Journal of Bone and Mineral Metabolism

, Volume 34, Issue 4, pp 447–456 | Cite as

Circulating sclerostin and Dickkopf-1 levels in patients with nonalcoholic fatty liver disease

  • Stergios A. PolyzosEmail author
  • Athanasios D. Anastasilakis
  • Jannis Kountouras
  • Polyzois Makras
  • Athanasios Papatheodorou
  • Panagiotis Kokkoris
  • Grigorios T. Sakellariou
  • Evangelos Terpos
Original Article


There is increasing evidence for bone-liver interplay. The main aim of this study was to determine serum sclerostin and Dickkopf (DKK)-1 levels in patients with nonalcoholic fatty liver disease (NAFLD) and their association with the disease severity. Patients with biopsy-proven NAFLD, 13 with nonalcoholic simple steatosis (SS) and 14 with steatohepatitis (NASH), and 20 gender-, age-, body mass index- and waist circumference-matched controls were enrolled. Serum sclerostin, DKK-1, bone turnover markers, vitamin D, insulin and standard biochemical and hematologic parameters were measured; lumbar spinal dual-energy X-ray absorptiometry was performed. We observed that there was a progressive decline in serum sclerostin levels from the controls (76.1 ± 6.8) to SS (53.5 ± 6.4) and NASH (46.0 ± 8.1 pmol/l) patients (p = 0.009); in adjusted pairwise comparisons, sclerostin was significantly higher in the controls than in NASH patients (p = 0.012). Although serum DKK-1 did not differ between groups (p = 0.135), there was a trend toward U-shaped distribution (controls 35.8 ± 2.8; SS 27.3 ± 2.9; NASH 36.8 ± 4.4 pmol/l). Higher DKK-1 levels were independently associated with NASH. Regarding specific histological lesions, DKK-1 levels were marginally lower in NAFLD patients with lower (≤33 %) than higher (>33 %) steatosis grade (27.7 ± 3.1 and 38.8 ± 4.7 pmol/l, respectively; p = 0.049). No other significant difference was observed within histological lesions. In conclusion, serum sclerostin levels were lower in NASH patients than in controls. DKK-1 levels were independently associated with NASH in NAFLD patients. The potential importance of these findings indicates a possible bone-liver interaction and warrants further investigation.


Bone turnover markers Dickkopf-1 Nonalcoholic fatty liver disease Nonalcoholic steatohepatitis Sclerostin 


Conflict of interest

All authors have no conflicts of interest.


