro osteoclastogenesis of hematopoietic cells derived from mutant mice was significantly increased. Moreover, treatment with a high dose of 1,25(OH)2D3 (0.5 μg/kg/d, 6 days, ip), to induce osteoclast-mediated bone resorption, resulted in a similar reduction in trabecular and cortical bone mass. In conclusion, osteoblastic Nrp2 expression is suggested to regulate bone homeostasis in a sex-specific manner.

The Effect of Melatonin and Its Agonist on Bone Metabolism

Objectives : To assess the effects of melatonin and its agonist on bone tissue through a scoping review of the literature. Materials and Methods: The keywords were searched on Scopus, Web of Science, and PubMed. Title and abstracts were reviewed to exclude the duplicates and irrelevant articles. The full-text articles were then screened in accordance with the inclusion criteria. Results: Of the 5,383 identified articles [PubMed=5,508, Web of Science=122, Scopus=53], only 3 studies qualified to be included in the scoping review based on the inclusion criteria. The first study assessed effects of the oral melatonin on bone integrity and mass in postmenopausal osteopenic women through dual X-ray absorptiometry, quantitative computed tomography (QCT), high-resolution peripheral QCT (HR-pQCT), determined calciotropic hormones and bone markers. The other two studies evaluated radiographic and clinical outcomes such as Perio test, Angulated Bleeding test, Pink Esthetic Score (PES), Gingival index (GI), Peri-implant sulcus depth (PD), Wound healing index (WHI), Linear measurements of bone loss around implant and Densitometric analysis of dental implants with the local application of melatonin. All studies showed an improved outcome parameters in comparison with the control group. Conclusion: Based on the findings of the included studies, it was found that melatonin improved bone mineral density, increased marginal bone level and minimized root resorption aiding in implant stability. The findings were suggestive that melatonin has osteoinductive properties and inhibitory effect on osteoclastic activity.

Negative impact on bone homeostasis in postmenopausal women with non-metastatic breast cancer during cytotoxic chemotherapy.

The burden and mechanisms of endocrine therapy-related bone loss are well known, while there are limited data on chemotherapy-induced bone resorption. The study aimed to evaluate the effect of cytotoxic chemotherapy on bone homeostasis among postmenopausal women with non-metastatic breast cancer. Early and locally advanced postmenopausal non-metastatic breast cancer patients aged 45 to 65 planned for three cycles of anthracycline and four cycles of taxane chemotherapy administered along with dexamethasone (cumulative dose-256mg) as an antiemetic from June 2018 to December 2021 were included. Bone mineral density (BMD), bone turnover markers, calciotropic hormones, pro-inflammatory cytokines, oxidative stress, and total antioxidant levels (TAS) were measured. We recruited 109 patients, with early 34 (31.2%) and locally advanced breast cancer 75 (68.8%) with median age 53 (45-65) years. There was a significant decrease in the % BMD at the lumbar spine, neck of the femur, and total hip post-chemotherapy. There was a significant increase in serum C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (PINP) levels post-chemotherapy. PINP/CTX ratio significantly decreased post-chemotherapy. Serum 25-OH vitamin D was significantly reduced with a compensatory increase in plasma iPTH levels. The change in CTX, PINP/CTX ratio, 25-OH vitamin D, iPTH, and oxidative stress index was more pronounced during anthracycline as taxane chemotherapy. There were no significant changes in pro-inflammatory cytokine levels. Chemotherapy and dexamethasone as antiemetic resulted in significant bone loss, as evidenced by bone turnover markers. Further studies are required to understand the mechanism of chemotherapy-induced bone loss and the need for bone-strengthening agents during chemotherapy.

Biochemical Markers of Bone Fragility in Patients with Diabetes. A Narrative Review by the IOF and the ECTS.

