calcitriol and Bone-Diseases--Metabolic

Reduction in serum 1,25 (OH) (2)D level plays an important role in the pathophysiology of altered bone and mineral metabolism among patients with advanced stages of CKD. The use of vitamin D receptor activators (VDRA) has brought great progress in medical management of CKD-MBD. A number of observational studies have shown that the nonuse of VDRA, and low serum concentrations of 1,25 (OH) (2)D or 25 (OH) D are the predictors of poor clinical outcomes in CKD patients including dialysis patients, raising a possibility that the pleiotropic actions of vitamin D may be systemically involved in the poor survival of patients with CKD-MBD. Randomized controlled trials are needed to clarify whether or not VDRA could be beneficial in the protection of the cardiovascular system and good longevity.

Topics: Bone Diseases, Metabolic; Cardiovascular Diseases; Cholecalciferol; Chronic Disease; Ergocalciferols; Humans; Kidney Diseases; Minerals; Randomized Controlled Trials as Topic; Receptors, Calcitriol; Risk; Vitamin D

Impaired kidney function and subsequent skeletal responses play a critical role in disrupting phosphate balance in chronic kidney disease (CKD) patients with mineral and bone disorder (CKD-MBD). In patients with CKD-MBD, the inability of the kidney to maintain normal mineral ion balance affects bone remodeling to induce skeletal fracture and extraskeletal vascular calcification. In physiological conditions, bone-derived fibroblast growth factor 23 (FGF23) acts on the kidney to reduce serum phosphate and 1,25-dihydroxyvitamin D levels. In humans, increased bioactivity of FGF23 leads to increased urinary phosphate excretion, which induces hypophosphatemic diseases (e.g., rickets/osteomalacia). However, reduced FGF23 activity is associated with hyperphosphatemic diseases (e.g., tumoral calcinosis). In patients with CKD, high serum levels of FGF23 fail to reduce serum phosphate levels and lead to numerous complications, including vascular calcification, one of the important determinants of mortality of CKD-MBD patients. Of particular significance, molecular, biochemical and morphological changes in patients with CKD-MBD are mostly due to osteo-renal dysregulation of mineral ion metabolism. Furthermore, hyperphosphatemia can partly contribute to the development of secondary hyperparathyroidism in patients with CKD-MBD. Relatively new pharmacological agents including sevelamer hydrochloride, calcitriol analogs and cinacalcet hydrochloride are used either alone, or in combination, to minimize hyperphosphatemia and hyperparathyroidism associated complications to improve morbidity and mortality of CKD-MBD patients. This article will briefly summarize how osteo-renal miscommunication can induce phosphate toxicity, resulting in extensive tissue injuries.

Topics: Animals; Bone and Bones; Bone Diseases, Metabolic; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Humans; Hyperparathyroidism; Hyperphosphatemia; Kidney; Klotho Proteins; Parathyroid Hormone; Phosphates; Renal Insufficiency, Chronic; Vitamin D

Fibroblast growth factor 23 (FGF23) is a hormone which is produced by osteocytes and lowers serum phosphate and 1,25-dihydroxyvitamin D levels by binding to Klotho-FGF receptor complex in kidney. It has been shown that excess actions of FGF23 cause hypophosphatemic diseases white deficient actions of FGF23 result in hyperphosphatemic disorders. It should be tested in the future whether development of methods to modify FGF23 actions leads to novel therapeutic approaches for bone and mineral disorders.

Topics: Animals; Bone Diseases, Metabolic; Calcium; Chronic Disease; Drug Design; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Humans; Kidney Diseases; Klotho Proteins; Phosphates; Receptors, Fibroblast Growth Factor; Vitamin D

Fibroblast growth factor (FGF) 23 is a hormone which is produced by bone and lowers serum phosphate and 1,25-dihydroxyvitamin D levels by acting on kidney. FGF23 works through binding to Klotho-FGF receptor complex. Because excess and deficient actions of FGF23 result in metabolic bone diseases, FGF23/Klotho pathway is physiologically important for maintaining normal bone metabolism.