  1. 1.
    Lazo M, Clark JM (2008) The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis 28:339–350CrossRefPubMedGoogle Scholar
  2. 2.
    Polyzos SA, Kountouras J, Zavos C (2009) Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines. Curr Mol Med 72:299–314CrossRefGoogle Scholar
  3. 3.
    Armstrong MJ, Adams LA, Canbay A, Syn WK (2014) Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology 59:1174–1197CrossRefPubMedGoogle Scholar
  4. 4.
    Yilmaz Y (2012) Review article: non-alcoholic fatty liver disease and osteoporosis-clinical and molecular crosstalk. Aliment Pharmacol Ther 36:345–352CrossRefPubMedGoogle Scholar
  5. 5.
    Musso G, Paschetta E, Gambino R, Cassader M, Molinaro F (2013) Interactions among bone, liver, and adipose tissue predisposing to diabesity and fatty liver. Trends Mol Med 19:522–535CrossRefPubMedGoogle Scholar
  6. 6.
    Cui R, Sheng H, Rui XF, Cheng XY, Sheng CJ, Wang JY, Qu S (2013) Low bone mineral density in chinese adults with nonalcoholic fatty liver disease. Int J Endocrinol 2013:396545CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Anastasilakis AD, Polyzos SA, Toulis KA (2011) Role of wingless tail signaling pathway in osteoporosis: an update of current knowledge. Curr Opin Endocrinol Diabetes Obes 18:383–388CrossRefPubMedGoogle Scholar
  8. 8.
    Bhattoa HP, Wamwaki J, Kalina E, Foldesi R, Balogh A, Antal-Szalmas P (2013) Serum sclerostin levels in healthy men over 50 years of age. J Bone Miner Metab 31:579–584CrossRefPubMedGoogle Scholar
  9. 9.
    Rossini M, Gatti D, Adami S (2013) Involvement of WNT/β-catenin signaling in the treatment of osteoporosis. Calcif Tissue Int 93:121–132CrossRefPubMedGoogle Scholar
  10. 10.
    Hampson G, Edwards S, Conroy S, Blake GM, Fogelman I, Frost ML (2013) The relationship between inhibitors of the Wnt signalling pathway (dickkopf-1(DKK1) and sclerostin), bone mineral density, vascular calcification and arterial stiffness in post-menopausal women. Bone 56:42–47CrossRefPubMedGoogle Scholar
  11. 11.
    Gaudio A, Privitera F, Pulvirenti I, Canzonieri E, Rapisarda R, Fiore CE (2014) The relationship between inhibitors of the Wnt signalling pathway (sclerostin and dickkopf-1) and carotid intima-media thickness in postmenopausal women with type 2 diabetes mellitus. Diabetes Vasc Dis Res 11:48–52CrossRefGoogle Scholar
  12. 12.
    Manolagas SC, Almeida M (2007) Gone with the Wnts: β-catenin, T-cell factor, forkhead box O, and oxidative stress in age-dependent diseases of bone, lipid, and glucose metabolism. Mol Endocrinol 21:2605–2614CrossRefPubMedGoogle Scholar
  13. 13.
    Mani A, Radhakrishnan J, Wang H, Mani A, Mani MA, Nelson-Williams C, Carew KS, Mane S, Najmabadi H, Wu D, Lifton RP (2007) LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315:1278–1282CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Smits MM, Ioannou GN, Boyko EJ, Utzschneider KM (2013) Non-alcoholic fatty liver disease as an independent manifestation of the metabolic syndrome: results of a US national survey in three ethnic groups. J Gastroenterol Hepatol 28:664–670CrossRefPubMedGoogle Scholar
  15. 15.
    Polyzos SA, Kountouras J, Slavakis A, Zafeiriadou E, Patsiaoura K, Katsiki E, Zavos C, Papatheodorou A, Terpos E (2013) A novel noninvasive index for nonalcoholic steatohepatitis: a pilot study. Biomarkers 18:607–613CrossRefPubMedGoogle Scholar
  16. 16.
    Kleiner DE, Brunt EM, Van NM, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41:1313–1321CrossRefPubMedGoogle Scholar
  17. 17.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419CrossRefPubMedGoogle Scholar
  18. 18.
