Sclerostin in chronic kidney disease–mineral bone disorder think first before you block it!

Sclerostin in chronic kidney disease–mineral bone disorder think first before you block it! Abstract Canonical Wnt signalling activity is a major player in physiological and adaptive bone metabolism. Wnt signalling is regulated by soluble inhibitors, with sclerostin being the most widely studied. Sclerostin’s main origin is the osteocyte and its major function is blockade of osteoblast differentiation and function. Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Consequently, blocking sclerostin via human monoclonal antibodies (such as romosozumab) represents a promising perspective for the treatment of (postmenopausal) osteoporosis. However, sclerostin’s physiology and the effects of sclerostin monoclonal antibody treatment are not limited to the skeleton. Specifically, the potential roles of sclerostin in chronic kidney disease (CKD) and associated pathologies covered by the term chronic kidney disease and mineral bone disorder (CKD-MBD), which also includes accelerated cardiovascular calcification, warrant specific attention. CKD-MBD is a complex disease condition in which sclerostin antibodies may interfere at different levels and influence the multiform interplay of hyperparathyroidism, renal osteodystrophy and vascular calcification, but the clinical sequelae remain obscure. The present review summarizes the potential effects of sclerostin blockade in CKD-MBD. We will address and summarize the urgent research targets that are being identified and that need to be addressed before a valid risk–benefit ratio can be established in the clinical setting of CKD. bone metabolism, calcification, cardiovascular complication, chronic kidney disease–mineral bone disorder, vascular calcification PHYSIOLOGY OF SCLEROSTIN: WHAT CLINICIANS SHOULD KNOW Wnt signalling encompasses several (at least three) different signalling pathways including the canonical Wnt/beta-catenin pathway [1, 2]. The predominant function of the canonical Wnt pathway is stabilization of beta-catenin by inhibiting the activity of the beta-catenin degradation complex [3]. The function of the beta-catenin degradation complex is to phosphorylate beta-catenin [4]. Phosphorylation renders beta-catenin susceptible to proteolysis, whereby it does not accumulate in the nucleus. Only unphosphorylated beta-catenin can translocate into the nucleus and modulate target gene transcription locally [4]. Secreted Wnt inhibitors are a group of proteins that interfere with the extracellular binding of Wnt ligands to the transmembrane receptor complex [3, 5]. Among these, sclerostin, and to a lesser extent Dickkopf-related protein 1 (DKK-1), has previously been studied intensively [6]. Sclerostin (22 kDa) is a member of the cystatin knot family of proteins and is a product of the SOST gene [7]. It is measurable in human serum [8] and also qualified as a therapeutic target in osteoporosis [9]. Sclerostin prevents beta-catenin nuclear translocation and subsequent gene expression. It is secreted almost exclusively by osteocytes, and to a lesser extent by other cell types including osteoclast precursors [10]. Hence, viable osteocytes regulate the proper functionality of the skeleton via sclerostin synthesis and release [6, 10, 11]. Sclerostin deficiency associates with high bone mass as impressively revealed by the murine knockout model [12] (Figure 1). Loss-of-function mutations were reported in patients with van Buchem disease, a disorder closely resembling sclerosteosis [13, 14]. These human disorders coincide with the reduced activity of sclerostin. Sclerosteosis is caused by loss-of-function mutations in the SOST gene on chromosome 17q12-q21, which encodes sclerostin. In contrast, patients with van Buchem disease have a 52-kb homozygous noncoding deletion 35 kb downstream of the SOST gene, which is essential for the transcription of the gene in bone [13, 14]. Life expectancy in sclerosteosis is reduced, with a large proportion of patients dying in early adulthood, mainly from complications of increased intracranial pressure [14]. FIGURE 1: View largeDownload slide Micro-computed tomography scans of the femur metaphysis and diaphysis of 35-week-old sclerostin knockout (SOST−/−) animals compared with wild-type (WT) littermates (N. Kaesler and A. Verhulst, data on file). FIGURE 1: View largeDownload slide Micro-computed tomography scans of the femur metaphysis and diaphysis of 35-week-old sclerostin knockout (SOST−/−) animals compared with wild-type (WT) littermates (N. Kaesler and A. Verhulst, data on file). Sclerostin overexpression revealed the expected opposite phenotype, i.e. low bone mass as a consequence of reduced bone formation [15]. Targeting sclerostin via monoclonal antibody treatment has the potential to become a cornerstone of osteoporosis therapy due to its potent osteoanabolic activity [9]. However, before introducing widespread therapeutic use in patients with chronic kidney disease (CKD) as well, it is crucial to consider the specific complex situation in these patients. Indeed, in CKD, the intricate skeletal (renal osteodystrophy), hormonal (hyperparathyroidism) and vascular (calcification) changes and sclerostin’s role herein should be carefully weighed against each other. SCLEROSTIN ANTIBODIES AND OSTEOPOROSIS: IT WORKS! The comprehensive insights into the osseous mode of action of sclerostin antibodies come from various animal models. Preclinical studies in monkeys [16] revealed that the application of a humanized sclerostin monoclonal antibody increased the bone mineral content and/or bone mineral density at the femoral neck, radial metaphysis and tibial metaphysis. Bone histomorphometry showed marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical and intracortical surfaces, consistent with increased recruitment, activation and/or survival of osteoblasts. In young rats, application of sclerostin antibodies augmented cancellous and cortical bone mass and induced a strong increase in bone formation rate [17]. Accordingly, administration of sclerostin antibodies in 6-month-old rats that had undergone femoral osteotomy resulted in a significantly increased mineral apposition rate, mineralized surface and bone formation rate in trabecular bone of the distal femora [18]. It is noteworthy that romosozumab, a human monoclonal sclerostin antibody, has a dual mode of action in that in addition to its predominant influence upon bone formation, romosozumab also suppresses bone resorption; in human interventional trials, romosozumab application led to a sustained decrease in beta-CTX of up to 50% [9]. Application of romosozumab is an effective treatment to increase bone mineral density and reduce vertebral fracture risk in humans. In a previous 12-month Phase II trial, romosozumab treatment significantly increased bone mass in postmenopausal osteoporosis [19]. These findings were confirmed and extended in a Phase III study—the FRAME trial [9], in which 6390 postmenopausal osteoporotic women received romosozumab or placebo. Active treatment significantly reduced the vertebral fracture risk after 12 months [risk ratio 0.27; 95% confidence interval (CI) 0.16–0.47; P < 0.001]. However, romosozumab therapy was less clearly effective in risk reduction for non-vertebral fractures (0.75; 95% CI 0.53–1.05; P = 0.10) [9]. Finally, the ARCH study confirmed fracture-reducing properties of romosozumab in about 4000 postmenopausal women [20]. Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-followed-by-alendronate group [6.2% (127 of 2046 patients)] than in the alendronate-followed-by-alendronate group [11.9% (243 of 2047 patients)] (P < 0.001) [20]. In the ARCH study, the risk of hip fractures was also lowered by 38% in the romosozumab group: 41 of 2046 patients (2.0%) versus 66 of 2047 patients (3.2%). Of note, the ARCH trial raised safety concerns regarding the use of the sclerostin monoclonal antibody: during year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate [50 of 2040 patients (2.5%) versus 38 of 2014 patients (1.9%)] [20]—a finding that will undergo comprehensive review below. In summary, romosozumab represents a novel and effective osteoanabolic treatment strategy in human osteoporosis, at least with regard to postmenopausal fractures. THE POTENTIAL ROLE OF SCLEROSTIN AND SCLEROSTIN BLOCKADE IN NEPHROLOGY The above-mentioned physiological aspects and first results in postmenopausal osteoporosis studies turn sclerostin into an interesting research domain within the field of nephrology. Serum sclerostin measurements recently gained some interest in CKD as sclerostin levels varied with renal function [21] and serum levels were associated with a favourable outcome (the higher, the better) [22]. However, a substantial inter-variability has been reported between various sclerostin assays [23]. It is noteworthy that the association between serum sclerostin and outcome varies among different cohorts [22, 24, 25]. Based on these contradictory results from studies investigating the role of sclerostin as a prognostic biomarker and weak standardization of assays, we currently cannot recommend measuring serum sclerostin in clinical routine. The anabolic property renders sclerostin blockade particularly interesting for nephrologists, who face the threat of adynamic bone disease in many of their patients [26]. Before applying it to CKD patients, however, we need to know more about sclerostin’s involvement in renal osteodystrophy; moreover, we need to examine what might happen with sclerostin antibody treatment in this particular clinical setting. SCLEROSTIN AND RENAL OSTEODYSTROPHY Sclerostin is increasingly acknowledged as a modulator of renal osteodystrophy. The jck mouse model, which is a model of moderate progressive renal failure, nicely shows the time course of CKD–mineral bone disorder (CKD-MBD) parameters as kidney dysfunction progresses [27]. Interestingly, osteocytic sclerostin expression and consecutive suppression of beta-catenin signalling in this mouse model occurs earlier (at Week 5) than changes of parathyroid hormone (PTH) or fibroblast growth factor-23 (FGF-23) (at Week 10) The increased sclerostin expression also preceded cardiovascular and skeletal changes, typically seen in CKD-MBD and starting at about Week 15 and Week 9, respectively. The rise in sclerostin-positive osteocytes was transient and diminished in parallel with the severity of the developing hyperparathyroidism. These findings allow speculation that sclerostin is involved early in the development of renal osteodystrophy with some PTH-mediated counter-regulatory effects. We acknowledge that these findings, which are indicative of a subtle time course of renal osteodystrophy changes, should be re-evaluated in other models of renal failure. Our understanding about the role of sclerostin in uraemic bone disease grew substantially with experiments about the development of renal osteodystrophy in the absence of this early rise in sclerostin. Two working groups examined the renal osteodystrophy phenotype of sclerostin-deficient mice that had undergone 5/6th nephrectomy [28, 29]. One CKD model revealed a low [28], the other one a pronounced renal hyperparathyroidism [29]. Overall, the sclerostin deficiency was characterized by high cortical thickness, lower cortical porosity, lower bone marrow area and particularly, high bone volume as detected by micro-computed tomography compared with wild-type mice. Both groups came to a similar conclusion upon analysis of the skeletal phenotype: the development of renal osteodystrophy was masked by the overwhelming phenotype of the homozygous sclerostin deficiency [28, 29]. It is currently unknown which phenotype the opposite genetic model, i.e. overexpression of skeletal sclerostin, might exhibit in the setting of CKD and what might be the effect on the development of renal osteodystrophy. Data regarding sclerostin’s involvement in human renal osteodystrophy are limited: a study in which 60 adult dialysis patients underwent a bone biopsy after tetracycline labelling revealed a statistically significant negative correlation between serum sclerostin and PTH [30]. Most importantly, sclerostin showed pronounced negative associations with parameters of bone turnover, pointing towards a role of increased sclerostin levels in the development of adynamic bone disease [30]. Another bone biopsy study was done in patients with various levels of CKD [31]. The authors quantified both serum and bone sclerostin and found a weak correlation between the two. They confirmed a potential association between skeletal expression of sclerostin and turnover, since patients with high turnover had lower bone sclerostin expression than those with low bone turnover [31]. Interestingly, the bone expression of sclerostin quantified by immunohistochemistry varied significantly between different stages of CKD and revealed its peak in CKD Stages 2 and 3. In all CKD stages, it was higher than in healthy controls [31]. Noteworthy, sclerostin is not a lone warrior: other CKD-MBD mediators and Wnt signalling inhibitors act in concert in this setting, i.e. they directly inhibit osteoblastic Wnt activity and promote skeletal resistance to anabolic stimuli such as FGF-23 [32] or klotho [33]. However, putting forward the hypothesis that the development of adynamic bone disease in humans is (in part) mediated by a state of overactivity or sclerostin and similar mediators, thereby counterbalancing other osteoanabolic effectors, is currently still highly speculative. It is, however, noteworthy that PTH and sclerostin interact strongly with each other on a physiological basis. Hence, the PTH–sclerostin ‘balance’ is a suitable target in modulating the development of renal osteodystrophy. SCLEROSTIN AND PTH AND THEIR PHYSIOLOGICAL INTERPLAY: THEY NEED EACH OTHER PTH downregulates sclerostin expression in osteocytes, and this interaction represents an important aspect of how PTH stimulates bone metabolism [34]. There is substantial experimental evidence available that a balanced crosstalk between PTH and sclerostin is relevant for bone physiology. In healthy conditions, the anabolic activity of PTH, to a certain extent, is mediated by suppressing the anti-anabolic activity of sclerostin. PTH administration rapidly reduces sclerostin mRNA as well as protein synthesis in osteocytes [34, 35]. Kramer et al. convincingly showed skeletal PTH actions to rely upon sclerostin physiology [12]. They investigated the skeletal effects of intermittent PTH administration in mouse models with sclerostin overexpression and also with sclerostin deficiency. Six-month-old genetically engineered mice of both types underwent a 2-month treatment period with PTH (1–34). Both sclerostin-deficient as well as sclerostin-overexpressing mice revealed the expected skeletal phenotype, i.e. high bone mass in the former and severe osteopenia in the latter. In both mouse models, the response to intermittent PTH treatment in terms of stimulation of bone metabolism was significantly diminished. Therefore, the authors came to the conclusion that suppression of sclerostin in osteocytes is necessary to mediate anabolic responses to PTH [12]. As discussed above, uraemia may impel sclerostin expression and this chronic stimulation may turn sclerostin irresponsive to PTH, and this might be one important factor in skeletal uraemia-associated PTH resistance. Alternatively, high