Abnormal Bone Mineral Metabolism Research Articles

The WNT/β-catenin system in chronic kidney disease-mineral bone disorder syndrome.

The WNT/β-catenin system is an evolutionarily conserved signaling pathway that plays a crucial role in morphogenesis and cell tissue formation during embryogenesis. Although usually suppressed in adulthood, it can be reactivated during organ damage and regeneration. Transient activation of the WNT/β-catenin pathway stimulates tissue regeneration after acute kidney injury, while persistent (uncontrolled) activation can promote the development of chronic kidney disease (CKD). CKD-MBD is a clinical syndrome that develops with systemic mineral and bone metabolism disorders caused by CKD, characterized by abnormal bone mineral metabolism and/or extraosseous calcification, as well as cardiovascular disease associated with CKD, including vascular stiffness and calcification. This paper aims to comprehensively review the WNT/β-catenin signaling pathway in relation to CKD-MBD, focusing on its components, regulatory molecules, and regulatory mechanisms. Additionally, this review highlights the challenges and opportunities for using small molecular compounds to target the WNT/β-catenin signaling pathway in CKD-MBD therapy. We conducted a comprehensive literature review using various scientific databases, including PubMed, Scopus, and Web of Science, to identify relevant articles. We searched for articles that discussed the WNT/β-catenin signaling pathway, CKD-MBD, and their relationship. We also reviewed articles that discussed the components of the WNT/β-catenin signaling pathway, its regulatory molecules, and regulatory mechanisms. The WNT/β-catenin signaling pathway plays a crucial role in CKD-MBD by promoting vascular calcification and bone mineral metabolism disorders. The pathway's components include WNT ligands, Frizzled receptors, and LRP5/6 co-receptors, which initiate downstream signaling cascades leading to the activation of β-catenin. Several regulatory molecules, including GSK-3β, APC, and Axin, modulate β-catenin activation. The WNT/β-catenin signaling pathway also interacts with other signaling pathways, such as the BMP pathway, to regulate CKD-MBD. The WNT/β-catenin signaling pathway is a potential therapeutic target for CKD-MBD. Small molecular compounds that target the components or regulatory molecules of the pathway may provide a promising approach to treat CKD-MBD. However, more research is needed to identify safe and effective compounds and to determine the optimal dosages and treatment regimens.

Nontraditional Biomarkers for Cardiovascular Disease in Patients With Chronic Kidney Disease

Cardiovascular disease (CVD) is the leading cause of death among patients who have chronic kidney disease (CKD). Nowadays, CKD per se is considered one of the coronary heart disease (CHD) risk equivalents. Apart from traditional CVD risk factors, there are several possible determinants for CVD in patients with CKD, for example, uremic toxins, increased inflammatory stage, abnormal bone mineral metabolism, and positive calcium balance. In this narrative review, we offer a summary of the extensively studied biomarkers for CVD in patients with CKD, including uremic toxins (p-cresol, indoxyl sulfate, and advanced glycated end products), and a novel indicator of arterial stiffness, cardio-ankle vascular index (CAVI), which is an independent prognostic predictor for CVD. For the uremic toxins, we reviewed their metabolisms, particularly, how the reduced renal function in CKD patients affect their clearance and their clearance with dialysis. Also, we pay attention to the recent evidence on how those uremic toxins contribute to CVD and their clinical associations. We do not include the possible treatment targeting at those uremic toxins. As for the novel indicator of arterial stiffness, we reviewed the clinical application of CAVI in comparison to the standard indicator for arterial stiffness, pulse wave velocity.

