Kidney Function and Bone Fragility

Diabetes, high blood pressure and obesity are risk factors for chronic kidney disease (CKD). Roughly 10% of the population worldwide is affected. As the function of the kidneys decline, bone fracture risk increases. Bone fragility is associated with kidney function. Sclerostin is a key molecule in bone metabolism. A novel antibody, blocking the actions of Sclerostin, has become available for treating severe osteoporosis. Whether Sclerostin inhibition is useful in the clinical setting of CKD is discussed in the following review:

Cardiovascular Safety of Anti-Sclerostin Therapy in Chronic Kidney Disease.

Cejka D. Metabolites. 2021 Nov 10;11(11):770. doi: 10.3390/metabo11110770. PMID: 34822428; PMCID: PMC8624769.

Abstract

The significance of sclerostin for bone and cardiovascular health in patients with chronic kidney disease (CKD) is complex and incompletely understood. Experimental evidence suggests that anti-sclerostin therapy shows diminished efficacy on bone in the setting of CKD. Limited clinical evidence suggests that the osteoanabolic and anti-resorptive activity is attenuated, but hypocalcemia is more prevalent in patients with advanced CKD (eGFR < 30 mL/min) treated with anti-sclerostin (romosozumab) therapy as compared to patients without kidney disease. Furthermore, sclerostin is prominently expressed in uremic arteries. Whether the inhibition of sclerostin has adverse effects on cardiovascular health in CKD is currently unknown. This review summarizes the current understanding of the physiology and pathophysiology of sclerostin in CKD, with a focus on the cardiovascular safety of anti-sclerostin therapy in patients with or without CKD.

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Related publications

Bone Fragility Fractures in CKD Patients.

Pimentel A, Ureña-Torres P, Bover J, Luis Fernandez-Martín J, Cohen-Solal M. Calcif Tissue Int. 2021 Apr;108(4):539-550. doi: 10.1007/s00223-020-00779-z. Epub 2020 Nov 21. PMID: 33219822; PMCID: PMC8052229.

Abstract

Chronic kidney diseases (CKD) are associated with mineral and bone diseases (MBD), including pain, bone loss, and fractures. Bone fragility related to CKD includes the risk factors observed in osteoporosis in addition to those related to CKD, resulting in a higher risk of mortality related to fractures. Unawareness of such complications led to a poor management of fractures and a lack of preventive approaches. The current guidelines of the Kidney Disease Improving Global Outcomes (KDIGO) recommend the assessment of bone mineral density if results will impact treatment decision. In addition to bone density, circulating biomarkers of mineral, serum bone turnover markers, and imaging techniques are currently available to evaluate the fracture risk. The purpose of this review is to provide an overview of the epidemiology and pathogenesis of CKD-associated bone loss. The contribution of the current tools and other techniques in development are discussed. We here propose a current view of how to better predict bone fragility and the therapeutic options in CKD.

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

Brandenburg VM, Verhulst A, Babler A, D’Haese PC, Evenepoel P, Kaesler N. Nephrol Dial Transplant. 2019 Mar 1;34(3):408-414. doi: 10.1093/ndt/gfy129. PMID: 29846712.

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.

Sclerostin: a new biomarker of CKD-MBD.

Figurek A, Rroji M, Spasovski G. Int Urol Nephrol. 2020 Jan;52(1):107-113. doi: 10.1007/s11255-019-02290-3. Epub 2019 Oct 14. PMID: 31612420.

Abstract

The causes of the increased cardiovascular risk associated with kidney diseases partly reside in the chronic kidney disease-mineral bone disorder (CKD-MBD) syndrome. Three cardiovascular risk factors [hyperphosphatemia, vascular calcification, and elevated fibroblast growth factor 23 (FGF23)] levels have been discovered within the CKD-MBD over the last decades. In addition, sclerostin is recently presented as a new bone and vascular disease biomarker. This 22-kDa glycoprotein, secreted mainly by osteocytes, is a soluble inhibitor of the canonical Wnt pathway that has a pivotal role in bone biology and turnover. CKD patients are reported with higher levels of sclerostin, and levels decrease during dialysis. Sclerostin is associated with vascular calcification and CV risk in CKD, although data are still controversial. The question whether serum sclerostin has protective or deleterious role in CKD-MBD pathophysiology, and therefore in cardiovascular risk and overall mortality, is still open and needs to be answered. The standardization of assays and the establishment of a clear cut-off values when sclerostin starts to switch from physiological to pathophysiological role have to be another important step. Further research is needed also to define its relationship with other CKD-MBD biomarkers for future diagnostic and therapeutic strategies.

Serum sclerostin in vascular calcification and clinical outcome in chronic kidney disease.

Zeng C, Guo C, Cai J, Tang C, Dong Z. Diab Vasc Dis Res. 2018 Mar;15(2):99-105. doi: 10.1177/1479164117742316. Epub 2017 Nov 23. PMID: 29168393.

Abstract

Sclerostin, a potent soluble inhibitor of the Wnt signalling pathway, is known to inhibit bone formation by suppressing osteocytes differentiation and function. Patients with chronic kidney disease have high levels of serum sclerostin. Sclerostin has been implicated in the pathogenesis of vascular calcification, which may promote the cardiovascular events of morbidity and mortality in chronic kidney disease patients. However, the role of sclerostin in vascular calcification and clinical prognosis in chronic kidney disease remains elusive. While some studies suggested a positive correlation between serum sclerostin and vascular calcification or clinical outcome, other studies showed no or even negative correlation between them. Small sample size, heterogeneity in enrolled patients, discrepancy in anatomical structure examined and differences in the applied assays may be responsible for the discrepant results. Nonetheless, anti-sclerostin antibodies may be a new therapeutic approach to increase bone mass and strength in chronic kidney disease. This review aims to have a better understanding of the relationship of serum sclerostin with vascular calcification and clinical outcome in chronic kidney disease patients, and propose the application of anti-sclerostin therapy in chronic kidney disease.

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Bioactive Sclerostin ELISA kit – cat.no. BI-20472