The risk of fragility fractures is increased in both type 1 and type 2 diabetes. Numerous biochemical markers reflecting bone and/or glucose metabolism have been evaluated in this context. This review summarizes current data on biochemical markers in relation to bone fragility and fracture risk in diabetes. Literature review by a group of experts from the International Osteoporosis Foundation (IOF) and European Calcified Tissue Society (ECTS) focusing on biochemical markers, diabetes, diabetes treatments and bone in adults. Although bone resorption and bone formation markers are low and poorly predictive of fracture risk in diabetes, osteoporosis drugs seem to change bone turnover markers in diabetics similarly to non-diabetics, with similar reductions in fracture risk. Several other biochemical markers related to bone and glucose metabolism have been correlated with BMD and/or fracture risk in diabetes, including osteocyte-related markers such as sclerostin, HbA1c and advanced glycation end products (AGEs), inflammatory markers and adipokines, as well as IGF-1 and calciotropic hormones. Several biochemical markers and hormonal levels related to bone and/or glucose metabolism have been associated with skeletal parameters in diabetes. Currently, only HbA1c levels seem to provide a reliable estimate of fracture risk, while bone turnover markers could be used to monitor the effects of anti-osteoporosis therapy.

Diffuse idiopathic skeletal hyperostosis (DISH) and trabecular bone score (TBS) in postmenopausal women: The Camargo cohort

ObjectivesThe potential relationship between diffuse idiopathic skeletal hyperostosis (DISH) and bone microstructure has not been studied in women. We aimed to assess the association between the trabecular bone score (TBS) and DISH in postmenopausal women, as well as the role of other parameters related to bone metabolism, such as bone mineral density (BMD), calciotropic hormones, and bone remodeling markers. MethodsCross-sectional study, nested in a prospective population-based cohort (Camargo cohort). Clinical covariates, DISH, TBS, vitamin D, parathormone, BMD and serum bone turnover markers, were analyzed. ResultsWe have included 1545 postmenopausal women (mean age, 62±9 years). Those with DISH (n = 152; 8.2%) were older and had a significantly higher prevalence of obesity, metabolic syndrome, hypertension, and type 2 diabetes mellitus (p<0.05). Moreover, they had lower TBS values (p = 0.0001) despite having a higher lumbar spine BMD (p<0.0001) and a higher prevalence of vertebral fractures than women without DISH (28.6% vs. 15.1%; p = 0.002). When analyzing DISH through Schlapbach grades, women without DISH had a median TBS value consistent with a normal trabecular structure while the values for women with DISH from grades 1 to 3 were consistent with a partially degraded trabecular structure. Women with vertebral fractures and DISH had a mean TBS corresponding to a degraded trabecular structure (1.219±0.1). After adjusting for confounders, the estimated TBS means were 1.272 (1.253–1.290) in the DISH group, and 1.334 (1.328–1.339) in the NDISH group (p<0.0001). ConclusionAn association between DISH and TBS has been shown in postmenopausal women, in which hyperostosis has been significantly and consistently related to trabecular degradation and, therefore, to deterioration in bone quality after adjusting for confounding variables.

Bone Metabolism in Patients with Hidradenitis Suppurativa: A Case-control Study.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the hair follicles. The aim of this case-control study was to assess whether HS is associated with disturbances in trabecular bone score, bone mineral density, bone remodelling markers, and calciotropic hormones. A total of 81 patients and 79 controls of similar age and sex were included. Demographic, anthropometric, laboratory data, trabecular bone score, bone mineral density, serum 25-hydroxyvitamin D (25OHD), serum amino-terminal pro-peptide of type 1 collagen (PINP), and C-terminal telopeptide of type 1 collagen (CTX) concentrations were assessed in both groups. Patients with HS had lower serum 25OHD levels than controls, and approximately 62% of them had vitamin D deficiency. Serum PINP was increased and CTX was decreased in patients with HS. Fully adjusted trabecular bone score values were lower in patients with HS compared with controls. Adjusted lumbar bone mineral density was similar in HS and controls, whilst total hip bone mineral density was lower in patients with HS. There were no statistical differences regarding disease severity in terms of 25OHD, serum turnover markers, bone mineral density, or trabecular bone score values. This study shows that patients with HS have lower trabecular bone score and total hip bone mineral density values than population-based controls. In addition, the prevalence of vitamin D deficiency is high in subjects with HS.