sclerostin levels may be the consequence of PTH resistance in the osteocytes. Additional research is needed to clarify this chicken-and-egg issue. In addition, sclerostin is believed to participate in several biochemical feedback loops, as evidenced by the fact that sclerostin-deficient mice reveal alterations in a number of classical biochemical CKD-MBD-related parameters [36]. While serum calcium and PTH levels were not different between sclerostin knockout and wild-type mice with normal renal function, FGF-23 levels were about 2.5 times lower in sclerostin-deficient mice compared with their wild-types, and conversely, 1, 25-dihydroxyvitamin D and serum phosphate levels were significantly elevated. Sclerostin also directly alters vitamin D synthesis in proximal tubular cells [36]. Taken together, the discovery of sclerostin sheds novel light on the long-standing discussion about skeletal PTH resistance in CKD and also on the pathophysiology of adynamic bone. From a therapeutic perspective, romosozumab appears to be an attractive option for haemodialysis patients, in particular because of the intermittent monthly application strategy, which might easily help overcome issues related to non-adherence in this patient cohort due to their particularly high pill burden. However, are we ready to apply romosozumab in severe CKD? SCLEROSTIN ANTIBODIES IN THE SETTING OF UNDERLYING RENAL OSTEODYSTROPHY: A NEW HOPE? In patients with normal renal function or only mildly impaired renal function, such as those participating in the Phase II and Phase III romosozumab trials mentioned above, application of the antibody was associated with a decrease in serum calcium and an increase in PTH levels. Such a finding can be interpreted as a reflection of stimulated bone anabolism or reduced bone resorption, respectively resulting in increased calcium incorporation into and/or decreased calcium efflux out of the bone, both resulting in consecutive PTH stimulation. Of note, in the FRAME trial [9], patients with <40 ng/mL 25-vitamin D levels at baseline received 50 000 to 60 000 IU of vitamin D, thus preventing incident hypocalcaemia. Due to lack of data, the magnitude and clinical meaning of such biochemical changes are unknown for patients with CKD Stages 3 or 4 or those on haemodialysis—a group of patients already prone to hypocalcaemia and secondary hyperparathyroidism (HPT). Hence, continuous attention is warranted. As the effects of sclerostin antibody treatment in humans with osteoporosis plus severe CKD Stages 3, 4 and 5 have not been investigated so far, fracture risk reduction or cellular effects are as yet undetermined in this population. However, the prospects behind romosozumab in renal osteodystrophy are enticing because such a treatment may hypothetically combine two modes of action: osteoanabolism plus a decrease in PTH resistance. Conditions associated with supra-physiological sclerostin activity may impede PTH-mediated bone anabolism. Adynamic bone disease is a subtype of renal osteodystrophy characterized by a substantially reduced bone formation rate, impaired remodelling activity and reduced osteoblastic and osteoclastic activity [37]. In uraemia, high sclerostin levels may exacerbate PTH resistance, which could cause and/or aggravate adynamic bone disease [26]. Therefore, blocking sclerostin is a valuable research target in treatment of low-turnover renal osteodystrophy and might help resuscitate cellular activity [10]. Newman et al. investigated the effects of sclerostin antibody treatment in Cy/+ rats, which resemble polycystic kidney disease [38]. Anti-sclerostin antibodies were applied in two different experimental settings—either in Cy/+ with uncontrolled hyperparathyroidism or in Cy/+ mice on a high calcium diet and with consecutively low PTH levels. Their data point towards relevant interactions between the status of underlying hyperparathyroidism and effects of anti-sclerostin antibody application. Sclerostin antibodies were effective in enhancing bone mass and ameliorating mechanical properties only if hyperparathyroidism was treated sufficiently (by high calcium intake) [38]. Only in the low-PTH group did sclerostin-antibody treatment reveal remarkable changes in renal osteodystrophy as evidenced by an increased cortical thickness and bone volume as well as an increase in bone quality/strength (as measured by ultimate load and energy to failure) [38]. Data from Moe et al. [39] point in comparable direction—i.e. the skeletal effects of sclerostin and sclerostin antibodies are different in renal failure versus healthy conditions and depend specifically upon the degree of renal hyperparathyroidism. In chronic renal failure rats, the researchers titrated renal hyperparathyroidism via calcium administration towards different levels of PTH and measured phosphorylated beta-catenin by western blot from total bone extracts. In the CKD animals, basal expression was 0.39 ± 0.18. In the CKD animals treated with anti-sclerostin antibody, the expression was 0.52 ± 0.28 in the high PTH group and 0.19 ± 0.17 in the low PTH group, with differences being significant between the two treated groups of P = 0.008). Phosphorylated beta-catenin expression represents degradation, and hence these data indicate a positive effect of the anti-sclerostin antibodies basically in the low PTH group, consistent with their bone volume findings. In summary, the application of sclerostin antibodies will certainly have an impact upon the degree and nature of renal osteodystrophy. Our current knowledge on sclerostin antibody treatment allows speculation about a potential amelioration of low bone turnover, and therefore, a future interventional trial targeting adynamic bone disease should be encouraged. However, any enthusiasm about increases in physiological mineralization or calcification induced by sclerostin antibodies should be weighed against the fact that similar processes are involved in cardiovascular calcification processes, which are another hallmark of CKD-MBD. Does sclerostin block ectopic mineralization processes as well? And most importantly, will this ectopic calcification ‘explode’ with sclerostin blockade? SCLEROSTIN AND CARDIOVASCULAR DISEASE: WHAT ABOUT VASCULAR CALCIFICATION? Wnt signalling and its alterations are not limited to the skeleton and play a role in human atherosclerosis [40, 41]. Figure 2 depicts the double role of sclerostin in the vascular wall and the bone compartment. Of note, ectopic vascular calcification and physiological bone formation share similarities in terms of the involved cellular processes [42]. FIGURE 2: View largeDownload slide Activity of Wnt signalling, and specifically of sclerostin as a Wnt antagonist, is not limited to the bone compartment. Wnt signalling also influences the integrity of the arterial wall. Hence, blocking sclerostin will impact the vascular calcification processes. Theoretically, sclerostin helps to prevent vascular calcification, as shown in the left part of the figure. FIGURE 2: View largeDownload slide Activity of Wnt signalling, and specifically of sclerostin as a Wnt antagonist, is not limited to the bone compartment. Wnt signalling also influences the integrity of the arterial wall. Hence, blocking sclerostin will impact the vascular calcification processes. Theoretically, sclerostin helps to prevent vascular calcification, as shown in the left part of the figure. In particular, the derangements in the Wnt signalling pathway and in the soluble Wnt inhibitors contribute to the development of uraemia-associated combined bone and vascular disease [43]. In consequence, we need to be cautious and not too optimistic regarding the likely absence of any potential cardiovascular