nach oben

Journal für Mineralstoffwechsel & Muskuloskelettale Erkrankungen

Tipp

Anti-Sklerostin-Therapie aus nephrologischer Sicht – mit einem Fokus auf kardiovaskuläre Sicherheit

verfasst von: Prim. PD Dr. Daniel Cejka

Erschienen in: Journal für Mineralstoffwechsel & Muskuloskelettale Erkrankungen | Ausgabe 3/2021

Einloggen, um Zugang zu erhalten

Zusammenfassung

Die Zusammenhänge zwischen Sklerostin und Knochendichte, Gefäßverkalkung, kardiovaskulärer Morbidität und Mortalität bei chronischer Niereninsuffizienz („chronic kidney disease“, CKD) sind komplex und unvollständig verstanden. Es gibt experimentelle Hinweise, dass eine Anti-Sklerostin-Therapie bei CKD eine verminderte Wirkung auf den Knochen hat. Da Sklerostin auch sehr prominent in urämischen Gefäßen exprimiert wird, sind die möglichen kardiovaskulären Folgen einer Sklerostin-Hemmung bei CKD unklar. Der vorliegende Review gibt einen Überblick über die Physiologie und Pathophysiologie von Sklerostin in Knochen und Gefäßen bei CKD, den aktuellen Kenntnisstand zur Wirksamkeit und kardiovaskulären Sicherheit der Hemmung von Sklerostin bei Nierengesunden und CKD sowie die daraus resultierenden therapeutischen Implikationen.

Vorheriger Artikel Stellenwert der JAK-Inhibitoren („small is beautiful“)

Nächster Artikel Der Einfluss von Adipositas auf die Krankheitsaktivität bei entzündlich rheumatischen Erkrankungen

Moe S, Drueke T, Cunningham J et al (2006) Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 69:1945–1953 PubMedCrossRef

Sprague SM, Bellorin-Font E, Jorgetti V et al (2016) Diagnostic accuracy of bone turnover markers and bone histology in patients with CKD treated by dialysis. Am J Kidney Dis 67(4):559–566 PubMedCrossRef

Maré A, Verhulst A, Cavalier E et al (2019) Clinical inference of serum and bone sclerostin levels in patients with end-stage kidney disease. J Clin Med 8(12):2027 PubMedCentralCrossRef

Mause SF, Deck A, Hennies M et al (2016) Validation of commercially available ELISAs for the detection of circulating sclerostin in hemodialysis patients. Discoveries (Craiova) 4:e55 CrossRef

Moyses RM, Jamal SA, Graciolli FG et al (2015) Can we compare serum sclerostin results obtained with different assays in hemodialysis patients? Int Urol Nephrol 47:847–850 PubMedCrossRef

Cejka D, Herberth J, Branscum AJ et al (2011) Sclerostin and Dickkopf‑1 in renal osteodystrophy. Clin J Am Soc Nephrol 6:877–882 PubMedPubMedCentralCrossRef

de Oliveira RA, Barreto FC, Mendes M et al (2015) Peritoneal dialysis per se is a risk factor for sclerostin-associated adynamic bone disease. Kidney Int 87:1039–1045 PubMedCrossRef

Boltenstal H, Qureshi AR, Behets GJ et al (2019) Association of serum sclerostin with bone sclerostin in chronic kidney disease is lost in glucocorticoid treated patients. Calcif Tissue Int 104:214–223 PubMedCrossRef

Pelletier S, Dubourg L, Carlier MC, Hadj-Aissa A, Fouque D (2013) The relation between renal function and serum sclerostin in adult patients with CKD. Clin J Am Soc Nephrol 8(5):819–823 PubMedPubMedCentralCrossRef

10.

Cejka D, Jäger-Lansky A, Kieweg H et al (2012) Sclerostin serum levels correlate positively with bone mineral density and microarchitecture in haemodialysis patients. Nephrol Dial Transplant 27(1):226–230 PubMedCrossRef

11.

