Circulating Sclerostin in Bone Sclerosing Disorders

  • Antoon H. van Lierop
  • Socrates E. PapapoulosEmail author
Reference work entry
Part of the Biomarkers in Disease: Methods, Discoveries and Applications book series (BDMDA)


Sclerostin is a negative regulator of bone formation, which is produced by osteocytes and acts on osteoblasts where it binds the LRP5/6 co-receptors and antagonizes canonical Wnt signaling in these cells. The availability of commercial assays to measure sclerostin in blood initiated numerous clinical studies to elucidate the role of this protein in physiological and disordered bone metabolism. In interpreting results of such studies it is important to consider that neither the active form of sclerostin nor its metabolism are currently known and values obtained with available assays are moderately correlated. However, measurement of circulating sclerostin can assist the differential diagnosis of patients with rare bone sclerosing disorders and high bone mass such as sclerosteosis, van Buchem disease, and the high bone mass phenotype.


DKK1 High bone mass phenotype Bone turnover LRP4 Sclerosteosis Sclerostin van Buchem disease Wnt signaling 

List of Abbreviations


Carboxyterminal collagen crosslinks


Differential screening-selected gene abberative in neuroblastoma


Dickkopf-related protein 1


High bone mass


Low-density lipoprotein receptor-related protein


Procollagen type 1 N-terminal propeptide


Parathyroid hormone


Receptor activator of nuclear factor kappa-B ligand




Van Buchem disease


Wingless-related integration site



Supported by a grant from the European Commission (HEALTH-F2-2008-20199, TALOS).


