Inhibition of tissue-nonspecific alkaline phosphatase protects against medial arterial calcification and improves survival probability in the CKD-MBD mouse model.

Medial arterial calcification (MAC) is a major complication of chronic kidney disease (CKD) and an indicator of poor prognosis. Aortic overexpression of tissue-nonspecific alkaline phosphatase (TNAP) accelerates MAC formation. The present study aimed to assess whether a TNAP inhibitor, SBI-425, protects against MAC and improves survival probability in a CKD-mineral and bone disorder (MBD) mouse model. CKD-MBD mice were divided in three groups: vehicle, SBI-10, and SBI-30. They were fed a 0.2% adenine and 0.8% phosphorus diet from 14 to 20 weeks of age to induce CKD, followed by a high-phosphorus (0.2% adenine and 1.8% phosphorus) diet for another 6 weeks. At 14-20 weeks of age, mice in the SBI-10 and SBI-30 groups were given 10 and 30 mg/kg SBI-425 by gavage once a day, respectively, while vehicle-group mice were given distilled water as vehicle. Control mice were fed a standard chow (0.8% phosphorus) between the ages of 8 and 20 weeks. Computed tomography imaging, histology, and aortic tissue calcium content revealed that, compared to vehicle animals, SBI-425 nearly halted the formation of MAC. Mice in the control, SBI-10 and SBI-30 groups exhibited 100% survival, which was significantly better than vehicle-treated mice (57.1%). Aortic mRNA expression of Alpl, encoding TNAP, as well as plasma and aortic tissue TNAP activity, were suppressed by SBI-425 administration, whereas plasma pyrophosphate increased. We conclude that a TNAP inhibitor successfully protected the vasculature from MAC and improved survival rate in a mouse CKD-MBD model, without causing any adverse effects on normal skeletal formation and residual renal function. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The Role of DMP1 in CKD-MBD.

PURPOSE OF REVIEW: Chronic kidney disease-mineral and bone disorder (CKD-MBD) has become a global health crisis with very limited therapeutic options. Dentin matrix protein 1 (DMP1) is a matrix extracellular protein secreted by osteocytes that has generated recent interest for its possible involvement in CKD-MBD pathogenesis. This is a review of DMP1 established regulation and function, and early studies implicating DMP1 in CKD-MBD. RECENT FINDINGS: Patients and mice with CKD show perturbations of DMP1 expression in bone, associated with impaired osteocyte maturation, mineralization, and increased fibroblast growth factor 23 (FGF23) production. In humans with CKD, low circulating DMP1 levels are independently associated with increased cardiovascular events. We recently showed that DMP1 supplementation lowers circulating FGF23 levels and improves bone mineralization and cardiac outcomes in mice with CKD. Mortality rates are extremely high among patients with CKD and have only marginally improved over decades. Bone disease and FGF23 excess contribute to mortality in CKD by increasing the risk of bone fractures and cardiovascular disease, respectively. Previous studies focused on DMP1 loss-of-function mutations have established its role in the regulation of FGF23 and bone mineralization. Recent studies show that DMP1 supplementation may fill a crucial therapeutic gap by improving bone and cardiac health in CKD.

Association of changes in bone mineral parameters with mortality in haemodialysis patients: insights from the ARO cohort.

