{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:10:08Z","timestamp":1792523408146,"version":"4.5.0"},"reference-count":69,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T00:00:00Z","timestamp":1613174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Sickle bone disease (SBD) is a chronic and invalidating complication of Sickle cell disease (SCD), a multisystem autosomal recessive genetic disorder affecting millions of people worldwide. Mechanisms involved in SBD are not completely known, especially in pediatric age. Among the hypothesized pathogenetic mechanisms underlying SBD are bone marrow compensatory hyperplasia and bone ischemic damage, both secondary to vaso-occlusive crisis (VOC), which leads to cell sickling, thus worsening local hypoxia with a negative impact on osteoblast recruitment. Furthermore, the hypoxia is a strong activator of erythropoietin, which in turn stimulates osteoclast precursors and induces bone loss. Hemolysis and iron overload due to a chronic transfusion regimen could also contribute to the onset of bone complications. Vitamin D deficiency, which is frequently seen in SCD subjects, may worsen SBD by increasing the resorptive state that is responsible for low bone mineral density, acute\/chronic bone pain, and high fracture risk. An imbalance between osteoblasts and osteoclasts, with a relative decrease of osteoblast recruitment and activity, is a further possible mechanism responsible for the impairment of bone health in SCD. Moreover, delayed pubertal growth spurt and low peak bone mass may explain the high incidence of fracture in SCD adolescents. The aim of this review was to focus on the pathogenesis of SBD, updating the studies on biochemical, instrumental, and biological markers of bone metabolism. We also evaluated the growth development and endocrine complications in subjects affected with SCD.<\/jats:p>","DOI":"10.3390\/ijerph18041832","type":"journal-article","created":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T02:08:12Z","timestamp":1613268492000},"page":"1832","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Mechanisms of Bone Impairment in Sickle Bone Disease"],"prefix":"10.3390","volume":"18","author":[{"given":"Paola","family":"Giordano","sequence":"first","affiliation":[{"name":"Paediatric Unit, Department of Biomedical Sciences and Human Oncology, University of Bari \u201cA. Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Urbano","sequence":"additional","affiliation":[{"name":"Paediatric Unit, Department of Biomedical Sciences and Human Oncology, University of Bari \u201cA. Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Lassandro","sequence":"additional","affiliation":[{"name":"Paediatric Unit, Department of Biomedical Sciences and Human Oncology, University of Bari \u201cA. Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1899-8337","authenticated-orcid":false,"given":"Maria Felicia","family":"Faienza","sequence":"additional","affiliation":[{"name":"Paediatric Unit, Department of Biomedical Sciences and Human Oncology, University of Bari \u201cA. Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/S0140-6736(12)61229-X","article-title":"Global epidemiology of sickle haemoglobin in neonates: A contemporary geostatistical model-based map and population estimates","volume":"381","author":"Piel","year":"2013","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"GBD 2013 Mortality and Causes of Death Collaborators (2015). Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990\u20132013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet, 385, 117\u2013171.","DOI":"10.1016\/S0140-6736(14)61682-2"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/ncomms1104","article-title":"Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis","volume":"1","author":"Piel","year":"2010","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3647","DOI":"10.1182\/blood-2012-04-383430","article-title":"Sickle cell pain: A critical reappraisal","volume":"120","author":"Ballas","year":"2012","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1034\/j.1600-0609.2000.90210.x","article-title":"Acute clinical events in 299 homozygous sickle cell patients living in France","volume":"65","author":"Neonato","year":"2000","journal-title":"Eur. J. Haematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/eye.2001.248","article-title":"Orbital involvement in sickle cell disease: A report of five cases and review literature","volume":"15","author":"Ganesh","year":"2001","journal-title":"Eye"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1111\/j.1365-2591.2004.00853.x","article-title":"Pulpal necrosis with sickle cell anaemia","volume":"37","author":"Demirbas","year":"2004","journal-title":"Int. Endodont J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1097\/MAJ.0b013e318172f5d2","article-title":"Fat embolism syndrome","volume":"336","author":"Stein","year":"2008","journal-title":"Am. J. Med. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Tsitsikas, D.A., Vize, J., and Abukar, J. (2020). Fat Embolism Syndrome in Sickle Cell Disease. J. Clin. Med., 9.","DOI":"10.3390\/jcm9113601"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1002\/ajh.20541","article-title":"High prevalence and correlates of low bone mineral density in young adults with sickle cell disease","volume":"81","author":"Miller","year":"2006","journal-title":"Am. J. Hematol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"35","DOI":"10.4137\/CMED.S24501","article-title":"Predictors of abnormal bone mass density in adult patients with homozygous sickle-cell disease","volume":"8","author":"Garadah","year":"2015","journal-title":"Clin. Med. Insights Endocrinol. Diabetes"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1097\/01.med.0000436192.25846.0b","article-title":"An update on the recent literature on sickle cell bone disease","volume":"20","author":"Osunkwo","year":"2013","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1007\/s11657-017-0364-x","article-title":"Evaluation of bone mineral density in children with sickle-cell anemia and its associated factors in the south of Iran: A case-control study","volume":"12","author":"Bordbar","year":"2017","journal-title":"Arch. Osteoporos."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1096\/fj.14-259085","article-title":"Erythropoietin directly stimulates osteoclast precursors and induces bone loss","volume":"29","author":"Liron","year":"2015","journal-title":"FASEB J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cmet.2017.10.005","article-title":"Advances in Hypoxia-Inducible Factor Biology","volume":"27","author":"Choudhry","year":"2018","journal-title":"Cell Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1097\/MPH.0b013e31828dc614","article-title":"Screening for coagulopathy and identification of children with acute lymphoblastic leukemia at a higher risk of symptomatic venous thrombosis: An AIEOP experience","volume":"35","author":"Santoro","year":"2013","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.3390\/nu7042324","article-title":"Chronic iron deficiency as an emerging risk factor for osteoporosis: A hypothesis","volume":"7","author":"Toxqui","year":"2015","journal-title":"Nutrients"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e10417","DOI":"10.1002\/jbm4.10417","article-title":"Controversies in Vitamin D: A Statement from the Third International Conference","volume":"4","author":"Giustina","year":"2020","journal-title":"JBMR Plus"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Nolan, V.G., Nottage, K.A., Cole, E.W., Hankins, J.S., and Gurney, J.G. (2015). Prevalence of vitamin D deficiency in sickle cell disease: A systematic review. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119908"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/j.jpeds.2004.06.055","article-title":"Low vitamin D status in children with sickle cell disease","volume":"145","author":"Buison","year":"2004","journal-title":"J. Pediatr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1002\/ajh.22010","article-title":"Vitamin D level among patients with sickle cell anemia and its influence on bone mass","volume":"86","author":"Sultan","year":"2011","journal-title":"Am. J. Hematol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0022-3476(00)90053-2","article-title":"Total and resting energy expenditure in children with sickle cell disease","volume":"136","author":"Barden","year":"2000","journal-title":"J. Pediatr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.bone.2012.10.005","article-title":"Relationship between vitamin D deficiency and bone fragility in sickle cell disease: A cohort study of 56 adults","volume":"52","author":"Arlet","year":"2013","journal-title":"Bone"},{"key":"ref_24","first-page":"813","article-title":"Osteoporosis and osteosclerosis in sickle cell\/\u03b2-thalassemia: The role of the RANKL\/osteoprotegerin axis","volume":"91","author":"Voskaridou","year":"2006","journal-title":"Haematologica"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"193","DOI":"10.4103\/0019-5359.40984","article-title":"Secondary osteoporosis due to sickle cell anemia: Do sex steroids play a role?","volume":"62","author":"Sultan","year":"2008","journal-title":"Indian J. Med. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/BF03345572","article-title":"Clinical, endocrine, and molecular findings in 17beta-hydroxysteroid dehydrogenase type 3 deficiency","volume":"31","author":"Faienza","year":"2008","journal-title":"J. Endocrinol. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.bone.2018.02.003","article-title":"High bone mineral density in sickle cell disease: Prevalence and characteristics","volume":"110","author":"Ranque","year":"2018","journal-title":"Bone"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1093\/ajcn\/76.1.218","article-title":"Body composition in children with sickle cell disease","volume":"76","author":"Barden","year":"2002","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1097\/00043426-200103000-00009","article-title":"Red blood cell folate and serum vitamin B12 status in children with sickle cell disease","volume":"23","author":"Kennedy","year":"2001","journal-title":"J. Pediatr. Hematol.