calcitriol and Bone-Diseases

Hypovitaminosis D in childhood is a re-emerging public health problem in developed countries. New life style habits, current "epidemics" of obesity in children and adolescents worldwide, and other preventable risk factors may play a role in favoring the occurrence of vitamin D deficiency. In addition to skeletal consequences, hypovitaminosis D has been found to be involved in the development of serious health extra-skeletal problems in childhood, including atopy and autoimmunity. The increasing concerns about the global health impact of vitamin D deficiency make further research necessary to fill the gaps of knowledge in this field, and particularly to establish universally accepted "normal" serum 25(OH)D levels in the pediatric population, and to improve strategies for the screening, prevention and treatment of hypovitaminosis D. This review discusses the key points of hypovitaminosis D in childhood in the light of new knowledge, and highlights the limitations of current strategies to control this condition.

Topics: Adolescent; Bone Diseases; Child; Child, Preschool; Dermatitis, Atopic; Developed Countries; Diabetes Mellitus, Type 1; Diet; Dietary Supplements; Humans; Infant; Infant Food; Nutritional Status; Polymorphism, Single Nucleotide; Reference Values; Rickets; Risk Factors; Sunlight; Vitamin D; Vitamin D Deficiency

Chronic kidney disease (CKD) affects approximately 10% of adults worldwide. Dysregulation of phosphorus homeostasis which occurs in CKD leads to development of CKD-Mineral Bone Disorder (CKD-MBD) and contributes to increased morbidity and mortality in these patients. Phosphorus is regulated by multiple hormones (parathyroid hormone (PTH), 1,25-dihyxdroxyvitamin D (1,25D), and fibroblast growth factor 23 (FGF23)) and tissues (kidney, intestine, parathyroid glands, and bone) to maintain homeostasis. In health, the kidneys are the major site of regulation for phosphorus homeostasis. However, as kidney function declines, the ability of the kidneys to adequately excrete phosphorus is reduced. The hormonal changes that occur with CKD would suggest that the intestine should compensate for impaired renal phosphorus excretion by reducing fractional intestinal phosphorus absorption. However, limited studies in CKD animal models and patients with CKD suggest that there may be a break in this homeostatic response where the intestine fails to compensate. As many existing therapies for phosphate management in CKD are aimed at reducing absolute intestinal phosphorus absorption, better understanding of the factors that influence fractional and absolute absorption, the mechanism by which intestinal phosphate absorption occurs, and how CKD modifies these is a much-needed area of study.

Topics: Animals; Bone Density; Bone Diseases; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Homeostasis; Humans; Intestinal Absorption; Intestines; Kidney; Malabsorption Syndromes; Parathyroid Hormone; Phosphorus; Phosphorus, Dietary; Renal Insufficiency, Chronic; Vitamin D

Vitamin D plays an important role in regulation of calcium homeostasis and bone metabolism. Among vitamin D metabolites, 25-hydroxyvitamin D (25-OH-D) can be used for the evaluation of vitamin D nutritional status. In contrast, 1,25-dihydroxyvitamin D (1,25 [OH] 2D) can be used for the diagnosis of hyperparathyroidism, renal malfunctions, and other calcium metabolism-related diseases. Serum 25-OH-D concentration can be measured with radioimmunoassay (RIA), enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA), chemiluminescence protein-binding assay (CLPBA), high performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS) methods. Likewise, serum 1,25 (OH) 2D can be measured with RIA, EIA, radioreceptorassay (RRA) and ELISA methods. Clinicians are required to recognize the characteristics of each method and use serum concentrations of 25-OH-D and 1,25 (OH) 2D as biochemical markers for the diagnosis of bone diseases.

Topics: Bone Diseases; Humans; Hyperparathyroidism; Kidney Diseases; Vitamin D

Hyperphosphatemia, vitamin D deficiency, hyperparathyroidism, and high serum fibroblast growth factor 23 (FGF23) levels, when studied separately, were found to predict the progression of CKD. However, studies with simultaneous measurement of mineral bone disorder (MBD)-related factors were scarce. This study aimed to identify factors predicting renal outcome independent of other factors.. This was a prospective cohort study of 738 Japanese predialysis outpatients in the nephrology departments of two hospitals. The outcome was defined as a doubling of serum creatinine or initiation of dialysis.. Mean estimated GFR (eGFR) was 35 ml/min per 1.73 m(2). At enrollment, the increase in intact FGF23 with decreasing eGFR was the earliest among changes in MBD-related factors, followed by 1,25-dihydroxyvitamin D decrease, parathyroid hormone increase, and phosphate increase. During a median duration of 4.4 years, 213 patients reached the endpoint. In a multivariable Cox model, high FGF23 and low 25-hydroxyvitamin D (25D) levels were the only MBD-related factors associated with a higher risk of renal endpoint (adjusted hazard ratio [95% confidence interval] per unit change of log FGF23 and 10 ng/ml of 25D: 1.83 [1.28-2.61] and 0.61 [0.41-0.90], respectively). There was no significant interaction between 25D and FGF23 (P=0.11). Active vitamin D therapy, serum phosphate, 1,25-dihydroxyvitamin D, and parathyroid hormone levels were not related to the renal endpoint. Treating death as a competing risk or multiple imputation for missing values yielded similar results.. Combined use of two markers is useful for the risk stratification of renal outcome.