BACKGROUND: There is little information in haemodialysis (HD) patients on whether temporal changes in serum calcium, phosphate or intact parathyroid hormone (iPTH) are associated with mortality. METHODS: We analysed associations of phosphate, total calcium and iPTH with all-cause and cardiovascular mortality in 8817 incident HD patients from the European second Analyzing Data, Recognizing Excellence and Optimizing Outcomes (AROii) cohort enrolled in 2007-09, which were prospectively followed for a median of 3 years, using time-dependent Cox proportional hazards models. We evaluated changes in risk over time depending on changes in phosphate, calcium or iPTH. RESULTS: The association of phosphate and iPTH with all-cause mortality was U-shaped, with the lowest risk ranges between 1.20 and 1.89 mmol/L for phosphate and between 239 and 710 ng/L for iPTH. For total calcium, the associations were J-shaped, with an increased risk for all-cause mortality at levels >2.36 mmol/L. Lowest risk ranges for cardiovascular mortality did not change markedly for all three parameters. If iPTH was below the lowest risk range at baseline (iPTH <239 ng/L), a subsequent increase in levels was associated with improved survival. For phosphate, an increase or decrease out of the lowest risk range was associated with increased mortality risk. For calcium, this was only the case when the values increased above the lowest risk range. CONCLUSION: In the AROii cohort, the ranges of bone mineral biomarkers associated with the lowest mortality ranges were largely consistent with the current Kidney Disease: Improving Global Outcomes chronic kidney disease-mineral and bone disorder guideline recommendations. Allowing a suppressed iPTH to increase was associated with a lower mortality, whereas shifts of phosphate or calcium outside the lowest risk range increased mortality.

Pathophysiology and treatment of cardiovascular disease in pediatric chronic kidney disease.

Life expectancy in patients with all stages of chronic kidney disease (CKD) falls far short of that in the general population. Cardiovascular disease is the leading cause of mortality in pediatric patients with CKD. In contrast to the intimal atherosclerotic lesions that characterize cardiovascular disease in the general population, vascular endothelial dysfunction, medial arterial calcification, and cardiac dysfunction contribute to cardiovascular pathological conditions in CKD. The pathogenesis of these lesions, the origins of which can be identified in the absence of traditional cardiovascular risk factors, is incompletely understood. CKD-mediated vascular calcification in CKD is characterized by a transition of vascular smooth muscle cells to an osteoblast-like phenotype and altered bone and mineral metabolism are strongly linked to progressive cardiovascular disease in this population. Renal osteodystrophy therapies, including phosphate binders, vitamin D analogs, and calcimimetics, have an impact on the progression of cardiovascular disease. However, cardiovascular disease has its origins before the development of secondary hyperparathyroidism, and optimal therapeutic regimens that minimize cardiac dysfunction, vascular calcification, and early mortality remain to be defined.

Klotho and activin A in kidney injury: plasma Klotho is maintained in unilateral obstruction despite no upregulation of Klotho biosynthesis in the contralateral kidney.

In a new paradigm of etiology related to chronic kidney disease-mineral and bone disorder (CKD-MBD), kidney injury may cause induction of factors in the injured kidney that are released into the circulation and thereby initiate and maintain renal fibrosis and CKD-MBD. Klotho is believed to ameliorate renal fibrosis and CKD-MBD, while activin A might have detrimental effects. The unilateral ureter obstruction (UUO) model is used here to examine this concept by investigating early changes related to renal fibrosis in the obstructed kidney, untouched contralateral kidney, and vasculature which might be affected by secreted factors from the obstructed kidney, and comparing with unilateral nephrectomized controls (UNX). Obstructed kidneys showed early Klotho gene and protein depletion, whereas plasma Klotho increased in both UUO and UNX rats, indicating an altered metabolism of Klotho. Contralateral kidneys had no compensatory upregulation of Klotho and maintained normal expression of the examined fibrosis-related genes, as did remnant UNX kidneys. UUO caused upregulation of transforming growth factor-ß and induction of periostin and activin A in obstructed kidneys without changes in the contralateral kidneys. Plasma activin A doubled in UUO rats after 10 days while no changes were seen in UNX rats, suggesting secretion of activin A from the obstructed kidney with potentially systemic effects on CKD-MBD. As such, increased aortic sclerostin was observed in UUO rats compared with UNX and normal controls. The present results are in line with the new paradigm and show very early vascular effects of unilateral kidney fibrosis, supporting the existence of a new kidney-vasculature axis.

Case report: Electron microscopic evaluation of bone from a patient treated with cinacalcet hydrochloride, maxacalcitol, and alfacalcidol for hyperparathyroid bone disease with secondary hyperparathyroidism.

