osteoprotegerin and Chronic-Kidney-Disease-Mineral-and-Bone-Disorder

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

Patients with end-stage renal disease (ESRD) develop various kinds of abnormalities in bone and mineral metabolism, widely known as renal osteodystrophy (ROD). Although the pathogenesis of ESRD may be similar in many patients, the response of the bone varies widely, ranging from high to low turnover. ROD is classified into several types, depending on the status of bone turnover, by histomorphometric analysis using bone biopsy samples [1,2]. In the mild type, bone metabolism is closest to that of persons with normal renal function. In osteitis fibrosa, bone turnover is abnormally activated. This is a condition of high-turnover bone. A portion of the calcified bone loses its lamellar structure and appears as woven bone. In the cortical bone also, bone resorption by osteoclasts is active, and a general picture of bone marrow tissue infiltration and the formation of cancellous bone can be observed. In osteomalacia, the bone surface is covered with uncalcified osteoid. This condition is induced by aluminum accumulation or vitamin D deficiency. The mixed type possesses characteristics of both osteitis fibrosa and osteomalacia. The bone turnover is so markedly accelerated that calcification of the osteoid cannot keep pace. In the adynamic bone type, bone resorption and bone formation are both lowered. While bone turnover is decreased, there is little osteoid. The existence of these various types probably accounts for the diversity in degree of renal impairment, serum parathyroid hormone (PTH) level, and serum vitamin D level in patients with ROD. However, all patients share a common factor, i.e., the presence of a uremic condition.

Topics: Aluminum; Bone and Bones; Bone Diseases; Bone Resorption; Chronic Kidney Disease-Mineral and Bone Disorder; Glycoproteins; Humans; Indican; Osteitis Fibrosa Cystica; Osteoprotegerin; Parathyroid Hormone; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Toxins, Biological; Uremia; Vitamin D

The idiom renal osteodystrophy (ROD) represents a heterogeneous pattern of bone disturbances caused by chronic renal insufficiency and concomitant diseases. For the clinical decision of therapy it is most important to differentiate between high and low or adynamic turnover ROD because the therapeutically consequences of these two ends of the ROD spectrum are fundamentally different. Bone histology remains the gold standard for the exact classification of ROD. Serological markers of bone metabolism are not suited for the accurate nomenclature of ROD but are useful for the sequential follow up of ROD after a clear diagnosis has been made. Similarly, radiological diagnosis of ROD using dual energy X-ray absorptiometry (DEXA) or quantitative computer tomography scan (q-CT) is inaccurate and thus more suited for the routine follow up of established disease. Besides mineralization, bone strength and the rate of fractures are strongly determined by the architecture of the bone matrix. This information, however, is also only available on bone biopsy sections and cannot be estimated by non-invasive diagnostic methods. In summary, bone biopsy should be used more liberally for correct classification of bone disease. The sequential follow up and guidance of therapy success can be performed by non-invasive procedures such as biochemical bone marker determination in blood. X-ray imaging and densitometry is suitable only for sequential evaluation of osteoporosis.

Topics: Acid Phosphatase; Alkaline Phosphatase; Biomarkers; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Resorption; Chronic Kidney Disease-Mineral and Bone Disorder; Collagen Type I; Humans; Isoenzymes; Osteocalcin; Osteogenesis; Osteoprotegerin; Parathyroid Hormone; Radiography; Risk Factors; Tartrate-Resistant Acid Phosphatase; Transforming Growth Factor beta

The relationship between bone and the kidney in renal osteodystrophy is a complex interplay of kidney to bone connections, bone to kidney connections, and cell to cell connections. In addition, such interactions have a profound effect on the vasculature. In this review, we discuss the role of the bone morphogenetic proteins (BMPs) in the skeleton, kidney, and vasculature. In addition, we propose that deficiencies of these BMPs seen in chronic kidney disease (CKD) result in decreased bone remodeling and a compensatory secondary hyperparathyroidism (high turnover state). Treatment of the hyperparathyroidism blocks this compensatory arm and thus decreased bone remodeling occurs (low turnover). We review animal models of CKD in which treatment with BMP-7 resulted in normalization of both high and low turnover states. Finally, we discuss vascular calcification as it relates to bone metabolism. We discuss the roles of BMP-7 and 2 other bone regulatory proteins, osteoprotegerin (OPG) and alpha2-HS glycoprotein (AHSG, human fetuin), in the human vasculature and their implications for vascular calcification.