Bone mineral density among virologically suppressed Asians older than 50 years old living with and without HIV: A cross-sectional study.

There are limited data regarding bone health in older people living with HIV (PWH), especially those of Asian ethnicity. We aimed to determine whether BMD in well-suppressed HIV-infected men and women aged ≥ 50 years are different from HIV-uninfected controls. In a cross-sectional study, BMD by dual-energy X-ray absorptiometry and calciotropic hormones were measured. A total of 481 participants were consecutively enrolled (209 HIV+ men, 88 HIV- men, 126 HIV+ women and 58 HIV- women). PWH were on average 2.5 years younger [men: 55.0 vs. 57.5 yr; women: 54.0 vs. 58.0 yr] and had lower body mass index (BMI) [men: 23.2 vs. 25.1 kg/m2; women: 23.1 vs. 24.7 kg/m2] compared to the controls. The median duration since HIV diagnosis was 19 (IQR 15-21) years in men and 18 (IQR 15-21) years in women. Three-quarters of PWH had been treated with tenofovir disoproxil fumarate-containing antiretroviral therapy for a median time of 7.4 (IQR 4.5-8.9) years in men and 8.2 (IQR 6.1-10) years in women. In an unadjusted model, HIV+men had significantly lower BMD (g/cm2) at the total hip and femoral neck whereas there was a tend toward lower BMD in HIV+women. After adjusting for age, BMI, and other traditional osteoporotic risk factors, BMD of virologically suppressed older PWH did not differ from participants without HIV (P>0.1). PWH had lower serum 25(OH)D levels but this was not correlated with BMD. In conclusion, BMD in well-suppressed PWH is not different from non-HIV people, therefore, effective control of HIV infection and minimization of other traditional osteoporosis risk factors may help maintain good skeletal health and prevent premature bone loss in Asian PWH. Clinical trial registration: Clinicaltrials.gov # NCT00411983.

Vasoactive intestinal peptide and cystic fibrosis transmembrane conductance regulator contribute to the transepithelial calcium transport across intestinal epithelium-like Caco-2 monolayer.

Vasoactive intestinal peptide (VIP) as a neurocrine factor released by enteric neurons has been postulated to participate in the regulation of transcellular active calcium transport across intestinal epithelium, but the preceding evidence is scant and inconclusive. Herein, transepithelial calcium flux and epithelial electrical parameters were determined by Ussing chamber technique with radioactive tracer in the intestinal epithelium-like Caco-2 monolayer grown on Snapwell. After 3-day culture, Caco-2 cells expressed mRNA of calcium transporters, i.e., TRPV6, calbindin-D9k, PMCA1b and NCX1, and exhibited transepithelial resistance of ~200 Ω cm2, a characteristic of leaky epithelium similar to the small intestine. VIP receptor agonist was able to enhance transcellular calcium flux, whereas VIP receptor antagonist totally abolished calcium fluxes induced by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Since the intestinal cystic fibrosis transmembrane conductance regulator (CFTR) could be activated by VIP and calciotropic hormones, particularly parathyroid hormone, we sought to determine whether CFTR also contributed to the 1,25(OH)2D3-induced calcium transport. A selective CFTR inhibitor (20-200 μM CFTRinh-172) appeared to diminish calcium fluxes as well as transepithelial potential difference and short-circuit current, both of which indicated a decrease in electrogenic ion transport. On the other hand, 50 μM genistein-a molecule that could rapidly activate CFTR-was found to increase calcium transport. Our in silico molecular docking analysis confirmed direct binding of CFTRinh-172 and genistein to CFTR channels. In conclusion, VIP and CFTR apparently contributed to the intestinal calcium transport, especially in the presence of 1,25(OH)2D3, thereby supporting the existence of the neurocrine control of intestinal calcium absorption.

