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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

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Abstract

Summary

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.

Introduction

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.

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References

  1. (2013) IDF Diabetes Atlas. International Diabetes Federation

  2. Schwartz AV, Sellmeyer DE (2007) Diabetes fracture and bone fragility. Curr Osteoporos Rep 5:105–111

    Article  PubMed  Google Scholar 

  3. Sealand R, Razavi C, Adler RA (2013) Diabetes mellitus and osteoporosis. Curr Diabetes Rep 13:411–418

    Article  CAS  Google Scholar 

  4. Jackuliak P, Payer J (2014) Osteoporosis, fractures, and diabetes. Int J Endocrinol 2014:820615

    Article  PubMed  PubMed Central  Google 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 18:427–444

    Article  CAS  Google Scholar 

  6. Rakel A, Sheehy O, Rahme E, LeLorier J (2008) Osteoporosis among patients with type 1 and type 2 diabetes. Diabetes Metab 34:193–205

    Article  CAS  PubMed  Google Scholar 

  7. Strotmeyer ES, Cauley JA (2007) Diabetes mellitus bone mineral density and fracture risk. Curr Opin Endocrinol Diabetes Obes 14:429–435

    Article  PubMed  Google Scholar 

  8. Salerno M, Argenziano A, Di Maio S, Gasparini N, Formicola S, De Filippo G, Tenore A (1997) Pubertal growth, sexual maturation, and final height in children with IDDM. Effects of age at onset and metabolic control. Diabetes Care 20:721–724

    Article  CAS  PubMed  Google Scholar 

  9. Ahmed M, Connors M, Drayer N, Jones J, Dunger D (1998) Pubertal growth in IDDM is determined by HbA1c levels, sex, and bone age. Diabetes Care 21:831–835

    Article  CAS  PubMed  Google Scholar 

  10. Thrailkill KM, Lumpkin CKJ, Bunn RC, Kemp SF, Fowlkes JL (2005) Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues. Am J Physiol Endocrinol Metab 289:E735–E745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Merlotti D, Gennari L, Dotta F, Lauro D, Nuti R (2010) Mechanisms of impaired bone strength in type 1 and 2 diabetes. Nutr Metab Cardiovasc Dis 20:683–690

    Article  CAS  PubMed  Google Scholar 

  12. Dhaon P, Shah VN (2014) Type 1 diabetes and osteoporosis: a review of literature. Indian J Endocrinol Metab 18:159–165

    Article  PubMed  PubMed Central  Google 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 25:1697–1708

    Article  CAS  Google Scholar 

  14. Kearns AE, Khosla S, Kostenuik PJ (2008) Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 29:155–192

    Article  CAS  PubMed  Google Scholar 

  15. Loureiro MB, Ururahy MA, Freire-Neto FP et al (2014) Low bone mineral density is associated to poor glycemic control and increased OPG expression in children and adolescents with type 1 diabetes. Diabetes Res Clin Pract 103:452–457

    Article  CAS  PubMed  Google Scholar 

  16. Galluzzi F, Stagi S, Salti R, Toni S, Piscitelli E, Simonini G, Falcini F, Chiarelli F (2005) Osteoprotegerin serum levels in children with type 1 diabetes: a potential modulating role in bone status. Eur J Endocrinol / Eur Fed Endocr Soc 153:879–885

    Article  CAS  Google Scholar 

  17. Abd El Dayem S, El-Shehaby A, Abd El Gafar A, Fawzy A, Salama H (2011) Bone density, body composition, and markers of bone remodeling in type 1 diabetic patients. Scand J Clin Lab Invest 71:387–393

    Article  CAS  PubMed  Google 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 2013:102120

    Article  PubMed  PubMed Central  Google Scholar 

  19. Tsentidis C, Gourgiotis D, Kossiva L, Marmarinos A, Doulgeraki A, Karavanaki K (2015) Sclerostin distribution in children and adolescents with type 1 diabetes mellitus and correlation with bone metabolism and bone mineral density. Pediatr Diabetes. doi:10.1111/pedi.12288

    PubMed  Google 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 17:304–312

    Article  Google 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 4:281–300

    Google Scholar 

  22. Gunczler P, Lanes IR, Paolil M, Martinis R, Villaroel O, Weisinger JR (2001) Decreased bone mineral density and bone formation markers shortly after diagnosis of clinical type 1 diabetes mellitus. J Pediatr Endocrinol Metab 14:525–528