Lima F, Mawad H, El-Husseini AA et al (2019) Serum bone markers in ROD patients across the spectrum of decreases in GFR: activin A increases before all other markers. Clin Nephrol 91:222–230 PubMedPubMedCentralCrossRef

12.

Cejka D, Marculescu R, Kozakowski N et al (2014) Renal elimination of sclerostin increases with declining kidney function. J Clin Endocrinol Metab 99(1):248–255 PubMedCrossRef

13.

Graciolli FG, Neves KR, Barreto F et al (2017) The complexity of chronic kidney disease-mineral and bone disorder across stages of chronic kidney disease. Kidney Int 91:1436–1446 PubMedCrossRef

14.

Sabbagh Y, Graciolli FG, O’Brien S et al (2012) Repression of osteocyte Wnt/beta-catenin signaling is an early event in the progression of renal osteodystrophy. J Bone Miner Res 27:1757–1772 PubMedCrossRef

15.

Araújo MJCLN, Bacelar Marques ID, Graciolli FG et al (2019) Comparison of serum levels with bone content and gene expression indicate a contradictory effect of kidney transplantation on sclerostin. Kidney Int 96:1100–1104 PubMedCrossRef

16.

Nordholm A, Mace ML, Gravesen E et al (2018) Klotho and activin A in kidney injury: plasma Klotho is maintained in unilateral obstruction despite no upregulation of Klotho biosynthesis in the contralateral kidney. Am J Physiol Renal Physiol 314:F753–F762 PubMedCrossRef

17.

Fayed A, Abdulazim DO, Amin M et al (2021) Serum sclerostin in acute kidney injury patients. Nefrologia. https://doi.org/10.1016/j.nefro.2021.01.010 CrossRefPubMed

18.

Moustafa A, Sugiyama T, Prasad J et al (2012) Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered. Osteoporos Int 23:1225–1234 PubMedCrossRef

19.

Gaudio A, Pennisi P, Bratengeier C et al (2010) Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss. J Clin Endocrinol Metab 95:2248–2253 PubMedCrossRef

20.

Zhu D, Mackenzie NC, Millan JL et al (2011) The appearance and modulation of osteocyte marker expression during calcification of vascular smooth muscle cells. PLoS ONE 6:e19595 PubMedPubMedCentralCrossRef

21.

Bisson SK, Ung RV, Picard S et al (2019) High calcium, phosphate and calcitriol supplementation leads to an osteocyte-like phenotype in calcified vessels and bone mineralisation defect in uremic rats. J Bone Miner Metab 37:212–223 PubMedCrossRef

22.

Rukov JL, Gravesen E, Mace ML et al (2016) Effect of chronic uremia on the transcriptional profile of the calcified aorta analyzed by RNA sequencing. Am J Physiol Renal Physiol 310:F477–F491 PubMedPubMedCentralCrossRef

23.

Zhou H, Yang M, Li M et al (2017) Radial artery sclerostin expression in chronic kidney disease stage 5 predialysis patients: a cross-sectional observational study. Int Urol Nephrol 49:1433–1437 PubMedCrossRef

24.

Li M, Zhou H, Yang M et al (2019) Relationship between serum sclerostin, vascular sclerostin expression and vascular calcification assessed by different methods in ESRD patients eligible for renal transplantation: a cross-sectional study. Int Urol Nephrol 51:311–323 PubMedCrossRef

25.

Qureshi AR, Olauson H, Witasp A et al (2015) Increased circulating sclerostin levels in end-stage renal disease predict biopsy-verified vascular medial calcification and coronary artery calcification. Kidney Int 88:1356–1364 PubMedCrossRef

26.

Brandenburg VM, Verhulst A, Babler A et al (2019) Sclerostin in chronic kidney disease-mineral bone disorder think first before you block it! Nephrol Dial Transplant 34:408–414 PubMedCrossRef

27.

