Role Of Parathyroid Hormone Research Articles

Prediagnostic Circulating Parathyroid Hormone Concentration and Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition Cohort

Parathyroid hormone (PTH) has been proposed to play a promoting role in carcinogenesis. However, no epidemiologic studies have yet directly investigated its role in colorectal cancer (CRC). A case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort was conducted with 1,214 incident, sporadic CRC cases matched to 1,214 controls. Circulating prediagnostic PTH and 25-hydroxy vitamin D [25(OH)D] concentrations were measured by enzyme-linked immunosorbent assays. Detailed dietary and lifestyle questionnaire data were collected at baseline. Multivariable conditional logistic regression was used to estimate the incidence rate ratio (RR) with 95% confidence intervals (95% CI) for the association between circulating PTH and CRC risk. In multivariate analyses [including adjustment for 25(OH)D concentration] with a priori defined cutoff points, high levels of serum PTH (≥65 ng/L) compared with medium PTH levels of 30-65 ng/L were associated with increased CRC risk (RR = 1.41, 95% CI: 1.03-1.93). In analyses by sex, the CRC risk was 1.77 (95% CI: 1.14-2.75) and 1.15 (95% CI: 0.73-1.84) in men and women, respectively (P(heterogeneity) = 0.01). In subgroup analyses by anatomical subsite, the risk for colon cancer was RR = 1.56, 95% CI: 1.03-2.34, and for rectal cancer RR = 1.20, 95% CI: 0.72-2.01 (P(heterogeneity) = 0.21). Effect modification by various risk factors was examined. The results of this study suggest that high serum PTH levels may be associated with incident, sporadic CRC in Western European populations, and in particular among men. To our knowledge, this is the first study on PTH and CRC. The role of PTH in carcinogenesis needs to be further investigated.

Overview paper: Complementary and overlapping role of Parathyroid Hormone (PTH) and PTH-related Protein (PTHrP) in regulating fetal mineral homeostasis

This review lecture will examine the available evidence about the roles of PTH and PTHrP in regulating mineral homeostasis during fetal development, and will demonstrate that these two hormones maintain interlocking, complementary, and at times overlapping roles. Each is unable to make up for loss of the other hormone. PTHrP is expressed within the growth plate, directs endochondral bone formation, and determines the fate of chondrocytes before bone formation can be initiated. It is expressed in placenta and is present at high levels in the fetal circulation. It stimulates placental calcium (and possibly magnesium) transfer, and raises blood minerals levels above ambient maternal values in order to effect mineralization of the skeleton. It does not upregulate in response to absence of PTH or hypocalcemia, and so its secretion may be regulated autonomously or in response to placental signals. Its actions on endochondral bone development require the PTH/PTHrP receptor (PTH1R); its actions on placental calcium transfer appear to require a midmolecular receptor; its actions to raise the blood calcium above the maternal level may require both receptors. PTH is expressed in fetal parathyroids and placenta. Despite circulating at low levels it has a more dominant effect than PTHrP in regulating the blood calcium and ensuring adequate mineralization of the skeleton by term. It probably does not affect the cartilaginous stages of endochondral bone development although it may influence bone formation in the steps that occur after the apoptosis of hypertrophic chondrocytes. Unlike PTHrP, it increases with fetal hypocalcemia, but its secretion is constrained by the calcium sensing receptor to maintain the adult calcium level, well below what the fetus normally achieves. PTH does have the ability to stimulate placental calcium transfer but whether this occurs normally or only in response to abnormal conditions (such as absence of PTHrP, or pharmacological treatment with PTH) remains unknown. Absence of PTH disrupts expression of calciotropic and other cation transporter genes within the placenta. All of the known actions of PTH require normal expression of the PTH1R. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared.