Topics: Bone Morphogenetic Proteins; Bone Remodeling; Cell Communication; Chronic Kidney Disease-Mineral and Bone Disorder; Glycoproteins; Humans; Kidney; Muscle, Smooth, Vascular; Osteoprotegerin; Parathyroid Hormone; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

The pathogenesis of adynamic bone disease (ABD) attributes to calcium overload, active vitamin D (VD) metabolism, increase in inactive PTH (parathyroid hormone) fragments, or derangement of bone metabolism regulation factors. In particular, increased Ca overload plays a critical role in the development of ABD. Thus, alleviated Ca load by sevelamer hydrochloride and appropriate VD administration could be effective on not only prevention, and also treatment of ABD.

Topics: Animals; Bone and Bones; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcium; Carrier Proteins; Chronic Kidney Disease-Mineral and Bone Disorder; Cinacalcet; Epoxy Compounds; Glycoproteins; Humans; Hyperparathyroidism, Secondary; Membrane Glycoproteins; Naphthalenes; Osteoprotegerin; Parathyroid Hormone; Polyamines; Polyethylenes; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Calcitriol; Receptors, Calcium-Sensing; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk; Sevelamer; Transforming Growth Factor beta; Vitamin D

The abnormal metabolism of calcium and bone is one of the most common complications seen in chronic dialysis patients. The activity of PTH has been mainly assessed by intact PTH assay; however, recent data suggest that this assay may overestimate PTH activity by detecting 7-84 PTH fragments in addition to 1-84 PTH molecules(whole PTH). Another issue in this field is that higher levels of PTH are needed to maintain normal bone turnover in uremic patients. Accumulated osteoprotegerin in uremic serum may be responsible for this skeletal resistance to PTH.

Topics: Biomarkers; Bone and Bones; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Glycoproteins; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Osteoprotegerin; Parathyroid Hormone; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis; Uremia

Topics: Bone Development; Bone Remodeling; Carrier Proteins; Chronic Kidney Disease-Mineral and Bone Disorder; Cytokines; Glycoproteins; Growth Substances; Humans; Membrane Glycoproteins; Osteoblasts; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Signal Transduction

Chronic kidney disease-mineral and bone disorder is a common complication in hemodialysis patients. The present study was designed to investigate the effects of flaxseed oil, a rich source of plant omega-3 fatty acid alpha-linolenic acid, on serum markers of bone formation and resorption in hemodialysis patients.. In this randomized controlled trial, 34 hemodialysis patients were randomly assigned to either the flaxseed oil or the control group. The patients in the flaxseed oil group received 6 g/d of flaxseed oil for 8 weeks, whereas the control group received 6 g/d of medium chain triglycerides oil. At baseline and the end of the 8th week, 7 mL of blood was obtained from each patient after a 12- to 14-hour fast and serum concentrations of osteocalcin, osteoprotegerin, N-telopeptide, and receptor activator of nuclear factor kappa B ligand were measured.. Serum N-telopeptide concentration decreased significantly up to 17% in the flaxseed oil group at the end of week 8, as compared to baseline (P < .01), and the reduction was significant in comparison with the control group. There were no significant differences between the two groups in the mean changes of serum osteocalcin, osteoprotegerin, or receptor activator of nuclear factor kappa B ligand.. This study indicates that daily consumption of 6 g/d of flaxseed oil may reduce bone resorption in hemodialysis patients.

Topics: Aged; Biomarkers; Bone Remodeling; Bone Resorption; Chronic Kidney Disease-Mineral and Bone Disorder; Collagen Type I; Dietary Supplements; Double-Blind Method; Female; Humans; Iran; Linseed Oil; Male; Middle Aged; Osteocalcin; Osteoprotegerin; Peptides; RANK Ligand; Renal Dialysis; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome

Chronic Kidney Disease (CKD)-Mineral and Bone Disorder (CKD-MBD) is a complex disease that is not completely understood. However, some factors secreted by the osteocytes might play an important role in its pathophysiology. Therefore, we evaluated the bone expression of proteins in a group of patients with CKD 2-3, CKD 4, and CKD 5 on dialysis and healthy individuals. We also tested several bone remodeling markers, and correlated these levels with bone biopsy findings. As expected, as serum calcium decreased, serum phosphate, alkaline phosphatase, fibroblast growth factor-23 (FGF-23), parathyroid hormone, and osteoprotegerin increased, as CKD progressed. Additionally, there was a gradual increase in bone resorption associated with a decrease in bone formation and impairment in bone mineralization. Bone expression of sclerostin and parathyroid hormone receptor-1 seemed to be increased in earlier stages of CKD, whereas FGF-23 and phosphorylated β-catenin had increased expression in the late stages of CKD, although all these proteins were elevated relative to healthy individuals. Immunohistochemical studies showed that FGF-23 and sclerostin did not co-localize, suggesting that distinct osteocytes produce these proteins. Moreover, there was a good correlation between serum levels and bone expression of FGF-23. Thus, our studies help define the complex mechanism of bone and mineral metabolism in patients with CKD. Linkage of serum markers to bone expression of specific proteins may facilitate our understanding and management of this disease.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; beta Catenin; Biomarkers; Biopsy; Bone and Bones; Bone Morphogenetic Proteins; Bone Remodeling; Calcium; Case-Control Studies; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Genetic Markers; Humans; Male; Middle Aged; Osteocytes; Osteoprotegerin; Parathyroid Hormone; Phosphorylation; Receptor, Parathyroid Hormone, Type 1; Renal Dialysis; Renal Insufficiency, Chronic; Severity of Illness Index

Chronic kidney disease-mineral and bone disorder (CKD-MBD) ranks among clinically and pathogenetically significant complications in patients with CKD. Numerous factors are involved in its development, and histomorphometric analysis of the bone tissue is still necessary for accurate diagnosis.. The open, pilot, prospective study aimed at performing a comprehensive histomorphometric bone analysis in 26 dialysis patients and assessing the relationships of different types of CKD-MBD to selected parameters of calcium and phosphate metabolism, densitometry, activity of parathyroid glands, presence of diabetes mellitus, and duration of dialysis treatment.. Comparison of the histomorphometric characteristics demonstrated statistically significant correlations between the volume of bone trabeculae and s-procollagen 1 (.754) as well as s-calcitonin (.856). Similarly, there was a positive correlation between the size of tetracycline lines and volume of bone trabeculae (.705) and a strong negative correlation with the thickness of trabeculae (-.442). When assessing the serum levels of s-osteoprotegerin and serum RANKL, there was a correlation with osteoid thickness and bone trabeculae thickness. In case of s-osteoprotegerin, a statistical power was demonstrated in relation to osteoid thickness (.880); in case of s-RANKL, a statistical power was demonstrated in relation to the thickness of trabeculae (.830). When assessing the influence of dialysis duration, relationships to the volume of trabecular bone (.665) and volume of bone trabeculae (.949) were demonstrated. Finally, a relationship between s-1,25-hydroxyvitamin D and s-osteoprotegerin was observed (.739); also the relationships demonstrated were significantly lower volume of bone trabeculae in men (p = 0.067) and lower values of s-osteocalcin and s-procollagen 1 in diabetic patients (p = 0.014).. The results provide new noninvasive possibilities of CKD-MBD detection that are based on selected serum parameters of bone metabolism. Presented are possibilities of noninvasive assessment of different types of CKD-MBD using serum osteomarkers in relation to comprehensive CKD-MBD histomorphometry.

Topics: Aged; Biomarkers; Bone and Bones; Bone Density; Calcitriol; Calcium; Cardiovascular Diseases; Chronic Kidney Disease-Mineral and Bone Disorder; Czech Republic; Female; Humans; Kidney; Male; Osteocalcin; Osteoprotegerin; Parathyroid Hormone; Pilot Projects; Prospective Studies; RANK Ligand; Renal Dialysis; Renal Insufficiency, Chronic; Reproducibility of Results; Risk Factors

The increased awareness of the potential role played by mineral and bone disorder in the appearance of cardiovascular disease in renal patients has produced research efforts aimed at discovering possible pathogenic links. Accordingly, the diagnostic significance of the classic bone markers of mineral disorders and of the new markers in the setting of chronic kidney disease-mineral and bone disorders (CKD-MBD) needs to be re-evaluated along with increasing information. In this article we include classic markers of bone metabolism and some of the noncollagenous bone proteins that are gaining experimental and clinical significance in CKD-MBD. Among classic markers of secondary hyperparathyroidism and of renal osteodystrophy, we analyzed parathyroid hormone, alkaline phosphatase, tartrate-resistant acid phosphatase, and bone collagen-derived peptides. We underlined, for each, the relevance of parent proteins (peptides or isoforms) that affect assay methods and, eventually, the diagnostic or prognostic significance. Also, we considered their relationship with cardiovascular mortality. Among the numerous noncollagenous bone proteins, we examined matrix Gla protein (MGP), osteocalcin (OC), osteoprotegerin, and the small integrin-binding ligand N-linked glycoprotein family. For MGP and OC we report the relevant involvement with the process of calcification (MGP) and with glucose and energy metabolism (OC). Both of these proteins require vitamin K to become active and this is a specific problem in renal patients who frequently are deficient of this vitamin. Finally, recent acquisitions on the fascinating family of the small integrin-binding ligand N-linked glycoprotein proteins are recapitulated briefly to underline their potential clinical interest and their complex involvement with all aspects of CKD-MBD. Their diagnostic role in clinical practice awaits further studies.