Mace ML, Gravesen E, Nordholm A et al (2021) Chronic kidney disease-induced vascular calcification impairs bone metabolism. J Bone Miner Res 36:510–522 PubMedCrossRef

28.

Brunkow ME, Gardner JC, Van NJ et al (2001) Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 68:577–589 PubMedPubMedCentralCrossRef

29.

Balemans W, Ebeling M, Patel N et al (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10:537–543 PubMedCrossRef

30.

Balemans W, Patel N, Ebeling M et al (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39:91–97 PubMedPubMedCentralCrossRef

31.

Hamersma H, Gardner J, Beighton P (2003) The natural history of sclerosteosis. Clin Genet 63:192–197 PubMedCrossRef

32.

Li X, Ominsky MS, Warmington KS et al (2009) Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 24:578–588 PubMedCrossRef

33.

Ominsky MS, Vlasseros F, Jolette J et al (2010) Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Miner Res 25:948–959 PubMedCrossRef

34.

Li X, Ominsky MS, Niu QT et al (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869 PubMedCrossRef

35.

Turk JR, Deaton AM, Yin J et al (2020) Nonclinical cardiovascular safety evaluation of romosozumab, an inhibitor of sclerostin for the treatment of osteoporosis in postmenopausal women at high risk of fracture. Regul Toxicol Pharmacol 115:104697 PubMedCrossRef

36.

Kaesler N, Verhulst A, De Mare A et al (2018) Sclerostin deficiency modifies the development of CKD-MBD in mice. Bone 107:115–123 PubMedCrossRef

37.

Bovijn J, Krebs K, Chen CY et al (2020) Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics. Sci Transl Med 12(549):eaay6570 PubMedPubMedCentralCrossRef

38.

Holdsworth G, Staley JR, Hall P et al (2021) Sclerostin downregulation globally by naturally occurring genetic variants, or locally in atherosclerotic plaques, does not associate with cardiovascular events in humans. J Bone Miner Res. https://doi.org/10.1002/jbmr.4287 CrossRefPubMed

39.

Desjardins L, Liabeuf S, Oliveira RB et al (2014) Uremic toxicity and sclerostin in chronic kidney disease patients. Nephrol Ther 10:463–470 PubMedCrossRef

40.

Hsu BG, Liou HH, Lee CJ et al (2016) Serum sclerostin as an independent marker of peripheral arterial stiffness in renal transplantation recipients: a cross-sectional study. Medicine 95:e3300 PubMedPubMedCentralCrossRef

41.

Jin S, Zhu M, Yan J et al (2016) Serum sclerostin level might be a potential biomarker for arterial stiffness in prevalent hemodialysis patients. Biomark Med 10:689–699 PubMedCrossRef

42.

Stavrinou E, Sarafidis PA, Koumaras C et al (2019) Increased sclerostin, but not Dickkopf‑1 protein, is associated with elevated pulse wave velocity in hemodialysis subjects. Kidney Blood Press Res 44:679–689 PubMedCrossRef

43.

Wu CF, Hou JS, Wang CH et al (2020) Serum sclerostin but not DKK‑1 correlated with central arterial stiffness in end stage renal disease patients. Int J Environ Res Public Health 17(4):1230 PubMedCentralCrossRef

44.

Kundakci Gelir G, Sengul S, Nergizoglu G et al (2018) Is sclerostin level associated with cardiovascular diseases in hemodialysis patients? Blood Purif 46:118–125 PubMedCrossRef

45.

Petrovic M, Baralic M, Brkovic V et al (2020) Significance of acPWV for survival of hemodialysis patients. Medicina (Kaunas) 56(9):435 CrossRef

46.

Thambiah S, Roplekar R, Manghat P et al (2012) Circulating sclerostin and Dickkopf‑1 (DKK1) in predialysis chronic kidney disease (CKD): relationship with bone density and arterial stiffness. Calcif Tissue Int 90:473–480 PubMedCrossRef

47.

