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
- 686 Downloads
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.
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.
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.
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.
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.
KeywordsBone metabolism Multivariate analysis Osteoporosis Osteoprotegerin Type 1 diabetes s-RANKL
Compliance with ethical standards
Conflicts of interest
Charalampos Tsentidis, Dimitrios Gourgiotis, Lydia Kossiva, Artemis Doulgeraki, Antonios Marmarinos, Assimina Galli-Tsinopoulou, and Kyriaki Karavanaki declare that they have no conflict of interest.
This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
- 1.(2013) IDF Diabetes Atlas. International Diabetes FederationGoogle Scholar
- 5.Vestergaard P (2007) Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes—a meta-analysis. Osteoporos Int : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 18:427–444CrossRefGoogle Scholar
- 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 : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 25:1697–1708CrossRefGoogle Scholar
- 18.Lambrinoudaki I, Tsouvalas E, Vakaki M, Kaparos G, Stamatelopoulos K, Augoulea A, Pliatsika P, Alexandrou A, Creatsa M, Karavanaki K (2013) Osteoprotegerin, Soluble Receptor Activator of Nuclear Factor- kappa B Ligand, and Subclinical Atherosclerosis in Children and Adolescents with Type 1 Diabetes Mellitus. Int J Endocrinol 2013:102120CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Magkos F, Manios Y, Babaroutsi E, Sidossis LS (2006) Development and validation of a food frequency questionnaire for assessing dietary calcium intake in the general population. Osteoporos Int : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 17:304–312CrossRefGoogle Scholar
- 21.Avgerinos A, Argiropoulou EC, Almond L, Michalopoulou M (2000) A new instrument for evaluating energy expenditure: convergent validity and reliability of the physical activity and lifestyle questionnaire (PALQ). Sport Perform Health 4:281–300Google Scholar
- 32.Saha MT, Sievanen H, Salo MK, Tulokas S, Saha HH (2009) Bone mass and structure in adolescents with type 1 diabetes compared to healthy peers. Osteoporos Int : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 20:1401–1406CrossRefGoogle Scholar