    Polyzos SA, Mantzoros CS (2014) Necessity for timely noninvasive diagnosis of nonalcoholic fatty liver disease. Metabolism 63:161–167CrossRefPubMedGoogle Scholar
  19. 19.
    Rhee Y, Kim WJ, Han KJ, Lim SK, Kim SH (2014) Effect of liver dysfunction on circulating sclerostin. J Bone Miner Metab 32:542–549CrossRefGoogle Scholar
  20. 20.
    González-Reimers E, Martín-González C, de la Vega-Prieto MJ, Pelazas-González R, Fernández-Rodríguez C, López-Prieto J, Alvisa-Negrín J, Santolaria-Fernández F (2013) Serum sclerostin in alcoholics: a pilot study. Alcohol Alcohol 48:278–282CrossRefPubMedGoogle Scholar
  21. 21.
    González-Reimers E, López-Prieto J, Pelazas-González R, Alemán-Valls MR, José de la Vega-Prieto M, Jorge-Ripper C, Durán-Castellón MC, Santolaria-Fernández F (2014) Serum sclerostin in hepatitis C virus infected patients. J Bone Metab 21:69–75CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Sapir-Koren R, Livshits G (2014) Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption–formation cycles? Osteoporos Int 25:2685–2700CrossRefPubMedGoogle Scholar
  23. 23.
    Okazaki K, Jingushi S, Ikenoue T, Urabe K, Sakai H, Iwamoto Y (2003) Expression of parathyroid hormone-related peptide and insulin-like growth factor I during rat fracture healing. J Orthop Res 21:511–520CrossRefPubMedGoogle Scholar
  24. 24.
    Lau KH, Baylink DJ, Zhou XD, Rodriguez D, Bonewald LF, Li Z, Ruffoni D, Müller R, Kesavan C, Sheng MH (2013) Osteocyte-derived insulin-like growth factor I is essential for determining bone mechanosensitivity. Am J Physiol Endocrinol Metab 305:E271–E281CrossRefPubMedGoogle Scholar
  25. 25.
    Thomas DM, Hards DK, Rogers SD, Ng KW, Best JD (1996) Insulin receptor expression in bone. J Bone Miner Res 11:1312–1320CrossRefPubMedGoogle Scholar
  26. 26.
    Anastasilakis AD, Polyzos SA, Gkiomisi A, Bisbinas I, Gerou S, Makras P (2013) Comparative effect of zoledronic acid versus denosumab on serum sclerostin and dickkopf-1 levels of naive postmenopausal women with low bone mass: a randomized, head-to-head clinical trial. J Clin Endocrinol Metab 98:3206–3212CrossRefPubMedGoogle Scholar
  27. 27.
    Polyzos SA, Kountouras J, Zavos C, Deretzi G (2012) Nonalcoholic fatty liver disease: multimodal treatment options for a pathogenetically multiple-hit disease. J Clin Gastroenterol 46:272–284CrossRefPubMedGoogle Scholar
  28. 28.
    Lattanzio S, Santilli F, Liani R, Vazzana N, Ueland T, Di Fulvio P, Formoso G, Consoli A, Aukrust P, Davi G (2014) Circulating dickkopf-1 in diabetes mellitus: association with platelet activation and effects of improved metabolic control and low-dose aspirin. J Am Heart Assoc. doi: 10.1161/JAHA.114.001000 Google Scholar
  29. 29.
    Garcia-Martin A, Reyes-Garcia R, Garcia-Fontana B, Morales-Santana S, Coto-Montes A, Munoz-Garach M, Rozas-Moreno P, Munoz-Torres M (2014) Relationship of dickkopf1 (DKK1) with cardiovascular disease and bone metabolism in Caucasian type 2 diabetes mellitus. PLoS One 9:e111703CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Freese JL, Pino D, Pleasure SJ (2010) Wnt signaling in development and disease. Neurobiol Dis 38:148–153CrossRefPubMedGoogle Scholar
  31. 31.
    Liang L, He H, Lv R, Zhang M, Huang H, An Z, Li S (2015) Preliminary mechanism on the methylation modification of Dkk-1 and Dkk-3 in hepatocellular carcinoma. Tumour Biol 36:1245–1250CrossRefPubMedGoogle Scholar
  32. 32.
    Ertle J, Dechene A, Sowa JP, Penndorf V, Herzer K, Kaiser G, Schlaak JF, Gerken G, Syn WK, Canbay A (2011) Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer 128:2436–2443CrossRefPubMedGoogle Scholar
  33. 33.