Topics: Acid Phosphatase; Alkaline Phosphatase; Animals; Biomarkers; Calcium-Binding Proteins; Chronic Kidney Disease-Mineral and Bone Disorder; Extracellular Matrix Proteins; Humans; Hyperparathyroidism, Secondary; Isoenzymes; Matrix Gla Protein; Osteocalcin; Osteoprotegerin; Parathyroid Hormone; Peptide Fragments; Procollagen; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Renal Insufficiency, Chronic; Tartrate-Resistant Acid Phosphatase

Chronic kidney disease-mineral and bone disorder (CKD-MBD) has been proposed to be the replacement of renal osteodystrophy by the Organization of Kidney Disease: Improving Global Outcomes since 2005 because the mineral disorder is not confined to the skeleton in CKD. Accordingly, laboratory and imaging tests have been emphasized for the clinical assessment of patients with CKD besides renal biopsy. The objective of the current study was to investigate whether osteoprotegerin (OPG) could be made a useful biomarker for early diagnosis of CKD-MBD.. Sixty pre-dialysis patients with CKD 1-5 were enrolled in this study. The serum calcium, phosphorus, blood urea nitrogen, creatinine, alkaline phosphatase, Osteocalcin, Calcitonin, intact parathyroid hormone and OPG were measured. Bone mineral densities of the lumbar spine (L2-L4), femoral neck, Ward's triangle and trochanter were measured by dual-energy X-ray absorptiometry.. Among all measured serum bone metabolism indexes, the changing of serum OPG level happened at the earliest time (CKD 3) and its correlation coefficient with estimated glomerular filtration rate (eGFR) was also the highest (r = -0.601, P = 0.001). In the multivariable analysis that included sex, age and eGFR as controlling factors, the serum OPG correlated with the bone mineral density (BMD) of Ward's triangle (r = -0.390, P = 0.041).. Serum OPG may be a useful biomarker for early diagnosis of CKD-MBD.

Topics: Absorptiometry, Photon; Adult; Analysis of Variance; Biomarkers; Bone Density; China; Chronic Disease; Chronic Kidney Disease-Mineral and Bone Disorder; Early Diagnosis; Female; Femur; Femur Neck; Glomerular Filtration Rate; Humans; Kidney Diseases; Lumbar Vertebrae; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Risk Assessment; Risk Factors; Severity of Illness Index

Receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin are newly identified molecules that contribute to the modulation of bone remodeling. RANKL activates osteoclast function by binding to RANK in either a soluble or membrane-bound form, whereas osteoprotegerin (OPG) neutralizes its effects. The aim of this study is the evaluation of soluble RANKL (sRANKL)-OPG in cohorts of hemodialysis patients and the establishment of possible correlations between their serum levels and those of other biochemical markers. We measured intact parathyroid hormone (iPTH), osteocalcin (OC), OPG, alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) and sRANKL in 104 hemodialysis patients. The patients were studied as a whole and in two subgroups according to their bone turnover state. In patients with low serum levels of bone turnover markers (intact parathyroid hormone [iPTH] < 100 pg/mL, ALP < 100 U/L, TRAP < 4 U/L; 33 patients), the following correlations were found: (i) positive correlations of iPTH with RANKL (r = 0.394, P = 0.023) and RANKL/OPG ratio (r = 0.49, P = 0.004); (ii) a negative correlation between iPTH and OPG (r = -0.365, P = 0.037). The subgroup of patients with normal or high serum levels of bone turnover markers (iPTH >or= 150 pg/mL, ALP >or= 100 U/L, OC >or= 40 ng/mL; 19 patients) exhibited the following significant correlations: (i) a positive correlation between OPG and iPTH serum level (r = 0.649, P = 0.003); and (ii) a negative correlation between RANKL/OPG ratio and iPTH (r = -0.464, P = 0.045). In conclusion, the observation that PTH favors RANKL and inhibits OPG production was only demonstrated in the serum of hemodialysis patients in a low turnover state. The positive correlation between serum OPG and iPTH in normal or high turnover rates implies a homeostatic mechanism to limit bone resorption, probably associated with skeletal resistance to PTH.