  1. Ai M, Holmen SL, van Hul W, Williams BO, et al. Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Mol Cell Biol. 2005;25:4946–55.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Appelman-Dijkstra NM, Papapoulos SE. Novel approaches to the treatment of osteoporosis. Best Pract Res Clin Endocrinol Metab. 2014;28:843–57.CrossRefPubMedGoogle Scholar
  3. Appelman-Dijkstra NM, Papapoulos SE. Modulating bone resorption and bone formation in opposite directions in the treatment of postmenopausal osteoporosis. Drugs. 2015;75:1049–58.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Ardawi MS, Al-Sibiany AM, Bakhsh TM, et al. Decreased serum sclerostin levels in patients with primary hyperparathyroidism: a cross-sectional and a longitudinal study. Osteoporos Int. 2012a;23:1789–97.CrossRefPubMedGoogle Scholar
  5. Ardawi MS, Rouzi AA, Al-Sibiani SA, et al. High serum sclerostin predicts the occurrence of osteoporotic fractures in postmenopausal women: the Center of Excellence for Osteoporosis Research Study. J Bone Miner Res. 2012b;27:2592–602.CrossRefPubMedGoogle Scholar
  6. Balemans W, Ebeling M, Patel N, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet. 2001;10:537–43.CrossRefPubMedGoogle Scholar
  7. Balemans W, Patel N, Ebeling M, et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet. 2002;39:91–7.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Balemans W, Cleiren E, Siebers U, et al. A generalized skeletal hyperostosis in two siblings caused by a novel mutation in the SOST gene. Bone. 2005;36:943–7.CrossRefPubMedGoogle Scholar
  9. Balemans W, Devogelaer JP, Cleiren E, et al. Novel LRP5 missense mutation in a patient with a high bone mass phenotype results in decreased DKK1-mediated inhibition of Wnt signaling. J Bone Miner Res. 2007;22:708–16.CrossRefPubMedGoogle Scholar
  10. Beighton P. Sclerosteosis. J Med Genet. 1988;25:200–3.CrossRefPubMedGoogle Scholar
  11. Belaya ZE, Rozhinskaya LY, Melnichenko GA, et al. Serum extracellular secreted antagonists of the canonical Wnt/β-catenin signalling pathway in patients with Cushing’s syndrome. Osteoporos Int. 2013;24:2191–9.CrossRefPubMedGoogle Scholar
  12. Belkhribchia MR, Collet C, Laplanche JL, et al. Novel SOST gene mutation in a sclerosteosis patient from Morocco, a case report. Eur J Med Genet. 2014;57:133–7.CrossRefPubMedGoogle Scholar
  13. Bhadada SK, Rastogi A, Steenackers E, et al. Novel SOST gene mutation in a sclerosteosis patient and her parents. Bone. 2013;52:707–10.CrossRefPubMedGoogle Scholar
  14. Biomedica. Sclerostin ELISA-assay performance and characteristics, viewed 1 December 2015, from
  15. Boschert V, van Dinther M, Weidauer S, et al. Mutational analysis of sclerostin shows importance of the flexible loop and the cystine-knot for Wnt-signaling inhibition. PLoS One. 2013;29:e81710.CrossRefGoogle Scholar
  16. Bourhis E, Wang W, Tam C, et al. Wnt antagonists bind through a short peptide to the first β-propeller domain of LRP5/6. Structure. 2011;19:1433–42.CrossRefPubMedGoogle Scholar
  17. Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002;346:1513–21.CrossRefPubMedGoogle Scholar
  18. Brunkow ME, Gardner JC, Van Ness J, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001;68:577–89.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Chang MK, Kramer I, Huber T, et al. Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels. Proc Natl Acad Sci U S A. 2014;111:E5187–95.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Choi HY, Dieckmann M, Herz J, et al. Lrp4, a novel receptor for Dickkopf 1 and sclerostin, is expressed by osteoblasts and regulates bone growth and turnover in vivo. PLoS One. 2009;4:e7930.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Clarke BL, Drake MT. Clinical utility of serum sclerostin measurements. BoneKEy Rep. 2013;2:361.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Costa AG, Cremers S, Rubin MR, et al. Circulating sclerostin in disorders of parathyroid gland function. J Clin Endocrinol Metab. 2011;96:3804–10.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Durosier C, van Lierop A, Ferrari S, et al. Association of circulating sclerostin with bone mineral mass, microstructure, and turnover biochemical markers in healthy elderly men and women. J Clin Endocrinol Metab. 2013;98:3873–83.CrossRefPubMedGoogle Scholar
  24. Fijalkowski I, Geets E, Steenackers E, et al. A novel domain-specific mutation in a sclerosteosis patient suggests a role of LRP4 as an anchor for sclerostin in human bone. J Bone Miner Res. 2016;31:874–81.Google Scholar