Phosphorus Levels in Iron Deficient Children Treated with Ferric Carboxymaltose

INTRODUCTION Intravenous iron therapy in children with iron deficiency anemia (IDA) has previously been limited to those with severe or refractory anemia. However, increased availability of intravenous iron preparations with improved safety profiles has increased its utilization in both the adult and pediatric patient populations. Ferric carboxymaltose (FCM) was approved for adult patients by the Food and Drug Administration (FDA) in 2014 and has lower rates of severe allergic reactions. However, literature on adult patients has reported the development hypophosphatemia in up 50% of those receiving the drug. In early stages, hypophosphatemia can lead to abnormal bone mineral metabolism and hypercalciuria. Rickets and osteomalacia can result after prolonged hypophosphatemia. Severe, prolonged hypophosphatemia (<1 mg/mL) is associated with neurologic, cardiopulmonary, muscular, and hematologic complications. Although not FDA approved for pediatric use, FCM is increasingly being utilized for IDA in children. Hypophosphatemia in children treated with FCM has not been formally evaluated or described. We sought to assess available phosphorus levels in children treated with FCM at a tertiary care center. METHODS This was a single center retrospective cohort study of all children who received FCM over the initial 2.5 year period for which the drug was added to our institution's formulary (November 1, 2016 through April 30, 2019). Pharmacy records of all FCM infusions administered over this period were obtained. Medical record numbers of all patients who received an infusion were then searched for any available phosphorus testing. Patients were included in the review if they had phosphorus laboratory results available from 1 to 6 weeks post-receipt of FCM and were less than 21 years of age at the time of infusion. Hypophosphatemia was defined as a phosphorus level below the lower limit of normal for age as delineated by our institution's central laboratory. Changes in phosphorus levels were calculated in those patients in whom pre-infusion phosphorus levels were also available within the 4 weeks prior to drug infusion. When multiple phosphorus levels were available within the post-infusion window, the lowest value was selected to calculate changes in levels. The electronic medical record (EMR) was reviewed in all patients in whom hypophosphatemia was identified to assess for administration of supplemental phosphorus, as well as other clinical factors that may affect phosphorus levels such as the administration of total parental nutrition (TPN) and/or renal medications (i.e. furosemide), as these are known risk factors for hypophosphatemia. RESULTS From November 1, 2016 through April 30, 2019, 1,081 infusions of FCM were administered in 656 patients. Post-infusion phosphorus testing was available in 165 patients in whom 247 infusions were administered (range 1 to 6). Patients' median age was 4.6 years (range 4 months to 20.6 years) and 56% (n=92) were female. Hypophosphatemia occurred after 36 (15%) infusions in 32 unique patients (19%). Six patients (19%) received potassium phosphorus supplementation (Table). In the 23 patients in whom phosphorus testing was available at 6 weeks, 15 (65%) continued to have phosphorus levels below the normal value for age. Of the entire cohort, pre- and post-infusion phosphorus levels were available relative to 197 infusions (80%) in 136 unique patients (82%). The median change in phosphorus was -0.6 mg/dL (IQR -0.1, -1.6). CONCLUSIONS The assessment of serum chemistries, including phosphorus, is not routinely performed in otherwise healthy children with iron deficiency. While over 650 children received over 1000 infusions of FCM during a 2.5 year period, only 165 patients had phosphorus testing available during the stated time frame of the infusion. In those in whom testing was available, and in which hypophosphatemia occurred, the majority were patients admitted to the hospital with co-morbid conditions or complex clinical care for which phosphorus levels may be affected. Our center has developed a clinical protocol to obtain baseline phosphorus levels in all children in whom intravenous FCM is being considered. Post FCM therapy, phosphorus monitoring is being performed to better identify those patients who may be at risk for hypophosphatemia and in whom phosphorus supplementation may be indicated. OffLabel Disclosure: Ferric carboxymaltose is FDA approved for treatment of iron deficiency in adults. This presentation will discuss the use of ferric carboxymaltose to treat iron deficiency in pediatric patients.

Effect of vitamin D supplementation on serum sclerostin levels in chronic kidney disease

