The Relationship between Serum Sclerostin Levels and Bone Mineral Disorders and Vascular Calcification in Hemodialysis Patients
DOI:
https://doi.org/10.3889/oamjms.2021.7578Keywords:
Bone mineral densitometry, End-stage renal disease, Hemodialysis, Vascular calcificationAbstract
Background and aim of the study: Sclerostin is produced by osteocytes and has been shown to down-regulate the synthesis of many markers of bone formation by osteogenic cells. The aim of this study to investigate the relationship between serum sclerostin levels and bone mineral disorders and vascular calcification in hemodialysis patients (HD).
Methods:This is a cross-sectional study of 70 patients with ESRD on regular HD for at least six months, Theodor Bilharz Research Institute, Giza, Egypt.Twenty-five subjects who matched the ages, genders, and demographics of the study patients were included as a control group.All patients and control groups included in the study underwent a full through history and clinical examination. Serum calcium, phosphorus, alkaline phosphatase and intact PTH (iPTH) levels were measured. Serum sclerostin was measured by an ELISA. Bone Mineral Densitometry Measurements BMD (g/cm2) was determined by dual-energy X-ray absorptiometry (DXA). CT scan was done to detect the presence or absence of vascular calcification and transthoracic echocardiogram to detect the presence or absence of valvular calcification.
Results:The mean seumscleostin levels was a statistically significant high in the HD patients when compared with the control group (156.8 ±121.4 Vs.29.38±0.84, p =0.0001 ) and statistically significant high mean ALP in the HD patients when compared with the control group (147.2 ± 94.3 Vs. 38.8 ±23.4, p = 0.0001). The mean BMD was statistically significant low in the HD patients when compared with the controls (0.839±0.086 g/ m2 Vs.1.306 ±0.153 g/ m2, p = 0.0001).The mean seumscleostin levels was statistically significant high in the HD patients with vascular and valvular calcification when compared with HD patients without calcification.Using spearman correlation coefficient analysis, there was statistically significant negative correlations between serum sclerostin levels and iPTH(r=-0.362, p =0.0021), ALP (r=-0.301, p =0.0114), and BMD (r=-0.469, p =0.0278 ), and there was a statistically significant positive correlation between serum sclerostin levels and phosphate(r=0.5829, p =0.0001 ).Independent predictors of BMD in HD patients were determined using multi-variate regression analysis. Sclerostin levels, iPTH, ALP, and age were found to be independent predictors of BMD.
Conclusion: High sclerostin levels in patients with ESRD on HD were associated with high risk of vascular and valvularcalcification and were independent predictors of low BMD in such population.
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Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skobier JE, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003;22(23):6267-76. https://doi.org/10.1093/emboj/cdg599. PMid:14633986 DOI: https://doi.org/10.1093/emboj/cdg599
van Bezooijen RL, Roelen BA, Visser A, van der Wee-Pals L, de Wilt E, Karperien M, et al. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med. 2004;199(6):805-14. https://doi.org/10.1084/jem.20031454 PMid:15024046 DOI: https://doi.org/10.1084/jem.20031454
Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Lowik CW, et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J. 2005;19(13):1842-4. https://doi.org/10.1096/fj.05-4221fje PMid:16123173 DOI: https://doi.org/10.1096/fj.05-4221fje
Moe S, Drueke T, Cunningham J, Goodman W, Martin K, Olgaard K, et al. Kidney disease: Improving global outcomes (KDIGO): Definition, evaluation, and classification of renal osteodystrophy: A position statement from kidney disease: Improving global outcomes (KDIGO). Kidney Int. 2006;69(11):1945-53. https://doi.org/10.1038/sj.ki.5000414 PMid:16641930 DOI: https://doi.org/10.1038/sj.ki.5000414
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2009;113:S1-130. https://doi.org/10.1038/ki.2009.188 PMid:19644521 DOI: https://doi.org/10.1038/ki.2009.188
Cannata-Andia JB, Roan-Garcia P, Hruska K. The connections between vascular calcification and bone health. Nephrol Dial Transplant. 2011;26(11):3429-36. https://doi.org/10.1093/ndt/gfr591 PMid:22039012 DOI: https://doi.org/10.1093/ndt/gfr591
Nitta K. Vascular calcification in patients with chronic kidney disease. Ther Apher Dial. 2011;15(6):513-21. https://doi.org/10.1111/j.1744-9987.2011.00979.x PMid:22107687 DOI: https://doi.org/10.1111/j.1744-9987.2011.00979.x
Krishnan V, Bryant HU, Macdougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest. 2006;116(5):1202-9. https://doi.org/10.1172/JCI28551 PMid:16670761 DOI: https://doi.org/10.1172/JCI28551
Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: From human mutations to treatments. Nat Med. 2013;19(2):179-92. https://doi.org/10.1038/nm.3074 PMid:23389618 DOI: https://doi.org/10.1038/nm.3074
Johnson ML, Kamel MA. The Wnt signaling pathway and bone metabolism. Curr Opin Rheumatol. 2007;19(4):376-82. https://doi.org/10.1097/BOR.0b013e32816e06f9 PMid:17551370 DOI: https://doi.org/10.1097/BOR.0b013e32816e06f9
Dejana E. The role of Wnt signaling in physiological and pathological angiogenesis. Circ Res. 2010;107(8):943-52. https://doi.org/10.1161/CIRCRESAHA.110.223750 PMid:20947863 DOI: https://doi.org/10.1161/CIRCRESAHA.110.223750
Vervloet MG, Massy ZA, Brandenburg VM, Mazzaferro S, Cozzolino M, Urena-Torres P, et al. Bone: A new endocrine organ at the heart of chronic kidney disease and mineral and bone disorders. Lancet Diabetes Endocrinol. 2014;2(5):427-36. https://doi.org/10.1016/S2213-8587(14)70059-2 PMid:24795256 DOI: https://doi.org/10.1016/S2213-8587(14)70059-2
Williams BO. Insights into the mechanisms of sclerostin action in regulating bone mass accrual. J Bone Miner Res. 2014;29(1):24-8. https://doi.org/10.1002/jbmr.2154 PMid:24285419 DOI: https://doi.org/10.1002/jbmr.2154
Brandenburg VM, Kramann R, Koos R, Kruger T, Schurgers L, Muhlenbruch G, et al. Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: A cross-sectional study. BMC Nephrol. 2013;14:219. https://doi.org/10.1186/1471-2369-14-219 PMid:24112318 DOI: https://doi.org/10.1186/1471-2369-14-219
Brandenburg VM, D’Haese P, Deck A, Mekahli D, Meijers B, Neven E, et al. From skeletal to cardiovascular disease in 12 steps-the evolution of sclerostin as a major player in CKD-MBD. Pediatr Nephrol. 2016;31(2):195-206. https://doi.org/10.1007/s00467-015-3069-7 PMid:25735207 DOI: https://doi.org/10.1007/s00467-015-3069-7