  25. Frost M, Andersen T, Gossiel F, et al. Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5. J Bone Miner Res. 2011;26:1721–8.CrossRefPubMedGoogle Scholar
  26. García-Fontana B, Morales-Santana S, Varsavsky M, et al. Sclerostin serum levels in prostate cancer patients and their relationship with sex steroids. Osteoporos Int. 2014;25:645–51.CrossRefPubMedGoogle Scholar
  27. García-Martín A, Rozas-Moreno P, Reyes-García R, et al. Circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2012;97:234–41.CrossRefPubMedGoogle Scholar
  28. Gardner JC, van Bezooijen RL, Mervis B, et al. Bone mineral density in sclerosteosis; affected individuals and gene carriers. J Clin Endocrinol Metab. 2005;90:6392–5.CrossRefPubMedGoogle Scholar
  29. Garnero P. New developments in biological markers of bone metabolism in osteoporosis. Bone 2014;66:46–55.CrossRefPubMedGoogle Scholar
  30. Garnero P, Sornay-Rendu E, Munoz F, et al. Association of serum sclerostin with bone mineral density, bone turnover, steroid and parathyroid hormones, and fracture risk in postmenopausal women, the OFELY study. Osteoporos Int. 2013;24:489–94.CrossRefPubMedGoogle Scholar
  31. Gong Y, Slee RB, Fukai N, et al. Osteoporosis-Pseudoglioma Syndrome Collaborative Group, LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107:513–23.CrossRefPubMedGoogle Scholar
  32. Gregson CL, Poole KE, McCloskey EV, et al. Elevated circulating sclerostin concentrations in individuals with high bone mass, with and without LRP5 mutations. J Clin Endocrinol Metab. 2014;99:2897–907.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Gregson CL, Wheeler L, Hardcastle SA, et al. Mutations in known monogenic high bone mass loci only explain a small proportion of high bone mass cases. J Bone Miner Res. 2015; [Epub ahead of print].Google Scholar
  34. Guañabens N, Gifre L, Peris P. The role of Wnt signalling and sclerostin in the pathogenesis of glucocorticoid-induced osteoporosis. Curr Osteoporos Rep. 2014;12(1):90–7.CrossRefPubMedGoogle Scholar
  35. Hamersma H, Gardner J, Beighton P. The natural history of sclerosteosis. Clin Genet. 2003;63:192–7. Erratum in: Clin Genet 2003;64:176.Google Scholar
  36. Hassler N, Roschger A, Gamsjaeger S, et al. Sclerostin deficiency is linked to altered bone composition. J Bone Miner Res. 2014;29:2144–51.CrossRefPubMedGoogle Scholar
  37. He WT, Chen C, Pan C, et al. Sclerosteosis caused by a novel nonsense mutation of SOST in a consanguineous family. Clin Genet. 2016;89:205–9.Google Scholar
  38. Kicijan R, Dinu S, Muschitz C, 2016. Sclerostin as biomarker in osteogenesis imperfecta. In: Patel VB, Preedy VR editors. Biomarkers in disease: methods, discoveries and applications. Doordrecht: Springer.Google Scholar
  39. Kim CA, Honjo R, Bertola D, et al. A known SOST gene mutation causes sclerosteosis in a familial and an isolated case from Brazilian origin. Genet Test. 2008;12:475–9.CrossRefPubMedGoogle Scholar
  40. Kwee ML, Balemans W, Cleiren E, et al. An autosomal dominant high bone mass phenotype in association with craniosynostosis in an extended family is caused by an LRP5 missense mutation. J Bone Miner Res. 2005;20:1254–60.CrossRefPubMedGoogle Scholar
  41. Lapauw B, Vandewalle S, Taes Y, et al. Serum sclerostin levels in men with idiopathic osteoporosis. Eur J Endocrinol. 2013;168:615–20.CrossRefPubMedGoogle Scholar
  42. Leupin O, Piters E, Halleux C, et al. Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem. 2011;286:19489–500.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Li X, Zhang Y, Kang H, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005;280:19883–7.CrossRefPubMedGoogle Scholar
  44. Little RD, Carulli JP, Del Mastro RG, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002;70:11–9.CrossRefPubMedGoogle Scholar
  45. McNulty M, Singh RJ, Li X, et al. Determination of serum and plasma sclerostin concentrations by enzyme-linked immunoassays. J Clin Endocrinol Metab. 2011;96:E1159–62.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Moysés RM, Schiavi SC. Sclerostin, osteocytes, and chronic kidney disease – mineral bone disorder. Semin Dial. 2015;28(6):578–86.CrossRefPubMedGoogle Scholar
  47. Niziolek PJ, MacDonald BT, Kedlaya R, et al. High bone mass-causing mutant LRP5 receptors are resistant to endogenous inhibitors in vivo. J Bone Miner Res. 2015;30:1822–30.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Piters E, Culha MM, et al. First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function. Hum Mutat. 2010;31:E1526–43.CrossRefPubMedGoogle Scholar