side effects when blocking sclerostin activity [44]. In fact, the above-mentioned ARCH trial underlined the need to create additional data regarding the cardiovascular safety of romosozumab [20]. The clinical relevance of the higher incidence of serious adverse cardiovascular events in romosozumab-treated patients (2.5%) versus those receiving alendronate (1.9%) is currently unknown, but they fuel the hypothesis that sclerostin and accordingly its antibody play a role in the cardiovascular system. To the best of our knowledge, there are no data regarding the cardiovascular status in human genetic diseases due to reduced sclerostin activity, such as sclerosteosis or van Buchem’s disease [45]. A specific model of vascular calcification has been shown to act via Wnt signalling, i.e. vitamin K antagonist treatment. Vitamin K antagonists, such as warfarin, are suspected to trigger vascular calcification [46, 47]. Beazley et al. showed that warfarin activates beta-catenin signalling in vascular smooth muscle cells (VSMCs) in vitro by (i) increasing the amount of total beta-catenin protein, (ii) upregulating its nuclear translocation and (iii) stimulating transcription of beta-catenin target genes [48]. It was recently shown that sclerostin is necessary to preserve or strengthen vascular health. An interesting experimental set-up to investigate sclerostin’s role in atherosclerosis was elaborated by Krishna et al. [49]. The authors used ApoE-null mice, which develop atherosclerosis and aortic aneurysms with infusion of angiotensin II (AngII) [49]. In this study, the putative protective role of sclerostin was examined via two different experimental approaches, i.e. transgenic overexpression and recombinant mouse sclerostin injection. In this way, the authors were able to demonstrate that sclerostin protects AngII-infused ApoE-null mice from atherosclerosis and inflammation, aortic matrix degradation, as well as macrophage infiltration. Recent research indicates that in human aortic valve tissue from haemodialysis patients with microscopic as well as macroscopic calcification, a significant local sclerostin mRNA upregulation is detectable that is absent in aortic valve tissue from haemodialysis patients without calcification [50]. Thus, it is not uraemia per se, but the calcification process itself that is seemingly responsible for local sclerostin expression in the vascular system. Experimental in vitro data from Zhu et al. confirm sclerostin expression in calcifying VSMCs [51]. In vitro, VSMCs express osteocytic markers when grown in a pro-calcific environment, which is indicative of an osteoblastic to osteocytic transition (terminal transdifferentiation) [51]. Accordingly, the same authors found in vivo expression of sclerostin in calcified mouse aortas. The occurrence of sclerostin in calcified aortic valve tissue is not only limited to haemodialysis patients, but occurs in patients with dominant calcific aortic stenosis as well [52]. Moreover, ectopic sclerostin production and deposition were also detectable in skin specimens from dialysis patients with calciphylaxis [53], while no such local sclerostin was found in control skin specimens from counterparts without cutaneous calcification. These and other previous experimental data indicate that Wnt signalling actively participates in atherosclerosis and vascular calcification [40, 49]. A missense mutation in LRP6, which encodes a co-receptor for sclerostin in the Wnt signalling pathway, was shown to be associated with autosomal dominant, early coronary artery disease [41]. Consequently, the particular role of sclerostin specifically in uraemic vascular disease is an interesting, novel, yet-to-be-investigated field [3]. However, these results are not without contradiction. Calcified epigastric artery specimens obtained at the time of renal transplantation were without relevant sclerostin mRNA and protein [54]. Interpretation of these heterogeneous and partly conflicting data, however, should take into account the anatomical structures (aortic valve, coronary artery, large elastic arteries) and heterogeneity of the study populations (particularly dialysis versus non-dialysis cohorts). With all these data in mind, the decisive question at this point in the discussion is: what happens when sclerostin activity is antagonized in the uraemic vascular wall, given the fact that local Wnt signalling is active in this setting [53]? The final answer is pending! We contend strongly for controlled human studies in which patients with combined bone and arteriosclerotic disease are investigated in the setting of sclerostin blockade with a thorough work-up for vascular and skeletal effects. SCLEROSTIN BLOCKADE IN CKD-MBD: THE GOOD, THE BAD, THE UGLY? Romosozumab is a potent osteoanabolic agent that promises to enrich our armamentarium in the treatment of osteoporosis. Nevertheless, future clinical practice inevitably will also have to deal with the fact that romosozumab-treated patients may suffer from or develop CKD-MBD—at least CKD Stage 3b patients. The two areas of interest identified in the discussion above in terms of sclerostin inhibition in the realm of CKD-MBD that should undergo further careful evaluation are as follows: Application of romosozumab in the treatment of renal osteodystrophy and particularly adynamic bone disease is appealing. It is presumably an over-simplification to attribute the driving force behind the development of adynamic bone solely to sclerostin overactivity. Nevertheless, blocking sclerostin opens fascinating prospects in terms of ameliorating PTH responsiveness as well as augmenting the bone metabolism by increasing the bone formation rate. Such a study could be adequately performed in the same order of magnitude as the previous BONAFIDE trial [55]. The BONAFIDE trial was a multicentre, single-arm study characterizing the skeletal response to cinacalcet in adult dialysis patients with plasma PTH levels of 300 pg/mL or more, serum calcium of 8.4 mg/dL or more, bone-specific alkaline phosphatase over 20.9 ng/mL and biopsy-proven high-turnover bone disease. Of 110 enrolled patients, 77 underwent a second bone biopsy with quantitative histomorphometry after 6–12 months of cinacalcet treatment. Assuming that sclerostin’s role in the vascular wall is similar to its physiological role in bone (i.e. decreasing mineralization), sclerostin blockade might actually stimulate mineralization, hence promoting vascular calcification. This should serve as a warning signal. 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PLoS One 2011 ; 6 : e19595 Google Scholar CrossRef Search ADS PubMed 52 Koos R , Brandenburg V , Mahnken AH et al. Sclerostin as a potential novel biomarker for aortic valve calcification: an in-vivo and ex-vivo study . J Heart Valve Dis 2013 ; 22 : 317 – 325 Google Scholar PubMed 53 Kramann R , Brandenburg VM , Schurgers LJ et al. Novel insights into osteogenesis and matrix remodelling associated with calcific uraemic arteriolopathy . Nephrol Dial Transplant 2013 ; 28 : 856 – 868 Google Scholar CrossRef Search ADS PubMed 54 Qureshi AR , Olauson H , Witasp A et al. Increased circulating sclerostin levels in end-stage renal disease predict biopsy-verified vascular medial calcification and coronary artery calcification . Kidney Int 2015 ; 88 : 1356 – 1364 Google Scholar CrossRef Search ADS PubMed 55 Behets GJ , Spasovski G , Sterling LR et al. Bone histomorphometry before and after long-term treatment with cinacalcet in dialysis patients with secondary hyperparathyroidism . Kidney Int 2015 ; 87 : 846 – 856 Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Sclerostin in chronic kidney disease–mineral bone disorder think first before you block it!