Vitamin D deficiency, cardiovascular disease and abnormal bone mineral metabolism are common in chronic kidney disease (CKD). Abnormal bone mineral metabolism has been linked to vascular calcification in CKD. Sclerostin has emerged as an important messenger in cross talk between bone-vascular axis. We analyzed sclerostin in subjects who participated in the randomized, double blind, placebo controlled trial investigating the effect of cholecalciferol supplementation on vascular function in non­diabetic CKD stage G3-4 and vitamin D ≤ 20 ng/ml [CTRI/2013/05/003648]. Patients were randomized (1:1) to receive either two directly observed oral doses of 300,000 IU of cholecalciferol or matching placebo at baseline and 8 weeks. Of the 120 subjects enrolled, 58 in the cholecalciferol group and 59 in the placebo group completed the study. At baseline, serum levels of sclerostin were similar in both groups (cholecalciferol - median;190pg/ml, IQR;140–260 pg/ml and placebo - median;180 pg/ml, IQR; 140–240 pg/ml, p = 0.67). 16 weeks after cholecalciferol supplementation, there was no change in level of sclerostin (mean change;1.10 pg/ml, 95%CI; −27.34 to 29.34 pg/ml, p = 0.25). However, a significant decrease in sclerostin level was noted in the placebo group (mean change; −31.94 pg/ml, 95%CI; −54.76 to −9.13 pg/ml, p = 0.002). Change (Δ) in sclerostin level at 16 weeks correlated negatively with Δ eGFR (r = −0.20, p = 0.03) and positively with Δuric acid (r = 0.37, p < 0.001) but not with Δ25(OH) D (r = 0.06, p = 0.54), Δ iPTH (r = − 0.03, p = 0.78) ΔFGF23 (r = − 0.08, p = 0.38) and Δ125 (OH)2 D (r = − 0.04, p = 0.65). In conclusion, high dose cholecalciferol supplementation did not change sclerostin levels in non-diabetic stage 3–4 CKD subjects.

Abstract P137: Walking Impairment and Vitamin D Deficiency in the Elderly, National Health and Nutrition Examination Survey 2001 to 2004

Introduction: Vitamin D deficiency has been reported in 36% of otherwise healthy adults and 57% of inpatients in the US. Vitamin D deficiency (&lt; 15 ng/ml) is linked to increased muscle weakenss, cardiovascular disease and abnormal bone mineral metabolism. The elderly are more prone to vitamin D deficiency because of decrease dietary intake, diminished sunlight exposure and reduced skin thickness among other risk factors. We hypothesized that walking impairment in subjects older than 60 years old is associated to abnormal serum levels of 25-hydroxyvitaminD levels independent of traditional cardiovascular risk factors. Methods: A multivariable adjustment was performed using the National Health and Nutrition Examination Survey database and a graded association was present between serum 25-hydroxyvitaminD levels and walking impairment. We analyzed data from 2,322 participants of the NHANES 2001-2004 survey ages 60 years or older who responded to the walking impairment (WI) questionnaire and had serum 25-hydroxyvitamin D levels measured. Walking impairment was defined as an affirmative answer to the question: “have you had pain in either leg while walking?” A 25 hydroxyvitamin D deficiency level was defined as a serum level of 15ng/dl or less. PAD was defined as an ABI of less than 0.9 in either leg. Results: The prevalence of individuals 60 year or older with walking impairment due to leg pain in the United States is 25 % (S.E, 1.3). Mexican Americans (31.43%) had a higher prevalence of WI than Whites (24.28%) or African Americans (28.67%). Walking impairment was also statistically significant among those with a history of diabetes mellitus, cardiovascular disease, and peripheral arterial disease. Results also showed that C-reactive protein and alkaline phosphates were higher among those with walking impairment. A multivariable adjustment was performed and a graded association was present between serum 25-hydroxyvitaminD levels and walking impairment. An odds ratio of 1.526186(p= 0.013) for walking impairment was present among vitamin D deficient subjects after adjusting for age, gender, and race-ethnicity. The association remained after further adjusting for C-reactive protein, chronic kidney disease, smoking, history of diabetes, PAD, and history of cardiovascular disease (O.R. =1.416255, p=0.045). Conclusion: Walking impairment is associated with 25-hydroxyvitaminD deficiency in the elderly independent of traditional cardiovascular risk factors. These results warrant further studies to determine if vitamin D supplementation improves functional capacity and reduces cardiovascular disease in the elderly.

Prevalence and predictors of abnormal bone mineral metabolism in recently diagnosed adult celiac patients