Topics: Acid Phosphatase; Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Biomarkers; Bone Remodeling; Chronic Kidney Disease-Mineral and Bone Disorder; Cohort Studies; Female; Humans; Isoenzymes; Male; Middle Aged; Osteocalcin; Osteoprotegerin; Parathyroid Hormone; RANK Ligand; Renal Dialysis; Tartrate-Resistant Acid Phosphatase; Young Adult

We evaluated serum markers of bone turnover (BT) in patients suspected to have low bone turnover (LBT) given their serum level of intact parathyroid hormone (iPTH). Studies were carried out in 30 dialyzed patients. In 9 patients, iPTH was below 100 pg/mL (LBT group), and in 21, it was above 100 pg/mL (non-LBT group). Other measured laboratory parameters included serum concentrations of cyclase inactivating parathyroid hormone (CAP), osteoprotegerin (OPG), OPG ligand (OPGL), inorganic phosphates, total calcium, creatinine, urea, serum alkaline phosphatase (ALP) activity, and blood pH. The LBT group showed significantly lower levels of iPTH (39.0 +/- 30.7 pg/mL), CAP (23.2 +/- 16.9 pg/mL), cyclase inactive parathyroid hormone (CIP: 15.8 +/- 15.0 pg/mL), and total ALP (83.9 +/- 26.2 IU/L) than did the non-LBT group (393 +/- 304 pg/mL, 268 +/- 216 pg/mL, 126 +/- 96 pg/mL, and 202 +/- 167 IU/L respectively). We observed no significant differences between the groups in the other examined parameters. When results were adjusted for sex, age, and dialysis modality and duration, differences remained significant only for iPTH and CIP. Our data indicate that a serum CIP concentration below 25 pg/mL has a significance similar to that of an iPTH concentration below 100 pg/mL in determining which dialyzed patients likely have LBT.

Topics: Biomarkers; Bone Remodeling; Calcium; Carrier Proteins; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Glycoproteins; Humans; Kidney Failure, Chronic; Male; Membrane Glycoproteins; Osteoprotegerin; Parathyroid Hormone; Phosphates; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis

A newly identified cytokine, osteoprotegerin (OPG) appears to be involved in the regulation of bone remodeling. In vitro studies suggest that OPG, a soluble member of the TNF receptor family of proteins, inhibits osteoclastogenesis by interrupting the intercellular signaling between osteoblastic stromal cells and osteoclast progenitors. As patients with chronic renal failure (CRF) often have renal osteodystrophy (ROD), we investigated the role of osteoprotegerin (OPG) in ROD, and investigated whether there was any relationship between serum OPG, intact parathyroid (PTH) (iPTH), vitamin D, and trabecular bone. Serum OPG combined with iPTH might be a useful tool in the noninvasive diagnosis of ROD, at least in cases in which the range of PTH values compromises reliable diagnosis. Thirty-six patients on maintenance hemodiafiltration (HDF) and a control group of 36 age and sex matched healthy subjects with no known metabolic bone disease were studied. The following assays were made on serum: iPTH, osteocalcin (BGP), bone alkaline phosphatase, 25(OH)-cholecalciferol, calcium, phosphate, OPG, IGF-1, estradiol, and free testosterone. Serum Ca++, P, B-ALP, BGP, IGF-1, iPTH, and OPG levels were significantly higher in HDF patients than in controls, while DXA measurements and quantitative ultrasound (QUS) parameters were significantly lower. On grouping patients according to their mean OPG levels, we observed significantly lower serum IGF-1, vitamin D3 concentrations, and lumbar spine and hip bone mineral density in the high OPG groups. No correlation was found between OPG and bone turnover markers, whereas a negative correlation was found between serum OPG and IGF-1 levels (r=-0.64, p=0.032). Serum iPTH concentrations were positively correlated with bone alkaline phosphatase (B-ALP) (r=0.69, p=0.038) and BGP (r=0.92, p<0.001). The findings made suggest that an increase in OPG levels may be a compensatory response to elevated bone loss. The low bone mineral density (BMD) levels found in the high OPG group might have been due to the significant decrease in serum IGF-1 and vitamin D3 observed. In conclusion, the findings made in the present study demonstrate that increased OPG in hemodiafiltration patients is only partly due to decreased renal clearance. As it may partly reflect a compensatory response to increased bone loss, this parameter might be helpful in the identification of patients with a marked reduction in trabecular BMD.