Evaluation of bone is of great importance in chronic kidney disease patients, as these patients are at an increased risk for fractures. We treated a hemodialysis patient suffering from hyperparathyroid bone disease with cinacalcet hydrochloride and concurrent administration of maxacalcitol and alfacalcidol for a year. Hyperparathyroid bone disease is characterized by cortical thinning, increased cortical porosity, reduced trabecular bone volume, and increased hypomineralized matrix volume, and there is little information to date about the effects of treatment with cinacalcet hydrochloride on the bone fragility in patients with hyperparathyroid bone disease. In the present study, histological and backscattered electron microscopic evaluation of this combination treatment revealed an excellent improvement of both bone volume and bone morphology. This treatment improved cortical thinning, cortical porosity, and trabecular thinning. Furthermore, the treatment also reduced hypomineralized matrix volume, indicative of improved mineralization by osteocytes. We speculate that the intermittent maxacalcitol administration may have effectively stimulated the vitamin D receptors expressed on osteocytes and osteoblasts, resulting in increased mineralization. Our approach for evaluating the bone in patients with chronic kidney disease by backscattered electron microscopy is novel.

Deterioration of Cortical Bone Microarchitecture: Critical Component of Renal Osteodystrophy Evaluation.

BACKGROUND: Cortical bone is a significant determinant of bone strength and its deterioration contributes to bone fragility. Thin cortices and increased cortical porosity have been noted in patients with chronic kidney disease (CKD), but the "Turnover Mineralization Volume" classification of renal osteodystrophy does not emphasize cortical bone as a key parameter. We aimed to assess trabecular and cortical bone microarchitecture by histomorphometry and micro-CT in patients with CKD G5 and 5D (dialysis). METHODS: Transiliac bone biopsies were performed in 14 patients undergoing kidney transplantation (n = 12) and parathyroidectomy (n = 2). Structural parameters were analysed by histomorphometry and micro-CT including trabecular bone volume, thickness (TbTh), number (TbN) and separation and cortical thickness (CtTh) and porosity (CtPo). Indices of bone remodelling and mineralisation were obtained and relationships to bone biomarkers examined. Associations were determined by Spearman's or Pearson's rank correlation coefficients. RESULTS: By micro-CT, trabecular parameters were within normal ranges in most patients, but all patients showed very low CtTh (127 ± 44 µm) and high CtPo (60.3 ± 22.5%). CtPo was inversely related to TbN (r = -0.56; p = 0.03) by micro-CT and to TbTh (r = -0.60; p = 0.024) by histomorphometry and correlated to parathyroid hormone values (r = 0.62; p = 0.021). By histomorphometry, bone turnover was high in 50%, low in 21% and normal in 29%, while 36% showed abnormal patterns of mineralization. Significant positive associations were observed between osteoblast surface, osteoclast surface, mineralization surface and bone turnover markers. CONCLUSIONS: Deterioration of cortical -microarchitecture despite predominantly normal trabecular parameters reinforces the importance of comprehensive cortical evaluation in patients with CKD.

Bone, inflammation and the bone marrow niche in chronic kidney disease: what do we know?

Recent improvements in our understanding of physiology have altered the way in which bone is perceived: no longer is it considered as simply the repository of divalent ions, but rather as a sophisticated endocrine organ with potential extraskeletal effects. Indeed, a number of pathologic conditions involving bone in different ways can now be reconsidered from a bone-centred perspective. For example, in metabolic bone diseases like osteoporosis (OP) and renal osteodystrophy (ROD), the association with a worse cardiovascular outcome can be tentatively explained by the possible derangements of three recently discovered bone hormones (osteocalcin, fibroblast growth factor 23 and sclerostin) and a bone-specific enzyme (alkaline phosphatase). Further, in recent years the close link between bone and inflammation has been better appreciated and a wide range of chronic inflammatory states (from rheumatoid arthritis to ageing) are being explored to discover the biochemical changes that ultimately lead to bone loss and OP. Also, it has been acknowledged that the concept of the bone-vascular axis may explain, for example, the relationship between bone metabolism and vessel wall diseases like atherosclerosis and arteriosclerosis, with potential involvement of a number of cytokines and metabolic pathways. A very important discovery in bone physiology is the bone marrow (BM) niche, the functional unit where stem cells interact, exchanging signals that impact on their fate as bone-forming cells or immune-competent haematopoietic elements. This new element of bone physiology has been recognized to be dysfunctional in diabetes (so-called diabetic mobilopathy), with possible clinical implications. In our opinion, ROD, the metabolic bone disease of renal patients, will in the future probably be identified as a cause of BM niche dysfunction. An integrated view of bone, which includes the BM niche, now seems necessary in order to understand the complex clinical entity of chronic kidney disease-mineral and bone disorders and its cardiovascular burden. Bone is thus becoming a recurrently considered paradigm for different inter-organ communications that needs to be considered in patients with complex diseases.