Topics: Aged; Biomarkers; Bone Diseases; Confidence Intervals; Creatinine; Disease Progression; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glomerular Filtration Rate; Humans; Male; Middle Aged; Multivariate Analysis; Parathyroid Hormone; Phosphates; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Renal Insufficiency, Chronic; Risk Assessment; Vitamin D

This study examined the characteristics of biochemical parameters, bone diseases, and vascular calcification in Korean patients with chronic kidney disease (CKD) not yet on dialysis. Serum levels of fibroblast growth factor 23 (FGF23), intact parathyroid hormone (iPTH), 25-hydroxyvitamin D3 (25D), and 1,25-dihydroxyvitamin D3 (1,25D); lumbar spine, total hip, and femur neck bone mineral densities; and brachial-to-ankle pulse wave velocity (baPWV) representing vascular calcification were measured at baseline for 2,238 CKD patients in the KoreaN Cohort Study for Outcomes in Patients With CKD (KNOW-CKD). Increases in serum FGF23 and iPTH preceded changes in serum calcium and phosphate, similar to Western populations. However, the 25D and 1,25D levels decreased earlier than serum FGF23 or iPTH increased, with a decreased estimated glomerular filtration rate (eGFR) in Korean CKD patients. Vitamin D deficiency occurred in 76.7% of patients with CKD stage 1. Bone mineral densities were lowest in CKD stage 5 (lumbar spine, -0.64 ± 1.67; total hip, -0.49 ± 1.21; femur neck, -1.02 ± 1.25). Osteoporosis was more prevalent in patients with higher CKD stages. The mean baPWV, abdominal aortic calcification (AAC), and coronary calcium score also increased, with declined eGFR. In conclusion, a decline in serum vitamin D levels was observed in early CKD stages before significant increases of FGF23 and iPTH in the Korean CKD population compared with that in Western populations. Increased bone disease and vascular calcification occurred in early-stage CKD.

Topics: Adult; Aged; Asian People; Bone Density; Bone Diseases; Calcitriol; Calcium; Cohort Studies; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glomerular Filtration Rate; Humans; Male; Middle Aged; Parathyroid Hormone; Phosphates; Pulse Wave Analysis; Renal Insufficiency, Chronic; Republic of Korea; Severity of Illness Index; Vitamin D; Vitamin D Deficiency

The X-linked hypophosphatemic (Hyp) mouse carries a loss-of-function mutation in the phex gene and is characterized by hypophosphatemia due to renal phosphate (Pi) wasting, inappropriately suppressed 1,25-dihydroxyvitamin D [1,25(OH)₂D] production, and rachitic bone disease. Increased serum fibroblast growth factor-23 concentration is responsible for the disordered metabolism of Pi and 1,25(OH)₂D. In the present study, we tested the hypothesis that chronic inhibition of fibroblast growth factor-23-induced activation of MAPK signaling in Hyp mice can reverse their metabolic derangements and rachitic bone disease. Hyp mice were administered the MAPK inhibitor, PD0325901 orally for 4 wk. PD0325901 induced a 15-fold and 2-fold increase in renal 1α-hydroxylase mRNA and protein abundance, respectively, and thereby higher serum 1,25(OH)₂D concentrations (115 ± 13 vs. 70 ± 16 pg/ml, P < 0.05), compared with values in vehicle-treated Hyp mice. With PD0325901, serum Pi levels were higher (5.1 ± 0.5 vs. 3 ± 0.2 mg/dl, P < 0.05), and the protein abundance of sodium-dependent phosphate cotransporter Npt2a, was greater than in vehicle-treated mice. The rachitic bone disease in Hyp mice is characterized by abundant unmineralized osteoid bone volume, widened epiphyses, and disorganized growth plates. In PD0325901-treated Hyp mice, mineralization of cortical and trabecular bone increased significantly, accompanied by a decrease in unmineralized osteoid volume and thickness, as determined by histomorphometric analysis. The improvement in mineralization in PD0325901-treated Hyp mice was confirmed by microcomputed tomography analysis, which showed an increase in cortical bone volume and thickness. These findings provide evidence that in Hyp mice, chronic MAPK inhibition improves disordered Pi and 1,25(OH)₂D metabolism and bone mineralization.