Viaene L, Behets GJ, Claes K et al (2013) Sclerostin: another bone-related protein related to all-cause mortality in haemodialysis? Nephrol Dial Transplant 28(12):3024–3030 PubMedCrossRef

48.

Kanbay M, Siriopol D, Saglam M et al (2014) Serum sclerostin and adverse outcomes in nondialyzed chronic kidney disease patients. J Clin Endocrinol Metab 99:E1854–E1861 PubMedCrossRef

49.

Drechsler C, Evenepoel P, Vervloet MG et al (2015) High levels of circulating sclerostin are associated with better cardiovascular survival in incident dialysis patients: results from the NECOSAD study. Nephrol Dial Transplant 30:288–293 PubMedCrossRef

50.

Jean G, Chazot C, Bresson E et al (2016) High serum sclerostin levels are associated with a better outcome in haemodialysis patients. Nephron 132:181–190 PubMedCrossRef

51.

Lips L, de Roij van Zuijdewijn CLM, Ter Wee PM et al (2017) Serum sclerostin: relation with mortality and impact of hemodiafiltration. Nephrol Dial Transplant 32:1217–1223 PubMed

52.

Chen A, Sun Y, Cui J et al (2018) Associations of sclerostin with carotid artery atherosclerosis and all-cause mortality in Chinese patients undergoing maintenance hemodialysis. BMC Nephrol 19:264 PubMedPubMedCentralCrossRef

53.

Kalousová M, Dusilová-Sulková S, Kuběna AA et al (2019) Sclerostin levels predict cardiovascular mortality in long-term hemodialysis patients: a prospective observational cohort study. Physiol Res 68:547–558 PubMedCrossRef

54.

Zou Y, Yang M, Wang J et al (2020) Association of sclerostin with cardiovascular events and mortality in dialysis patients. Ren Fail 42:282–288 PubMedPubMedCentralCrossRef

55.

Zeng S, Slowinski T, Pommer W et al (2020) Sclerostin is an independent risk factor for all-cause mortality in kidney transplant recipients. Clin Exp Nephrol 24:1177–1183 PubMedPubMedCentralCrossRef

56.

Stavrinou E, Sarafidis PA, Loutradis C et al (2021) Associations of serum sclerostin and Dickkopf-related protein‑1 proteins with future cardiovascular events and mortality in haemodialysis patients: a prospective cohort study. Clin Kidney J 14:1165–1172 PubMedCrossRef

57.

Goncalves FL, Elias RM, dos Reis LM et al (2014) Serum sclerostin is an independent predictor of mortality in hemodialysis patients. BMC Nephrol 15:190 PubMedPubMedCentralCrossRef

58.

Gong L, Zheng D, Yuan J et al (2018) Elevated levels of serum sclerostin are linked to adverse cardiovascular outcomes in peritoneal dialysis patients. Int Urol Nephrol 50:955–961 PubMedCrossRef

59.

Sato M, Hanafusa N, Kawaguchi H et al (2018) A prospective cohort study showing no association between serum sclerostin level and mortality in maintenance hemodialysis patients. Kidney Blood Press Res 43:1023–1033 PubMedCrossRef

60.

Ge Y, Wu B, Yu X et al (2021) Association of serum sclerostin level, coronary artery calcification, and patient outcomes in maintenance dialysis patients. Blood Purif. https://doi.org/10.1159/000516410 CrossRefPubMed

61.

Jørgensen HS, Winther S, Dupont L et al (2018) Sclerostin is not associated with cardiovascular event or fracture in kidney transplantation candidates. Clin Nephrol 90:18–26 PubMedCrossRef

62.

Kirkpantur A, Balci M, Turkvatan A et al (2016) Serum sclerostin levels, arteriovenous fistula calcification and 2‑years all-cause mortality in prevalent hemodialysis patients. Nefrologia 36:24–32 PubMedCrossRef

63.