Topics: Animals; Bone and Bones; Bone Diseases, Metabolic; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Humans; Klotho Proteins; Phosphates; Protein Binding; Receptors, Fibroblast Growth Factor; Vitamin D

Topics: Adult; Aged; Biomarkers; Bone Diseases, Metabolic; Calcitriol; Cholecalciferol; Dietary Supplements; Female; Humans; Male; Middle Aged; Minerals; Parathyroid Hormone; Renal Insufficiency, Chronic; Vitamin D

Significant decreases in bone mineral density (BMD) occur on the hemiplegic side in chronic stroke patients, which correlate with the degree of paralysis and hypovitaminosis D. In this double-blind, randomized, and prospective study of 98 patients with hemiplegia involving both an upper and lower extremity (55 males and 53 females; mean age, 71.4 +/- 0.6 years) after an acute stroke, 49 were given etidronate for 56 weeks and 49 received a placebo. The BMD was measured by computed X-ray densitometry (CXD) of the second metacarpal bone bilaterally. Forty age-matched control subjects were followed for 56 weeks. At baseline, both groups had 25-hydroxyvitamin D [25(OH)D] insufficiency, increased serum ionized calcium and pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), and low serum concentrations of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25(OH)2D], suggesting immobilization-induced hypercalcemia and inhibition of renal synthesis of 1,25(OH)2D. The BMD on the hemiplegic side decreased by 2.3% and 4.8% in the etidronate and placebo groups, respectively (p = 0.0003). After treatment, the serum 1,25(OH)2D concentration increased by 62.2% in the etidronate group and decreased by 12.4% in the placebo group. The etidronate group had significant decreases in the serum ionized calcium and ICTP and increases in PTH and bone Gla protein (BGP), whereas the placebo group had higher serum calcium and ICTP concentrations but stable PTH. These results suggest that etidronate can prevent decreases in the BMD in hemiplegic stroke patients because it decreases the serum calcium through inhibition of bone resorption and causes a subsequent increase in the serum 1,25(OH)2D concentration.

Topics: Absorptiometry, Photon; Aged; Amino Acids; Bone Density; Bone Diseases, Metabolic; Calcium; Collagen; Collagen Type I; Double-Blind Method; Etidronic Acid; Female; Hemiplegia; Humans; Male; Parathyroid Hormone; Peptides; Prospective Studies; Stroke; Vitamin D

1ɑ,25-dihydroxyvitamin D3 (1,25D) and fibroblast growth factor 23 (FGF23) play important roles in bone metabolism through mutual regulation. However, the underlying mechanism between 1,25D and FGF23 in diabetes-induced bone metabolism disorders has not yet been elucidated. In this study, we investigated the effect of 1,25D on FGF23 under diabetic condition both in vitro and in vivo. The results showed that 1,25D down-regulated the expression of FGF23 in osteoblast significantly though a dose-dependent manner in vitro within high glucose environment. Western blot and immunofluorescence analysis indicated that 1,25D activated PI3K/Akt signalling through binding to vitamin D receptor (VDR), which inhibited the phosphorylation of the transcription factor Forkhead Box O1 (FOXO1). Decreased phosphorylation of FOXO1 down-regulated the expression Dickkopf-1 (DKK1), a well-known inhibitor of Wnt signalling. In addition, we observed that 1,25D remarkably ameliorated osteogenic phenotypic markers such as Ocn and Runx2 and rescued diabetes-induced bone loss in vivo. Our results suggested that 1,25D could promote osteogenesis though down-regulating FOXO1/FGF23 in diabetes.

Topics: Animals; Bone Diseases, Metabolic; Cells, Cultured; Diabetes Mellitus, Experimental; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Forkhead Box Protein O1; Gene Expression Regulation; Male; Mice; Osteoblasts; Osteogenesis; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptors, Calcitriol; Vitamin D; Wnt Signaling Pathway

Topics: Animals; Bone Density; Bone Diseases, Metabolic; Calcium; Female; Halogenation; Osteogenesis; Ovariectomy; Rats; Rats, Wistar; Vitamin D; Vitamins

There is little information on the potential impact of serum 1,25-dihydroxyvitamin D [1,25(OH)2D] on bone health including turnover.. The objective of the study was to determine the influence of 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] on bone health in middle-aged and older European men.. Men aged 40-79 years were recruited from population registers in 8 European centers. Subjects completed questionnaires that included questions concerning lifestyle and were invited to attend for quantitative ultrasound (QUS) of the heel, assessment of height and weight, and a fasting blood sample from which 1,25(OH)2D, 25(OH)D, and PTH were measured. 1,25(OH)2D was measured using liquid chromatography tandem mass spectrometry. Bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (β-cTX) were also measured. Dual-energy x-ray absorptiometry (DXA) of the hip and lumbar spine was performed in 2 centers.. QUS of the heel, bone markers P1NP and β-cTX, and DXA of the hip and lumbar spine were measured.. A total of 2783 men, mean age 60.0 years (SD 11.0) were included in the analysis. After adjustment for age and center, 1,25(OH)2D was positively associated with 25(OH)D but not with PTH. 25(OH)D was negatively associated with PTH. After adjustment for age, center, height, weight, lifestyle factors, and season, 1,25(OH)2D was associated negatively with QUS and DXA parameters and associated positively with β-cTX. 1,25(OH)2D was not correlated with P1NP. 25(OH)D was positively associated with the QUS and DXA parameters but not related to either bone turnover marker. Subjects with both high 1,25(OH)2D (upper tertile) and low 25(OH)D (lower tertile) had the lowest QUS and DXA parameters and the highest β-cTX levels.. Serum 1,25(OH)2D is associated with higher bone turnover and poorer bone health despite being positively related to 25(OH)D. A combination of high 1,25(OH)2D and low 25(OH)D is associated with the poorest bone health.