Goncalves FL, Elias RM, dos Reis LM, Graciolli FG, Zampieri FG, Oliveira RB, et al. Serum sclerostin is an independent predictor of mortality in hemodialysis patients. BMC Nephrol. 2014;15:190. https://doi.org/10.1186/1471-2369-15-190 PMid:25465028 DOI: https://doi.org/10.1186/1471-2369-15-190
Spencer K. Analytical reviews in clinical biochemistry: The estimation of creatinine. Ann Clin Biochem. 1986;23(1):1-25. https://doi.org/10.1177/000456328602300101 PMid:3532908 DOI: https://doi.org/10.1177/000456328602300101
Zein N, Ganuza C, Kushner I. Significance of serum C-reactive protein elevation in patients with systemic lupus erythematosus. Arthritis Rheum. 1979;22(1):7-12. https://doi.org/10.1002/art.1780220102 PMid:103559 DOI: https://doi.org/10.1002/art.1780220102
Okuno S, Inaba M, Kitatani K, Ishimura E, Yamakawa T, Nishizawa Y. Serum levels of C-terminal telopeptide of Type I collagen: A useful new marker of cortical bone loss in hemodialysis patients. Osteoporos Int. 2005;16(5):501-9. https://doi.org/10.1007/s00198-004-1712-4 PMid:15309383 DOI: https://doi.org/10.1007/s00198-004-1712-4
Kumeda Y, Inaba M, Tahara H, Kurioka Y, Ishikawa T, Morii H, et al. Persistent increase in bone turnover in Graves’ patients with subclinical hyperthyroidism. J Clin Endocrinol Metab. 2000;85(11):4157-61. https://doi.org/10.1210/jcem.85.11.6979 PMid:11095447 DOI: https://doi.org/10.1210/jcem.85.11.6979
Cejka D, Herberth J, Branscum AJ, Fardo DW, Monier- Faugere MC, Diarra D, et al. Sclerostin and dickkopf-1 in renal osteodystrophy. Clin J Am Soc Nephrol. 2011;6(4):877-82. https://doi.org/10.2215/CJN.06550810 PMid:21164019 DOI: https://doi.org/10.2215/CJN.06550810
Ardawi MS, Maimani AA, Bahksh TA, Rouzi AA, Qari MH, Radaddi RM. Reference intervals of biochemical bone turnover markers for Saudi Arabian women: A cross-sectional study. Bone. 2010;47(4):804-14. https://doi.org/10.1016/j.bone.2010.07.017 PMid:20659600 DOI: https://doi.org/10.1016/j.bone.2010.07.017
World Health Organization. Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis. Technical Report Series No. 843. Geneva: World Health Organization; 1994.
Canalis E. Wnt signaling in osteoporosis: Mechanisms and novel therapeutic approaches. Nat Rev Endocrinol. 2013;9(10):575-83. https://doi.org/10.1038/nrendo.2013.154 PMid:23938284 DOI: https://doi.org/10.1038/nrendo.2013.154
Viaene L, Behets GJ, Vlaes K, Meijers B, Blocki F, Brandenburg V, et al. Sclerostin: Another bone-related protein related to all-cause mortality in haemodialysis? Nephrol Dial Transplant. 2013;28(12):3024-30. https://doi.org/10.1093/ndt/gft039 PMid:23605174 DOI: https://doi.org/10.1093/ndt/gft039
Moorthi RN, Moe S. Recent advances in the noninvasive diagnosis of renal osteodystrophy. Kidney Int. 2013;84(5):886- 94. https://doi.org/10.1038/ki.2013.254 PMid:23802194 DOI: https://doi.org/10.1038/ki.2013.254
Cejka D, Marculescu R, Kozakowski N, Pischke M, Reiter T, Gessl A, et al. Renal elimination of sclerostin increases with declining kidney function. J Clin Endocrinol Metab. 2014;99(1):248-55. https://doi.org/10.1210/jc.2013-2786 PMid:24187403 DOI: https://doi.org/10.1210/jc.2013-2786
Roforth MM, Fujita K, McGregor UI, Kirmani S, McCready LK, Peterson JM, et al. Effects of age on bone mRNA levels of sclerostin and other genes relevant to bone metabolism in humans. Bone. 2014;59:1-6. https://doi.org/10.1016/j.bone.2013.10.019 PMid:24184314 DOI: https://doi.org/10.1016/j.bone.2013.10.019