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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0931-0509
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Abstract

Abstract Canonical Wnt signalling activity is a major player in physiological and adaptive bone metabolism. Wnt signalling is regulated by soluble inhibitors, with sclerostin being the most widely studied. Sclerostin’s main origin is the osteocyte and its major function is blockade of osteoblast differentiation and function. Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Consequently, blocking sclerostin via human monoclonal antibodies (such as romosozumab) represents a promising perspective for the treatment of (postmenopausal) osteoporosis. However, sclerostin’s physiology and the effects of sclerostin monoclonal antibody treatment are not limited to the skeleton. Specifically, the potential roles of sclerostin in chronic kidney disease (CKD) and associated pathologies covered by the term chronic kidney disease and mineral bone disorder (CKD-MBD), which also includes accelerated cardiovascular calcification, warrant specific attention. CKD-MBD is a complex disease condition in which sclerostin antibodies may interfere at different levels and influence the multiform interplay of hyperparathyroidism, renal osteodystrophy and vascular calcification, but the clinical sequelae remain obscure. The present review summarizes the potential effects of sclerostin blockade in CKD-MBD. We will address and summarize the urgent research targets that are being identified and that need to be addressed before a valid risk–benefit ratio can be established in the clinical setting of CKD. bone metabolism, calcification, cardiovascular complication, chronic kidney disease–mineral bone disorder, vascular calcification PHYSIOLOGY OF SCLEROSTIN: WHAT CLINICIANS SHOULD KNOW Wnt signalling encompasses several (at least three) different signalling pathways including the canonical Wnt/beta-catenin pathway [1, 2]. The predominant function of the canonical Wnt pathway is stabilization of beta-catenin by inhibiting the activity of the beta-catenin degradation complex [3]. The function of the beta-catenin degradation complex is to phosphorylate beta-catenin [4]. Phosphorylation renders beta-catenin susceptible to proteolysis, whereby it does not accumulate in the nucleus. Only unphosphorylated beta-catenin can translocate into the nucleus and modulate target gene transcription locally [4]. Secreted Wnt inhibitors are a group of proteins that interfere with the extracellular binding of Wnt ligands to the transmembrane receptor complex [3, 5]. Among these, sclerostin, and to a lesser extent Dickkopf-related protein 1 (DKK-1), has previously been studied intensively [6]. Sclerostin (22 kDa) is a member of the cystatin knot family of proteins and is a product of the SOST gene [7]. It is measurable in human serum [8] and also qualified as a therapeutic target in osteoporosis [9]. Sclerostin prevents beta-catenin nuclear translocation and subsequent gene expression. It is secreted almost exclusively by osteocytes, and to a lesser extent by other cell types including osteoclast precursors [10]. Hence, viable osteocytes regulate the proper functionality of the skeleton via sclerostin synthesis and release [6, 10, 11]. Sclerostin deficiency associates with high bone mass as impressively revealed by the murine knockout model [12] (Figure 1). Loss-of-function mutations were reported in patients with van Buchem disease, a disorder closely resembling sclerosteosis [13, 14]. These human disorders coincide with the reduced activity of sclerostin. Sclerosteosis is caused by loss-of-function mutations in the SOST gene on chromosome 17q12-q21, which encodes sclerostin. In contrast, patients with van Buchem disease have a 52-kb homozygous noncoding deletion 35 kb downstream of the SOST gene, which is essential for the transcription of the gene in bone [13, 14]. Life expectancy in sclerosteosis is reduced, with a large proportion of patients dying in early adulthood, mainly from complications of increased intracranial pressure [14]. FIGURE 1: View largeDownload slide Micro-computed tomography scans of the femur metaphysis and diaphysis of 35-week-old sclerostin knockout (SOST−/−) animals compared with wild-type (WT) littermates (N. Kaesler and A. Verhulst, data on file). FIGURE 1: View largeDownload slide Micro-computed tomography scans of the femur metaphysis and diaphysis of 35-week-old sclerostin knockout (SOST−/−) animals compared with wild-type (WT) littermates (N. Kaesler and A. Verhulst, data on file). Sclerostin overexpression revealed the expected opposite phenotype, i.e. low bone mass as a consequence of reduced bone formation [15]. Targeting sclerostin via monoclonal antibody treatment has the potential to become a cornerstone of osteoporosis therapy due to its potent osteoanabolic activity [9]. However, before introducing widespread therapeutic use in patients with chronic kidney disease (CKD) as well, it is crucial to consider the specific complex situation in these patients. Indeed, in CKD, the intricate skeletal (renal osteodystrophy), hormonal (hyperparathyroidism) and vascular (calcification) changes and sclerostin’s role herein should be carefully weighed against each other. SCLEROSTIN ANTIBODIES AND OSTEOPOROSIS: IT WORKS! The comprehensive insights into the osseous mode of action of sclerostin antibodies come from various animal models. Preclinical studies in monkeys [16] revealed that the application of a humanized sclerostin monoclonal antibody increased the bone mineral content and/or bone mineral density at the femoral neck, radial metaphysis and tibial metaphysis. Bone histomorphometry showed marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical and intracortical surfaces, consistent with increased recruitment, activation and/or survival of osteoblasts. In young rats, application of sclerostin antibodies augmented cancellous and cortical bone mass and induced a strong increase in bone formation rate [17]. Accordingly, administration of sclerostin antibodies in 6-month-old rats that had undergone femoral osteotomy resulted in a significantly increased mineral apposition rate, mineralized surface and bone formation rate in trabecular bone of the distal femora [18]. It is noteworthy that romosozumab, a human monoclonal sclerostin antibody, has a dual mode of action in that in addition to its predominant influence upon bone formation, romosozumab also suppresses bone resorption; in human interventional trials, romosozumab application led to a sustained decrease in beta-CTX of up to 50% [9]. Application of romosozumab is an effective treatment to increase bone mineral density and reduce vertebral fracture risk in humans. In a previous 12-month Phase II trial, romosozumab treatment significantly increased bone mass in postmenopausal osteoporosis [19]. These findings were confirmed and extended in a Phase III study—the FRAME trial [9], in which 6390 postmenopausal osteoporotic women received romosozumab or placebo. Active treatment significantly reduced the vertebral fracture risk after 12 months [risk ratio 0.27; 95% confidence interval (CI) 0.16–0.47; P < 0.001]. However, romosozumab therapy was less clearly effective in risk reduction for non-vertebral fractures (0.75; 95% CI 0.53–1.05; P = 0.10) [9]. Finally, the ARCH study confirmed fracture-reducing properties of romosozumab in about 4000 postmenopausal women [20]. Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-followed-by-alendronate group [6.2% (127 of 2046 patients)] than in the alendronate-followed-by-alendronate group [11.9% (243 of 2047 patients)] (P < 0.001) [20]. In the ARCH study, the risk of hip fractures was also lowered by 38% in the romosozumab group: 41 of 2046 patients (2.0%) versus 66 of 2047 patients (3.2%). Of note, the ARCH trial raised safety concerns regarding the use of the sclerostin monoclonal antibody: during year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate [50 of 2040 patients (2.5%) versus 38 of 2014 patients (1.9%)] [20]—a finding that will undergo comprehensive review below. In summary, romosozumab represents a novel and effective osteoanabolic treatment strategy in human osteoporosis, at least with regard to postmenopausal fractures. THE POTENTIAL ROLE OF SCLEROSTIN AND SCLEROSTIN BLOCKADE IN NEPHROLOGY The above-mentioned physiological aspects and first results in postmenopausal osteoporosis studies turn sclerostin into an interesting research domain within the field of nephrology. Serum sclerostin measurements recently gained some interest in CKD as sclerostin levels varied with renal function [21] and serum levels were associated with a favourable outcome (the higher, the better) [22]. However, a substantial inter-variability has been reported between various sclerostin assays [23]. It is noteworthy that the association between serum sclerostin and outcome varies among different cohorts [22, 24, 25]. Based on these contradictory results from studies investigating the role of sclerostin as a prognostic biomarker and weak standardization of assays, we currently cannot recommend measuring serum sclerostin in clinical routine. The anabolic property renders sclerostin blockade particularly interesting for nephrologists, who face the threat of adynamic bone disease in many of their patients [26]. Before applying it to CKD patients, however, we need to know more about sclerostin’s involvement in renal osteodystrophy; moreover, we need to examine what might happen with sclerostin antibody treatment in this particular clinical setting. SCLEROSTIN AND RENAL OSTEODYSTROPHY Sclerostin is increasingly acknowledged as a modulator of renal osteodystrophy. The jck mouse model, which is a model of moderate progressive renal failure, nicely shows the time course of CKD–mineral bone disorder (CKD-MBD) parameters as kidney dysfunction progresses [27]. Interestingly, osteocytic sclerostin expression and consecutive suppression of beta-catenin signalling in this mouse model occurs earlier (at Week 5) than changes of parathyroid hormone (PTH) or fibroblast growth factor-23 (FGF-23) (at Week 10) The increased sclerostin expression also preceded cardiovascular and skeletal changes, typically seen in CKD-MBD and starting at about Week 15 and Week 9, respectively. The rise in sclerostin-positive osteocytes was transient and diminished in parallel with the severity of the developing hyperparathyroidism. These findings allow speculation that sclerostin is involved early in the development of renal osteodystrophy with some PTH-mediated counter-regulatory effects. We acknowledge that these findings, which are indicative of a subtle time course of renal osteodystrophy changes, should be re-evaluated in other models of renal failure. Our understanding about the role of sclerostin in uraemic bone disease grew substantially with experiments about the development of renal osteodystrophy in the absence of this early rise in sclerostin. Two working groups examined the renal osteodystrophy phenotype of sclerostin-deficient mice that had undergone 5/6th nephrectomy [28, 29]. One CKD model revealed a low [28], the other one a pronounced renal hyperparathyroidism [29]. Overall, the sclerostin deficiency was characterized by high cortical thickness, lower cortical porosity, lower bone marrow area and particularly, high bone volume as detected by micro-computed tomography compared with wild-type mice. Both groups came to a similar conclusion upon analysis of the skeletal phenotype: the development of renal osteodystrophy was masked by the overwhelming phenotype of the homozygous sclerostin deficiency [28, 29]. It is currently unknown which phenotype the opposite genetic model, i.e. overexpression of skeletal sclerostin, might exhibit in the setting of CKD and what might be the effect on the development of renal osteodystrophy. Data regarding sclerostin’s involvement in human renal osteodystrophy are limited: a study in which 60 adult dialysis patients underwent a bone biopsy after tetracycline labelling revealed a statistically significant negative correlation between serum sclerostin and PTH [30]. Most importantly, sclerostin showed pronounced negative associations with parameters of bone turnover, pointing towards a role of increased sclerostin levels in the development of adynamic bone disease [30]. Another bone biopsy study was done in patients with various levels of CKD [31]. The authors quantified both serum and bone sclerostin and found a weak correlation between the two. They confirmed a potential association between skeletal expression of sclerostin and turnover, since patients with high turnover had lower bone sclerostin expression than those with low bone turnover [31]. Interestingly, the bone expression of sclerostin quantified by immunohistochemistry varied significantly between different stages of CKD and revealed its peak in CKD Stages 2 and 3. In all CKD stages, it was higher than in healthy controls [31]. Noteworthy, sclerostin is not a lone warrior: other CKD-MBD mediators and Wnt signalling inhibitors act in concert in this setting, i.e. they directly inhibit osteoblastic Wnt activity and promote skeletal resistance to anabolic stimuli such as FGF-23 [32] or klotho [33]. However, putting forward the hypothesis that the development of adynamic bone disease in humans is (in part) mediated by a state of overactivity or sclerostin and similar mediators, thereby counterbalancing other osteoanabolic effectors, is currently still highly speculative. It is, however, noteworthy that PTH and sclerostin interact strongly with each other on a physiological basis. Hence, the PTH–sclerostin ‘balance’ is a suitable target in modulating the development of renal osteodystrophy. SCLEROSTIN AND PTH AND THEIR PHYSIOLOGICAL INTERPLAY: THEY NEED EACH OTHER PTH downregulates sclerostin expression in osteocytes, and this interaction represents an important aspect of how PTH stimulates bone metabolism [34]. There is substantial experimental evidence available that a balanced crosstalk between PTH and sclerostin is relevant for bone physiology. In healthy conditions, the anabolic activity of PTH, to a certain extent, is mediated by suppressing the anti-anabolic activity of sclerostin. PTH administration rapidly reduces sclerostin mRNA as well as protein synthesis in osteocytes [34, 35]. Kramer et al. convincingly showed skeletal PTH actions to rely upon sclerostin physiology [12]. They investigated the skeletal effects of intermittent PTH administration in mouse models with sclerostin overexpression and also with sclerostin deficiency. Six-month-old genetically engineered mice of both types underwent a 2-month treatment period with PTH (1–34). Both sclerostin-deficient as well as sclerostin-overexpressing mice revealed the expected skeletal phenotype, i.e. high bone mass in the former and severe osteopenia in the latter. In both mouse models, the response to