Topics: Absorptiometry, Photon; Adult; Aged; Aging; Biomarkers; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Calcaneus; Calcitriol; Collagen Type I; Hip Joint; Humans; Life Style; Lumbar Vertebrae; Male; Middle Aged; Parathyroid Hormone; Peptides; Surveys and Questionnaires; Ultrasonography; Vitamin D; Vitamin D Deficiency; White People

Low bone remodeling and relatively low serum parathyroid hormone (PTH) levels characterize adynamic bone disease (ABD). The impact of renal transplantation (RT) on the course of ABD is unknown. We studied prospectively 13 patients with biopsy-proven ABD after RT. Bone histomorphometry and bone mineral density (BMD) measurements were performed in the 1st and 12th months after RT. Serum PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and osteocalcin were measured regularly throughout the study. Serum PTH levels were slightly elevated at transplantation, normalized at the end of the third month and remained stable thereafter. Bone biopsies performed in the first month after RT revealed low bone turnover in all patients, with positive bone aluminum staining in 5. In the 12th month, second biopsies were performed on 12 patients. Bone histomorphometric dynamic parameters improved in 9 and were completely normalized in 6, whereas no bone mineralization was detected in 3 of these 12 patients. At 12 months post-RT, no bone aluminum was detected in any patient. We also found a decrease in lumbar BMD and an increase in femoral BMD. Patients suffering from ABD, even those with a reduction in PTH levels, may present partial or complete recovery of bone turnover after successful renal transplantation. However, it is not possible to positively identify the mechanisms responsible for the improvement. Identifying these mechanisms should lead to a better understanding of the physiopathology of ABD and to the development of more effective treatments.

Topics: Absorptiometry, Photon; Adult; Biomarkers; Biopsy; Bone Density; Bone Diseases, Metabolic; Female; Humans; Kidney Transplantation; Male; Middle Aged; Osteocalcin; Parathyroid Hormone; Prospective Studies; Vitamin D

To elucidate the influence of immobilization-induced hypercalcemia on bone metabolism in Parkinson's disease (PD), we measured serum biochemical indexes and bone mineral density (BMD) in the second metacarpals of 142 elderly PD patients and 99 age-matched healthy controls. Serum concentrations of 25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D (1,25-[OH](2)D), ionized calcium, intact parathyroid hormone (PTH), and intact bone Gla protein (BGP) were measured. Urinary deoxypyridinoline (D-Pyr) was also measured. Increased serum calcium levels (mean, 1.27 mmol/L) were observed in PD patients, and the levels correlated negatively with the Unified Parkinson's Disease Rating Scale III (UPDRS III), indicating the presence of immobilization-induced bone resorption with resultant hypercalcemia. Decreased serum concentrations of 1,25-[OH](2)D (mean, 88.7 pmol/L) and 25-OHD (mean, 29.7 nmol/L) were noted. Serum PTH was decreased (mean, 25.2 ng/L). Serum BGP was decreased while urinary D-Pyr concentration elevated. A negative correlation was observed between 1,25-[OH](2)D levels and serum calcium or UPDRS III (P < 0.0001). In disabled PD patients, immobilization-induced hypercalcemia may inhibit secretion of PTH, which in turn suppresses 1,25-[OH](2)D production. 25-OHD insufficiency may also contribute to decreased 1,25-[OH](2)D. These abnormalities may be corrected by the suppression of bone resorption with bisphoshonate, and supplementations of calcium and vitamin D should be avoided in these patients.

