Association of bone fracture type and degree of callus formation with leptin concentration in children with long bone fractures
Abstract
Background/Aim. Recent studies indicate that adipokines have an important role in bone physiology and pathology. Recent data indicate that adipokine leptin functions as a regulator of bone growth at multiple levels, systemically and locally. So far, it has been shown that leptin influences bone volume and bone mineral density in a population with metabolic and/or hormonal abnormality. Data concerning leptin values in non-obese children with fractures are scarce. Methods. This study included 93 non-obese children with long bone fractures (LBF), 14 children with short bone fractures (SBF), and 19 healthy children. Leptin concentration was determined in two blood samples (day 0 and day 21) and analyzed according to gender, fracture type, anatomical localization of the fracture, fracture topography, callus formation, and the healing outcome. Results. Children with LBF demonstrated significantly increased leptin levels compared to the control group (both day 0/day 21). In the control group, girls had significantly more leptin than boys. Leptin value was significantly influenced by anatomical localization since boys and girls with humerus fracture and girls with femur fracture had the highest average leptin concentration in the initial sample. Boys with incomplete callus formation had the highest leptin concentration (both day 0 /day 21), significantly elevated compared to boys’ samples in the control group, boys’ samples with an intermediary and well-formed callus, and also increased compared to the initial samples of girls with incomplete callus. Better callus formation in girls was associated with an increment of leptin concentrations in the second over the initial sample. Girls with partially and satisfactorily formed callus had significantly increased leptin concentration in the second sample (day 21) compared to the boys’ group. Conclusion. Leptin concentration was significantly increased (both samples) in children with LBF compared to children with SBF and corresponding controls. Leptin concentration was highly influenced by gender. High blood leptin concentrations in boys or low leptin concentrations in girls immediately upon fracture could be used to identify groups of children with incomplete callus formation.
References
Cho TJ, Gerstenfeld LC, Barnes GL, Einhorn TA. Cytokines and fracture healing. Curr Opin Orth 2001; 12: 403‒8.
Einhorn TA, Majeska RJ, Rush EB, Levine PM, Horowitz MC. The expression of cytokine activity by fracture callus. J Bone Miner Res 1995; 10(8): 1272‒81.
Solheim E. Growth factors in bone. Int Orthop 1998; 22(6): 410‒6.
Veillette CJH, McKee MD. Growth factors – BMPs, DBMs, and buffy coat products: are there any proven differences amongst them? Injury, Int J Care Injured 2007; 38(Suppl 1): S38‒S48.
Tsiridis E, Upadhyay N, Giannoudis P. Molecular aspects of fracture healing: which are the important molecules? Injury, Int J Care Injured 2007; 38(Suppl 1): S11‒S25.
Liu Y, Song CY, Wu SS, Liang QH, Yuan LQ, Liao EY. Novel adipokines and bone metabolism. Int J Endocrinol 2013; 2013: 895045.
Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflam-mation and metabolic disease. Nat Rev Immunol 2011; 11(2): 85‒97.
Lee YJ, Park JH, Ju SK, You KH, Ko JS, Kim HM. Leptin recep-tor isoform expression in rat osteoblasts and their functional analysis. FEBS Lett 2002; 528(1‒3): 43‒7.
Scheller EL, Song J, Dishowitz MI, Soki FN, Hankenson KD, Krebsbach PH. Leptin functions peripherally to regulate differ-entiation of mesenchymal progenitor cells. Stem Cells 2010; 28(6): 1071‒80.
Burguera B, Brunetto A, Garcia-Ocana A, Teijeiro R, Esplen J, Thomas T, et al. Leptin increases proliferation of human osteo-sarcoma cells through activation of PI(3)-K and MAPK pathways. Med Sci Monit 2006; 12(11): BR341‒9.
Cornish J, Callon KE, Bava U, Lin C, Naot D, Hill BL, et al. Leptin directly regulates bone cell function in vitro and reduc-es bone fragility in vivo. J Endocrinol 2002; 175(2): 405‒15.
Thomas T, Gori F, Khosla S, Jensen MD, Burguera B, Riggs BL. Leptin acts on human marrow stromal cells to enhance differ-entiation to osteoblasts and to inhibit differentiation to adi-pocytes. Endocrinology 1999; 140(4): 1630‒8.