Systemic Activation of Activin A Signaling Causes Chronic Kidney Disease-Mineral Bone Disorder.

The high cardiovascular mortality associated with chronic kidney disease (CKD) is caused in part by the CKD-mineral bone disorder (CKD-MBD) syndrome. The CKD-MBD consists of skeletal, vascular and cardiac pathology caused by metabolic derangements produced by kidney disease. The prevalence of osteopenia/osteoporosis resulting from the skeletal component of the CKD-MBD, renal osteodystrophy (ROD), in patients with CKD exceeds that of the general population and is a major public health concern. That CKD is associated with compromised bone health is widely accepted, yet the mechanisms underlying impaired bone metabolism in CKD are not fully understood. Therefore, clarification of the molecular mechanisms by which CKD produces ROD is of crucial significance. We have shown that activin A, a member of the transforming growth factor (TGF)-ß super family, is an important positive regulator of receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis with Smad-mediated signaling being crucial for inducing osteoclast development and function. Recently, we have demonstrated systemic activation of activin receptors and activin A levels in CKD mouse models, such as diabetic CKD and Alport (AL) syndrome. In these CKD mouse models, bone remodeling caused by increased osteoclast numbers and activated osteoclastic bone resorption was observed and treatment with an activin receptor ligand trap repaired CKD-induced-osteoclastic bone resorption and stimulated individual osteoblastic bone formation, irrespective of parathyroid hormone (PTH) elevation. These findings have opened a new field for exploring mechanisms of activin A-enhanced osteoclast formation and function in CKD. Activin A appears to be a strong candidate for CKD-induced high-turnover ROD. Therefore, the treatment with the decoy receptor for activin A might be a good candidate for treatment for CKD-induced osteopenia or osteoporosis, indicating that the new findings from in these studies will lead to the identification of novel therapeutic targets for CKD-related and osteopenia and osteoporosis in general. In this review, we describe the impact of CKD-induced Smad signaling in osteoclasts, osteoblasts and vascular cells in CKD.

[Arteriosklerosis and "osteoporosis" in patients with chronic kidney disease: same same, but different!] / Arteriosklerose und «Osteoporose¼ bei Niereninsuffizienz: same same, but different!

Arteriosklerosis and "osteoporosis" in patients with chronic kidney disease: same same, but different! Abstract. Vascular calcifications should be considered a dynamic process sharing many similarities with bone formation. Even though the underlying pathophysiology of renal insufficiency-related vascular and bone disorders has just begun to be revealed, they appear to be closely related to each other and together appear to have an enormous impact on cardiovascular morbidity and mortality. Vascular and bone disorders are highly prevalent in the general population. In patients with chronic kidney disease (CKD), not only the progression of these disorders appears to be accelerated, but they also appear to be governed by different pathophysiological mechanisms, and hence should be managed differently. One should be especially cautious about the use of some "standard drugs" like calcium supplements or bisphosphonates when treating patients with CKD. Unfortunately, no evidence-based therapeutic options of vascular and bone disorders in patients with CKD are yet available with proven positive effect on hard endpoints such as overall mortality or fracture risk.