Topics: Aged; Analysis of Variance; Bone Density; Bone Diseases, Metabolic; Calcium; Case-Control Studies; Female; Humans; Immobilization; Linear Models; Male; Middle Aged; Parkinson Disease; Retrospective Studies; Vitamin D

Cyclosporine A (CsA) induces high turnover osteopenia in the rat and there is evidence for this in humans. Recent studies suggest that increases in parathyroid hormone (PTH) may be involved in posttransplantation bone loss. However, human studies are difficult to interpret since transplant patients usually receive a cocktail of immunosuppressants and have underlying disease. Our aim was to try to resolve the influence of the absence or presence of PTH on CsA-induced bone disease. Male Sprague Dawley rats aged 7-9 months, either sham operated or parathyroidectomized (PTX), were randomly divided into vehicle and CsA groups. All PTX rats were given oral calcium supplementation ad libitum. The rats were divided into groups: basal, sham/vehicle, sham/CsA, PTX/vehicle, and PTX/CsA. Serial biochemistry was performed 0, 14, and 28 days after the start of the experimental period; bone histomorphometry was performed 28 days after the start of the experimental period. Statistical analysis consisted of group comparisons and factorial analyses. The results showed that CsA alone produced a high turnover osteopenia consistent with previous studies. In the PTX animals there was an increase in bone mass. PTX also decreased osteoblast activity and recruitment, and serum 1,25OH2D levels. Serum levels of osteocalcin (BGP) were unaffected by PTX. The combination group (PTX/CsA) did not differ statistically from the controls in most of the histomorphometric parameters measured, with the exception of reduced mineral apposition and bone formation rates, reflecting the effects of PTX. Serum BGP and 1,25OH2D levels did not differ, but PTH was reduced from the control. Explanations for these results are (1) CsA and PTX exert their effects via separate mechanisms, negating each other; (2) in the absence of PTH, CsA managed to cause bone loss, and thus PTH may not be essential for CsA-induced bone loss; or (3) the profound accelerated bone loss produced by CsA in normal rats requires PTH. These findings may help explain the discrepancies found in clinical studies where bone loss occurs with either elevated or normal PTH levels.

Topics: Animals; Binding, Competitive; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Calcium; Cyclosporine; Drug Interactions; Male; Organ Size; Osteocalcin; Parathyroid Hormone; Parathyroidectomy; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Tibia; Vitamin D

The purpose of this study was to determine the prevalence of osteoporosis, to estimate the bone turnover and hormonal status, and to identify the factors associated with bone disease in patients with end-stage liver disease who were referred for orthotopic liver transplantation. A prospective study was performed on 58 cirrhotic patients (6 with primary biliary cirrhosis, 14 with alcoholic cirrhosis, and 38 with posthepatitic cirrhosis), who were referred for orthotopic liver transplantation. Patients, excluding those with primary biliary cirrhosis, were classified in Child-Pugh groups according to the severity of liver disease (class B [28 patients], class C [24 patients]). Biochemical parameters of bone mineral metabolism and standard liver function tests were measured in all patients. Additionally, serum osteocalcin, urinary hydroxyproline/creatinine ratio, serum intact parathyroid hormone, serum 25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, follicle-stimulating hormone, and luteinizing hormone levels were determined in patients and controls within the same age range. Plasma testosterone, sex hormone-binding globulin levels, and free testosterone index were obtained for all men included in the study. Bone mass of the lumbar spine and femur were measured by dual X-ray absorptiometry (DPX-L), and were expressed as a standard deviation of mean values (Z-score) from a sex and age-matched control group. Spinal X-rays were obtained to assess vertebral fractures. Osteoporosis was considered as a factor in spinal bone mineral density with a Z-score below 2 or at least one vertebral fracture. Twenty-five patients (43%) had osteoporosis, with lower bone mass measurements in the lumbar spine than in the femoral neck (P < 0.005). Alcoholic and Child-Pugh C patients showed the lowest femoral bone mineral density values. Cirrhotic patients showed lower osteocalcin levels than controls (14.3 +/- 5.9 vs. 18.2 +/- 8.1 ng/ml; P < 0.05) and showed increased urinary hydroxyproline (125.1 +/- 51.5 vs. 107.9 +/- 26.6 nM/mg creatinine; P < 0.05). Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone levels were significantly lower in cirrhotic patients than in controls (10.3 +/- 9.1 vs. 23.1 +/- 26.6 ng/ml; P = 0.000), (12.9 +/- 9.1 vs. 48.3 +/- 11.5 pg/ml; P = 0.000), (16.6 +/- 9.2 vs. 27.9 +/- 8.2 pg/ml; P = 0.000), with no differences between Child-Pugh groups. Alcoholic Child-Pugh C patients showed the lowest 25-hydroxyvitamin D serum values (4.

