osteoprotegerin and Vitamin-D-Deficiency

Disorders of bone and mineral metabolism affect almost all patients with advanced chronic kidney disease (CKD). High prevalence of decreased bone mineral density has been reported in this population; however, the role and diagnostic utility of bone density measurements are not well established. The incidence of bone fractures is high in patients with ESRD, but the association between fractures and bone density is not obvious. A recent meta-analysis suggested that decreased density at the radius might be associated with higher overall fracture risk. Changes in bone mineral density reflect several underlying pathological processes, such as vitamin D deficiency, estrogen deficiency and changes in bone turnover. The response of bone to these factors and processes is not uniform: it can vary in different compartments of the same bone or in different bones of the skeleton. Therefore, it is important to differentiate between the various types of bone. This may be possible by proper selection of the measurement site or using methods such as quantitative bone computed tomography. Previous studies used different methods and measured bone mineral density at diverse sites of the skeleton, which makes the comparison of their results very difficult. The association between changes in bone mineral metabolism and cardiovascular mortality is well known in ESRD patients. Studies also suggest that low bone density itself might be an indicator for high risk of cardiovascular events and poor overall outcome in this population. Some of the risk factors of low bone mineral density, such as vitamin D or estrogen deficiency, are potentially modifiable. Further studies are needed to elucidate if interventions modifying these risk factors will have an impact on clinical outcomes. In this review, we discuss the options for and problems of assessment of bone density and summarize the literature about factors associated with low bone density and its link to clinical outcomes in patients on maintenance dialysis.

Topics: Absorptiometry, Photon; Bone Density; Chronic Kidney Disease-Mineral and Bone Disorder; Estrogens; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fractures, Spontaneous; Humans; Kidney Failure, Chronic; Osteoprotegerin; Parathyroid Hormone; Peritoneal Dialysis; Renal Dialysis; Risk Factors; Vitamin D Deficiency

Magnesium (Mg) is the second most abundant intracellular cation where it plays an important role in enzyme function and trans-membrane ion transport. Mg deficiency has been associated with a number of clinical disorders including osteoporosis. Osteoporosis is common problem accounting for 2 million fractures per year in the United States at a cost of over $17 billion dollars. The average dietary Mg intake in women is 68% of the RDA, indicating that a large proportion of our population has substantial dietary Mg deficits. The objective of this paper is to review the evidence for Mg deficiency-induced osteoporosis and potential reasons why this occurs, including a cumulative review of work in our laboratories and well as a review of other published studies linking Mg deficiency to osteoporosis. Epidemiological studies have linked dietary Mg deficiency to osteoporosis. As diets deficient in Mg are also deficient in other nutrients that may affect bone, studies have been carried out with select dietary Mg depletion in animal models. Severe Mg deficiency in the rat (Mg at <0.0002% of total diet; normal = 0.05%) causes impaired bone growth, osteopenia and skeletal fragility. This degree of Mg deficiency probably does not commonly exist in the human population. We have therefore induced dietary Mg deprivation in the rat at 10%, 25% and 50% of recommended nutrient requirement. We observed bone loss, decrease in osteoblasts, and an increase in osteoclasts by histomorphometry. Such reduced Mg intake levels are present in our population. We also investigated potential mechanisms for bone loss in Mg deficiency. Studies in humans and and our rat model demonstrated low serum parathyroid hormone (PTH) and 1,25(OH)(2)-vitamin D levels, which may contribute to reduced bone formation. It is known that cytokines can increase osteoclastic bone resorption. Mg deficiency in the rat and/or mouse results in increased skeletal substance P, which in turn stimulates production of cytokines. With the use of immunohistocytochemistry, we found that Mg deficiency resulted in an increase in substance P, TNFalpha and IL1beta. Additional studies assessing the relative presence of receptor activator of nuclear factor kB ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG), found a decrease in OPG and an increase in RANKL favoring an increase in bone resorption. These data support the notion at dietary Mg intake at levels not uncommon in humans may perturb bone and mineral metabolis

Topics: Animals; Bone and Bones; Bone Resorption; Disease Models, Animal; Female; Humans; Magnesium; Magnesium Deficiency; Osteoporosis; Osteoprotegerin; Parathyroid Hormone; Prevalence; RANK Ligand; Rats; Vitamin D Deficiency