LBSUN152 The Warburg Effect And Complex Thermomics Inform Phenotypic Expression

Abstract Introduction As technology reveals biological complexity, integration of vast clinical and multi-omic data utilizing artificial intelligence promises to clarify confusion. We have utilized challenge tests to inform algorithmic graphs recognizing heat as foundational for understanding phenotypic variation. Thermomics, describing complex thermic influences that are difficult to objectively quantify thereby compromising application to AI, are readily included in practice-derived models. Methods For the past 45 years cases have been evaluated with oral calcium challenge and immersion in water while observing changes in urinary composition. Between 2001 and 2010 respiratory gas exchange following a high carbohydrate meal combined with pulsatile insulin revealed metabolic variance that combined with basic, translational and clinical data of others informed generation of algorithmic graphs. COVID 19 served to clarify the effect of ACE2 disruption by predicting divergent phenotypic expression mediated by calciotropic hormones. Results Extraction of O2 from glucose, a consequence of fatty acid synthesis producing R/Q &amp;gt; 1 is modeled as foundational for metabolic evolution. This Warburg effect, recognized in proliferating malignant cells, was observed at the systemic level in humans and, modeled as mediated by hypoxia inducible factors regulating glucose uptake and suppression of beta-oxidation. Higher order orchestration is governed by a signaling structure including PTH, PTHrP, FGF23, Klotho, prolactin, growth hormone, IGFs, insulin, SGLT2, thyroid, adrenal and vit D while salt inducible kinase contributes to understanding of terrestrial adaptation. Inclusion of thermomics leads to prediction of a favorable effect of sub-cutaneous adipose beiging on CNS function mediated by circulating Klotho as a constraint on FGF23 in amelioration of Long COVID by phentermine that is also effective in hypophosphatasia where the exercise induced beiging, induced by irisin is known to be dependent upon alkaline phosphatase. The post-exertional malaise of Myalgic Encephalomyelitis, where exercise induces elevation in R/Q and reduced work capacity, has informed modeling of the systemic Warburg effect. The models are further validated with mechanistic explanation for recent reports of marked increases of R/Q in human Paget's disease and CEBPb expression dependence mimicking Alzheimer's and limiting life span in mice. Conclusions The value of practice is demonstrated by the ability to model thermomics even when difficult to quantify. The work is validated by explanation of old conundrums, discovery of treatment for unresolved problems, facilitation of case-based discovery and integration of emerging data from basic sciences. The Warburg effect when recognized as foundational to biology, contributes to a General Theory of Metabolism applicable to effective personalization of care. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Sex-specific differences in bone mineral density loss after sleeve gastrectomy

Sleeve gastrectomy is an effective bariatric procedure; however, sleeve gastrectomy-related adverse skeletal outcomes have been increasingly reported. High levels of sex hormone-binding globulin (SHBG) have been documented to be a risk factor of bone mineral density (BMD) loss with different effects observed between sexes. The aim of this study was to identify sex-specific changes in BMD following sleeve gastrectomy and to evaluate the role of SHBG in this process. This retrospective study included 19 middle-aged men and 30 non-menopausal women with obesity who underwent sleeve gastrectomy in China. Anthropometrics, bone turnover markers, calciotropic hormones, BMD, SHBG, and gonadal steroids were measured preoperatively and at 6 and 12 months postoperatively. Longitudinal changes in BMD, bone turnover markers and SHBG were compared between sexes by linear mixed models. Multiple stepwise regression analysis was used to identify the predictors of BMD loss at the investigated bone sites. Over the 12-month study period, total hip and femoral neck BMD decreased, while lumbar spine BMD remained largely unchanged in both sexes. Linear mixed models revealed significant sex × time interaction effects in total hip BMD and SHBG, showing that men had a significantly greater reduction in total hip BMD and less increase in SHBG after sleeve gastrectomy than women. In the multivariate model, SHBG was significantly associated with total hip BMD loss in men (adjusted β = -0.533, P = 0.019) but not women while total estrogen was significantly associated with total hip BMD loss in women (adjusted β = 0.508, P = 0.01) but not men. Significant sex-specific BMD changes were observed after sleeve gastrectomy in the current study. Sleeve gastrectomy-related increase in SHBG may be a specific risk factor for total hip BMD loss in men. Our results indicate that sex-specific screening may be warranted to facilitate personalized postoperative bone care in this population.