Ishimura E, Okuno S, Ichii M et al (2014) Relationship between serum sclerostin, bone metabolism markers, and bone mineral density in maintenance hemodialysis patients. J Clin Endocrinol Metab 99:4315–4320 PubMedCrossRef

64.

Kuo TH, Lin WH, Chao JY et al (2019) Serum sclerostin levels are positively related to bone mineral density in peritoneal dialysis patients: a cross-sectional study. BMC Nephrol 20:266 PubMedPubMedCentralCrossRef

65.

Ho TY, Chen NC, Hsu CY et al (2019) Evaluation of the association of Wnt signaling with coronary artery calcification in patients on dialysis with severe secondary hyperparathyroidism. BMC Nephrol 20:345 PubMedPubMedCentralCrossRef

66.

Elsalam MA, El-Abden MZ, Mahmoud E et al (2019) Correlation between serum sclerostin level and bone density status in children on regular hemodialysis. Saudi J Kidney Dis Transpl 30:1022–1031 PubMedCrossRef

67.

Szulc P, Boutroy S, Vilayphiou N et al (2013) Correlates of bone microarchitectural parameters and serum sclerostin levels in men—the STRAMBO study. J Bone Miner Res 28(8):1760–1770 PubMedCrossRef

68.

Atteritano M, Di Mauro E, Canale V et al (2017) Higher serum sclerostin levels and insufficiency of vitamin D are strongly associated with vertebral fractures in hemodialysis patients: a case control study. Osteoporos Int 28:577–584 PubMedCrossRef

69.

Malluche HH, Davenport DL, Cantor T et al (2014) Bone mineral density and serum biochemical predictors of bone loss in patients with CKD on dialysis. Clin J Am Soc Nephrol 9:1254–1262 PubMedPubMedCentralCrossRef

70.

Malluche HH, Monier-Faugere MC, Blomquist G et al (2018) Two-year cortical and trabecular bone loss in CKD-5D: biochemical and clinical predictors. Osteoporos Int 29:125–134 PubMedCrossRef

71.

Ferrari SL (2018) Romosozumab to rebuild the foundations of bone strength. Nat Rev Rheumatol 14:128–128 PubMedCrossRef

72.

Cosman F, Crittenden DB, Adachi JD et al (2016) Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 375(16):1532–1543 PubMedCrossRef

73.

Saag KG, Petersen J, Brandi ML et al (2017) Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med 377:1417–1427 PubMedCrossRef

74.

Lewiecki EM, Blicharski T, Goemaere S et al (2018) A phase III randomized placebo-controlled trial to evaluate efficacy and safety of romosozumab in men with osteoporosis. J Clin Endocrinol Metab 103:3183–3193 PubMedCrossRef

75.

Lv F, Cai X, Yang W et al (2020) Denosumab or romosozumab therapy and risk of cardiovascular events in patients with primary osteoporosis: systematic review and meta-analysis. Bone 130:115121 PubMedCrossRef

76.

Li L, Gong M, Bao D et al (2020) Denosumab and romosozumab do not increase the risk of cardiovascular events in patients with primary osteoporosis: a reanalysis of the meta-analysis. Bone 134:115270 PubMedCrossRef

77.

Cummings SR, McCulloch C (2020) Explanations for the difference in rates of cardiovascular events in a trial of alendronate and romosozumab. Osteoporos Int 31:1019–1021 PubMedCrossRef

78.

Langdahl BL, Hofbauer LC, Forfar JC (2021) Cardiovascular safety and sclerostin inhibition. J Clin Endocrinol Metab 106:1845–1853 PubMedCrossRef

79.

Kang JH, Keller JJ, Lin HC (2013) Bisphosphonates reduced the risk of acute myocardial infarction: a 2-year follow-up study. Osteoporos Int 24:271–277 PubMedCrossRef

80.