\/Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.jclinepi.2009.06.006","article-title":"The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration","volume":"62","author":"Liberati","year":"2009","journal-title":"J. Clin. Epidemiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1002\/pbc.21147","article-title":"Markers of bone turnover are associated with growth and development in young subjects with sickle cell anemia","volume":"50","author":"Fung","year":"2008","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1177\/1076029615594001","article-title":"Tartrate-resistant acid phosphatase 5b in young patients with sickle cell disease and trait siblings: Relation to vasculopathy and bone mineral density","volume":"23","author":"Mokhtar","year":"2017","journal-title":"Clin. Appl. Thromb. Hemost."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.3324\/haematol.2011.042499","article-title":"Predictors of osteoclast activity in patients with sickle cell disease","volume":"96","author":"Nouraie","year":"2011","journal-title":"Haematologica"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.bone.2015.07.021","article-title":"Mechanisms of enhanced osteoclastogenesis in girls and young women with Turner Syndrome","volume":"81","author":"Faienza","year":"2015","journal-title":"Bone"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/0009-8981(91)90301-R","article-title":"Urinary hydroxyproline and serum alkaline phosphatase in sickle cell disease","volume":"203","author":"Mohammed","year":"1991","journal-title":"Clin. Chim. Acta"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1556\/APhysiol.97.2010.3.5","article-title":"Osteocalcin and specific markers of bone resorption in sickle cell disease","volume":"97","author":"Bolarin","year":"2010","journal-title":"Acta Physiol. Hung."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1111\/j.1365-2141.2010.08458.x","article-title":"Vitamin D deficiency and chronic pain in Sickle Cell Disease","volume":"153","author":"Osunkwo","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1002\/pbc.25399","article-title":"Vitamin D deficiency and acute vaso-occlusive complications in children with sickle cell disease","volume":"62","author":"Lee","year":"2015","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1111\/bjh.15270","article-title":"Risk factors for vitamin D deficiency in sickle cell disease","volume":"181","author":"Han","year":"2018","journal-title":"Br. J. Haematol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"NS20160009","DOI":"10.1042\/NS20160009","article-title":"Glycinergic transmission: Glycine transporter GlyT2 in neuronal pathologies","volume":"1","author":"Zafra","year":"2016","journal-title":"Neuronal Signal."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Gr\u00e9goire-Pelchat, P., Pastore, Y., Robitaille, N., LeMay, S., Khamessan, A., Kleiber, N., Nyalendo, C., Gagn\u00e9, N., Alos, N., and Mailhot, G. (2020). Comparison of two vitamin D supplementation strategies in children with sickle cell disease: A randomized controlled trial. Br. J. Haematol.","DOI":"10.1111\/bjh.17119"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1007\/s00467-014-2834-3","article-title":"Bone health in children and adolescents with steroid-sensitive nephrotic syndrome assessed by DXA and QUS","volume":"29","author":"Aceto","year":"2014","journal-title":"Pediatr. Nephrol."},{"key":"ref_43","unstructured":"Kanis, J.A., and On behalf of the World Health Organization Scientific Group (2007). Assessment of Osteoporosis at the Primary Health-Care Level, World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield. Technical Report."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1002\/jbmr.5650080915","article-title":"Vertebral fracture assessment using a semiquantitative technique","volume":"8","author":"Genant","year":"1993","journal-title":"J. Bone Miner. Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"De Franceschi, L., Gabbiani, D., Giusti, A., Forni, G., Stefanoni, F., Pinto, V.M., Sartori, G., Balocco, M., Dal Zotto, C., and Valenti, M.T. (2020). Development of algorithm for clinical management of sickle cell bone disease: Evidence for a role of vertebral fractures in patient follow-up. J. Clin. Med., 9.","DOI":"10.3390\/jcm9051601"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1111\/j.1600-0609.2009.01333.x","article-title":"Osteopenia and vitamin D deficiency in children with sickle cell disease","volume":"83","author":"Chapelon","year":"2009","journal-title":"Eur. J. Haematol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1542\/peds.2004-2582","article-title":"Bone area and bone mineral content deficits in children with sickle cell disease","volume":"116","author":"Buison","year":"2005","journal-title":"Pediatrics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"25103","DOI":"10.1074\/jbc.R109.041087","article-title":"Cellular and Molecular Mechanisms of Bone Remodeling","volume":"285","author":"Raggatt","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"575936","DOI":"10.1155\/2013\/575936","article-title":"Postmenopausal osteoporosis: The role of immune system cells","volume":"2013","author":"Faienza","year":"2013","journal-title":"Clin. Dev. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.bone.2018.02.019","article-title":"Bone and blood interactions in human health and disease","volume":"119","author":"Wu","year":"2019","journal-title":"Bone"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1007\/s12519-018-0198-7","article-title":"An update on the role of RANKL-RANK\/osteoprotegerin and WNT-\u00df-catenin signaling pathways in pediatric diseases","volume":"15","author":"Brunetti","year":"2019","journal-title":"World J. Pediatr."