Abstract 5046: Antimyeloma effect of proteasome inhibition and Parathyroid Hormone pathway

Abstract Bone disease is a key feature in multiple myeloma (MM) and can impact substantially on patient morbidity and quality-of-life. Our recent studies have demonstrated specific serum Parathyroid Hormone (PTH) variations associated with proteasome inhibitor response in multiple myeloma patients. The rapid increase in PTH observed following bortezomib treatment suggests that the change in PTH could have triggered the significant osteoblastic response and bone anabolism. In this study we have tested the role of PTH and Parathyroid Hormone Receptor 1(PTHR1) after proteasome inhibition in vitro and in a mouse model.The effects of proteasome inhibition, PTH and {[TYR34]bPTH-(7-34)} compound (a specific PTH-(7-34) antagonist) were firstly evaluated at various concentrations and the same compounds and their combinations were also tested on C57BL/KaLwRij mouse model. Cell line viability, mice survival and myeloma response by serum IgG level were recorded. The 5TGM1 cell line was initially derived from a 5T33 myeloma cell line that arose spontaneously in aged C57BL/KaLwRij mice. The C57BL/KaLwRij mouse model is known for its spontaneous susceptibility to develop monoclonal gammopathies. The bone marrow of aging mice shows monoclonal expansion of plasmacells and skeletal radiography reveals osteoporosis with occasional osteolytic lesions. This model has been proved useful in studies on the effect of bisphosphonate in the treatment of bone disease in MM. The inoculation of 5TGM1 cells in the inbred C57BL/KaLwRij is able to rapidly induce a disease with similar features of human myeloma with severe osteolysis and Ig production and also with terminal involvement of nonbone organs including liver and kidney. We have first demonstrated the 5TGM1cell line is sensitivity to proteasome inhibition as well as PTH infusion in a dose-dependent fashion. 5TGM1 cells viability was not affected by exposure to {[TYR34]bPTH-(7-34)} peptide, a specific PTHR1inhibitor. We rather observed a suppression of bortezomib anti-myeloma effect when {[TYR34]bPTH-(7-34)} was used in combination (P = 0.0001).C57BL/KaLwRij mice treated with proteasome inhibitors showed a significantly prolonged survival benefit compared to controls (P = 0.04). When mice were concomitantly treated with a proteasome inhibitor and PTHR1 inhibitor, the survival benefit was completely abrogated. Similar results were observed in the serum IgG2b changes of the different cohorts of mice. The treatment with proteasome inhibitor, PTH or their combination induced a statistically significative decrease of IgG2b levels compared to controls (P = 0.02). These experiments strongly suggest that the proteasome inhibitory effect on myeloma growth in vitro and in mouse model is dependent on the PTHR1 pathway function. These data support a critical role of PTHR1 in the anti-myeloma effect associated with proteasome inhibition Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5046. doi:10.1158/1538-7445.AM2011-5046

Role of Parathyroid Hormone in Bone Fragility of Postmenopausal Women with Vitamin D Insufficiency

Vitamin D insufficiency is related to an increase in PTH, which might be critical for an increase in bone fragility. However, the role of endogenous PTH in vitamin D insufficiency-induced fracture risk remains unclear. The present study was performed to examine the relationships among vitamin D insufficiency, bone fragility, and PTH in 202 Japanese postmenopausal women. Serum 25-hydroxyvitamin D (25[OH]D) levels were measured. The percentages of subjects with 25(OH)D levels below 10, 15, and 20 ng/ml were 5.0, 41.0, and 80.7%, respectively. Serum 25(OH)D levels were negatively related to age and serum levels of Cr and PTH; they were positively related to bone mineral density (BMD). In multiple regression analysis, BMD was significantly related to 25(OH)D levels when adjusted for age, body mass index (BMI), and serum levels of Cr and PTH. Multiple logistic regression analysis showed that lower 25(OH)D levels were significantly related to prevalent fracture risk when adjusted for age, BMI, serum levels of Cr and PTH, as well as femoral neck BMD. The proportion of subjects with prevalent fractures was significantly higher in the group with lower PTH and lower 25(OH)D than in the group with lower PTH and higher 25(OH)D or higher PTH and higher 25(OH)D. In conclusion, vitamin D insufficiency was found to be related to prevalent fracture risk independently of PTH. Functional hypoparathyroidism, rather than functional hyperparathyroidism, might be a risk factor for bone fragility in vitamin D insufficiency.