    Yang H, Chen GD, Fang F, Liu Z, Lau SH, Zhang JF, Lau WY, Yang LY (2013) Dickkopf-1: as a diagnostic and prognostic serum marker for early hepatocellular carcinoma. Int J Biol Markers 28:286–297CrossRefPubMedGoogle Scholar
  34. 34.
    Moon SS, Lee YS, Kim SW (2012) Association of nonalcoholic fatty liver disease with low bone mass in postmenopausal women. Endocrine 42:423–429CrossRefPubMedGoogle Scholar
  35. 35.
    Pardee PE, Dunn W, Schwimmer JB (2012) Non-alcoholic fatty liver disease is associated with low bone mineral density in obese children. Aliment Pharmacol Ther 35:248–254CrossRefPubMedGoogle Scholar
  36. 36.
    Li M, Xu Y, Xu M, Ma L, Wang T, Liu Y, Dai M, Chen Y, Lu J, Liu J, Bi Y, Ning G (2012) Association between nonalcoholic fatty liver disease (NAFLD) and osteoporotic fracture in middle-aged and elderly Chinese. J Clin Endocrinol Metab 97:2033–2038CrossRefPubMedGoogle Scholar
  37. 37.
    Purnak T, Beyazit Y, Ozaslan E, Efe C, Hayretci M (2012) The evaluation of bone mineral density in patients with nonalcoholic fatty liver disease. Wien Klin Wochenschr 124:526–531CrossRefPubMedGoogle Scholar
  38. 38.
    Kaya M, Işık D, Beştaş R, Evliyaoğlu O, Akpolat V, Büyükbayram H, Kaplan MA (2013) Increased bone mineral density in patients with non-alcoholic steatohepatitis. World J Hepatol 5:627–634PubMedPubMedCentralGoogle Scholar
  39. 39.
    Polyzos SA, Anastasilakis AD, Bratengeier C, Woloszczuk W, Papatheodorou A, Terpos E (2012) Serum sclerostin levels positively correlate with lumbar spinal bone mineral density in postmenopausal women—the six-month effect of risedronate and teriparatide. Osteoporos Int 23:1171–1176CrossRefPubMedGoogle Scholar
  40. 40.
    Paccou J, Mentaverri R, Renard C, Liabeuf S, Fardellone P, Massy ZA, Brazier M, Kamel S (2014) The relationships between serum sclerostin, bone mineral density and vascular calcification in rheumatoid arthritis. J Clin Endocrinol Metab 99:4740–4748CrossRefPubMedGoogle Scholar
  41. 41.
    Voskaridou E, Christoulas D, Plata E, Bratengeier C, Anastasilakis AD, Komninaka V, Kaliontzi D, Gkotzamanidou M, Polyzos SA, Dimopoulou M, Terpos E (2012) High circulating sclerostin is present in patients with thalassemia-associated osteoporosis and correlates with bone mineral density. Horm Metab Res 44:909–913CrossRefPubMedGoogle Scholar
  42. 42.
    Musso G (2012) Non-alcoholic fatty liver, adipose tissue, and the bone: a new triumvirate on the block. Endocrine 42:237–239CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer Japan 2015

Authors and Affiliations

  • Stergios A. Polyzos
    • 1
    • 2
    Email author
  • Athanasios D. Anastasilakis
    • 3
  • Jannis Kountouras
    • 1
  • Polyzois Makras
    • 4
  • Athanasios Papatheodorou
    • 5
  • Panagiotis Kokkoris
    • 5
  • Grigorios T. Sakellariou
    • 6
  • Evangelos Terpos
    • 7
  1. 1.Second Medical ClinicAristotle University of Thessaloniki, Ippokration HospitalThessalonikiGreece
  2. 2.Division of Endocrinology, Diabetes and Metabolism, Department of Internal MedicineBeth Israel Deaconess Medical Center, Harvard Medical SchoolBostonUSA
  3. 3.Department of Endocrinology424 General Military HospitalThessalonikiGreece
  4. 4.Department of Endocrinology and Diabetes251 Hellenic Air Force and VA General HospitalAthensGreece
  5. 5.Department of Medical Research251 Hellenic Air Force and VA General HospitalAthensGreece
  6. 6.Department of Rheumatology424 General Military HospitalThessalonikiGreece
  7. 7.Department of Clinical TherapeuticsUniversity of Athens School of MedicineAthensGreece

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