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1080\/03630269.2020.1811116","article-title":"Receptor Activator of Nuclear Factor \u03ba-\u0392 Ligand\/Osteoprotegerin Axis in Adults with Hb S\/\u03b2-Thalassemia and \u03b2-Thalassemia Trait","volume":"44","author":"Tombak","year":"2020","journal-title":"Hemoglobin"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.1182\/blood-2015-04-641969","article-title":"Hypoxia-reperfusion affects osteogenic lineage and promotes sickle cell bone disease","volume":"126","author":"Carbonare","year":"2015","journal-title":"Blood"},{"key":"ref_54","first-page":"110","article-title":"Bone marrow neutrophil aging in sickle cell disease mice is associated with impaired osteoblast functions","volume":"16","author":"Rana","year":"2018","journal-title":"Biochem. Biophys. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Mandese, V., Bigi, E., Bruzzi, P., Palazzi, G., Predieri, B., Lucaccioni, L., Cellini, M., and Iughetti, L. (2019). Endocrine and metabolic complications in children and adolescents with Sickle Cell Disease: An Italian cohort study. BMC Pediatr., 19.","DOI":"10.1186\/s12887-019-1423-9"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"25","DOI":"10.4274\/tjh.2012.0001","article-title":"Frequency and risk factors of endocrine complications in Turkish children and adolescents with sickle cell anemia","volume":"30","author":"Ozen","year":"2013","journal-title":"Turk. J. Haematol."},{"key":"ref_57","first-page":"101","article-title":"Growth and growth hormone-Insulin Like Growth Factor\u2014I (GH-IGF-I) axis in chronic anemias","volume":"88","author":"Soliman","year":"2017","journal-title":"Acta Biomed."},{"key":"ref_58","first-page":"211","article-title":"Growth hormone and insulin-like growth factor I axis and growth of children with different sickle cell anemia haplotypes","volume":"20","author":"Luporini","year":"2007","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1007\/s00431-012-1817-2","article-title":"Status of vitamin D in children with sickle cell disease living in Madrid, Spain","volume":"171","author":"Garrido","year":"2012","journal-title":"Eur. J. Pediatr."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.pcad.2013.10.015","article-title":"The uncertain significance of low vitamin D levels in African descent populations: A review of the bone and cardiometabolic literature","volume":"56","author":"Thoreson","year":"2013","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1136\/jclinpath-2012-201301","article-title":"Vitamin D: A negative acute phase reactant","volume":"66","author":"Waldron","year":"2013","journal-title":"J. Clin. Pathol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1001\/archinternmed.2008.604","article-title":"Demographic differences and trends of vitamin D insufficiency in the US population, 1988\u20132004","volume":"169","author":"Ginde","year":"2009","journal-title":"Arch. Intern. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1007\/s00198-010-1383-2","article-title":"Racial differences in the relationship between vitamin D, bone mineral density, and parathyroid hormone in the National Health and Nutrition Examination Survey","volume":"22","author":"Gutierrez","year":"2011","journal-title":"Osteoporos. Int."},{"key":"ref_64","first-page":"332","article-title":"Prevalence of vitamin D deficiency in adults with sickle cell disease","volume":"102","author":"Goodman","year":"2010","journal-title":"J. Natl. Med. Assoc."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3389\/fendo.2016.00034","article-title":"Bone Fragility in Turner Syndrome: Mechanisms and Prevention Strategies","volume":"7","author":"Faienza","year":"2016","journal-title":"Front. Endocrinol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1007\/BF03345738","article-title":"17beta-Hydroxysteroid dehydrogenase-3 deficiency: From pregnancy to adolescence","volume":"32","author":"Bertelloni","year":"2009","journal-title":"J. Endocrinol. Investig."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"338","DOI":"10.7150\/ijms.5181","article-title":"Risk factors for subclinical atherosclerosis in diabetic and obese children","volume":"10","author":"Faienza","year":"2013","journal-title":"Int. J. Med. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/ncpendmet0702","article-title":"Therapy insight: Metabolic and endocrine disorders in sickle cell disease","volume":"4","author":"Smiley","year":"2008","journal-title":"Nat. Clin. Pract. Endocrinol. Metab."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.ijcard.2014.04.115","article-title":"Insulin resistance and endothelial function in children and adolescents","volume":"174","author":"Miniello","year":"2014","journal-title":"Int. J. Cardiol."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/18\/4\/1832\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:23:50Z","timestamp":1760160230000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/18\/4\/1832"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,13]]},"references-count":69,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijerph18041832"],"URL":"https:\/\/doi.org\/10.3390\/ijerph18041832","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,13]]}}}