Role of Parathyroid Hormone (PTH) and PTH-related Protein (PTHrP) in Regulating Mineral Homeostasis during Fetal Development

Parathyroid hormone (PTH) and PTH-related protein (PTHrP) play complementary and overlapping roles in regulating fetal mineral homeostasis. PTHrP is expressed within the growth plate, directs endochondral bone formation, and determines the fate of chondrocytes before bone formation can be initiated. It is expressed in placenta and is present at high levels in the fetal circulation. It stimulates placental calcium (and possibly magnesium) transfer and raises blood mineral levels above ambient maternal values in order to effect mineralization of the skeleton. It does not upregulate in response to absence of PTH or hypocalcemia, and thus, its secretion may be regulated autonomously or in response to placental signals. PTH is expressed in fetal parathyroids and placenta. Despite circulating at low levels, it has a more dominant effect than PTHrP in regulating the blood calcium and ensuring adequate mineralization of the skeleton. It may also have effects on bone formation in the steps that occur after apoptosis of hypertrophic chondrocytes. Unlike PTHrP, it increases with fetal hypocalcemia, but its secretion is constrained by the calcium-sensing receptor to maintain the adult calcium level, well below what the fetus normally achieves. PTH also stimulates placental calcium transfer, and its absence disrupts placental expression of calciotropic and cation transporter genes.

Effects of Parathyroid Hormone on Immune Function

Parathyroid hormone (PTH) function as immunologic mediator has become interesting with the recent usage of PTH analogue (teriparatide) in the management of osteoporosis. Since the early 1980s, PTH receptors were found on most immunologic cells (neutrophils, B and T cells). The in vitro evaluations for a possible role of PTH as immunomodulator have shown inconsistent results mainly due to methodological heterogeneity of these studies: it used different PTH formulations (rat, bovine, and human), at different dosages and different incubating periods. In some of these studies, the lymphocytes were collected from uremic patients or animals, which renders the interpretation of the results problematic due to the effect of uremic toxins. Parathyroidectomy has been found to reverse the immunologic defect in patients with high PTH levels. Nonetheless, the clinical significance of these findings is unclear. Further studies are needed to define if PTH does have immunomodulatory effects.

Elevation of PTH and PTHrp Induced by Excessive Fluoride in Rats on a Calcium-deficient Diet

Study on the role of parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrp) in the process of skeletal fluorosis, involved especially in calcium deficiency, is rare. We evaluated the level of serum PTH and mRNA expression of PTHrp in femur when rats were exposed to excessive fluoride with low-calcium diet. Wistar rats (n = 60) was divided into four groups, a control group, fluoride group, low-calcium group, and low-calcium fluoride group. The fluoride groups were treated with fluoride by drinking tap water containing 100 mg F-/L. The low-calcium diet contained 0.05% calcium. Serum was collected in the first, fourth, eighth, and 12th of phase for the detemination of PTH and Ca(2+). RNA extraction from femora was used to analyze the mRNA express of PTHrp, osteopontin (OPN), and osteocalcin (OCN) after 12 weeks of fluoride dosing. Results showed that serum PTH increased gradually with the extension of fluoride exposure, but Ca2+ decreased, both of which embodied a time-dependent relationship. Cotreatment of excessive fluoride with low-calcium diet largely stimulated the secretion of PTH. The low dietary calcium markedly increased mRNA expression of PTHrp in animals with fluoride treatment. Expression of OPN and OCN significantly increased in the rats treated with excessive fluoride and low-calcium diet. We demonstrated that fluoride by itself affected the body's calcium metabolism and stimulate the secretion of PTH. PTH may play an important role in anabolic effect of excessive fluoride on bone turnover of skeletal fluorosis and calcium deficiency exacerbated the action of PTH and PTHrp on the characteristic bone lesion of fluorosis.

Dual role of parathyroid hormone in endothelial progenitor cells and marrow stromal mesenchymal stem cells

Hematopoietic stem cells derive regulatory information also from parathyroid hormone (PTH). To explore the possibility that PTH may have a role in regulation of other stem cells residing in bone marrow, such as mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) we assessed the effect of this hormone on the in vitro behavior of MSCs and EPCs. We evidenced that MSCs were much more responsive to PTH than EPCs. PTH increased the proliferation rate of MSCs with a diminution of senescence and apoptosis. Taken together, our results may suggest a protective effect of PTH on MSCs that reduces stress phenomena and preserve genome integrity. At the opposite, PTH did not modify the fate of EPCs in culture.