Cejka D, Jager-Lansky A, Kieweg H, Weber M, Bieglmayer C, Haider DG, et al. Sclerostin serum levels correlate positively with bone mineral density and microarchitecture in haemodialysis patients. Nephrol Dial Transplant. 2012;27(1):226-30. https://doi.org/10.1093/ndt/gfr270 PMid:21613383 DOI: https://doi.org/10.1093/ndt/gfr270
Malluche HH, Davenport DL, Cantor T, Monier-Faugere MC. Bone mineral density and serum biochemical predictors of bone loss in patients with CKD on dialysis. Clin J Am Soc Nephrol. 2014;9(7):1254-62. https://doi.org/10.2215/CJN.09470913 PMid:24948144 DOI: https://doi.org/10.2215/CJN.09470913
Pelletier S, Dubourg L, Carlier MC, Hadj-Aissa A, Fouque D. The relation between renal function and serum sclerostin in adult patients with CKD. Clin J Am Soc Nephrol. 2013;8(5):819-23. https://doi.org/10.2215/CJN.07670712 PMid:23430206 DOI: https://doi.org/10.2215/CJN.07670712
Ishimura E, Okuno S, Ichii M, Norimine K, Yamakawa T, Shoji S, et al. Relationship between serum sclerostin, bone metabolism markers, and bone mineral density in maintenance hemodialysis patients. J Clin Endocrinol Metab. 2014;99(11):4315-20. https://doi.org/10.1210/jc.2014-2372 PMid:25093620 DOI: https://doi.org/10.1210/jc.2014-2372
Drechsler C, Evenepoel P, Vervloet MG, Wanner C, Ketteler M, Marx N, et al. High levels of circulating sclerostin are associated with better cardiovascular survival in incident dialysis patients: Results from the NECOSAD study. Nephrol Dial Transplant. 2015;30(2):288-93. https://doi.org/10.1093/ndt/gfu301 PMid:25248363 DOI: https://doi.org/10.1093/ndt/gfu301
Sabbagh Y, Graciolli FG, O’Brien S, Tang W, dos Reis LM, Ryan S, et al. Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy. J Bone Miner Res. 2012;27(8):1757-72. https://doi.org/10.1002/jbmr.1630 PMid:22492547 DOI: https://doi.org/10.1002/jbmr.1630
Bonani M, Rodriguez D, Fehr T, Mohebbi N, Brockmann J, Blum M, et al. Sclerostin blood levels before and after kidney transplantation. Kidney Blood Press Res. 2014;39(4):230-9. https://doi.org/10.1159/000355781. Epub 2014 Jul 31. https://doi.org/10.1159/000355781 PMid:25118597 DOI: https://doi.org/10.1159/000355781
Delanaye P, Krzesinski JM, Warling X, Moonen M, Smelten N, Medart L, et al. Clinical and biological determinants of sclerostin plasma concentration in hemodialysis patients. Nephron Clin Pract. 2014;128(1-2):127-34. https://doi.org/10.1159/000366449 PMid:25377055 DOI: https://doi.org/10.1159/000366449
Asamiya Y, Yajima A, Shimizu S, Otsubo S, Tsuchiya K, Nitta K. Association between the levels of sclerostin, phosphate, and fibroblast growth factor-23 and treatment with vitamin D in hemodialysis patients with low intact PTH level. Osteoporos Int. 2015;26(3):1017-28. https://doi.org/10.1007/s00198-014-2934-8 PMid:25366373 DOI: https://doi.org/10.1007/s00198-014-2934-8
Mirza FS, Padhi ID, Raisz LG, Lorenzo JA. Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. J Clin Endocrinol Metab. 2010;95(4):1991-7. https://doi.org/10.1210/jc.2009-2283 PMid:20156921 DOI: https://doi.org/10.1210/jc.2009-2283