Peng M, Chen S, Fang W, Yu X. Effects of leptin on the ex-pression of a1 (I) collagen gene in human osteoblast-like MG63 cells. Biochem Cell Biol 2010; 88(4): 683‒6.
Steppan CM, Crawford DT, Chidsey-Frink KL, Ke H, Swick AG. Leptin is a potent stimulator of bone growth in ob/ob mice. Regul Pept 2000; 92(1‒3): 73‒8.
Burguera B, Hofbauer LC, Thomas T, Gori F, Evans GL, Khosla S, et al. Leptin reduces ovariectomy-induced bone loss in rats. Endocrinology 2001; 142(8): 3546‒53.
Jackson MA, Iwaniec UT, Turner RT, Wronski TJ, Kalra SP. Ef-fects of increased hypothalamic leptin gene expression on ovariectomy-induced bone loss in rats. Peptides 2011; 32(8): 1575‒80.
Ruhl CE, Everhart JE. Relationship of serum leptin concentra-tion with bone mineral density in the United States popula-tion. J Bone Miner Res 2002; 17(10): 1896–903.
Blain H, Vuillemin A, Guillemin F, Durant R, Hanesse B, de Ta-lance N, et al. Serum leptin level is a predictor of bone mineral density in postmenopausal women. J Clin Endocrinol Metab 2002; 87(3): 1030‒5.
Kontogianni MD, Dafni UG, Routsias JG, Skopouli FN. Blood leptin and adiponectin as possible mediators of the relation between fat mass and BMD in perimenopausal women. J Bone Miner Res 2004; 19(4): 546–51.
Scotece M, Conde J, Vuolteenaho K, Koskinen A, López V, Gómez-Reino J, et al. Adipokines as drug targets in joint and Bone dis-ease. Drug Discov Today 2014; 19(3): 241‒58.
Elwakil WAA, Mohasseb D, Elkaffash D, Elshereef S, Elshafey M. Serum leptin and osteoporosis in postmenopausal women with primary knee osteoarthritis. Egypt Rheumatol 2016; 38(3): 209–15.
Pilcová R, Sulcová J, Hill M, Bláha P, Lisá L. Leptin levels in obese children: effects of gender, weight reduction and andro-gens. Physiol Res 2003; 52(1): 53‒60.
Abdul Wahab A, Maarafiya MM, Soliman A, Younes NB, Chan-dra P.Serum Leptin and Adiponectin Levels in Obese and Nonobese Asthmatic School Children in relation to Asthma Control. J Allergy (Cairo) 2013; 2013: 654104.
Erhardt E, Foraita R, Pigeot I, Barba G, Veidebaum T, Tornaritis M, et al. IDEFICS consortium. Reference values for leptin and adiponectin in children below the age of 10 based on the IDEFICS cohort Int J Obes (Lond) 2014; 38(Suppl 2): S32‒8.
Kelesidis T, Kelesidis I, Chou S, Mantzoros CS. Narrative review: the role of leptin in human physiology: emerging clinical appli-cations. Ann Intern Med 2012; 152(2): 93‒100.
Conde J, Scotece M, Gomez R, Lopez V, Gomez-Reino JJ, Lago F, et al. Adipokines: biofactors from white adipose tissue. A complex hub among inflammation, metabolism, and immuni-ty. Biofactors 2011; 37: 413‒20.
Chen M, Wang B, Xu Y, Deng Z, Xue H, Wang L, et al. Diag-nostic value of serum leptin and a promising novel diagnostic model for sepsis. Exp Ther Med 2014; 7(4): 881‒6.
Chang ML, Kuo CJ, Huang HC, Chu YY, Chiu CT. Association between Leptin and Complement in Hepatitis C Patients with Viral Clearance: Homeostasis of Metabolism and Immunity. PLoS One. 2016; 11(11): e0166712.
Lipsey CC, Harbuzariu A, Daley-Brown D, Gonzalez-Perez RR. Oncogenic role of leptin and Notch interleukin-1 leptin cross-talk outcome in cancer. World J Methodol 2016; 6(1): 43‒55.
Maury E, Brichard SM. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol 2010; 314(1): 1‒16.
Hamrick MW, Ferrari SL. Leptin and the sympathetic connec-tion of fat to bone. Osteoporos Int 2008; 19(7): 905‒12.
Gordeladze JO, Reseland JE. A unified model for the action of leptin on bone turnover. J Cell Biochem 2003; 88(4): 706‒12.
Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, et al. Leptin regulates bone formation via the sympathetic nervous system. Cell 2002; 111(3): 305‒17.
Oguz S, Tapisiz OL, Aytan H, Gunyeli I, Erdem S, Tuncay G, et al. Is leptin a significant predictor of bone mineral density in postmenopausal Turkish women? Rheumatol Int 2009; 29(4): 393‒6.
King GA, Deemer SE, Thompson DL.Relationship between lep-tin, adiponectin, bone mineral density, and measures of adi-posity among pre-menopausal hispanic and caucasian women. Endocr Res 2010; 35(3): 106‒17.
Wu N, Wang QP, Li H, Wu XP, Sun ZQ, Luo XH. Relation-ships between serum adiponectin, leptin concentrations and bone mineral density, and bone biochemical markers in Chi-nese women. Clin Chim Acta 2010; 411(9‒10): 771‒5.
Zhang H, Xie H, Zhao Q, Xie GQ, Wu XP, Liao EY, et al. Relationships between serum adiponectin, apelin, leptin, resis-tin, visfatin levels and bone mineral density, and bone bio-chemical markers in postmenopausal Chinese women. J Endo-crinol Invest 2010; 33(10): 707‒11.
Iida T, Domoto T, Takigawa A, Nakamura S, Kato Y, Togo M, et al. Relationships among blood leptin and adiponectin levels, fat mass, and bone mineral density in Japanese pre- and post-menopausal women. Hiroshima J Med Sci 2011; 60(4): 71‒8.
Sherk VD, Malone SP, Bemben MG, Knehans AW, Palmer IJ, Bemben DA. Leptin, fatmass, and bone mineral density in healthy pre- and postmenopausal women. J Clin Densitom 2011; 14(3): 321‒5.
Barbour KE, Zmuda JM, Boudreau R, Strotmeyer ES, Horwitz MJ, Evans RW, et al. The Effects of Adiponectin and Leptin on Changes in Bone Mineral Density. Osteoporos Int 2012; 23(6): 1699–710.
Rhie YJ, Lee KH, Chung SC, Kim HS, Kim DH. Effects of body composition, leptin, and adiponectin on bone mineral density in prepubertal girls. J Korean Med Sci 2010; 25(8): 1187‒90.
Wei Y, Wang L, Clark JC, Dass CR, Choong PF. Elevated lep-tin expression in a rat model of fracture and traumatic brain injury. J Pharm Pharmacol 2008 ;60(12): 1667‒72.
Wang L, Yuan JS, Zhang HX, Ding H, Tang XG, Wei YZ. Ef-fect of leptin on bone metabolism in rat model of traumatic brain injury and femoral fracture. Chin J Traumatol 2011; 14(1): 7‒13.
Chou SH, Chamberland JP, Liu X, Matarese G, Gao C, Stefanakis R, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A2011; 108(16):6585–90.
Chou SH, Mantzoros C. 20 years of leptin: Role of leptin in human reproductive disorders. J Endocrinol 2014; 223(1): T49–T62.
Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004; 351(10): 987–97.
Sienkiewicz E, Magkos F, Aronis KN, Brinkoetter M, Chamberland JP, Chou S, et al. Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism 2011; 60(9): 1211–21.
Feng W, Liu B, Liu D, Hasegawa T, Wang W, Han X, et al. Long- Term Administration of High-Fat Diet Corrects Ab-normal Bone Remodeling in the Tibiae of Interleukin-6-Deficient Mice. J Histochem Cytochem 2016; 64(1): 42‒53.
García-Jiménez S, Bernal Fernández G, Martínez Salazar MF, Monroy Noyola A, Toledano Jaimes C, Meneses Acosta A, et al. Se-rum leptin is associated with metabolic syndrome in obese Mexican subjects. J Clin Lab Anal 2015; 29(1): 5‒9.
Faggioni R, Moser A, Feingold KR, Grunfeld C. Reduced leptin levels in starvation increase susceptibility to endotoxic shock. Am J Pathol 2000; 156(5): 1781‒7.
Fernandez-Riejos P, Najib S, Santos-Alvarez J, Martin-Romero C, Perez-Perez A, Gonzalez-Yanes C, et al. Role of leptin in the ac-tivation of immune cells. Mediators Inflamm 2010; 2010: 568343.
Bornstein SR, Licinio J, Tauchnitz R, Engelmann L, Negrao AB, Gold P, et al. Plasma leptin levels are increased in survivors of acute sepsis: associated loss of diurnal rhythm, in cortisol and leptin secretion. J Clin Endocrinol Metab 1998; 83: 280‒3.
Lin J, Yan GT, Wang LH, Xue H, Hao XH, Zhang K. Effect of long tubular bone fracture on serum levels of leptin, acute phase proteins and biochemical markers for organ functions. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2006; 18(1): 19‒23. (Chinese)
Boes M, Kain M, Kakar S, Nicholls F, Cullinane D, Gerstenfeld L, et al. Osteogenic effects of traumatic brain injury on experi-mental fracture-healing. J Bone Joint Surg Am 2006; 88(4): 738‒43.
Wei Y, Wang L, Clark JC, Dass CR, Choong PF. Elevated lep-tin expression in a rat model of fracture and traumatic brain injury. J Pharm Pharmacol 2008; 60(12): 1667‒72.
Gautschi OP, Cadosch D, Frey SP, Skirving AP, Filgueira L, Zell-weger R. Serum-mediated osteogenic effect in traumatic brain-injured patients. ANZ J Surg 2009; 79(6): 449‒55.
Cadosch D Gautschi OP, Thyer M, Song S, Skirving AP, Filgueira L, et al. Humoral factors enhance fracture-healing and callus formation in patients with traumatic brain injury. J Bone Joint Surg Am 2009; 91(2): 282‒8.
Zhang D, Zhang P, Wang Y, Han N, Tang C, Jiang B. The influ-ence of brain injury or peripheral nerve injury on calcitonin gene-related peptide concentration variation and fractures healing process. Artif Cells Blood Substit Immobil Biotechnol 2009; 37(2): 85‒91.
Song Y, Bi L, Zhang Z, Huang Z, Hou W, Lu X, et al. Increased levels of calcitonin gene-related peptide in serum accelerate fracture healing following traumatic brain injury. Mol Med Rep 2012; 5(2): 432‒8.
Yang S, Ma Y, Liu Y, Que H, Zhu C, Liu S. Arachidonic acid: a bridge between traumatic brain injury and fracture healing, J Neurotrauma 2012; 29(17): 2696‒705.
Wang L, Liu L, Pan Z, Zeng Y. Serum leptin, bone mineral density and the healing of long bone fractures in men with spinal cord injury. Bosn J Basic Med Sci 2015; 15(4): 69‒74.
Saad MF, Damani S, Gingerich RL, Riad-Gabriel MG, Khan A, Boyadjian R, et al. Sexual dimorphism in plasma leptin concen-tration. J Clin Endocrinol Metab 1997; 82(2): 579‒84.
Licinio J, Negrao AB, Mantzoros C, Kaklamani V, Wong ML, Bongiorno PB, et al. Sex differences in circulating human leptin pulse amplitude: Clinical implications. J Clin Endocrinol Metab 1998; 83(11): 4140‒7.
Montague CT, Prins JB, Sanders L, Digby JE, O’Rahilly S. Depo-tand sex-specific differences in human leptin mRNA expres-sion: Implications for the control of regional fat distribution. Diabetes 1997; 46(3): 342‒7.
McConway MG, Johnson D, Kelly A, Griffin D, Smith J, Wallace AM. Difference in circulating concentrations of total, free and bound leptin relate to gender and body composition in adult humans. Ann Clin Biochem 2000; 37(Pt 5): 717‒23.
Halleux CM, Servais I, Reul BA, Detry R, Brichard SM. Multi-hormonal control of ob gene expression and leptin secretion from cultured human visceral adipose tissue: Increased respon-siveness to glucocorticoids in obesity. J Clin Endocrinol Metab 1998; 83(3): 902‒10.