Topics: Absorptiometry, Photon; Aged; Analysis of Variance; Biomarkers; Bone Density; Case-Control Studies; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Glycoproteins; Hemodiafiltration; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Probability; Prognosis; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reference Values; Risk Assessment; Sensitivity and Specificity

Bone turnover is regulated by local concentrations of cytokines such as osteoprotegerin (OPG) and receptor activator of nuclear factor kappaB ligand (RANKL). It is not known whether these cytokines can predict renal osteodystrophy in peritoneal dialysis (PD) patients. We measured serum levels of OPG, RANKL, intact parathyroid hormone (iPTH), calcium, phosphorus, and biologic parameters of bone turnover [carboxy-terminal propeptide of type I procollagen (PICP) and beta-crosslaps (betaCL)] in 21 PD patients and 42 healthy subjects matched for age and sex, who served as controls. Bone mineral density (BMD) was also evaluated (Z-scores) in the PD patients. Circulating levels of OPG were significantly higher in PD patients than in healthy subjects (p < 0.001). Mean levels of RANKL did not differ from normal. However, RANKL levels were increased in the group of patients with iPTH levels above 322 pg/mL. Biologic parameters of bone turnover (PICP and betaCL) were significantly increased in PD patients (p < 0.001). We found a positive correlation between serum levels of betaCL and iPTH. At several skeletal sites, betaCL also correlated with the BMD Z-score. No correlations were observed between OPG, RANKL, PICP, betaCL, CaxP, or time on dialysis. Circulating levels of OPG and RANKL do not reflect bone status in PD patients. The value of betaCL is a good marker of bone resorption that correlates with iPTH and BMD.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Bone Remodeling; Carrier Proteins; Chronic Kidney Disease-Mineral and Bone Disorder; Collagen; Cytokines; Female; Glycoproteins; Humans; Male; Membrane Glycoproteins; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Peptide Fragments; Peritoneal Dialysis; Procollagen; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Osteoclast function is important in the development of renal osteodystrophy (ROD). Osteoclast activity is modulated by the osteoprotegerin ligand-osteoprotegerin (OPGL/OPG) system. In the present study, we checked levels of serum OPG and soluble OPGL in dialyzed patients and correlated those levels with routinely measured parameters of bone metabolism. The study was carried out in 39 patients on hemodialysis (HD) and 29 on peritoneal dialysis (PD). The control group included 13 healthy volunteers. Patients on HD had lower OPGL (p = 0.027) and higher OPG (p = 0.000) levels than control subjects did [OPGL: 0.6 pmol/L (median) and 0.0 - 10.0 pmolL (range) vs. 1.9 pmo1/L (median) and 0.0 - 10.5 pmol/L (range); OPG: 7.7 pmol/L (median) and 0.9 - 16.5 pmol/L (range) vs. 2.2 pmol/L (median) and 1.0- 3.9 pmol/L (range)]. Patients on PD differed from controls only in OPG level [4.0 pmol/L (median) and 2.1 - 13.4 pmol/L (range), p = 0.043]. Patients on HD and on PD both had a lower OPGL/OPG ratio than did the control subjects [HD: 0.09 (median) and 0.00 - 1.45 (range), p = 0.000; PD: 0.35 (median) and 0.00 - 3.89 (range), p = 0.018; controls: 1.07 (median) and 0.00 - 5.14 (range)]. Patients on HD did not differ from patients on PD in levels of OPGL and OPGL/OPG, but they had a higher OPG level (p = 0.001). Patients on HD also showed significantly higher total alkaline phosphatase (ALP) activity and higher inorganic phosphate (iP), but lower total calcium and blood pH. In PD patients, OPGL and OPG both correlated with pH (OPGL positively and OPG negatively). In HD patients, OPGL showed a positive correlation with ALP and a negative correlation with calcium; OPG correlated positively with iP In 36 patients on HD (92.3%) and 15 patients on PD (51.7%), OPG was elevated above the normal value. Differences in serum OPG and OPGL/OPG ratio between groups of dialyzed patients and of control subjects indicate that ROD is more advanced in HD patients than in PD patients. Higher serum OPG and lower serum OPGL in the HD group is probably an effect of higher osteoclast activity. In about 50% of PD patients, osteoclast function is also disturbed, as indicated by elevated OPG levels.

