title: Higher levels of s-RANKL and osteoprotegerin in children and adolescents with type 1 diabetes mellitus may indicate increased osteoclast signaling and predisposition to lower bone mass: a multivariate cross-sectional analysis.
abstract: Simultaneous lower bone mineral density, metabolic bone markers, parathyroid hormone (PTH), magnesium, insulin-like growth factor 1 (IGF1), and higher levels of total soluble receptor activator of nuclear factor-kappa B ligand (s-RANKL), osteoprotegerin (OPG), and alkaline phosphatase (ALP) are indicative of lower osteoblast and increased osteoclast signaling in children and adolescents with type 1 diabetes mellitus, predisposing to adult osteopenia and osteoporosis.
  
  
  BACKGROUND
  Type 1 diabetes mellitus (T1DM) is a risk factor for reduced bone mass, disrupting several bone metabolic pathways. We aimed at identifying association patterns between bone metabolic markers, particularly OPG, s-RANKL, and bone mineral density (BMD) in T1DM children and adolescents, in order to study possible underlying pathophysiologic mechanisms of bone loss.
  
  
  METHODS
  We evaluated 40 children and adolescents with T1DM (mean ± SD age 13.04 ± 3.53 years, T1DM duration 5.15 ± 3.33 years) and 40 healthy age- and gender-matched controls (aged12.99 ± 3.3 years). OPG, s-RANKL, osteocalcin, C-telopeptide cross-links (CTX), IGF1, electrolytes, PTH, and total 25(OH)D were measured, and total body along with lumbar spine BMD were evaluated with dual energy X-ray absorptiometry (DXA). Multivariate regression and factor analysis were performed after classic inference.
  
  
  RESULTS
  Patients had significantly lower BMD, with lower bone turnover markers, PTH, magnesium, and IGF1 than controls, indicating lower osteoblast signaling. Higher levels of total s-RANKL, OPG, and total ALP were observed in patients, with log(s-RANKL) and OPG correlation found only in controls, possibly indicating increased osteoclast signaling in patients. Coupling of bone resorption and formation was observed in both groups. Multivariate regression confirmed simultaneous lower bone turnover, IGF1, magnesium, and higher total s-RANKL, OPG, and ALP in patients, while factor analysis indicated possible activation of RANK/RANKL/OPG system in patients and its association with magnesium and IGF1. Patients with longer disease duration or worse metabolic control had lower BMD.
  
  
  CONCLUSIONS
  T1DM children and adolescents have impaired bone metabolism which seems to be multifactorial. Reduced osteoblast and increased osteoclast signaling, resulting from multiple simultaneous disturbances, could lead to reduced peak bone accrual in early adulthood, predisposing to adult osteopenia and osteoporosis.
authors.affiliation: Diabetes Clinic, 2nd Department of Pediatrics, Athens University Medical School, "P&A Kyriakou" Children's Hospital, Thivon & Livadias, 11527, Ampelokipi, Athens, Greece. tsentidis@yahoo.gr.
authors.forename: C
authors.initials: C
authors.lastname: Tsentidis
authors.affiliation: Laboratory of Clinical Biochemistry-Molecular Diagnostics, 2nd Department of Pediatrics, Athens University Medical School, "P&A Kyriakou" Children's Hospital, Athens, Greece.
authors.forename: D
authors.initials: D
authors.lastname: Gourgiotis
authors.affiliation: Diabetes Clinic, 2nd Department of Pediatrics, Athens University Medical School, "P&A Kyriakou" Children's Hospital, Thivon & Livadias, 11527, Ampelokipi, Athens, Greece.
authors.forename: L
authors.initials: L
authors.lastname: Kossiva
authors.affiliation: Department of Bone and Mineral Metabolism, Institute of Child Health, "Aghia Sophia" Children's Hospital, Athens, Greece.
authors.forename: A
authors.initials: A
authors.lastname: Doulgeraki
authors.affiliation: Laboratory of Clinical Biochemistry-Molecular Diagnostics, 2nd Department of Pediatrics, Athens University Medical School, "P&A Kyriakou" Children's Hospital, Athens, Greece.
authors.forename: A
authors.initials: A
authors.lastname: Marmarinos
authors.affiliation: Fourth Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece.
authors.forename: A
authors.initials: A
authors.lastname: Galli-Tsinopoulou
authors.affiliation: Diabetes Clinic, 2nd Department of Pediatrics, Athens University Medical School, "P&A Kyriakou" Children's Hospital, Thivon & Livadias, 11527, Ampelokipi, Athens, Greece.
authors.forename: K
authors.initials: K
authors.lastname: Karavanaki
mesh_terms: D015502:Absorptiometry, Photon / Q000379:methods; D000293:Adolescent; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000502:physiology; D001851:Bone Diseases, Metabolic / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D016723:Bone Remodeling / Q000502:physiology; D016022:Case-Control Studies; D002648:Child; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000150:complications / Q000503:physiopathology; D005260:Female; D006801:Humans; D008159:Lumbar Vertebrae / Q000503:physiopathology; D008297:Male; D010010:Osteoclasts / Q000502:physiology*; D010024:Osteoporosis / Q000097:blood / Q000209:etiology / Q000503:physiopathology; D053244:Osteoprotegerin / Q000097:blood*; D053245:RANK Ligand / Q000097:blood*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D015415:Biomarkers; D053244:Osteoprotegerin; D053245:RANK Ligand; C505688:TNFSF11 protein, human
keywords: Bone metabolism; Multivariate analysis; Osteoporosis; Osteoprotegerin; Type 1 diabetes; s-RANKL