Gennari L, Merlotti D, Valenti R, Ceccarelli E, Ruvio M, Pietrini MG, et al. Circulating sclerostin levels and bone turnover in Type 1 and Type 2 diabetes. J Clin Endocrinol Metab. 2012;97(5):1737-44. https://doi.org/10.1210/jc.2011-2958 PMid:22399511 DOI: https://doi.org/10.1210/jc.2011-2958
Zhu D, Mackenzie NC, Millan JL, Farquharson C, MacRae VE. The appearance and modulation of osteocyte marker expression during calcification of vascular smooth muscle cells. PLoS One. 2011;6(5):e19595-10. https://doi.org/10.1371/journal.pone.0019595 PMid:21611184 DOI: https://doi.org/10.1371/journal.pone.0019595
Koos R, Brandenburg V, Mahnken AH, Schneider RK, Dohmen G, Autschbach R, et al. Sclerostin as potential novel biomarker for artic valve calcification: An in vivo and ex vivo study. J Heart Valve Dis. 2013;22(3):317-26. PMid:24151757
Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D’Agostin D, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res. 2008;23(6):860-9. https://doi.org/10.1359/jbmr.080216 PMid:18269310 DOI: https://doi.org/10.1359/jbmr.080216
Ke HZ, Richards WG, Li X, Ominsky MS. Sclerostin and dickkopf-1 as therapeutic targets in bone diseases. Endocr Rev. 2012;33(5):747-83. https://doi.org/10.1210/er.2011-1060 PMid:22723594 DOI: https://doi.org/10.1210/er.2011-1060
Thambiah S, Roplekar R, Manghat P, Fogelman I, Fraser WD, Goldsmith D, et al. Circulating sclerostin and Dickkopf-1 (DKK1) in predialysis chronic kidney disease (CKD): Relationship with bone density and arterial stiffness. Calcif Tissue Int. 2012;90(6):473-80. https://doi.org/10.1007/s00223-012-9595-4 PMid:22527202 DOI: https://doi.org/10.1007/s00223-012-9595-4
Mödder UI, Hoey KA, Amin S, McCready LK, Achenbach SJ, Riggs BL, et al. Relation of age, gender, and bone mass to circulating sclerostin levels in women and men. J Bone Miner Res. 2011;26(2):373-9. https://doi.org/10.1002/jbmr.217 PMid:20721932 DOI: https://doi.org/10.1002/jbmr.217
Jean G, Chazot C. Sclerostin in CKD-MBD: One more paradoxical bone protein? Nephrol Dial Transplant. 2013;28(12):2932-5. https://doi.org/10.1093/ndt/gft222 PMid:24030835 DOI: https://doi.org/10.1093/ndt/gft222
Kirmani S, Amin S, McCready LK, Atkinson EJ, Melton LJ 3rd, Müller R, et al. Sclerostin levels during growth in children. Osteoporos Int. 2012;23:1123-130. https://doi.org/10.1007/s00198-011-1669-z PMid:21617991 DOI: https://doi.org/10.1007/s00198-011-1669-z
Amrein K, Amrein S, Drexler C, Dimai HP, Dobnig H, Pfeifer K, et al. Sclerostin and its association with physical activity, age, gender, body composition, and bone mineral content in healthy adults. J Clin Endocrinol Metab. 2012;97(1):148-54. https://doi.org/10.1210/jc.2011-2152 PMid:21994959 DOI: https://doi.org/10.1210/jc.2011-2152
Register TC, Hruska KA, Divers J, Bowden DW, Palmer ND, et al. Sclerostin is positively associated with bone mineral density in men and women and negatively associated with carotid calcified atherosclerotic plaque in men from the African American-diabetes heart study. J Clin Endocrinol Metab. 2014;99(1):315-21. https://doi.org/10.1210/jc.2013-3168 PMid:24178795 DOI: https://doi.org/10.1210/jc.2013-3168
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Copyright (c) 2020 Emad Abdallah, Nevine Sherif, Osama Mosbah, Amna Metwally (Author); Ibrahim Abd ElAzim; Ola Mahmoud, Mohamed Farouk, Samah Mamdouh, Samya El-Shishtawy, Asmaa Mohamed (Author)
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