Topics: Alkaline Phosphatase; Biomarkers; Calcium; Carrier Proteins; Chronic Kidney Disease-Mineral and Bone Disorder; Glycoproteins; Humans; Hydrogen-Ion Concentration; Membrane Glycoproteins; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Peritoneal Dialysis; Phosphates; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis

The hormone leptin is considered to have a role in the prevention of osteoporosis and probably acts on bone tissue through inhibition of osteoclasia. Its action has been attributed to interference in osteoprotegerin (OPG)/OPG-ligand equilibrium. Contradictory data also have been reported, casting doubts on the positive effect on bone mass of the hormone, at least in males. To date, the relation between serum leptin levels of dialysis patients and renal osteodystrophy, defined by histomorphometric and histodynamic parameters of bone, has not been studied.. The study included 46 hemodialysis patients (32 men, 14 women; age, 57.2 +/- 11.4 years). A transiliac bone biopsy after double-tetracycline labeling was performed for histological, histomorphometric, and histodynamic studies. Blood samples were drawn for leptin, intact parathyroid hormone (PTH), whole PTH (PTH1-84), OPG, bone alkaline phosphatase, calcium, phosphate, 25-hydroxycholecalciferol, and calcitriol. Serum leptin was measured by means of a radioimmunoassay.. Eighteen patients had mixed osteodystrophy (MO); 17 patients, hyperparathyroidism; 9 patients, adynamic bone disease (ABD); and 2 patients, osteomalacia. Aluminum histochemistry results were positive in 1 patient with ABD and 1 patient with MO. A sex difference was found in serum leptin levels (48.9 +/- 38 ng/mL in women and 12.2 +/- 13.2 ng/mL in men; P < 0.0002). In the entire population, lnleptin correlated significantly with body mass index (BMI; P < 0.01). SD score (SDS) leptin (adjusted for BMI, sex, and age) correlated inversely with PTH1-84 level and osteoclastic surface (OcS/BS; P < 0.05) and had a borderline correlation with bone formation rate. Correlations between leptin levels and other parameters were enhanced in men. SDS leptin correlated inversely with OcS/BS (P < 0.01), osteoclastic number (P < 0.01), and mineral apposition rate (P < 0.01). In addition, SDS leptin had a borderline inverse correlation with osteoblast surface (P < 0.06) and significant correlation with OPG level (P < 0.05). No difference was found in serum leptin levels between histological groups.. The reported data confirm the finding of a positive relation between serum leptin level and BMI and greater levels in women compared with men. Serum leptin level is connected to bone resorption and also bone formation, both inversely related to serum leptin levels. The decrease in osteoclasia that accompanies increasing serum leptin levels does not seem to be related to an enhanced OPG effect because it was accompanied by decreased OPG levels. Low-turnover bone disease does not appear to be caused by increased serum leptin levels. The nature of the interrelation between serum leptin and PTH1-84 levels requires further study.

Topics: Aged; Biomarkers; Body Mass Index; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Glycoproteins; Humans; Hyperthyroidism; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Osteomalacia; Osteoprotegerin; Parathyroid Hormone; Receptors, Cytoplasmic and Nuclear; Receptors, Leptin; Receptors, Tumor Necrosis Factor; Renal Dialysis; Sex Factors; Statistics as Topic

Recently identified soluble circulating osteoprotegerin (OPG), a member of tumor necrosis factor receptor family, is the osteoclastogenesis inhibitory factor (OCIF). It acts as a "decoy" receptor for receptor activator of NF-kappaB ligand (RANKL) and antagonises RANKL/RANK activity. This way OPG exerts the protective effect on bone, which is also important in hyperparathyroidism. The studies measuring OPG levels in secondary hyperparathyroidism have shown contradictory results and inconsistent conclusions. The aim of our work was to evaluate OPG levels in hemodialysis patients and their correlation with the intensity of bone turnover, bone formation and bone resorption. Serum OPG levels, bone alkaline phosphatase activity (bALP) and beta-CrossLaps (CTx) were measured in a control group (n = 20, age 30+/-6.7 years) and in two groups of dialysis patients: the first group with serum intact parathyroid hormone (iPTH) concentration below 200 pg/ml (n = 28, age 62.6+/-14.8 years) and the second group with iPTH concentration above 200 pg/ml (n = 16, age 63.7+/-14.8 years). Compared to controls, serum OPG levels were 6.4-fold higher in dialysis patients. OPG levels in patients with high PTH were approximately 1.2-fold higher than in the low-PTH group. OPG correlated weakly with bALP (r = 0.277, p = 0.153), as well as with CTx (r = 0.018, p = 0.929) in the low-PTH group, and there was an insignificant negative correlation in the high-PTH group (r = -0.145, p = 0.593 and r = -0.219, p = 0.416, respectively). In conclusion, 6.4-fold increase in OPG might protect bone against intensive bone loss in hemodialysis patients, but this increase is probably not mediated by the increased bone formation; rather, it seems to be the consequence of the imbalance of bone kinetics in renal disease. The precise role of OPG in the pathogenesis of renal osteodystrophy remains unknown and establishing it requires further studies.