Associations of Serum Concentrations of 25-Hydroxyvitamin D and Parathyroid Hormone With Surrogate Markers of Insulin Resistance Among U.S. Adults Without Physician-Diagnosed Diabetes: NHANES, 2003–2006

OBJECTIVETo examine whether concentrations of serum 25-hydroxyvitamin D (25[OH]D) and parathyroid hormone (PTH) are associated with surrogate markers of insulin resistance (IR) in U.S. adults without physician-diagnosed diabetes.RESEARCH DESIGN AND METHODSCross-sectional data (n = 3,206) from the National Health and Nutrition Examination Survey (NHANES) 2003–2006 were analyzed.RESULTSThe age-adjusted prevalence of hyperinsulinemia, high homeostasis model assessment-IR, high GHb, and fasting and 2-h hyperglycemia decreased linearly across quintiles of 25(OH)D but increased linearly across quintiles of PTH (except for a quadratic trend for fasting hyperglycemia). After extensive adjustment for potential confounders, the relationships between 25(OH)D and the markers of IR and 2-h hyperglycemia persisted. Only hyperinsulinemia was positively associated with PTH (P < 0.05).CONCLUSIONSAmong U.S. adults without physician-diagnosed diabetes, low concentrations of serum 25(OH)D were associated with markers of IR. The role of PTH in IR deserves further investigation.

Acute Hypocalcemia Enhances Prolactin Levels : A Study before and after Oophorectomy

The effect of acute hypocalcemia on serum prolactin values was investigated in 13 female subjects before and after oophorectomy. An infusion of disodium-EDTA (50 mg/kg b.w., for 120 min) was administered to each patient. Ionized calcium, immunoreactive parathyroid hormone and prolactin serum levels were determined 15 min prior to the infusion, at the beginning of each infusion and thereafter at every 30 min interval. The decrease in serum ionized calcium induced by Na2-EDTA infusion was not influenced by surgery. Serum prolactin and parathyroid hormone values before and after oophorectomy showed a significant (p less than 0.01) increase at 90 and 120 min. The maximum serum prolactin increase was achieved at 120 min and was not influenced by oophorectomy. The results demonstrate that acute hypocalcemia increases serum prolactin levels in female subjects and suggest a possible role for parathyroid hormone and dopaminergic system, even if their interaction remains speculative.

Identification and characterization of Runx2 phosphorylation sites involved in matrix metalloproteinase-13 promoter activation

Matrix metalloproteinase-13 (MMP-13) plays a critical role in parathyroid hormone (PTH)-induced bone resorption. PTH acts via protein kinase A (PKA) to phosphorylate and stimulate the transactivation of Runx2 for MMP-13 promoter activation. We show here that PTH stimulated Runx2 phosphorylation in rat osteoblastic cells. Runx2 was phosphorylated on serine 28 and threonine 340 after 8-bromo cyclic adenosine mono phosphate (8-Br-cAMP) treatment. We further demonstrate that in the presence of 8-Br-cAMP, the wild-type Runx2 construct stimulated MMP-13 promoter activity, while the Runx2 construct having mutations at three phosphorylation sites (S28, S347 and T340) was unable to stimulate MMP-13 promoter activity. Thus, we have identified the Runx2 phosphorylation sites necessary for PKA stimulated MMP-13 promoter activation and this event may be critical for bone remodeling.

The role of parathyroid hormone and insulin-like growth factors in hematopoietic niches: Physiology and pharmacology

Hematopoietic stem cells (HSC) capable of both self-renewal and differentiation into all blood lineages reside within the bone marrow in specialized microenvironmental niches. While the precise location and composition of these niches largely remains unknown, it is now believed that osteoblasts at the endosteal surface play critical roles. Among the molecules demonstrated to influence the function of these niches are parathyroid hormone (PTH) and the insulin-like growth factors (IGF). Administration of PTH to both mice and men expands the number of bone marrow HSC, and an increase in the number of those cells in peripheral blood following treatment with mobilizing agents. Several molecules downstream of PTH are capable of signaling to HSC, including IGF that appear to regulate both the survival and expansion of hematopoietic stem and progenitor cells. As our current understanding of the role for PTH and IGF in hematopoietic niches is limited, we believe it is important that both their physiological importance and pharmacological potential be more fully investigated.