Osteoporosis is a disorder in which loss of bone strength leads to fragility fractures. This review examines the fundamental pathogenetic mechanisms underlying this disorder, which include: (a) failure to achieve a skeleton of optimal strength during growth and development; (b) excessive bone resorption resulting in loss of bone mass and disruption of architecture; and (c) failure to replace lost bone due to defects in bone formation. Estrogen deficiency is known to play a critical role in the development of osteoporosis, while calcium and vitamin D deficiencies and secondary hyperparathyroidism also contribute. There are multiple mechanisms underlying the regulation of bone remodeling, and these involve not only the osteoblastic and osteoclastic cell lineages but also other marrow cells, in addition to the interaction of systemic hormones, local cytokines, growth factors, and transcription factors. Polymorphisms of a large number of genes have been associated with differences in bone mass and fragility. It is now possible to diagnose osteoporosis, assess fracture risk, and reduce that risk with antiresorptive or other available therapies. However, new and more effective approaches are likely to emerge from a better understanding of the regulators of bone cell function.

Topics: Animals; Bone and Bones; Bone Density; Bone Remodeling; Calcium; Cell Differentiation; Collagen; Estrogens; Fractures, Bone; Glycoproteins; Hematopoietic Stem Cells; Hormones; Humans; Leptin; Ligands; Mice; Models, Biological; Neurons; NF-kappa B; Nitric Oxide; Osteoblasts; Osteoporosis; Osteoporosis, Postmenopausal; Osteoprotegerin; Parathyroid Hormone; Prostaglandins; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vitamin D; Vitamin D Deficiency

Vitamin D deficiency is common in peritoneal dialysis (PD) patients, so its supplementation has been advocated as potentially beneficial.. Double-blind, placebo-controlled, randomized clinical trial. Subjects on PD treated with high calcium peritoneal dialysate (Ca 3.5 mEq/l) and serum levels of 25-hydroxi vitamin D (25D) < 20 ng/ml were randomized to receive cholecalciferol (4800 IU/daily) or placebo for 16 weeks. The outcome measures were the effects on the osteogenic biomarkers osteoprotegerin (primary endpoint), intact fibroblast growth factor-23 (iFGF23), osteocalcin, osteopontin, iPTH, 1,25-dyhydroxivitamin D (1,25D), and interleukin-6.. Fifty-eight subjects were randomly assigned. Baseline characteristics were similar in both groups. Cholecalciferol supplemented subjects had a significant increase in serum 25D (from 11.4 ± 5.0 to 28.3 ± 10.3 ng/ml), 1,25D and iFGF23 compared with placebo group. iFGF23 levels increased an average of 10,875 pg/ml per month (95% CI 11,778-88,414) in the cholecalciferol group and was unchanged in the placebo group (2829 pg/ml, 95% CI - 2181 to 14,972). Extremely high iFGF23 levels (> 30,000 pg/ml) were observed in 74% of subjects receiving cholecalciferol although iFGF23 returned to baseline values after 32 weeks of withdrawal. The observed changes in iFGF23 correlated with 1,25D levels and were not modified by other variables. No difference was observed between groups in osteoprotegerin or other osteogenic biomarkers levels.. Cholecalciferol supplementation increases serum 25D levels in subjects on PD exposed to high calcium dialysate, yet it induces an exponential increase of iFGF23 in most patients, which disappear after withdrawal of supplementation and may be a major concern for this maneuver.

Topics: Adult; Aged; Biomarkers; Carotid Intima-Media Thickness; Cholecalciferol; Dietary Supplements; Double-Blind Method; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Interleukin-6; Male; Middle Aged; Osteocalcin; Osteopontin; Osteoprotegerin; Parathyroid Hormone; Peritoneal Dialysis; Prospective Studies; Renal Insufficiency, Chronic; Vitamin D; Vitamin D Deficiency; Vitamins

Our aim was to investigate any adverse effects of long-term valproic acid (VPA) therapy on bone biochemical markers in ambulatory children and adolescents with epilepsy, and the possible benefits of vitamin D supplementation on the same markers.. In this single center, the prospective interventional study levels of 25-hydroxyvitamin D (25OHD) and the bone turnover indices of Crosslaps (CTX), total alkaline phosphatase (tALP), osteoprotegerin (OPG), and the receptor activator for nuclear factor kB (RANK) ligand (sRANKL) were assessed before and after one year of vitamin D intake (400 IU/d) and were compared with those of clinically healthy controls. Fifty-four ambulatory children with mean (±standard deviation [SD]) age 9.0 ± 4.5 yrs on VPA (200-1200 mg/d) long-term monotherapy (mean: 3.2 ± 2.6 yrs) were studied, before and after a year's vitamin D intake (400 IU/d).. Nearly half of the cases were vitamin D insufficient/deficient with mean levels 23.1 ± 12.8 vs 31.8 ± 16.2 ng/mL of controls (p = 0.004) and after the year of vitamin D intake increased to 43.2 ± 21.7 ng/mL (p < 0.0001). In parallel, serum CTX and tALP had a decreasing trend approaching control levels but OPG and sRANKL did not change and were not different from controls. However, after vitamin D intake, a positive correlation was seen between 25OHD and OPG but not before.. The findings imply a higher bone turnover in the young patients on long-term VPA therapy that decreased after vitamin D intake.