intermittent PTH treatment in terms of stimulation of bone metabolism was significantly diminished. Therefore, the authors came to the conclusion that suppression of sclerostin in osteocytes is necessary to mediate anabolic responses to PTH [12]. As discussed above, uraemia may impel sclerostin expression and this chronic stimulation may turn sclerostin irresponsive to PTH, and this might be one important factor in skeletal uraemia-associated PTH resistance. Alternatively, high sclerostin levels may be the consequence of PTH resistance in the osteocytes. Additional research is needed to clarify this chicken-and-egg issue. In addition, sclerostin is believed to participate in several biochemical feedback loops, as evidenced by the fact that sclerostin-deficient mice reveal alterations in a number of classical biochemical CKD-MBD-related parameters [36]. While serum calcium and PTH levels were not different between sclerostin knockout and wild-type mice with normal renal function, FGF-23 levels were about 2.5 times lower in sclerostin-deficient mice compared with their wild-types, and conversely, 1, 25-dihydroxyvitamin D and serum phosphate levels were significantly elevated. Sclerostin also directly alters vitamin D synthesis in proximal tubular cells [36]. Taken together, the discovery of sclerostin sheds novel light on the long-standing discussion about skeletal PTH resistance in CKD and also on the pathophysiology of adynamic bone. From a therapeutic perspective, romosozumab appears to be an attractive option for haemodialysis patients, in particular because of the intermittent monthly application strategy, which might easily help overcome issues related to non-adherence in this patient cohort due to their particularly high pill burden. However, are we ready to apply romosozumab in severe CKD? SCLEROSTIN ANTIBODIES IN THE SETTING OF UNDERLYING RENAL OSTEODYSTROPHY: A NEW HOPE? In patients with normal renal function or only mildly impaired renal function, such as those participating in the Phase II and Phase III romosozumab trials mentioned above, application of the antibody was associated with a decrease in serum calcium and an increase in PTH levels. Such a finding can be interpreted as a reflection of stimulated bone anabolism or reduced bone resorption, respectively resulting in increased calcium incorporation into and/or decreased calcium efflux out of the bone, both resulting in consecutive PTH stimulation. Of note, in the FRAME trial [9], patients with <40 ng/mL 25-vitamin D levels at baseline received 50 000 to 60 000 IU of vitamin D, thus preventing incident hypocalcaemia. Due to lack of data, the magnitude and clinical meaning of such biochemical changes are unknown for patients with CKD Stages 3 or 4 or those on haemodialysis—a group of patients already prone to hypocalcaemia and secondary hyperparathyroidism (HPT). Hence, continuous attention is warranted. As the effects of sclerostin antibody treatment in humans with osteoporosis plus severe CKD Stages 3, 4 and 5 have not been investigated so far, fracture risk reduction or cellular effects are as yet undetermined in this population. However, the prospects behind romosozumab in renal osteodystrophy are enticing because such a treatment may hypothetically combine two modes of action: osteoanabolism plus a decrease in PTH resistance. Conditions associated with supra-physiological sclerostin activity may impede PTH-mediated bone anabolism. Adynamic bone disease is a subtype of renal osteodystrophy characterized by a substantially reduced bone formation rate, impaired remodelling activity and reduced osteoblastic and osteoclastic activity [37]. In uraemia, high sclerostin levels may exacerbate PTH resistance, which could cause and/or aggravate adynamic bone disease [26]. Therefore, blocking sclerostin is a valuable research target in treatment of low-turnover renal osteodystrophy and might help resuscitate cellular activity [10]. Newman et al. investigated the effects of sclerostin antibody treatment in Cy/+ rats, which resemble polycystic kidney disease [38]. Anti-sclerostin antibodies were applied in two different experimental settings—either in Cy/+ with uncontrolled hyperparathyroidism or in Cy/+ mice on a high calcium diet and with consecutively low PTH levels. Their data point towards relevant interactions between the status of underlying hyperparathyroidism and effects of anti-sclerostin antibody application. Sclerostin antibodies were effective in enhancing bone mass and ameliorating mechanical properties only if hyperparathyroidism was treated sufficiently (by high calcium intake) [38]. Only in the low-PTH group did sclerostin-antibody treatment reveal remarkable changes in renal osteodystrophy as evidenced by an increased cortical thickness and bone volume as well as an increase in bone quality/strength (as measured by ultimate load and energy to failure) [38]. Data from Moe et al. [39] point in comparable direction—i.e. the skeletal effects of sclerostin and sclerostin antibodies are different in renal failure versus healthy conditions and depend specifically upon the degree of renal hyperparathyroidism. In chronic renal failure rats, the researchers titrated renal hyperparathyroidism via calcium administration towards different levels of PTH and measured phosphorylated beta-catenin by western blot from total bone extracts. In the CKD animals, basal expression was 0.39 ± 0.18. In the CKD animals treated with anti-sclerostin antibody, the expression was 0.52 ± 0.28 in the high PTH group and 0.19 ± 0.17 in the low PTH group, with differences being significant between the two treated groups of P = 0.008). Phosphorylated beta-catenin expression represents degradation, and hence these data indicate a positive effect of the anti-sclerostin antibodies basically in the low PTH group, consistent with their bone volume findings. In summary, the application of sclerostin antibodies will certainly have an impact upon the degree and nature of renal osteodystrophy. Our current knowledge on sclerostin antibody treatment allows speculation about a potential amelioration of low bone turnover, and therefore, a future interventional trial targeting adynamic bone disease should be encouraged. However, any enthusiasm about increases in physiological mineralization or calcification induced by sclerostin antibodies should be weighed against the fact that similar processes are involved in cardiovascular calcification processes, which are another hallmark of CKD-MBD. Does sclerostin block ectopic mineralization processes as well? And most importantly, will this ectopic calcification ‘explode’ with sclerostin blockade? SCLEROSTIN AND CARDIOVASCULAR DISEASE: WHAT ABOUT VASCULAR CALCIFICATION? Wnt signalling and its alterations are not limited to the skeleton and play a role in human atherosclerosis [40, 41]. Figure 2 depicts the double role of sclerostin in the vascular wall and the bone compartment. Of note, ectopic vascular calcification and physiological bone formation share similarities in terms of the involved cellular processes [42]. FIGURE 2: View largeDownload slide Activity of Wnt signalling, and specifically of sclerostin as a Wnt antagonist, is not limited to the bone compartment. Wnt signalling also influences the integrity of the arterial wall. Hence, blocking sclerostin will impact the vascular calcification processes. Theoretically, sclerostin helps to prevent vascular calcification, as shown in the left part of the figure. FIGURE 