Abstract
Summary
This meta-analysis aimed to investigate the associations between osteocalcin (Ocn) and fasting plasma glucose (FPG) and glycated hemoglobin A1c (HbA1c). It was revealed that both total Ocn and undercarboxylated Ocn (unOcn) were negatively related with FPG and HbA1c, and the association of unOcn with FPG was more pronounced in men.
Introduction
The aim of this study was to investigate the strength of associations between Ocn and FPG and HbA1c using a meta-analysis approach.
Methods
A search was carried out using the databases of PubMed, ISI Web of Science, and the Cochrane library from 2007 to 2014 to identify related studies. A pooled effect size with 95 % confidence intervals (CI) was derived.
Results
The meta-analysis included 39 studies involving 23,381 participants. The overall correlation was −0.16 (95 % CI, −0.19 to −0.14) between total Ocn (tOcn) and FPG and −0.15 (95 % CI, −0.20 to −0.11) between undercarboxylated Ocn (unOcn) and FPG. In the analysis of the association between Ocn and HbA1c, the pooled correlation was −0.16 (95 % CI, −0.18 to −0.14) for tOcn and −0.16 (95 % CI, −0.23 to −0.08) for unOcn. The magnitude of the correlation between unOcn and FPG is significantly higher in men than in women (r = −0.18, 95 % CI, −0.21 to −0.14; r = −0.09, 95 % CI, −0. 13 to −0.05, respectively; P for interaction < 0.05). Similar trend was also found between unOcn and HbA1c but without significance (for men, r = −0.19, 95 % CI, −0.24 to −0.14; for women, r = −0.09, 95 % CI, −0.22 to 0.04, respectively; P for interaction > 0.05). No indication of significant publication bias was found in any method.
Conclusions
This meta-analysis demonstrated that both unOcn and tOcn were similarly and negatively correlated with FPG and HbA1c in humans. The negative correlations between unOcn and glucose metabolism appear to be more pronounced in men than in women.
This is a preview of subscription content, access via your institution.



References
Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130:456–469
Ferron M, McKee MD, Levine RL, Ducy P, Karsenty G (2012) Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. Bone 50:568–575
Ferron M, Hinoi E, Karsenty G, Ducy P (2008) Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci U S A 105:5266–5270
Kindblom JM, Ohlsson C, Ljunggren O, Karlsson MK, Tivesten A, Smith U, Mellstrom D (2009) Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. J Bone Miner Res 24:785–791
Zhou M, Ma X, Li H, Pan X, Tang J, Gao Y, Hou X, Lu H, Bao Y, Jia W (2009) Serum osteocalcin concentrations in relation to glucose and lipid metabolism in Chinese individuals. Eur J Endocrinol 161:723–729
Saleem U, Mosley TH Jr, Kullo IJ (2010) Serum osteocalcin is associated with measures of insulin resistance, adipokine levels, and the presence of metabolic syndrome. Arterioscler Thromb Vasc Biol 30:1474–1478
Im JA, Yu BP, Jeon JY, Kim SH (2008) Relationship between osteocalcin and glucose metabolism in postmenopausal women. Clin Chim Acta 396:66–69
Bae SJ, Choe JW, Chung YE, Kim BJ, Lee SH, Kim HY, Koh JM, Kim HK, Kim GS (2011) The association between serum osteocalcin levels and metabolic syndrome in Koreans. Osteoporos Int 22:2837–2846
Bao Y, Zhou M, Lu Z, Li H, Wang Y, Sun L, Gao M, Wei M, Jia W (2011) Serum levels of osteocalcin are inversely associated with the metabolic syndrome and the severity of coronary artery disease in Chinese men. Clin Endocrinol (Oxf) 75:196–201
Kim SH, Lee JW, Im JA, Hwang HJ (2010) Serum osteocalcin is related to abdominal obesity in Korean obese and overweight men. Clin Chim Acta 411:2054–2057
Zhang Y, Qi L, Gu W, Yan Q, Dai M, Shi J, Zhai Y, Chen Y, Liu J, Wang W, Ning G, Hong J (2010) Relation of serum osteocalcin level to risk of coronary heart disease in Chinese adults. Am J Cardiol 106:1461–1465
Buday B, Pach FP, Literati-Nagy B, Vitai M, Vecsei Z, Koranyi L (2013) Serum osteocalcin is associated with improved metabolic state via adiponectin in females versus testosterone in males. Gender specific nature of the bone-energy homeostasis axis. Bone 57:98–104
Caglar GS, Ozdemir ED, Kiseli M, Demirtas S, Cengiz SD (2014) The association of osteocalcin and adiponectin with glucose metabolism in nondiabetic postmenopausal women. Gynecol Obstet Invest 77:255–260
Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S, Sugimoto T (2011) Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2 diabetes mellitus. Osteoporos Int 22:187–194
Lee SW, Jo HH, Kim MR, You YO, Kim JH (2012) Association between obesity, metabolic risks and serum osteocalcin level in postmenopausal women. Gynecol Endocrinol 28:472–477
Liao M, Guo X, Yu X, Pang G, Zhang S, Li J, Tan A, Gao Y, Yang X, Zhang H, Qin X, Mo L, Lu Z, Wu C, Mo Z (2013) Role of metabolic factors in the association between osteocalcin and testosterone in Chinese men. J Clin Endocrinol Metab 98:3463–3469
Rupinski MT, Dunlap WP (1996) Approximating Pearson Product-Moment Correlations from Kendall’s Tau and Spearman’s Rho. Educ Psychol Meas 56:419–429
Borenstein M, Hedges LV, Higgins JPT, Rothstein HR (2009) Introduction to meta-analysis. John Wiley & Sons, Ltd., United Kingdom
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188
Leeflang MM, Deeks JJ, Gatsonis C, Bossuyt PM, Cochrane Diagnostic Test Accuracy Working Group (2008) Systematic reviews of diagnostic test accuracy. Ann Intern Med 149:889–897
Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558
Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634
Aoki A, Muneyuki T, Yoshida M, Munakata H, Ishikawa SE, Sugawara H, Kawakami M, Kakei M (2011) Circulating osteocalcin is increased in early-stage diabetes. Diabetes Res Clin Pract 92:181–186
Bao YQ, Zhou M, Zhou J, Lu W, Gao YC, Pan XP, Tang JL, Lu HJ, Jia WP (2011) Relationship between serum osteocalcin and glycaemic variability in Type 2 diabetes. Clin Exp Pharmacol Physiol 38:50–54
Garcia-Martin A, Cortes-Berdonces M, Luque-Fernandez I, Rozas-Moreno P, Quesada-Charneco M, Munoz-Torres M (2011) Osteocalcin as a marker of metabolic risk in healthy postmenopausal women. Menopause 18:537–541
Levinger I, Zebaze R, Jerums G, Hare DL, Selig S, Seeman E (2011) The effect of acute exercise on undercarboxylated osteocalcin in obese men. Osteoporos Int 22:1621–1626
Iki M, Tamaki J, Fujita Y, Kouda K, Yura A, Kadowaki E, Sato Y, Moon JS, Tomioka K, Okamoto N, Kurumatani N (2012) Serum undercarboxylated osteocalcin levels are inversely associated with glycemic status and insulin resistance in an elderly Japanese male population: Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Study. Osteoporos Int 23:761–770
Movahed A, Larijani B, Nabipour I, Kalantarhormozi M, Asadipooya K, Vahdat K, Akbarzadeh S, Farrokhnia M, Assadi M, Amirinejad R, Bargahi A, Sanjdideh Z (2012) Reduced serum osteocalcin concentrations are associated with type 2 diabetes mellitus and the metabolic syndrome components in postmenopausal women: the crosstalk between bone and energy metabolism. J Bone Miner Metab 30:683–691
Ngarmukos C, Chailurkit LO, Chanprasertyothin S, Hengprasith B, Sritara P, Ongphiphadhanakul B (2012) A reduced serum level of total osteocalcin in men predicts the development of diabetes in a long-term follow-up cohort. Clin Endocrinol (Oxf) 77:42–46
Wieczorek-Baranowska A, Nowak A, Pilaczynska-Szczesniak L (2012) Osteocalcin and glucose metabolism in postmenopausal women subjected to aerobic training program for 8 weeks. Metabolism 61:542–545
Wiklund P, Nordstrom A, Hogstrom M, Alfredson H, Engstrom P, Gustafsson T, Franks PW, Nordstrom P (2012) High-impact loading on the skeleton is associated with a decrease in glucose levels in young men. Clin Endocrinol (Oxf) 77:823–827
Alfadda AA, Masood A, Shaik SA, Dekhil H, Goran M (2013) Association between osteocalcin, metabolic syndrome, and cardiovascular risk factors: role of total and undercarboxylated osteocalcin in patients with type 2 diabetes. Int J Endocrinol 2013:197519
Bao Y, Ma X, Yang R, Wang F, Hao Y, Dou J, He H, Jia W (2013) Inverse relationship between serum osteocalcin levels and visceral fat area in Chinese men. J Clin Endocrinol Metab 98:345–351
dos Santos B, Magalhaes K, Magalhaes MM, Diniz ET, Lucena CS, Griz L, Bandeira F (2013) Metabolic syndrome and central fat distribution are related to lower serum osteocalcin concentrations. Ann Nutr Metab 62:183–188
Chen L, Li Q, Yang Z, Ye Z, Huang Y, He M, Wen J, Wang X, Lu B, Hu J, Liu C, Ling C, Qu S, Hu R (2013) Osteocalcin, glucose metabolism, lipid profile and chronic low-grade inflammation in middle-aged and elderly Chinese. Diabet Med 30:309–317
Dou J, Ma X, Fang Q, Hao Y, Yang R, Wang F, Zhu J, Bao Y, Jia W (2013) Relationship between serum osteocalcin levels and non-alcoholic fatty liver disease in Chinese men. Clin Exp Pharmacol Physiol 40:282–288
Furusyo N, Ihara T, Hayashi T, Ikezaki H, Toyoda K, Ogawa E, Okada K, Kainuma M, Murata M, Hayashi J (2013) The serum undercarboxylated osteocalcin level and the diet of a Japanese population: results from the Kyushu and Okinawa Population Study (KOPS). Endocrine 43:635–642
Liu JM, Zhao HY, Zhao L, Chen Y, Zhang LZ, Tao B, Sun LH, Zhao YJ, Wang WQ, Xu MY, Chen JL, Ning G (2013) An independent positive relationship between the serum total osteocalcin level and fat-free mass in healthy premenopausal women. J Clin Endocrinol Metab 98:2146–2152
Ogawa-Furuya N, Yamaguchi T, Yamamoto M, Kanazawa I, Sugimoto T (2013) Serum osteocalcin levels are inversely associated with abdominal aortic calcification in men with type 2 diabetes mellitus. Osteoporos Int 24:2223–2230
Schwetz V, Gumpold R, Graupp M, Hacker N, Schweighofer N, Trummer O, Pieber TR, Ballon M, Lerchbaum E, Obermayer-Pietsch B (2013) Osteocalcin is not a strong determinant of serum testosterone and sperm count in men from infertile couples. Andrology 1:590–594
Sheng L, Cao W, Cha B, Chen Z, Wang F, Liu J (2013) Serum osteocalcin level and its association with carotid atherosclerosis in patients with type 2 diabetes. Cardiovasc Diabetol 12:22
Wang Q, Zhang B, Xu Y, Xu H, Zhang N (2013) The relationship between serum osteocalcin concentration and glucose metabolism in patients with type 2 diabetes mellitus. Int J Endocrinol 2013:842598
Weiler HA, Lowe J, Krahn J, Leslie WD (2013) Osteocalcin and vitamin D status are inversely associated with homeostatic model assessment of insulin resistance in Canadian Aboriginal and white women: the First Nations Bone Health Study. J Nutr Biochem 24:412–418
Chen X, Wu Y, Liu L, Tian H, Yu X (2014) Osteocalcin is inversely associated with glucose levels in middle-aged Tibetan men with different degrees of glucose tolerance. Diabetes Metab Res Rev 30:476–482
Choudhury AB, Sarkar PD, Sakalley DK, Petkar SB (2014) Role of adiponectin in mediating the association of osteocalcin with insulin resistance and type 2 diabetes: a cross sectional study in pre- and post-menopausal women. Arch Physiol Biochem 120:73–79
Cui R, Su B, Sheng C, Cheng X, Yang P, Bu L, Li H, Wang J, Sheng H, Qu S (2014) Total osteocalcin in serum predicts testosterone level in male type 2 diabetes mellitus. Int J Clin Exp Med 7:1145–1149
Maddaloni E, D'Onofrio L, Lauria A, Maurizi AR, Strollo R, Palermo A, Napoli N, Angeletti S, Pozzilli P, Manfrini S (2014) Osteocalcin levels are inversely associated with Hba1c and BMI in adult subjects with long-standing type 1 diabetes. J Endocrinol Invest 37:661–666
Rui X, Xu B, Su J, Pan C, Zhan C, Su B, Li H, Wang J, Sheng H, Qu S (2014) Differential pattern for regulating insulin secretion, insulin resistance, and lipid metabolism by osteocalcin in male and female T2DM patients. Med Sci Monit 20:711–719
Wei J, Hanna T, Suda N, Karsenty G, Ducy P (2014) Osteocalcin promotes beta-cell proliferation during development and adulthood through Gprc6a. Diabetes 63:1021–1031
Wei J, Ferron M, Clarke CJ, Hannun YA, Jiang H, Blaner WS, Karsenty G (2014) Bone-specific insulin resistance disrupts whole-body glucose homeostasis via decreased osteocalcin activation. J Clin Invest 124:1–13
Starup-Linde J, Eriksen SA, Lykkeboe S, Handberg A, Vestergaard P (2014) Biochemical markers of bone turnover in diabetes patients–a meta-analysis, and a methodological study on the effects of glucose on bone markers. Osteoporos Int 25:1697–1708
Gundberg CM, Lian JB, Booth SL (2012) Vitamin K-dependent carboxylation of osteocalcin: friend or foe? Adv Nutr 3:149–157
Ferron M, Wei J, Yoshizawa T, Ducy P, Karsenty G (2010) An ELISA-based method to quantify osteocalcin carboxylation in mice. Biochem Biophys Res Commun 397:691–696
Nishimura J, Arai N, Tohmatsu J (2007) Measurement of serum undercarboxylated osteocalcin by ECLIA with the “Picolumi ucOC” kit. Clin Calcium 17:1702–1708
Booth SL, Centi A, Smith SR, Gundberg C (2013) The role of osteocalcin in human glucose metabolism: marker or mediator? Nat Rev Endocrinol 9:43–55
Kirmani S, Atkinson EJ, Melton LJ 3rd, Riggs BL, Amin S, Khosla S (2011) Relationship of testosterone and osteocalcin levels during growth. J Bone Miner Res 26:2212–2216
Kumar R, Vella A (2011) Carbohydrate metabolism and the skeleton: picking a bone with the beta-cell. J Clin Endocrinol Metab 96:1269–1271
Binkley NC, Krueger DC, Engelke JA, Foley AL, Suttie JW (2000) Vitamin K supplementation reduces serum concentrations of under-gamma-carboxylated osteocalcin in healthy young and elderly adults. Am J Clin Nutr 72:1523–1528
Yeap BB, Alfonso H, Chubb SA, Gauci R, Byrnes E, Beilby JP, Ebeling PR, Handelsman DJ, Allan CA, Grossmann M, Norman PE, Flicker L (2015) Higher serum undercarboxylated osteocalcin and other bone turnover markers are associated with reduced diabetes risk and lower estradiol concentrations in older men. J Clin Endocrinol Metab 100:63–71
Oury F, Sumara G, Sumara O, Ferron M, Chang H, Smith CE, Hermo L, Suarez S, Roth BL, Ducy P, Karsenty G (2011) Endocrine regulation of male fertility by the skeleton. Cell 144:796–809
Kooptiwut S, Hanchang W, Semprasert N, Junking M, Limjindaporn T, Yenchitsomanus PT (2015) Testosterone reduces AGTR1 expression to prevent beta-cell and islet apoptosis from glucotoxicity. J Endocrinol 224:215–224
Palomar-Morales M, Morimoto S, Mendoza-Rodriguez CA, Cerbon MA (2010) The protective effect of testosterone on streptozotocin-induced apoptosis in beta cells is sex specific. Pancreas 39:193–200
Kapoor D, Goodwin E, Channer KS, Jones TH (2006) Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 154:899–906
Grossmann M, Hoermann R, Wittert G, Yeap BB (2014) Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: a systematic review and meta-analysis of randomized controlled clinical trials. Clin Endocrinol (Oxf). doi:10.1111/cen.12664
Yasui T, Uemura H, Tomita J, Miyatani Y, Yamada M, Miura M, Irahara M (2006) Association of serum undercarboxylated osteocalcin with serum estradiol in pre-, peri- and early post-menopausal women. J Endocrinol Invest 29:913–918
Funding
This work was supported by the National Nature Science Foundation of China (grants 81370977 and 81170804) and Doctoral Innovation Fund Projects from Shanghai Jiao Tong University School of Medicine (BXJ201410).
Conflicts of interest
Dong-mei Liu, Xing-zhi Guo, Hai-jun Tong, Bei Tao, Li-hao Sun, Hong-Yan Zhao, Guang Ning, and Jian-min Liu declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding authors
Additional information
D.-M. Liu and X.-Z. Guo contributed equally to this work.
Rights and permissions
About this article
Cite this article
Liu, DM., Guo, XZ., Tong, HJ. et al. Association between osteocalcin and glucose metabolism: a meta-analysis. Osteoporos Int 26, 2823–2833 (2015). https://doi.org/10.1007/s00198-015-3197-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-015-3197-8