Kim DH, Rogers JR, Fulchino LA et al (2015) Bisphosphonates and risk of cardiovascular events: a meta-analysis. PLoS ONE 10:e122646 PubMedPubMedCentralCrossRef

81.

Kranenburg G, Bartstra JW, Weijmans M et al (2016) Bisphosphonates for cardiovascular risk reduction: a systematic review and meta-analysis. Atherosclerosis 252:106–115 PubMedCrossRef

82.

Cummings SR, Lui LY, Eastell R et al (2019) Association between drug treatments for patients with osteoporosis and overall mortality rates: a meta-analysis. JAMA Intern Med 179:1491–1500 PubMedPubMedCentralCrossRef

83.

Vestergaard Kvist A, Faruque J, Vallejo-Yague E et al (2021) Cardiovascular safety profile of romosozumab: a pharmacovigilance analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS). J Clin Med 10(8):1660 PubMedPubMedCentralCrossRef

84.

FDA (2019) Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee. 16. Jan. 2019. Meeting announcement

85.

Cejka D, Parada-Rodriguez D, Pichler S et al (2016) Only minor differences in renal osteodystrophy features between wild-type and sclerostin knockout mice with chronic kidney disease. Kidney Int 90(4):828–834 PubMedPubMedCentralCrossRef

86.

Moe SM, Chen NX, Newman CL et al (2015) Anti-sclerostin antibody treatment in a rat model of progressive renal osteodystrophy. J Bone Miner Res 30(3):499–509 PubMedCrossRef

87.

Miller PAJ, Albergari B, Cheung AM, Chines A, Gielen E, Langdahl B, Miyauchi A, Oates M, Reid I, Ruiz Santiago N, Vanderkelen M, Yang W, Yu Z (2020) Efficacy and safety of romosozumab among postmenopausal women with osteoporosis and mild-to-moderate chronic kidney disease. Ann Rheum Dis 79:185 CrossRef

88.

ClinicalTrials.gov (2021) Study of romosozumab (AMG 785) administered to healthy participants and patients with stage 4 renal impairment or stage 5 renal impairment requiring hemodialysis

89.

Amgentrials.com (2015) A phase 1, open-label, single-dose study of romosozumab (AMG 785). Administered subcutaneously to healthy subjects and subjects with stage 4 renal impairment or stage 5 renal impairment requiring hemodialysis

Titel: Anti-Sklerostin-Therapie aus nephrologischer Sicht – mit einem Fokus auf kardiovaskuläre Sicherheit
verfasst von: Prim. PD Dr. Daniel Cejka
Publikationsdatum: 11.08.2021
Verlag: Springer Vienna
Erschienen in: Journal für Mineralstoffwechsel & Muskuloskelettale Erkrankungen / Ausgabe 3/2021
Print ISSN: 2412-8260
Elektronische ISSN: 2412-8287
DOI: https://doi.org/10.1007/s41970-021-00162-w

Home

Zeitschriften

Zeitungen

Podcast

Gesundheitspolitik

Praxis

Leben

Jobs

Fachgebiete

Subfächer Innere Medizin

Fortbildungen

Springer Medizin Österreich

Tipp

Weitere Artikel dieser Ausgabe durch Wischen aufrufen

Anti-Sklerostin-Therapie aus nephrologischer Sicht – mit einem Fokus auf kardiovaskuläre Sicherheit

Zusammenfassung

Fachgebiete

Subfächer Innere Medizin

Fortbildungen

Springer Medizin Österreich

Tipp

Weitere Artikel dieser Ausgabe durch Wischen aufrufen

Zusammenfassung

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2021

Der Einfluss von Adipositas auf die Krankheitsaktivität bei entzündlich rheumatischen Erkrankungen

Mitteilungen des Magnesiumforum Bad Radkersburg

News-Screen Osteologie

News-Screen Orthopädie & Traumatologie

News-Screen Physikalische Medizin

Stellenwert der JAK-Inhibitoren („small is beautiful“)