Stem cell mobilization versus stem cell homing: potential role for parathyroid hormone?

Stem cells are considered as potential candidates to regenerate the injured myocardium. It has been shown that stem cells are able to differentiate into cardiomyocytes, as recently reviewed.2 It is still an open question, however, whether such myocytes contribute to the functional recovery of the post-infarcted heart. This process is limited by the small number of cells that differentiate into cardiomyocytes, the limited coupling of pre-existing cardiomyocytes to these newly formed myocytes, and the question whether the overall increases in ejection fractions indeed depend on the amount of cardiomyocytes newly formed by stem cells. A specific pattern of matrix proteins may be expressed by these cells, they may mediate anti-apoptotic effects, or they may improve vascularization independent of a possible differentiation into cardiomyocytes. Such effects may be modified by stem cells acting in a paracrine manner. Irrespective of these open questions, research is ongoing to develop treatment protocols that increase the number of systemic stem cells that home to the injured myocardium.3,4 Zaruba et al. 1 used a novel and innovative approach to improve the homing of bone marrow-derived stem cells, as described in their article in the current issue of Cardiovascular Research . They tried to improve bone marrow-derived stem cell mobilization by application of parathyroid hormone (PTH), which affects … *Corresponding author. Tel. +49 641 99 47222; fax +49 641 99 47239. E-mail address : klaus-dieter.schlueter{at}physiologie.med.uni-giessen.de

Relationship between Endogenous Parathyroid Hormone and Bone Metabolism/Geometry in Female Patients Treated with Glucocorticoid

Although the role of PTH (parathyroid hormone) has been debated in glucocorticoid (GC)-induced osteoporosis (GIO), clinical data about the relation of endogenous PTH to bone metabolism in patients treated with GC are still lacking. The present study was performed to examine the relationship of PTH to bone metabolic indices, bone mineral density (BMD), and bone geometry in 174 female patients treated with oral GC for more than 6 months. Dual-energy X-ray absorptiometry and peripheral quantitative computed tomography (pQCT) were employed for the assessment of BMD and bone geometry. No elevation of serum PTH levels was observed in patients treated with GC. Although serum levels of osteocalcin were not related to serum PTH levels, urinary levels of deoxypiridinoline were positively correlated. Serum PTH levels were negatively related to BMD at any site. In pQCT, serum PTH levels were negatively correlated to both trabecular and cortical volumetric BMD. As for bone morphometric indices, serum PTH levels were significantly related to endocortical circumferences, cortical thickness, and cortical area. Moreover, serum PTH levels were significantly higher in patients with vertebral fractures, compared with those without vertebral fractures in GC-treated patients. In the present study, serum PTH levels were related to the elevation of bone resorption marker, decreased BMD, cortical thinning, and an increase of vertebral fracture risk. The elevation of sensitivity to PTH in bone might play some role in the pathogenesis of GIO.

Parathyroid and bone. Role of parathyroid hormone in the treatment of osteoporosis

Parathyroid hormone (PTH) , a potent anabolic agent, produces larger increments in bone mass than those seen with antiresorptive agents. No further benefit is expected in PTH and antiresorptive combinations in treatment-naïve patients of osteoporosis, but in cases achieving the plateau level of BMD with established alendronate PTH can stimulate bone formation and increase BMD again. Alendronate treatment after PTH therapy can maintain gains in BMD at lumbar spine and hip as well. Many possibilities are expected in the role of PTH therapy in osteoporosis treatment.

Progress, Paradox, and Potential

With the advent of advances in chemical and molecular biology, the structure of parathyroid hormone (PTH); the related protein, parathyroid-related protein (PTHrP); and their principal receptor (PTH/PTHrP receptor [PTHR1]) were established over recent decades. Tests with purified hormonal peptide in humans led to the surprising, even paradoxical, finding that PTH can be used pharmacologically to build bone, providing a dramatic therapeutic impact on osteoporosis. These developments plus recent insights into previously unappreciated ligand-receptor conformations that cause prolonged biological activation have stimulated the field of calcium and bone biology and posed new questions about the role of PTH and PTHrP as well as possible new directions in the therapy of osteoporosis and calcium-deficit states.