This study aimed to evaluate the prevalence of low bone mineral density (BMD) in recently diagnosed adult celiac patients and to identify the factors associated with this. We investigated 54 newly diagnosed adult celiac patients between February 2008 and April 2009. BMD was measured in all patients and its correlation with clinical and biochemical parameters was analyzed. Fifty-four (24 male) newly diagnosed celiac patients with a mean±SD age of 30.6 ± 9.3 years (range 18-50) were included. Thirty-nine (72.2 %) presented with intestinal symptoms, and the rest with extraintestinal symptoms. Low vitamin D levels were seen in 11 (20.3 %) patients and elevated iPTH (secondary hyperparathyroidism) in 12 (22.2 %) patients. Twenty-one (39 %) patients had normal BMD, 23 (43 %) had osteopenia (T-score -1 to -2.5), and 10 (18 %) patients had osteoporosis (T-score <-2.5). A statistically significant association was seen between BMD and age of onset, duration of illness, serum tTGA levels, serum vitamin D levels, and histopathological changes. Low BMD is common in newly diagnosed adult celiac patients with approximately one fifth of them having osteoporosis. BMD should be measured in all newly diagnosed celiac patients and calcium and vitamin D supplementation included in the treatment regimen.

Changes in bone and mineral metabolism in kidney transplant patients with chronic kidney disease

Recently, the Foundation has proposed new definitions KDIGO to refer to the alterations of bone - mineral metabolism in patients with chronic renal disease (CRD), relegating the traditional term of renal osteodystrophy (ODR). RECOMMEND: The term ODR exclusively to define alterations in bone morphology and architecture characteristic of the ERC. - And the term of bone-mineral alteration associated with the CRD to describe biochemical changes, and skeletal calcifications that occur as a result of alterations in mineral metabolism in the CRD. The different metabolic abnormalities are secondary to the progressive loss of renal mass and renal function that leads to retention of phosphorus and a decrease in the levels of calcitriol which are responsible for the skeletal resistance to the action of PTH. The main clinical manifestations of abnormal bone mineral metabolism are posttransplantation osteoporosis and osteopenia producing an increase in fractures, osteonecrosis, and bone pain. Biochemical parameters (calcium, phosphorus, PTH, 25 hydroxyvitamin D), X-ray bone densitometry and bone biopsy. (Evidence B). THERAPEUTIC ALTERNATIVES: It is recommended for the treatment and prevention of osteopenia - osteoporosis in transplant patients based on data from clinical evidence available from other study populations, such as in patients with chronic kidney disease. In addition to specific treatment, we must take into account the preventive measures to reduce the risk of fractures. Treatment includes specific measures for the prevention of bone loss (active metabolite of vitamin D analogues and bisphosphonates) and the treatment of persistent hyperparathyroidism (calcimiméticos). (Evidence B).

Bone mineral metabolism in pediatric inflammatory bowel disease

The development of reliable techniques to measure bone densitometry and evolving effective drug treatment have kindled great interest in the diagnosis and treatment of osteoporosis in adults with inflammatory bowel disease. A number of studies have examined the prevalence of abnormal bone mineral metabolism in children and adolescents. Studies, conducted over the past decade, indicate a greater likelihood of clinically significant problems in Crohn's disease than in ulcerative colitis. Corticosteroids have been proven to impair bone mineral status. It is increasingly clear that inflammation and other factors play a bigger role than malabsorbtion of minerals or vitamin D in most patients. As the use of the bisphonate class of drugs is limited in pediatric patients, there is a need to emphasize the role of diet and exercise in children and teenagers, particularly in those affected by inflammatory bowel disease.

Association of mineral metabolism with an increase in cellular adhesion molecules: another link to cardiovascular risk in maintenance haemodialysis?

Abnormal mineral metabolism is associated with increased cardiovascular morbidity and mortality. The exact pathogenesis linking mineral metabolism to cardiovascular risk is unknown. This study was undertaken to investigate the association between serum phosphate and/or Ca x PO(4) product with serum levels of soluble E-selectin (sE-selectin), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 and the degree of carotid artery atherosclerosis in patients on haemodialysis. Seventy-three patients (46 male, 27 female; mean age 48+/-13 years, on haemodialysis for 82+/-80 months) were included in the study. All patients were stable, had no evidence of vascular disease and/or active infection. Consecutive 6 months clinical and laboratory data were obtained for each patient from their medical records and mean values were used for analysis. Serum levels of soluble adhesion molecules were assayed by ELISA. All subjects underwent a detailed evaluation of the carotid arteries. The percentage of patients who met all three targets of NKF-K/DOQI for phosphate, calcium and Ca x PO(4) product was 27.1%, whereas those who did not achieve the target in one, two or three parameters was 28.1, 17.7 and 14.6%, respectively. The sICAM-1 levels were significantly higher in patients who had hyperphosphataemia (serum phosphate >5.5 mg/dl; P = 0.044) and hypercalcaemia (serum calcium >9.5 mg/dl; P = 0.014), both sE-selectin and sICAM-1 levels were significantly higher in patients with Ca x PO(4) product levels above 55 mg(2)/dl(2) (P = 0.002 and P = 0.000, respectively). Soluble E-selectin and sICAM levels demonstrated a near-linear increase in parallel to the degree of deviation from mineral metabolism targets. Soluble E-selectin and sICAM levels were correlated with serum phosphate and Ca x PO(4) product, but there were no correlations between adhesion molecules and carotid measurements. These findings suggest that in stable haemodialysis patients abnormal bone mineral metabolism was associated with increased soluble adhesion molecules. These alterations in adhesion molecules may favour the development of cardiovascular changes and contribute to high cardiovascular morbidity and mortality in patients with abnormal mineral metabolism.