  49. Poole KE, van Bezooijen RL, Loveridge N, et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J. 2005;19:1842–4.PubMedGoogle Scholar
  50. Rickels MR, Zhang X, Mumm S, et al. Oropharyngeal skeletal disease accompanying high bone mass and novel LRP5 mutation. J Bone Miner Res. 2005;20:878–85.CrossRefPubMedGoogle Scholar
  51. Semenov M, Tamai K, He X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem. 2005;280:26770–5.CrossRefPubMedGoogle Scholar
  52. Simpson CA, Foer D, Lee GS, et al. Serum levels of sclerostin, Dickkopf-1, and secreted frizzled-related protein-4 are not changed in individuals with high bone mass causing mutations in LRP5. Osteoporos Int. 2014;25:2383–8.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Staehling-Hampton K, Proll S, Paeper BW, et al. A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. Am J Med Genet. 2002;110:144–52.CrossRefPubMedGoogle Scholar
  54. TECOmedical. Sclerostin TECO® high sensitive product information, viewed 1 December 2015, from
  55. Terpos E, Christoulas D, Katodritou E, et al. Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: reduction post-bortezomib monotherapy. Int J Cancer. 2012;131:1466–71.CrossRefPubMedGoogle Scholar
  56. van Bezooijen RL, Roelen BA, Visser A, et al. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med. 2004;199:805–14.CrossRefPubMedPubMedCentralGoogle Scholar
  57. van Lierop AH, Hamdy NA, Papapoulos SE. Glucocorticoids are not always deleterious for bone. J Bone Miner Res. 2010a;25:2796–800.CrossRefPubMedGoogle Scholar
  58. van Lierop AH, Witteveen J, Hamdy N, et al. Patients with primary hyperparathyroidism have lower circulating sclerostin levels than euparathyroid controls. Eur J Endocrinol. 2010b;163:833–7.CrossRefPubMedGoogle Scholar
  59. van Lierop AH, Hamdy NA, Hamersma H, et al. Patients with sclerosteosis and disease carriers, human models of the effect of sclerostin on bone turnover. J Bone Miner Res. 2011;26:2804–11.CrossRefPubMedGoogle Scholar
  60. van Lierop AH, Hamdy NA, van Bezooijen RL, et al. The role of sclerostin in the pathophysiology of sclerosing bone dysplasias. Clin Rev Bone Miner Metab. 2012a;10:108–16.CrossRefGoogle Scholar
  61. van Lierop AH, van der Eerden AW, Hamdy NA, et al. Circulating sclerostin levels are decreased in patients with endogenous hypercortisolism and increase after treatment. J Clin Endocrinol Metab. 2012b;97:E1953–7.CrossRefPubMedPubMedCentralGoogle Scholar
  62. van Lierop AH, Hamdy NAT, van der Meer RW, et al. Distinct effects of pioglitazone and metformin on circulating sclerostin and biochemical markers of bone turnover in men with Type 2 Diabetes Mellitus. Eur J Endocrinol. 2012c;166:711–6.CrossRefPubMedGoogle Scholar
  63. van Lierop AH, Hamdy NA, van Egmond ME, et al. Van Buchem disease, clinical, biochemical, and densitometric features of patients and disease carriers. J Bone Miner Res. 2013;28:848–54.CrossRefPubMedGoogle Scholar
  64. van Lierop AH, Moester MJ, Hamdy NA, et al. Serum Dickkopf 1 levels in sclerostin deficiency. J Clin Endocrinol Metab. 2014;99:E252–6.CrossRefPubMedGoogle Scholar
  65. Van Wesenbeeck L, Cleiren E, Gram J, et al. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet. 2003;72:763–71.CrossRefPubMedPubMedCentralGoogle Scholar
  66. Veverka V, Henry AJ, Slocombe PM, et al. Characterization of the structural features and interactions of sclerostin, molecular insight into a key regulator of Wnt-mediated bone formation. J Biol Chem. 2009;284:10890–900.CrossRefPubMedPubMedCentralGoogle Scholar
  67. Weidauer SE, Schmieder P, Beerbaum M, et al. NMR structure of the Wnt modulator protein Sclerostin. Biochem Biophys Res Commun. 2009;380:160–5.CrossRefPubMedGoogle Scholar
  68. Whyte MP, Reinus WH, Mumm S. High-bone-mass disease and LRP5. N Engl J Med. 2004;350:2096–9.CrossRefPubMedGoogle Scholar
  69. Yavropoulou MP, van Lierop AH, Hamdy NA, et al. Serum sclerostin levels in Paget’s disease and prostate cancer with bone metastases with a wide range of bone turnover. Bone. 2012;51:153–7.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  • Antoon H. van Lierop
    • 2
  • Socrates E. Papapoulos
    • 1
    Email author
  1. 1.Department of Endocrinology and Metabolic Diseases, Center for Bone QualityLeiden University Medical CenterLeidenThe Netherlands
  2. 2.Department of Internal MedicineAmsterdam Medical CenterAmsterdam-ZuidoostThe Netherlands

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