Topics: Animals; Benzamides; Bone and Bones; Bone Diseases; Diphenylamine; Disease Models, Animal; Enzyme Inhibitors; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Hypophosphatemia; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Minerals; Mitogen-Activated Protein Kinase Kinases; Mutation; PHEX Phosphate Regulating Neutral Endopeptidase; Phosphates; Signal Transduction; Vitamin D

Cadmium is a widespread environmental pollutant, which is associated with increased risk of osteoporosis. It has been proposed that cadmium's toxic effect on bone is exerted via impaired activation of vitamin D, secondary to the kidney effects. To test this, we assessed the association of cadmium-induced bone and kidney effects with serum 1,25-dihydroxyvitamin D (1,25(OH)(2)D); measured by enzyme immunoassay. For the assessment, we selected 85 postmenopausal women, based on low (0.14-0.39 microg/L) or high (0.66-2.1 microg/L) urinary cadmium, within a cross-sectional population-based women's health survey in Southern Sweden. We also measured 25-hydroxy vitamin D, cadmium in blood, bone mineral density and several markers of bone remodeling and kidney effects. Although there were clear differences in both kidney and bone effect markers between women with low and high cadmium exposure, the 1,25(OH)(2)D concentrations were not significantly different (median, 111 pmol/L (5-95th percentile, 67-170 pmol/L) in low- and 125 pmol/L (66-200 pmol/L) in high-cadmium groups; p=0.08). Also, there was no association between 1,25(OH)(2)D and markers of bone or kidney effects. It is concluded that the low levels of cadmium exposure present in the studied women, although high enough to be associated with lower bone mineral density and increased bone resorption, were not associated with lower serum concentrations of 1,25(OH)(2)D. Hence, decreased circulating levels of 1,25(OH)(2)D are unlikely to be the proposed link between cadmium-induced effects on kidney and bone.

Topics: Bone and Bones; Bone Density; Bone Diseases; Cadmium; Cross-Sectional Studies; Environmental Exposure; Female; Humans; Kidney; Kidney Diseases; Menopause; Middle Aged; Osteoporosis; Population Surveillance; Risk Assessment; Risk Factors; Sweden; Vitamin D

Oncogenic osteomalacia, or tumour-induced osteomalacia (TIO), is a rare paraneoplastic syndrome characterised by hypophosphataemia, phosphaturia, inappropriately low serum levels of 1,25-dihydroxyvitamin D for hypophosphataemia. TIO is caused by mesenchymal tumours that secrete phosphaturic substances, leading to increased renal wasting of phosphates. These tumours are very small in size and grow slowly. Localisation of these tumours has always been difficult with the available biochemical and imaging techniques. At times, despite all efforts, the tumour could not be localised. We report our experience with a 42-year-old woman with TIO where whole-body magnetic resonance imaging could not localise the tumour, a scapular haemangiopericytoma. PET/CT was helpful in the localisation of the tumour which, when surgically removed, resulted in the normalisation of biochemical parameters with clinical improvement.

Topics: Adult; Bone Diseases; Contrast Media; Female; Fluorodeoxyglucose F18; Hemangiopericytoma; Humans; Magnetic Resonance Imaging; Osteomalacia; Paraneoplastic Syndromes; Positron-Emission Tomography; Radiopharmaceuticals; Scapula; Tomography, X-Ray Computed; Vitamin D

A line of mice deficient in vitamin D binding protein (DBP) was generated by targeted mutagenesis to establish a model for analysis of DBP's biological functions in vitamin D metabolism and action. On vitamin D-replete diets, DBP-/- mice had low levels of total serum vitamin D metabolites but were otherwise normal. When maintained on vitamin D-deficient diets for a brief period, the DBP-/-, but not DBP+/+, mice developed secondary hyperparathyroidism and the accompanying bone changes associated with vitamin D deficiency. DBP markedly prolonged the serum half-life of 25(OH)D and less dramatically prolonged the half-life of vitamin D by slowing its hepatic uptake and increasing the efficiency of its conversion to 25(OH)D in the liver. After an overload of vitamin D, DBP-/- mice were unexpectedly less susceptible to hypercalcemia and its toxic effects. Peak steady-state mRNA levels of the vitamin D-dependent calbindin-D9K gene were induced by 1,25(OH)2D more rapidly in the DBP-/- mice. Thus, the role of DBP is to maintain stable serum stores of vitamin D metabolites and modulate the rates of its bioavailability, activation, and end-organ responsiveness. These properties may have evolved to stabilize and maintain serum levels of vitamin D in environments with variable vitamin D availability.

Topics: Animals; Bone Diseases; Calbindins; Calcifediol; Calcification, Physiologic; Gene Targeting; Hypercalcemia; Hyperparathyroidism, Secondary; Kidney; Liver; Mice; Mice, Knockout; Parathyroid Hormone; RNA, Messenger; S100 Calcium Binding Protein G; Transcriptional Activation; Vitamin D; Vitamin D Deficiency; Vitamin D-Binding Protein