Topics: Adult; Bone Density; Bone Diseases, Metabolic; Creatinine; Female; Fractures, Bone; Humans; Hydroxyproline; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Osteocalcin; Osteoporosis; Parathyroid Hormone; Prevalence; Prospective Studies; Risk Factors; Testosterone; Vitamin D

Our laboratory has previously demonstrated that the T-lymphocyte is critical in the development of cyclosporin A-induced osteopenia in the rat model. A similar state of osteopenia is induced by estrogen depletion in the ovariectomized (OVX) rat, which is the animal model of postmenopausal bone loss. However, the role of the immune system, and particularly the T-lymphocyte, in estrogen deplete osteopenia has not been elucidated. We used the Rowett athymic nude rat as our model of T-lymphocyte deficiency. In this study, the experimental rats were divided into four groups as follows: (1) sham-operated Rowett heterozygous (rnu/+) euthymic rats (control group); (2) OVX Rowett heterozygous (rnu/+) euthymic rats; (3) sham-operated Rowett homozygous (rnu/rnu) athymic nude rats, which are T-lymphocyte deficient; and (4) ovariectomized Rowett homozygous (rnu/rnu) rats. Rats were weighed, and venous blood was taken in weeks 2, 4, and 6 for determination of serum osteocalcin. Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) was determined on the day of sacrifice. Following sacrifice, histomorphometry was performed on double-labeled proximal tibial metaphyses. Flow cytometric analysis of splenic mononu-clear cell isolates stained for OX19-positive (CD5) T-lymphocytes was performed. T-lymphocyte analysis revealed significant reductions in both athymic nude groups, while OVX euthymic rats demonstrated a diminished number of T-cells relative to their sham-operated counterparts. Histomorphometric data indicated that both OVX groups exhibited a significant loss of trabecular volume, with associated increases in indices for bone formation and resorption, with resorption likely outstripping formation, resulting in osteopenia. Serum osteocalcin was significantly elevated in the ovariectomized euthymic group throughout the experimental period compared with the control group (p < 0.01); it was elevated in the ovariectomized athymic group on week 4 only (p < 0.01 vs. control). It appears that the T-lymphocyte may not be an essential component in the pathogenesis of estrogen deficiency osteopenia. The contribution of circulating T-lymphocytes as well as other T-lymphocyte-rich organs needs to be explored further.

Topics: Animals; Body Weight; Bone Diseases, Metabolic; Cyclosporine; Disease Models, Animal; Estrogens; Female; Osteocalcin; Ovariectomy; Ovary; Rats; Rats, Nude; T-Lymphocytes; Tibia; Vitamin D

X-linked hypophosphatemia is a metabolic bone disease occurring in both humans and mice. In mice, two different mutations (Hyp and Gy), occurring at separate but closely linked loci, have been proposed as models for this disease. Varying reports of the Vitamin D status of these two mutants has led us to reexamine the influence of diet on circulating calcitrophic hormones and mineral metabolism in both mutants. Hyp and Gy mice were raised on the B6C3H background, and both normal females and heterozygous mutant females were studied at 10 weeks of age. Animals were fed one of three diets at random: high (1.5% Ca and 1.0% P); medium (0.6% Ca and 0.6% P); or low (0.0% Ca and 0.6% P). After 3 days, serum and urine samples were collected. In comparison to mutant mice fed the high diet, both Hyp and Gy mice fed the low diet had decreased serum calcium levels, and further elevations in both serum alkaline phosphatase and serum parathyroid hormone (PTH). Serum 1,25-dihydroxyvitamin D levels were elevated by both the medium and low diets in all groups of mice over values obtained with the high diet. Mutant mice were significantly higher in serum PTH on all diets compared to normal mice fed the same diet. Mutant mice were not elevated in serum 1,25-dihydroxyvitamin D over normal mice when fed the high diet. However, both Hyp and Gy mice fed the medium and low diets were elevated in serum 1,25-dihydroxyvitamin D over normal mice. Serum PTH levels were correlated to serum 1,25-dihydroxyvitamin D levels with Hyp and Gy mice lying on the same line (r = 0.86; p < 0.0001). In summary, when Hyp and Gy mice are studied on the same genetic background and fed the same diet, similar responses are seen in PTH levels and 1,25-dihydroxyvitamin D levels. Both mutants should be useful in elucidating the pathophysiology of this poorly understood human disease.

Topics: Alkaline Phosphatase; Analysis of Variance; Animals; Bone Diseases, Metabolic; Calcium; Calcium, Dietary; Diet; Female; Genetic Linkage; Hypophosphatemia; Mice; Mice, Mutant Strains; Parathyroid Hormone; Phosphates; Random Allocation; Vitamin D; X Chromosome