Topics: Adolescent; Alkaline Phosphatase; Anticonvulsants; Biomarkers; Bone and Bones; Bone Remodeling; Child; Dietary Supplements; Epilepsy; Female; Humans; Hydroxycholecalciferols; Male; NF-kappa B; Osteoprotegerin; Prospective Studies; Valproic Acid; Vitamin D; Vitamin D Deficiency; Vitamins

Juvenile Paget's disease (JPD) is a rare heritable osteopathy characterized biochemically by markedly increased serum alkaline phosphatase (ALP) activity emanating from generalized acceleration of skeletal turnover. Affected infants and children typically suffer bone pain and fractures and deformities, become deaf, and have macrocranium. Some who survive to young adult life develop blindness from retinopathy engendered by vascular microcalcification. Most cases of JPD are caused by osteoprotegerin (OPG) deficiency due to homozygous loss-of-function mutations within the TNFRSF11B gene that encodes OPG. We report a 3-year-old Iranian girl with JPD and craniosynostosis who had vitamin D deficiency in infancy. She presented with fractures during the first year-of-life followed by bone deformities, delayed development, failure-to-thrive, and pneumonias. At 1 year-of-age, biochemical studies of serum revealed marked hyperphosphatasemia together with low-normal calcium and low inorganic phosphate and 25-hydroxyvitamin D levels. Several family members in previous generations of this consanguineous kindred may also have had JPD and vitamin D deficiency. Mutation analysis showed homozygosity for a unique missense change (c.130T>C, p.Cys44Arg) in TNFRSF11B that would compromise the cysteine-rich domain of OPG that binds receptor activator of NF-κB ligand (RANKL). Both parents were heterozygous for this mutation. The patient's serum OPG level was extremely low and RANKL level markedly elevated. She responded well to rapid oral vitamin D repletion followed by pamidronate treatment given intravenously. Our patient is the first Iranian reported with JPD. Her novel mutation in TNFRSF11B plus vitamin D deficiency in infancy was associated with severe JPD uniquely complicated by craniosynostosis. Pamidronate treatment with vitamin D sufficiency can be effective therapy for the skeletal disease caused by the OPG deficiency form of JPD.

Topics: Adult; Amino Acid Substitution; Bone Density Conservation Agents; Child, Preschool; Craniosynostoses; Diphosphonates; Female; Homozygote; Humans; Iran; Male; Mutation, Missense; Osteitis Deformans; Osteoprotegerin; Pamidronate; Pedigree; RANK Ligand; Vitamin D; Vitamin D Deficiency

Patients with locally advanced breast cancer treated with neoadjuvant chemotherapy are at risk of cancer treatment-induced bone loss and consequently of increased skeletal morbidity. In addition, this situation could be worsened by the fact that only a minority of patients with breast cancer have sufficient vitamin D. A comprehensive evaluation of bone homeostasis is critical in this context. We retrospectively evaluated the serum levels of calcium, vitamin D, TRAIL, RANK ligand (RANKL), Osteoprotegerin (OPG), Bone TRAP, CrossLaps and DKK1 in 77 patients (median age: 50 years; range 25-74), with locally advanced breast cancer treated in our institute with anthracyclines-taxane neoadjuvant chemotherapy (7 cycles of 21 days/each) between March 2007 and August 2008. Serum samples were collected before the first (baseline) and the last treatment cycle. Variations and correlations between biomarker levels were evaluated. At baseline, 79.5 % of patients had vitamin D insufficiency (<30 ng/ml), increasing to 97.4 % at the end of the neoadjuvant chemotherapy (p < 0.0001). Calcium and RANKL serum concentrations were also significantly decreased, while OPG was significantly increased, resulting in lower RANKL/OPG ratio. Calcium and vitamin D, RANKL and vitamin D and RANKL and OPG levels were significantly correlated (Spearman's coefficient r = 0.2721, p = 0.0006; r = 0.1916, p = 0.002; and r = -0.179, p = 0.03, respectively). Nearly all included patients suffered from vitamin D insufficiency by the end of the neoadjuvant chemotherapy with changes in the calcium/RANKL/OPG axis that are evocative of deregulation of a functional regulatory mechanism. Further studies are needed to determine how drugs modulate this regulatory mechanism to preserve bone homeostasis in patients with breast cancer.