    Article  CAS  PubMed  Google Scholar 

  23. Valerio G, del Puente A, Esposito-del Puente A, Buono P, Mozzillo E, Franzese A (2002) The lumbar bone mineral density is affected by long-term poor metabolic control in adolescents with type 1 diabetes mellitus. Horm Res 58:266–272

    CAS  PubMed  Google Scholar 

  24. Camurdan MO, Ciaz P, Bideci A, Demirel F (2007) Role of hemoglobin A(1c), duration and puberty on bone mineral density in diabetic children. Pediatr Int : Off J Japan Pediatr Soc 49:645–651

    Article  CAS  Google Scholar 

  25. Hamed EA, Faddan NH, Elhafeez HA, Sayed D (2011) Parathormone–25(OH)-vitamin D axis and bone status in children and adolescents with type 1 diabetes mellitus. Pediatr Diabetes 12:536–546

    Article  CAS  PubMed  Google Scholar 

  26. Moyer-Mileur L, Slater H, Jordan K, Murray M (2008) IGF-1 and IGF-binding proteins and bone mass, geometry, and strength: relation to metabolic control in adolescent girls with type 1 diabetes. J Bone Miner Res 23:1884–1891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Maggio ABR, Ferrari S, Kraenzlin M, Marchand LM, Schwitzgebel V, Beghetti M, Rizzoli R, Farpour-Lambert NJ (2010) Decreased bone turnover in children and adolescents with well controlled type 1 diabetes. J Pediatr Endocrinol Metab 23:697–707

    Article  CAS  PubMed  Google Scholar 

  28. AboElAsrar M, Elbarbary N, Elshennawy D, Omar A (2012) Insulin-like growth factor-1 cytokines cross-talk in type 1 diabetes mellitus: relationship to microvascular complications and bone mineral density. Cytokine 59:86–93

    Article  CAS  PubMed  Google Scholar 

  29. Heap J, Murray MA, Miller SC, Jalili T, Moyer-Mileur LJ (2004) Alterations in bone characteristics associated with glycemic control in adolescents with type 1 diabetes mellitus. J Pediatr 144:56–62

    Article  CAS  PubMed  Google Scholar 

  30. Mastrandrea LD, Wactawski-Wende J, Donahue RP, Hovey KM, Clark A, Quattrin T (2008) Young women with type 1 diabetes have lower bone mineral density that persists over time. Diabetes Care 31:1729–1735

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ersoy B, Gökşen D, Darcan S, Mavi E, Oztürk C (1999) Evaluation of bone mineral density in children with diabetes mellitus. Indian J Pediatr 66:375–379

    Article  CAS  PubMed  Google 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 20:1401–1406

    Article  CAS  Google Scholar 

  33. Moyer-Mileur LJ, Dixon SB, Quick JL, Askew EW, Murray MA (2004) Bone mineral acquisition in adolescents with type 1 diabetes. J Pediatr 145:662–669

    Article  PubMed  Google Scholar 

  34. Brandao FR, Vicente EJ, Daltro CH, Sacramento M, Moreira A, Adan L (2007) Bone metabolism is linked to disease duration and metabolic control in type 1 diabetes mellitus. Diabetes Res Clin Pract 78:334–339

    Article  CAS  PubMed  Google Scholar 

  35. Karagüzel G, Akçurin S, Ozdem S, Boz A, Bircan I (2006) Bone mineral density and alterations of bone metabolism in children and adolescents with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 19:805–814

    PubMed  Google Scholar 

  36. Aboelasrar M, Farid S, El Maraghy M, Mohamedeen A (2010) Serum osteocalcin, zinc nutritive status and bone turnover in children and adolescents with type1 diabetes mellitus. Pediatr Diabetes 11:35–113

    Article  Google Scholar 

  37. Pater A, Sypniewska G, Pilecki O (2010) Biochemical markers of bone cell activity in children with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 23:81–86

    Article  CAS  PubMed  Google Scholar 

  38. Xiang GD, Sun HL, Zhao LS (2007) Changes of osteoprotegerin before and after insulin therapy in type 1 diabetic patients. Diabetes Res Clin Pract 76:199–206

    Article  CAS  PubMed  Google Scholar 

  39. Van Sickle B, Simmons J, Hall R, Raines M, Ness K, