Abstract
Undercarboxylated osteocalcin (ucOC) may play a role in glucose homeostasis and cardiometabolic health. This review examines the epidemiological and interventional evidence associating osteocalcin (OC) and ucOC with metabolic risk and cardiovascular disease. The complexity in assessing such correlations, due to the observational nature of human studies, is discussed. Several studies have reported that higher levels of ucOC and OC are correlated with lower fat mass and HbA1c. In addition, improved measures of glycaemic control via pharmacological and non-pharmacological (e.g. exercise or diet) interventions are often associated with increased circulating levels of OC and/or ucOC. There is also a relationship between lower circulating OC and ucOC and increased measures of vascular calcification and cardiovascular disease. However, not all studies have reported such relationship, some with contradictory findings. Equivocal findings may arise because of the observational nature of the studies and the inability to directly assess the relationship between OC and ucOC on glycaemic control and cardiovascular health in humans. Studying OC and ucOC in humans is further complicated due to numerous confounding factors such as sex differences, menopausal status, vitamin K status, physical activity level, body mass index, insulin sensitivity (normal/insulin resistance/T2DM), tissue-specific effects and renal function among others. Current observational and indirect interventional evidence appears to support a relationship between ucOC with metabolic and cardiovascular disease. There is also emerging evidence to suggest a direct role of ucOC in human metabolism. Further mechanistic studies are required to (a) clarify causality, (b) explore mechanisms involved and (c) define the magnitude of this effect and its clinical importance.
Similar content being viewed by others
References
Seeman E, Delmas PD (2006) Bone quality—the material and structural basis of bone strength and fragility. N Engl J Med 354:2250–2261
Hadjidakis DJ, Androulakis II (2006) Bone remodeling. Ann N Y Acad Sci 1092:385–396
Ducy P (2011) The role of osteocalcin in the endocrine cross-talk between bone remodelling and energy metabolism. Diabetologia 54:1291–1297
Hauschka PV, Lian JB, Gallop PM (1975) Direct identification of the calcium-binding amino acid, gamma-carboxyglutamate, in mineralized tissue. Proc Natl Acad Sci U S A 72:3925–3929
Price PA, Otsuka AA, Poser JW, Kristaponis J, Raman N (1976) Characterization of a gamma-carboxyglutamic acid-containing protein from bone. Proc Natl Acad Sci U S A 73:1447–1451
Hauschka PV, Lian JB, Cole DE, Gundberg CM (1989) Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev 69:990–1047
Lee NK et al (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130:456–469
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
Clemens TL, Karsenty G (2011) The osteoblast: an insulin target cell controlling glucose homeostasis. J Bone Min Res 26:677–680
Karsenty G, Ferron M (2012) The contribution of bone to whole-organism physiology. Nature 481:314–320
Brennan-Speranza TC et al (2012) Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism. J Clin Inv 122:4172–4189
Lambert LJ et al (2016) Increased trabecular bone and improved biomechanics in an osteocalcin null rat model created by CRISPR/Cas9 technology. Dis Models Mech 1:1169–1179
Gao J et al (2016a) The PLC/PKC/Ras/MEK/Kv channel pathway is involved in uncarboxylated osteocalcin-regulated insulin secretion in rats. Peptides 86:72–79
Gao J et al (2016b) Inhibition of voltage-gated potassium channels mediates uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic beta cells. Eur J Pharmacol 777:41–48
Kover K et al (2015) Osteocalcin protects pancreatic beta cell function and survival under high glucose conditions. Biochem Biophys Res Comm 462:21–26
Delmas PD, Wilson DM, Mann KG, Riggs BL (1983) Effect of renal function on plasma levels of bone gla-protein. J Clin Endocrinol Metab 57:1028–1030
Price PA, Williamson MK, Lothringer JW (1981) Origin of the vitamin K-dependent bone protein found in plasma and its clearance by kidney and bone. J Biol Chem 256:12760–12766
Erkkilä AT, Booth SL (2008) Vitamin K intake and atherosclerosis. Curr Opinion Lipidol 19:39–42
Furie B, Bouchard BA, Furie BC (1999) Vitamin K-dependent biosynthesis of γ-carboxyglutamic acid. Blood 93:1798–1808
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
Gundberg CM, Nieman SD, Abrams S, Rosen H (1998) Vitamin K status and bone health: an analysis of methods for determination of undercarboxylated osteocalcin. J Clin Endocrinol Metab 83:3258–3266
Vergnaud P et al (1997) Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women: the EPIDOS study. J Clin Endocrinol Metab 82:719–724
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
Yeap BB et al (2010) Reduced serum total osteocalcin is associated with metabolic syndrome in older men via waist circumference, hyperglycemia, and triglyceride levels. Eur J Endocrinol 163:265–272
Foresta C et al (2010) Evidence for osteocalcin production by adipose tissue and its role in human metabolism. J Clin Endocrinol Metab 95:3502–3506
Prats-Puig A et al (2010) Carboxylation of osteocalcin affects its association with metabolic parameters in healthy children. Diabetes Care 33:661–663
Iki M et al (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. Osteopor Int. 23:761–770
Okuno S et al (2013) Significant inverse relationship between serum undercarboxylated osteocalcin and glycemic control in maintenance hemodialysis patients. Osteopor Int 24:605–612
Rosato MT, Schneider SH, Shapses SA (1998) Bone turnover and insulin-like growth factor I levels increase after improved glycemic control in noninsulin-dependent diabetes mellitus. Calc tissue Int 63:107–111
Levinger I et al (2011) The effect of acute exercise on undercarboxylated osteocalcin in obese men. Osteoporos Int 22:1621–1626
Oz SG et al (2006) Evaluation of bone metabolism and bone mass in patients with type-2 diabetes mellitus. J Natl Med Assoc 98:1598–1604
Kindblom JM et al (2009) Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. J Bone Min Res 24:785–791
Yeap BB et al (2015a) 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
Im JA, Yu BP, Jeon JY, Kim SH (2008) Relationship between osteocalcin and glucose metabolism in postmenopausal women. Clin Chim Acta 396:66–69
Liu DM et al (2015) Association between osteocalcin and glucose metabolism: a meta-analysis. Osteopor Int 26:2823–2833
Kanazawa I et al (2011a) Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2 diabetes mellitus. Osteopor Int 22:187–194
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 Bio 30:1474–1478
Pittas AG, Harris SS, Eliades M, Stark P, Dawson-Hughes B (2009) Association between serum osteocalcin and markers of metabolic phenotype. Journal Clin Endocrinol Metabol 94:827–832
Fernandez-Real JM et al (2009) The relationship of serum osteocalcin concentration to insulin secretion, sensitivity, and disposal with hypocaloric diet and resistance training. J Clin Endocrinol Metab 94:237–245
Hwang YC, Jeong IK, Ahn KJ, Chung HY (2009) The uncarboxylated form of osteocalcin is associated with improved glucose tolerance and enhanced beta-cell function in middle-aged male subjects. Diabetes Metab Res Rev 25:768–772
Hwang YC, Jeong IK, Ahn KJ, Chung HY (2012a) Circulating osteocalcin level is associated with improved glucose tolerance, insulin secretion and sensitivity independent of the plasma adiponectin level. Osteopor Int 23:1337–1342
Bullo M, Moreno-Navarrete JM, Fernandez-Real JM, Salas-Salvado J (2012) Total and undercarboxylated osteocalcin predict changes in insulin sensitivity and beta cell function in elderly men at high cardiovascular risk. Am J Clin Nutr 95:249–255
Ngarmukos C et al (2012) A reduced serum level of total osteocalcin in men predicts the development of diabetes in a long-term follow-up cohort. Clin Endocrinol 77:42–46
Shea MK et al (2009) Gamma-carboxylation of osteocalcin and insulin resistance in older men and women. Am J Clin Nutr 90:1230–1235
Hwang YC et al (2012b) Circulating osteocalcin level is not associated with incident type 2 diabetes in middle-aged male subjects: mean 8.4-year retrospective follow-up study. Diabetes Care 35:1919–1924
Sabek OM et al (2015) Osteocalcin effect on human beta-cells mass and function. Endocrinol 156:3137–3146
De Toni L et al (2016a) Osteocalcin and sex hormone binding globulin compete on a specific binding site of GPRC6A. Endocrinol 157:4473–4486
De Toni L et al (2016b) Polymorphism rs2274911 of GPRC6A as a novel risk factor for testis failure. J Clin Endocrinol Metab 101:953–961
Di Nisio A et al (2017) The rs2274911 polymorphism in GPRC6A gene is associated with insulin resistance in normal weight and obese subjects. Clin Endocrinol 86:185–191
Oury F et al (2013) Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. J Clin Inv 123:2421–2433
Kanazawa I et al (2009a) Adiponectin is associated with changes in bone markers during glycemic control in type 2 diabetes mellitus. J Clin Endocrinol Metab 94:3031–3037
Sayinalp S, Gedik O, Koray Z (1995) Increasing serum osteocalcin after glycemic control in diabetic men. Calc Tissue Int 57:422–425
Bao YQ et al (2011) Relationship between serum osteocalcin and glycaemic variability in type 2 diabetes. Clin Exp Pharmacol Physiol 38:50–54
Szulc P, Chapuy MC, Meunier PJ, Delmas PD (1993) Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J Clin Inv 91:1769–1774
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 Nut 72:1523–1528
Kumar R, Binkley N, Vella A (2010) Effect of phylloquinone supplementation on glucose homeostasis in humans. Am J Clin Nut 92:1528–1532
Sakamoto N, Nishiike T, Iguchi H, Sakamoto K (1999) Relationship between acute insulin response and vitamin K intake in healthy young male volunteers. Diabetes Nutr Metab 12:37–41
Shea MK, Dawson-Hughes B, Gundberg CM, Booth SL (2016) Reducing undercarboxylated osteocalcin with vitamin K supplementation does not promote lean tissue loss or fat gain over 3 years in older women and men: a randomized controlled trial. J Bone Min Res. doi:10.1002/jbmr.2989
Vestergaard P (2011) Risk of newly diagnosed type 2 diabetes is reduced in users of alendronate. Calc Tissue Int 89:265–270
Chan DC et al (2015) The use of alendronate is associated with a decreased incidence of type 2 diabetes mellitus—a population-based cohort study in Taiwan. PLoS One 10:e0123279
Schwartz AV et al (2013) Effects of antiresorptive therapies on glucose metabolism: results from the FIT, HORIZON-PFT, and FREEDOM trials. J Bone Min Res 28:1348–1354
Holloszy JO (2005) Exercise-induced increase in muscle insulin sensitivity. J Appl Physiol 99:338–343
Funai K, Schweitzer GG, Sharma N, Kanzaki M, Cartee GD (2009) Increased AS160 phosphorylation, but not TBC1D1 phosphorylation, with increased postexercise insulin sensitivity in rat skeletal muscle. Am J Physiol Endocrinol Metabol 297:E242–E251
Levinger I et al (2014) The effect of acute exercise on undercarboxylated osteocalcin and insulin sensitivity in obese men. J Bone Min Res 29:2571–2576
Guillemant J, Accarie C, Peres G, Guillemant S (2004) Acute effects of an oral calcium load on markers of bone metabolism during endurance cycling exercise in male athletes. Cal Tissue Int 74:407–414
Scott JP et al (2010) The effect of training status on the metabolic response of bone to an acute bout of exhaustive treadmill running. J Clin Endocrinol Metab 95:3918–3925
Mera P et al (2016) Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise. Cell metabol 23:1078–1092
Levinger I et al (2016) Glucose-loading reduces bone remodeling in women and osteoblast function in vitro. Physiol Rep 4
Holvik K et al (2014) Plasma osteocalcin levels as a predictor of cardiovascular disease in older men and women: a population-based cohort study. Eur J Endocrinol 171:161–170
Ling Y et al (2016) A common polymorphism rs1800247 in osteocalcin gene is associated with hypertension and diastolic blood pressure levels: the Shanghai Changfeng study. J Human Hyperten 30:679–684
Iwakiri T et al (2012) Usefulness of carotid intima-media thickness measurement as an indicator of generalized atherosclerosis: findings from autopsy analysis. Atherosclerosis 225:359–362
Cohen GI et al (2013) Relationship between carotid disease on ultrasound and coronary disease on CT angiography. JACC Cardiovasc Imaging 6:1160–1167
Lewis JR et al (2016) Abdominal aortic calcification identified on lateral spine images from bone densitometers are a marker of generalized atherosclerosis in elderly women. Arterioscler Thromb Vasc Bio 36:166–173
Kim KM et al (2016) Lower uncarboxylated osteocalcin and higher sclerostin levels are significantly associated with coronary artery disease. Bone 83:178–183
Zhang M, Ni Z, Zhou W, Qian J (2015a) Undercarboxylated osteocalcin as a biomarker of subclinical atherosclerosis in non-dialysis patients with chronic kidney disease. J Biomed Sci 22:75
Janda K et al (2015) Cardiovascular risk in chronic kidney disease patients: intima-media thickness predicts the incidence and severity of histologically assessed medial calcification in radial arteries. BMC Nephrol 16:78
Kanazawa I, Yamaguchi T, Sugimoto T (2011b) Relationship between bone biochemical markers versus glucose/lipid metabolism and atherosclerosis; a longitudinal study in type 2 diabetes mellitus. Diabetes Res Clin Pract 92:393–399
Thompson B, Towler DA (2012) Arterial calcification and bone physiology: role of the bone-vascular axis. Nat Rev Endocrinol 8:529–543
Bostrom KI (2016) Where do we stand on vascular calcification? Vasc Pharmacol 84:8–14
Oei H-HS et al (2002) The association between coronary calcification assessed by electron beam computed tomography and measures of extracoronary atherosclerosis: the Rotterdam coronary calcification study. J Am Coll Cardiol 39:1745–1751
Johnson RC, Leopold JA, Loscalzo J (2006) Vascular calcification: pathobiological mechanisms and clinical implications. Circul Res 99:1044–1059
Vliegenthart R et al (2005) Coronary calcification improves cardiovascular risk prediction in the elderly. Circulation 112:572–577
Idelevich A, Rais Y, Monsonego-Ornan E (2011) Bone Gla protein increases HIF-1alpha-dependent glucose metabolism and induces cartilage and vascular calcification. Arterioscler Thromb Vasc Biol 31:e55–e71
Sheng L et al (2013) Serum osteocalcin level and its association with carotid atherosclerosis in patients with type 2 diabetes. Cardiovasc Diabetol 12:22
Zhang H et al (2015b) Correlation between osteocalcin-positive endothelial progenitor cells and spotty calcification in patients with coronary artery disease. Clin Exp Pharmacol Physiol 42:734–739
Murshed M, Schinke T, McKee MD, Karsenty G (2004) Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins. J Cell Bio 165:625–630
Maser RE, Lenhard MJ, Sneider MB, Pohlig RT (2015) Osteoprotegerin is a better serum biomarker of coronary artery calcification than osteocalcin in type 2 diabetes. Endocr Pract 21:14–22
Choi BH et al (2015) Coronary artery calcification is associated with high serum concentration of undercarboxylated osteocalcin in asymptomatic Korean men. Clin Endocrinol 83:320–326
Confavreux CB et al (2013) Higher serum osteocalcin is associated with lower abdominal aortic calcification progression and longer 10-year survival in elderly men of the MINOS cohort. J Clin Endocrinol Metab 98:1084–1092
Jie KG, Bots ML, Vermeer C, Witteman JC, Grobbee DE (1996) Vitamin K status and bone mass in women with and without aortic atherosclerosis: a population-based study. Calc Tissue Int 59:352–356
Parker BD, Bauer DC, Ensrud KE, Ix JH (2010) Association of osteocalcin and abdominal aortic calcification in older women: the study of osteoporotic fractures. Calc Tissue Int 86:185–191
Kanazawa I et al (2009b) Serum osteocalcin level is associated with glucose metabolism and atherosclerosis parameters in type 2 diabetes mellitus. J Clin Endocrinol Metab 94:45–49
Goliasch G et al (2011) Markers of bone metabolism in premature myocardial infarction (</= 40 years of age). Bone 48:622–626
Yeap BB et al (2012) Associations of total osteocalcin with all-cause and cardiovascular mortality in older men. The health in men study. Osteopor Int 23:599–606
Fahrleitner-Pammer A et al (2008) Bone markers predict cardiovascular events in chronic kidney disease. J Bone Min Res 23:1850–1858
Yamashita T, Okano K, Tsuruta Y, Akiba T, Nitta K (2013) Serum osteocalcin levels are useful as a predictor of cardiovascular events in maintenance hemodialysis patients. Int Urol Nephrol 45:207–214
van der Leeuw J et al (2016) Novel biomarkers to improve the prediction of cardiovascular event risk in type 2 diabetes mellitus. J Am Heart Assoc 5
Lerchbaum E et al (2013) Association of bone turnover markers with mortality in men referred to coronary angiography. Osteopor int 24:1321–1332
Lerchbaum E, Schwetz V, Pilz S, Boehm BO, Marz W (2014) Association of bone turnover markers with mortality in women referred to coronary angiography: the Ludwigshafen risk and cardiovascular health (LURIC) study. Osteopor int 25:455–465
Hwang YC et al (2015) Association between the circulating total osteocalcin level and the development of cardiovascular disease in middle-aged men: a mean 8.7-year longitudinal follow-up study. J Atheroscler Thromb 22:136–143
Yeap BB et al (2015b) Proportion of undercarboxylated osteocalcin and serum P1NP predict incidence of myocardial infarction in older men. J Clin Endocrinol Metabo 100:3934–3942
Acknowledgements
A/Prof Levinger was supported by Future Leader Fellowship (ID: 100040) from the National Heart Foundation of Australia. Dr. Tara C Brennan-Speranza was supported by an NHMRC Early Career Fellowship (ID: 1013295). Dr. Lewis is supported by a National Health and Medical Research Council of Australia Career Development Fellowship (ID: 1107474).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
None.
Rights and permissions
About this article
Cite this article
Levinger, I., Brennan-Speranza, T.C., Zulli, A. et al. Multifaceted interaction of bone, muscle, lifestyle interventions and metabolic and cardiovascular disease: role of osteocalcin. Osteoporos Int 28, 2265–2273 (2017). https://doi.org/10.1007/s00198-017-3994-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-017-3994-3