Topics: Acid Phosphatase; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Bone and Bones; Breast Neoplasms; Calcium; Carcinoma, Ductal, Breast; Chemotherapy, Adjuvant; Collagen; Cyclophosphamide; Docetaxel; Epirubicin; Female; Fluorouracil; Humans; Intercellular Signaling Peptides and Proteins; Isoenzymes; Middle Aged; Neoadjuvant Therapy; Osteoprotegerin; Peptide Fragments; Prevalence; RANK Ligand; Retrospective Studies; Statistics, Nonparametric; Tartrate-Resistant Acid Phosphatase; Taxoids; TNF-Related Apoptosis-Inducing Ligand; Vitamin D; Vitamin D Deficiency

Vitamin D is considered as an important determinant of bone turnover as well as cancer growth. Using a murine model of bone metastasis, we investigated the effect of vitamin D deficiency on prostate cancer cell growth in bone.. Three-week-old male nude mice were fed either normal chow (control) or a diet deficient in vitamin D. The latter diet resulted in severe hypovitaminosis D within 6 weeks. At this point of time, 5 × 10(4)  cells of the prostate cancer cell line, PC-3, were injected either into the bone marrow (tibia) or subcutaneously into soft tissues. Osteoprotegerin (OPG) was co-administered in subgroups of mice to suppress bone remodeling. Osteolytic lesions were monitored by serial X-ray, while soft tissue tumor growth was measured by caliper. All tissues were analyzed by micro-CT and histology at endpoint.. Bone turnover was significantly accelerated in vitamin D deficient compared to vitamin D sufficient mice from week 6 onwards. Intra-tibially implanted PC-3 cells resulted in mixed osteolytic and osteosclerotic lesion. At endpoint, osteolytic and osteosclerotic lesion areas, total tumor area, and tumor mitotic activity were all significantly increased in vitamin D deficient mice compared to controls. Regardless of diet, OPG reduced bone turnover, total tumor, and osteosclerotic area as well as tumor mitotic activity, while promoting cell apoptosis. In contrast, vitamin D deficiency did not alter tumor growth in soft tissues.. Vitamin D deficiency stimulates prostate cancer growth in bone through modulating the bone microenvironment.

Topics: Acid Phosphatase; Animals; Bone Neoplasms; Bone Remodeling; Calcitriol; Cell Line, Tumor; Histocytochemistry; Isoenzymes; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Osteoprotegerin; Peptide Fragments; Procollagen; Prostatic Neoplasms; Specific Pathogen-Free Organisms; Tartrate-Resistant Acid Phosphatase; Tomography, X-Ray Computed; Vitamin D; Vitamin D Deficiency

Vitamin D exerts antiproliferative, prodifferentiation, and proapoptotic effects on nonclassic target tissues such as breast. Blood levels of 25-hydroxyvitamin D [25(OH)D], the most sensitive indicator of vitamin D status, are inversely correlated with breast cancer risk; however, a causal relationship between vitamin D deficiency and breast cancer growth in bone has not been assessed. We examined the effect of vitamin D deficiency on the intraskeletal growth of the human breast cancer cell line MDA-MB-231-TxSA in a murine model of malignant bone lesions. Subsets of mice were treated concurrently with osteoprotegerin (OPG) to abrogate bone resorption. Outcomes were assessed by repeated radiographic and end-point micro-computed tomography and histologic analyses. Mice weaned onto a vitamin D-free diet developed vitamin D deficiency within 4 weeks [mean +/- SE serum 25(OH)D: 11.5 +/- 0.5 nmol/L], which was sustained throughout the study and was associated with secondary hyperparathyroidism and accelerated bone turnover. Osteolytic lesions appeared earlier and were significantly larger in vitamin D-deficient than in vitamin D-sufficient mice after 2 weeks (radiographic osteolysis: +121.5%; histologic tumor area: +314%; P < 0.05). Although OPG treatment reduced the size of radiographic osteolyses and tumor area in both groups, tumors remained larger in OPG-treated vitamin D-deficient compared with OPG-treated vitamin D-sufficient mice (0.53 +/- 0.05 mm(2) versus 0.19 +/- 0.05 mm2; P < 0.05). We conclude that vitamin D deficiency promotes the growth of human breast cancer cells in the bones of nude mice. These effects are partly mediated through secondary changes in the bone microenvironment, along with direct effects of vitamin D on tumor growth.