Klotho expression in osteocytes regulates bone metabolism and controls bone formation.

Osteocytes within the mineralized bone matrix control bone remodeling by regulating osteoblast and osteoclast activity. Osteocytes express the aging suppressor Klotho, but the functional role of this protein in skeletal homeostasis is unknown. Here we identify Klotho expression in osteocytes as a potent regulator of bone formation and bone mass. Targeted deletion of Klotho from osteocytes led to a striking increase in bone formation and bone volume coupled with enhanced osteoblast activity, in sharp contrast to what is observed in Klotho hypomorphic (kl/kl) mice. Conversely, overexpression of Klotho in cultured osteoblastic cells inhibited mineralization and osteogenic activity during osteocyte differentiation. Further, the induction of chronic kidney disease with high-turnover renal osteodystrophy led to downregulation of Klotho in bone cells. This appeared to offset the skeletal impact of osteocyte-targeted Klotho deletion. Thus, our findings establish a key role of osteocyte-expressed Klotho in regulating bone metabolism and indicate a new mechanism by which osteocytes control bone formation.

Renal Osteodystrophy-Time for Common Nomenclature.

PURPOSE OF REVIEW: The term renal osteodystrophy has been used to describe a wide variety of bone problems facing patients with chronic kidney disease (CKD). Here, we review the history of the use of this term. RECENT FINDINGS: Bone disease resulting from CKD was first noticed in 1890. The term "renal osteodystrophy" was used to define the bone disease in 1942. Since then, important discoveries have increased our knowledge of the complexities of bone physiology in these patients. At the same time, secular changes in the disease have occurred. The terms used to describe the bone histological findings have changed as well, reflecting new understanding of the physiological processes. However, since different investigators used the terms in different ways, the need to standardize the nomenclature has become increasingly important. Ongoing international collaboration about nosography will allow more optimal communication among scientists and clinicians as we continue to make new discoveries.

Brown tumor: clinical findings of secondary hyperparathyroidism in patients with renal osteodystrophy.

A brown tumor, or osteoclastoma, is a nonneoplastic bony lesion associated with hyperparathyroidism and directly related to increased levels of parathyroid hormone. These tumors result from excessive osteoclastic activity. This article presents 3 cases of brown tumor localized in facial bones. The lesions were the result of secondary hyperparathyroidism associated with chronic renal failure. The patients were two 42-year-old men and a 39-year-old woman. All patients had been treated systemically by hemodialysis for more than 10 years. This article highlights the importance of proper diagnosis and management of dental patients presenting with a brown tumor.

Changing bone patterns with progression of chronic kidney disease.

It is commonly held that osteitis fibrosa and mixed uremic osteodystrophy are the predominant forms of renal osteodystrophy in patients with chronic kidney disease. Osteitis fibrosa is a high-turnover bone disease resulting mainly from secondary hyperparathyroidism, and mixed uremic osteodystrophy is in addition characterized by a mineralization defect most often attributed to vitamin D deficiency. However, there is ancient and more recent evidence that in early chronic kidney disease stages adynamic bone disease characterized by low bone turnover occurs first, at least in a significant proportion of patients. This could be due to the initial predominance of bone turnover-inhibitory conditions such as resistance to the action of parathyroid hormone (PTH), reduced calcitriol levels, sex hormone deficiency, diabetes, and, last but not least, uremic toxins leading to repression of osteocyte Wnt/ß-catenin signaling and increased expression of Wnt antagonists such as sclerostin, Dickkopf-1, and sFRP4. The development of high-turnover bone disease would occur only later on, when serum PTH levels are able to overcome peripheral PTH resistance and the other inhibitory factors of bone formation. Whether FGF23 and Klotho play a direct role in the transition from low- to high-turnover bone disease or participate only indirectly via regulating PTH secretion remains to be seen.

Therapeutic effect of CNP on renal osteodystrophy by antagonizing the FGF-23/MAPK pathway.