The Role of Parathyroid Hormone as a Uremic Toxin: Current Concepts

The Role of Parathyroid Hormone as a Uremic Toxin: Current Concepts

Role of parathyroid hormone in the mechanosensitivity of fracture healing

The mechanical environment at a fracture site can influence the course of healing. Intermittent parathyroid hormone (PTH) has been shown to accelerate fracture healing. Intact bone models show that mechanical loading and PTH have a synergistic beneficial effect on osteogenesis. We hypothesized that PTH and mechanical loading would have a similar synergistic effect on fracture healing. Eighty mice underwent surgical osteotomy and intramedullary nailing of the tibia. The mice were divided into four groups: one underwent daily loading, one received daily subcutaneous PTH injections (30 microg/kg/day), one received both loading and PTH, and a control group received sham loading and vehicle injection. Daily loading was applied to the ends of the tibia with an external loading device for 2 weeks. Fracture healing was assessed by microcomputed tomography, histology, and biomechanical testing. The group with both loading and PTH had increased osteoblast and osteoclast activity and was the only group with a significantly larger callus mineral density and bone volume fraction. The PTH only group had significantly more osteoid in the callus compared to the control group, indicating enhanced early osteoblast activity. This group also had a significantly higher bone mineral content and total bone volume compared to controls. The group that received loading as the only intervention had significantly greater osteoclast activity versus controls. The contribution of loading and PTH administration to the fracture healing cascade indicates a synergistic effect. This finding may be of potential clinical utility when weight bearing is utilized to stimulate lower extremity fracture healing.

Full length parathyroid hormone (1?84) in the treatment of osteoporosis in postmenopausal women

To review the pharmacological properties and the available clinical data of full length parathyroid hormone (PTH) in post-menopausal osteoporosis. A MEDLINE search was completed, together with a review of information obtained from the manufacturer and from the medicine regulatory agencies. STUDY AND DATA SELECTION: Studies were selected according to relevance and availability. Relevant information (design, objectives, patients' characteristics, outcomes, adverse events, dosing, etc) was analyzed. Different studies have shown that, when administered intermittently as a subcutaneous injection in the abdomen, PTH increases bone mineral density (BMD) and prevents vertebral fractures. On completion of PTH therapy (up to 24 months), there is evidence that sequential treatment with alendronate is associated with a therapeutic benefit in terms of increase in BMD. Further trials are necessary to determine long-term safety and the role of PTH in combination with other treatments for osteoporosis and the effect of repeated cycles of PTH followed by an anti-catabolic agent. There are currently no completed comparative trials with other osteoporosis treatments. Full length PTH, given intermittently as an abdominal subcutaneous injection, appears to be a safe and efficacious treatment option for high risk osteoporosis. More data are needed to determine its specific role in osteoporosis treatment.

Bone Health in Chronic Kidney Disease–Mineral and Bone Disease

Chronic kidney disease (CKD) is accompanied by disturbances in calcium, phosphate, vitamin D, and parathyroid hormone (PTH) homeostasis that play an important role in the pathophysiology of renal bone disease. The increased cardiovascular morbidity and mortality observed among patients with CKD has recently been recognized to be associated with these disturbances in mineral metabolism. Thus, disturbances in mineral metabolism observed in renal failure results in a multisystem disorder, making the development of a standardized definition of these disorders a top priority. Therefore, the Board of Directors of Kidney Disease: Improving Global Outcomes proposed to define the broader category of mineral disorders associated with CKD as CKD-mineral and bone disorder (CKD-MBD). This newly proposed definition will include the disorders of mineral metabolism, bone histology (renal osteodystrophy), and the extraskeletal manifestations such as vascular calcification. This new definition and stratification of disease should result in improvement not only in the clinical management of patients but also will facilitate the interpretation and translation of clinical research. Renal osteodystrophy is now considered as 1 component of this disorder and will be defined as a morphologic alteration only, based on unification of the histomorphometric definitions that will include parameters of turnover, mineralization, and volume. An internationally accepted classification system will enable the consensus for bone biopsy evaluation as well as for the role of biomarkers. This article will focus on the newly proposed definitions of bone disease as part of CKD-MBD, based on the complex pathophysiologic process underlying bone disease in CKD stages 2 to 5.