10-Day-Old Male Infant With Electrolyte Derangement and Abnormal Calciotropic Hormone Profile.

10-Day-Old Male Infant With Electrolyte Derangement and Abnormal Calciotropic Hormone Profile.

Determinants of Low Bone Turnover in Type 2 Diabetes-the Role of PTH

Determinants of low bone turnover in type 2 diabetes (T2DM) are poorly understood. To investigate the relationship between markers of bone turnover, glycaemic control, disease duration and calciotropic hormones in T2DM we assessed baseline biochemical data from the DiabOS Study, a prospective multicenter observational cohort study. In a cross-sectional study-design data from 110 postmenopausal women and men aged 50–75 years diagnosed with T2DM for at least 3 years and 92 non-diabetic controls were evaluated. Biochemical markers of bone formation (N-terminal propeptide of type I procollagen [PINP]), bone-specific alkaline phosphatase [BAP]) and resorption (C-terminal cross-linking telopeptide of type I collagen [CTX]), measures of calcium homeostasis (intact parathormone [iPTH], 25-Hydroxyvitamin D, calcium, magnesium) and glycaemic control were assessed. After adjustment for age, gender and body mass index (BMI), patients with T2DM had lower serum levels of PINP (p < 0.001), CTX (p < 0.001), iPTH (p = 0.03) and magnesium (p < 0.001) compared to controls. Serum calcium, creatinine, 25-Hydroxyvitamin D and sclerostin did not differ between both groups. In multivariate linear regression analyses only serum iPTH remained an independent determinant of bone turnover markers in T2DM (PINP: p = 0.02; CTX: p < 0.001 and BAP: p < 0.01), whereas glycated haemoglobin (HbA1c), disease duration, age and BMI were not associated with bone turnover. In conclusion low bone turnover in T2DM is associated with low iPTH. The underlying mechanism remains to be elucidated.

Calcium, Its Regulatory Hormones, and Their Causal Role on Blood Pressure: A Two-Sample Mendelian Randomization Study.

Vitamin D (Vit-D), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23) are the major calciotropic hormones involved in the regulation of blood calcium levels from the intestine, kidney, and bone through a tight endocrine feedback loop system. Altered levels of calcium itself or through the effect of its regulatory hormones could affect blood pressure (BP), but the exact mechanisms remain unclear. To evaluate whether a causal relationship exists between serum calcium level and/or the regulatory hormones involved in its homeostasis with BP, we performed a two-sample Mendelian randomization (MR) study. From 4 large genome-wide association studies (GWAS) we obtained independent (r2 < 0.001) single nucleotide polymorphisms (SNPs) associated with serum calcium (119 SNPs), Vit-D (78 SNPs), PTH (5 SNPs), and FGF23 (5 SNPs), to investigate through MR their association with systolic BP (SBP) and diastolic BP (DBP) in a Swedish urban-based study, the Malmö Diet and Cancer study (n = 29 298). Causality was evaluated by the inverse variance weighted method (IVW) and weighted median, while MR Egger and MR-PRESSO were used as sensitivity analyses. Genetically predicted serum calcium level was found to be associated with DBP (IVW: beta = 0.10, SE = 0.04, P = 0.007) and SBP (IVW: beta = 0.07, SE = 0.04, P = 0.04). Genetically predicted Vit-D and PTH showed no association with the traits, while FGF23 was inversely associated with SBP (IVW: beta = -0.11, SE = 0.04, P = 0.01), although this association lost statistical significance in sensitivity analysis. Our study shows a direct association between genetically predicted calcium level and DBP, and a weaker association with SBP. No such clear association was found for genetically predicted calciotropic hormone levels. It is of interest to detect which target genes involved in calcium homeostasis mediate the effect of calcium on BP, particularly for improving personalized intervention strategies.