Renal osteodystrophy (ROD) is highly prevalent in chronic kidney disease (CKD). Because most patients with ROD are asymptomatic in the early stage and bone biopsy remains not a routine procedure in many clinical settings; therefore, several biochemical parameters may help to identify the existence of ROD. C-type natriuretic peptide (CNP) is considered as a positive regulator of bone formation. Both urinary excretion and renal expression of CNP are markedly up-regulated in the early stages of CKD, whereas they are still progressively declined accompanied by CKD progression, which invites speculation that the progressive decline of CNP may contribute, in part, to the pathogenesis of ROD. In addition, fibroblast growth factor (FGF)-23 is a bone-derived endocrine regulator of phosphate homeostasis. The elevation of serum FGF-23 has been recognized as a common feature in CKD to maintain normophosphatemia at the expense of declining 1,25-dihydroxyvitamin D values. Since the effects of CNP and FGF-23 on bone formation appear to oppose each other, it is reasonable to propose a direct interaction of their signaling pathways during the progression of ROD. CNP and FGF-23 act through a close or reciprocal pathway and are in agreement with recent studies demonstrating a down-regulatory role of the mitogen-activated protein kinase activity by CNP. The specific node may act at the level of RAF-1 through the activation of cyclic guanosine monophosphate-dependent protein kinases II.

[The expanding concept of CKD-MBD].

Almost seven years have passed since the publication of the KDIGO clinical practice guideline on chronic kidney disease-mineral and bone disorder(CKD-MBD). During this period, several new medications for osteoporosis that may be applicable to patients with CKD have become available. Clinical studies have also shown the utility of bone mineral density to assess fracture risk in CKD. These new data charges us with the task of reconciling the concept of renal osteodystrophy(ROD)and osteoporosis in CKD. This review summarize the recent advances in the management of bone disease in CKD and the key points raised during the discussion for the KDIGO guideline revision, and address the problems to be solved in future.

Peritoneal dialysis per se is a risk factor for sclerostin-associated adynamic bone disease.

Chronic kidney disease--mineral bone disorder (CKD-MBD) is a complex syndrome influenced by various factors, such as age, CKD etiology, uremic toxins, and dialysis modality. Although extensively studied in hemodialysis (HD) patients, only a few studies exist for peritoneal dialysis (PD) patients. Since most of these older studies contain no bone biopsy data, we studied the pattern of renal osteodystrophy in 41 prevalent PD patients. The most common presentation was adynamic bone disease (49%). There was a significant inverse association between serum sclerostin (a Wnt/ß-catenin pathway inhibitor that decreases osteoblast action and bone formation) and the bone formation rate. Bone alkaline phosphatase had the best sensitivity and specificity to detect both high- and low-turnover diseases. The comparison between nondiabetic PD and HD patients, matched by age, gender, parathyroid hormone level, and length of dialysis, revealed low 25-hydroxyvitamin D levels, worse bone mineralization, and low bone turnover in the nondiabetic PD group. Thus, adynamic bone disease was the most frequent type of renal osteodystrophy in PD patients. Sclerostin seems to participate in the pathophysiology of adynamic bone disease and bone alkaline phosphatase was the best serum marker of bone turnover in these patients.

Bone alkaline phosphatase isoforms in hemodialysis patients with low versus non-low bone turnover: a diagnostic test study.