Topics: Animals; Bone Neoplasms; Bone Resorption; Breast Neoplasms; Calcifediol; Calcitriol; Cell Growth Processes; Cell Line, Tumor; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Osteoprotegerin; Steroid Hydroxylases; Transplantation, Heterologous; Vitamin D; Vitamin D Deficiency; Vitamin D3 24-Hydroxylase

Previous studies revealed some comorbidity of Alzheimer's disease and osteoporosis not only for advanced disease, but also for the incipient conditions cognitive decline and decline of bone mineral density. To detect comorbidity with osteoporosis at a subclinical level, we studied concentrations of biochemical osteoporosis markers in blood plasma of subjects with mild cognitive impairment and mild Alzheimer's disease compared to subjects with primary osteoporosis and age-matched cognitively normal controls in an explorative approach. Regarding disease-spanning molecular pathology we also studied osteoprotegerin, a decoy receptor of RANKL and TRAIL. Equally increased C-terminal collagen fragments, marking bone catabolism, were seen in osteoporosis and Alzheimer's disease (+68%) versus controls. Osteocalcin, marking bone remodelling and anabolism, was concomitantly increased in osteoporosis (+63%), as a trend, and significantly in Alzheimer's disease (+76%). Osteoprotegerin was unchanged between patient groups and controls. 25 (OH) vitamin D plasma levels were low normal and of equal amount in all groups except for the osteoporosis group. These results point to increased bone catabolism and concomitant remodelling/anabolism unrelated to vitamin D state in mild Alzheimer's disease, but not in mild cognitive impairment. This corroborates previous findings of comorbidity of Alzheimer's disease with osteoporosis in the early disease course at the level of biochemical blood markers. Regarding osteoprotegerin, previously reported plasma level increases in Alzheimer's disease were not observed in this study, which does not rule out subtle changes to be detected in larger samples or the possibility that other components of osteoprotegerin pathways are affected in Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Bone and Bones; Bone Remodeling; Cognition Disorders; Collagen; Comorbidity; Female; Humans; Male; Middle Aged; Osteocalcin; Osteoporosis; Osteoprotegerin; Peptide Fragments; Predictive Value of Tests; Sensitivity and Specificity; Vitamin D; Vitamin D Deficiency

To characterize osteoprotegerin (OPG) levels, bone remodelling and bone mineral density (BMD) in heavily pretreated HIV-infected patients on antiretroviral therapy, and to evaluate the clinical factors associated with bone density decline.. Heavily pretreated (> 5 years) HIV-positive patients were enrolled in this cross-sectional, observational study, which was based on a total body bone densitometry examination and a comprehensive evaluation of bone and mineral parameters.. Sixty-eight patients (55 male and 13 female) with a median age of 41 years (range 25-60 years) were included in the study. Their antiretroviral treatment lasted for 82 months. On the basis of the World Health Organization criteria, nine patients (13.2%) were osteoporotic [T-score < -2.5 standard deviation (SD)] and 19 patients (27.9%) were osteopenic (T-score between -1 and -2.5). The principal outcomes associated with the presence of a low BMD were high OPG and lysylpyridinoline/creatinine ratio (Dpd) values. Most of the patients (39 of 48; 81.25%) showed vitamin D insufficiency [Vitamin D (25(OH)D) < 18 ng/mL] with secondary hyperparathyroidism (13 of 50 patients: 26%), which proved to be correlated to osteocalcin (BGP) levels [parathyroid hormone (PTH) vs. BGP: r = 0.34; P < 0.01]. There was an inverse correlation between T-scores and serum osteocalcin and alkaline phosphatase (AP) levels, on one hand, and Dpd, on the other. High AP and Dpd values were associated with relative risks of 4.1 [95% confidence interval (CI) = 1.01-17.6] and 7.2 (95% CI = 1.67-31.03), respectively, of a pathological T-score. Multivariate analysis revealed that the factors associated with the presence of osteopenia or osteoporosis were older age and lower body mass index.. About 40% of our heavily pretreated subjects with advanced HIV infection had a low BMD, and 56% (24 of 44 patients) showed a high bone turnover rate with marked osteoclast activation. High OPG levels may protect against bone resorption.

Topics: Adult; Age Factors; Alkaline Phosphatase; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biomarkers; Body Mass Index; Bone Diseases, Metabolic; Bone Remodeling; Creatine; Cross-Sectional Studies; Female; Glycoproteins; HIV Infections; Humans; Hyperparathyroidism, Secondary; Lymphocyte Count; Male; Middle Aged; Multivariate Analysis; Osteocalcin; Osteoporosis; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; T-Lymphocytes; Time Factors; Vitamin D Deficiency