2: View largeDownload slide Activity of Wnt signalling, and specifically of sclerostin as a Wnt antagonist, is not limited to the bone compartment. Wnt signalling also influences the integrity of the arterial wall. Hence, blocking sclerostin will impact the vascular calcification processes. Theoretically, sclerostin helps to prevent vascular calcification, as shown in the left part of the figure. In particular, the derangements in the Wnt signalling pathway and in the soluble Wnt inhibitors contribute to the development of uraemia-associated combined bone and vascular disease [43]. In consequence, we need to be cautious and not too optimistic regarding the likely absence of any potential cardiovascular side effects when blocking sclerostin activity [44]. In fact, the above-mentioned ARCH trial underlined the need to create additional data regarding the cardiovascular safety of romosozumab [20]. The clinical relevance of the higher incidence of serious adverse cardiovascular events in romosozumab-treated patients (2.5%) versus those receiving alendronate (1.9%) is currently unknown, but they fuel the hypothesis that sclerostin and accordingly its antibody play a role in the cardiovascular system. To the best of our knowledge, there are no data regarding the cardiovascular status in human genetic diseases due to reduced sclerostin activity, such as sclerosteosis or van Buchem’s disease [45]. A specific model of vascular calcification has been shown to act via Wnt signalling, i.e. vitamin K antagonist treatment. Vitamin K antagonists, such as warfarin, are suspected to trigger vascular calcification [46, 47]. Beazley et al. showed that warfarin activates beta-catenin signalling in vascular smooth muscle cells (VSMCs) in vitro by (i) increasing the amount of total beta-catenin protein, (ii) upregulating its nuclear translocation and (iii) stimulating transcription of beta-catenin target genes [48]. It was recently shown that sclerostin is necessary to preserve or strengthen vascular health. An interesting experimental set-up to investigate sclerostin’s role in atherosclerosis was elaborated by Krishna et al. [49]. The authors used ApoE-null mice, which develop atherosclerosis and aortic aneurysms with infusion of angiotensin II (AngII) [49]. In this study, the putative protective role of sclerostin was examined via two different experimental approaches, i.e. transgenic overexpression and recombinant mouse sclerostin injection. In this way, the authors were able to demonstrate that sclerostin protects AngII-infused ApoE-null mice from atherosclerosis and inflammation, aortic matrix degradation, as well as macrophage infiltration. Recent research indicates that in human aortic valve tissue from haemodialysis patients with microscopic as well as macroscopic calcification, a significant local sclerostin mRNA upregulation is detectable that is absent in aortic valve tissue from haemodialysis patients without calcification [50]. Thus, it is not uraemia per se, but the calcification process itself that is seemingly responsible for local sclerostin expression in the vascular system. Experimental in vitro data from Zhu et al. confirm sclerostin expression in calcifying VSMCs [51]. In vitro, VSMCs express osteocytic markers when grown in a pro-calcific environment, which is indicative of an osteoblastic to osteocytic transition (terminal transdifferentiation) [51]. Accordingly, the same authors found in vivo expression of sclerostin in calcified mouse aortas. The occurrence of sclerostin in calcified aortic valve tissue is not only limited to haemodialysis patients, but occurs in patients with dominant calcific aortic stenosis as well [52]. Moreover, ectopic sclerostin production and deposition were also detectable in skin specimens from dialysis patients with calciphylaxis [53], while no such local sclerostin was found in control skin specimens from counterparts without cutaneous calcification. These and other previous experimental data indicate that Wnt signalling actively participates in atherosclerosis and vascular calcification [40, 49]. A missense mutation in LRP6, which encodes a co-receptor for sclerostin in the Wnt signalling pathway, was shown to be associated with autosomal dominant, early coronary artery disease [41]. Consequently, the particular role of sclerostin specifically in uraemic vascular disease is an interesting, novel, yet-to-be-investigated field [3]. However, these results are not without contradiction. Calcified epigastric artery specimens obtained at the time of renal transplantation were without relevant sclerostin mRNA and protein [54]. Interpretation of these heterogeneous and partly conflicting data, however, should take into account the anatomical structures (aortic valve, coronary artery, large elastic arteries) and heterogeneity of the study populations (particularly dialysis versus non-dialysis cohorts). With all these data in mind, the decisive question at this point in the discussion is: what happens when sclerostin activity is antagonized in the uraemic vascular wall, given the fact that local Wnt signalling is active in this setting [53]? The final answer is pending! We contend strongly for controlled human studies in which patients with combined bone and arteriosclerotic disease are investigated in the setting of sclerostin blockade with a thorough work-up for vascular and skeletal effects. SCLEROSTIN BLOCKADE IN CKD-MBD: THE GOOD, THE BAD, THE UGLY? Romosozumab is a potent osteoanabolic agent that promises to enrich our armamentarium in the treatment of osteoporosis. Nevertheless, future clinical practice inevitably will also have to deal with the fact that romosozumab-treated patients may suffer from or develop CKD-MBD—at least CKD Stage 3b patients. The two areas of interest identified in the discussion above in terms of sclerostin inhibition in the realm of CKD-MBD that should undergo further careful evaluation are as follows: Application of romosozumab in the treatment of renal osteodystrophy and particularly adynamic bone disease is appealing. It is presumably an over-simplification to attribute the driving force behind the development of adynamic bone solely to sclerostin overactivity. Nevertheless, blocking sclerostin opens fascinating prospects in terms of ameliorating PTH responsiveness as well as augmenting the bone metabolism by increasing the bone formation rate. Such a study could be adequately performed in the same order of magnitude as the previous BONAFIDE trial [55]. The BONAFIDE trial was a multicentre, single-arm study characterizing the skeletal response to cinacalcet in adult dialysis patients with plasma PTH levels of 300 pg/mL or more, serum calcium of 8.4 mg/dL or more, bone-specific alkaline phosphatase over 20.9 ng/mL and biopsy-proven high-turnover bone disease. Of 110 enrolled patients, 77 underwent a second bone biopsy with quantitative histomorphometry after 6–12 months of cinacalcet treatment. Assuming that sclerostin’s role in the vascular wall is similar to its physiological role in bone (i.e. decreasing mineralization), sclerostin blockade might actually stimulate mineralization, hence promoting vascular calcification. This should serve as a warning signal. 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Kidney Int 2015 ; 87 : 846 – 856 Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Nephrology Dialysis TransplantationOxford University Press

Published: May 24, 2018

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