BACKGROUND: Renal osteodystrophy encompasses the bone histologic abnormalities seen in patients with chronic kidney disease (CKD). The bone-specific alkaline phosphatase (bALP) isoform B1x is exclusively found in serum of some patients with CKD. STUDY DESIGN: The aim of this cross-sectional diagnostic test study was to examine the relationship between serum bALP isoform activity and histomorphometric parameters of bone in patients with CKD receiving maintenance hemodialysis. SETTINGS & PARTICIPANTS: Anterior iliac crest bone biopsy samples from 40 patients with CKD were selected on the basis of bone turnover for histomorphometric analysis. There were samples from 20 patients with low and 20 with non-low bone turnover. INDEX TEST: In serum, bALP, bALP isoforms (B/I, B1x, B1, and B2), and parathyroid hormone (PTH) were measured. REFERENCE TEST: Low bone turnover was defined by mineral apposition rate < 0.36µm/d. Non-low bone turnover was defined by mineral apposition rate ≥ 0.36µm/d. OTHER MEASUREMENTS: PTH. RESULTS: B1x was found in 21 patients (53%) who had lower median levels of bALP, 18.6 versus 46.9U/L; B/I, 0.10 versus 0.22 µkat/L; B1, 0.40 versus 0.88 µkat/L; B2, 1.21 versus 2.66 µkat/L; and PTH, 49 versus 287pg/mL, compared with patients without B1x (P<0.001). 13 patients (65%) with low bone turnover and 8 patients (40%) with non-low bone turnover (P<0.2) had detectable B1x. B1x correlated inversely with histomorphometric parameters of bone turnover. Receiver operating characteristic curves showed that B1x can be used for the diagnosis of low bone turnover (area under the curve [AUC], 0.83), whereas bALP (AUC, 0.89) and PTH (AUC, 0.85) are useful for the diagnosis of non-low bone turnover. LIMITATIONS: Small number of study participants. Requirement of high-performance liquid chromatography methods for measurement of B1x. CONCLUSIONS: B1x, PTH, and bALP have similar diagnostic accuracy in distinguishing low from non-low bone turnover. The presence of B1x is diagnostic of low bone turnover, whereas elevated bALP and PTH levels are useful for the diagnosis of non-low bone turnover.

Sclerostin, Osteocytes, and Chronic Kidney Disease - Mineral Bone Disorder.

Osteocytes respond to kidney damage by increasing production of secreted factors important to bone and mineral metabolism. These circulating proteins include the antianabolic factor, sclerostin, and the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Elevated sclerostin levels correlate with increased FGF23, localized reduction in Wnt/ß-catenin signaling in the skeleton and reduced osteoblast differentiation/activity. Decreased Wnt/ß-catenin signaling occurs regardless of the overall changes in bone formation rates, suggesting that a reduction in the anabolic response may be a common feature of renal bone disorders but additional mechanisms may contribute to the diversity of osteodystrophy phenotypes. Recent preclinical studies support this hypothesis, as treatment with antisclerostin antibodies improved bone quality in the context of low but not high turnover renal osteodystrophy. Sclerostin also appears in the circulation suggesting additional roles outside the skeleton in normal and disease states. In patients with chronic kidney disease (CKD), serum levels are elevated several fold relative to healthy individuals. Emerging data suggest that these changes are associated with increased fracture rates but the relationship between sclerostin and cardiovascular disease is unclear. Additional epidemiologic studies that examine stage specific and patient sub-populations are needed to assess whether sclerostin elevations influence comorbidities associated with CKD.

Can one evaluate bone disease in chronic kidney disease without a biopsy?

PURPOSE OF REVIEW: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a complex disorder of bone and mineral metabolism that results in an excess risk of fractures, cardiovascular events and mortality. The management of the bone disorder aspect of CKD-MBD may require bone biopsy to determine appropriate treatment strategies. However, it is unclear when biopsy may be necessary and whether or not state-of-the art imaging and serologic testing can supplant the bone biopsy as a tool to assist with management decisions. RECENT FINDINGS: Advances in imaging methods now permit the noninvasive assessment of structural aspects of bone quality. Furthermore, common bone imaging tools, such as dual-energy X-ray absorptiometry, can be used to stratify for fracture risk. Circulating markers of bone turnover can be used to assess the risk of bone loss and fracture, but they are less useful in diagnosing the type of renal osteodystrophy. SUMMARY: Although advances in imaging now permit the assessment of fracture risk more accurately in CKD patients, the assessment of the type of renal osteodystrophy remains poor without bone biopsy. The virtual bone biopsy will be possible only when we are able to noninvasively assess turnover with good accuracy. A bone biopsy is needed when the bone turnover is unclear.