Topics: Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Chronic Kidney Disease-Mineral and Bone Disorder; Collagen; Female; Glycoproteins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Peptide Fragments; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis

Numerous growth factors and cytokines are known to modulate bone turnover. An important, recently discovered complex involved in osteoclastogenesis is the osteoprotegerin/osteoprotegerin-ligand (OPG/OPGL) cytokine complex, which is produced by osteoblasts. Many factors, including parathyroid hormone (PTH), appear to affect bone turnover through this pathway. In this disorder, the role of the OPG/OPGL system in the pathogenesis of renal osteodystrophy, a disease with either low or high bone turnover, has not been investigated so far.. Thirty-nine chronic haemodialysis patients had bone biopsies, including histomorphometric and histodynamic examinations. In addition, the following serum biochemistry parameters were measured: serum OPG, intact PTH, PTH 1-84, total PTH, osteocalcin, total and bone alkaline phosphatases, 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol.. On average, serum OPG levels were above the normal range. They were lower in adynamic bone disease (ABD) patients, than in patients with predominant hyperparathyroidism (HP) or mixed osteodystrophy (MO). Significant negative correlations were found between serum OPG and PTH levels, and between serum OPG and parameters of bone resorption (ES/BS) and bone formation (ObS/BS and BFR/BS) in HP and MO patients with PTH values < or =1000 pg/ml. For intact PTH levels < or =300 pg/ml, serum OPG was significantly lower in the group with ABD than in those with HP or MO (P<0.05).. In renal osteodystrophy the OPG/OPGL system is involved in the regulation of bone turnover induced by PTH. The determination of serum OPG levels could be of use in the diagnosis of low turnover bone disease, at least in association with PTH levels < or =300 pg/ml.

Topics: Aged; Bone and Bones; Bone Remodeling; Bone Resorption; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Glycoproteins; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis

Osteoprotegerin (OPG) has a profound inhibitory effect on osteoclast differentiation and bone resorption. Because high-turnover renal osteodystrophy (ROD) is characterized by increased osteoclast activity, serum OPG concentrations might be used to distinguish between forms of ROD. Twenty-six patients on maintenance hemodialysis therapy underwent a transiliac crest biopsy for evaluation of histopathologic characteristics and histomorphometric studies. ROD was diagnosed as type II (normal or low turnover) or type III (high turnover plus osteoidosis) disease. Bone mineralization density distribution (BMDD) was characterized by measuring the mean trabecular calcium concentration in the biopsy specimen with quantitative backscattered electron imaging. Patients underwent additional dual-energy x-ray absorptiometry (DEXA) of the spine and hip and measurement of such biochemical markers of bone turnover as OPG, intact parathyroid hormone (iPTH), osteocalcin, calcitonin, bone alkaline phosphatase, and cross-laps. OPG levels were significantly reduced in patients with ROD III compared with ROD II (118 +/- 38 versus 204 +/- 130 pg/mL; P < 0.05) and correlated with BMDD (r = 0.43; P < 0.05). Patients with ROD III showed significantly lower BMDD compared with healthy controls (21.42% +/- 0.12% versus 22.17% +/- 0.81% weight; P < 0.01). Besides iPTH, which showed significantly greater levels in patients with ROD III than ROD II (382 +/- 322 versus 136 +/- 156 pg/mL; P < 0.05), none of the serological markers or DEXA was useful in separation of the groups. Discriminant function analysis showed that a combination of OPG and iPTH correctly classifies ROD II in 72% and ROD III in 88% of patients. We conclude that OPG in combination with iPTH can be used as a marker for noninvasive diagnosis of ROD in hemodialysis patients. Furthermore, OPG serum levels might be used to estimate trabecular bone mineralization in these subjects.

Topics: Biomarkers; Biopsy; Bone Density; Bone Resorption; Chronic Kidney Disease-Mineral and Bone Disorder; Glycoproteins; Humans; Osteoprotegerin; Parathyroid Hormone; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis; Statistics, Nonparametric