Detection of hydroxyl ions in bone mineral by solid-state NMR spectroscopy.

Previous measurements of the hydroxyl (OH-) ion content of the calcium phosphate crystals of bone mineral have indicated a substantial depletion or near-absence of OH-, despite its presumed status as a constituent of the hydroxyapatite lattice. Analytical methods for determining bone crystal OH- content have depended on procedures or assumptions that may have biased the results, such as chemical pretreatment to eliminate interference from the organic matrix. We demonstrate a two-dimensional solid-state nuclear magnetic resonance (NMR) spectroscopy technique that detects the proton spectrum of bone crystals while suppressing the interfering matrix signals, eliminating the need for specimen pretreatment other than cryogenic grinding. Results on fresh-frozen and ground whole bone of several mammalian species show that the bone crystal OH- is readily detectable; a rough estimate yields an OH- content of human cortical bone of about 20% of the amount expected in stoichiometric hydroxyapatite. This finding sheds light on the biochemical processes underlying normal and abnormal bone mineral metabolism.

The effects of bone marrow transplantation on X-linked hypophosphatemic mice.

The genes responsible for X-linked hypophosphatemic (XLH) vitamin D-resistant rickets and the murine homolog, hypophosphatemic mice (Hyp), were identified as PHEX and Phex (phosphate-regulating gene with homology to endopeptidases on the X chromosome), respectively. However, the mechanism by which inactivating mutations of PHEX cause XLH remains unknown. We investigated the mechanisms by syngeneic bone marrow transplantation (BMT) from wild mice to Hyp mice. The expression of the Phex gene was detected in mouse BM cells. BMT introduced a chimerism in recipient Hyp mice and a significant increase in the serum phosphorus level. The renal sodium phosphate cotransporter gene expression was significantly increased. The effect of BMT on the serum phosphorus level depended on engraftment efficiencies, which represent the dosage of normal gene. Similarly, the serum alkaline phosphatase (ALP) activity was decreased and bone mineral density was increased. Furthermore, the renal expression of 25-hydroxyvitamin D3 24-hydroxylase, which is a key enzyme in the catabolic pathway and is increased in XLH/Hyp, was improved. From these results, we conclude that transplantation of normal BM cells improved abnormal bone mineral metabolism and deranged vitamin D metabolism in Hyp by replacing defective gene product(s) with normal gene product(s). This result may provide strong evidence for clinical application of BMT in metabolic bone disorders.

55-Year-Old Woman With Worsening Seizure Control

55-Year-Old Woman With Worsening Seizure Control

Bone mineral metabolism in pediatric inflammatory bowel disease.

The development of reliable techniques to measure bone densitometry and evolving effective drug treatment have kindled great interest in the diagnosis and treatment of osteoporosis in adults with inflammatory bowel disease. A number of studies have examined the prevalence of abnormal bone mineral metabolism in children and adolescents. Studies, conducted over the past decade, indicate a greater likelihood of clinically significant problems in Crohn's disease than in ulcerative colitis. Corticosteroids have been proven to impair bone mineral status. It is increasingly clear that inflammation and other factors play a bigger role than malabsorbtion of minerals or vitamin D in most patients. As the use of the bisphonate class of drugs is limited in pediatric patients, there is a need to emphasize the role of diet and exercise in children and teenagers, particularly in those affected by inflammatory bowel disease.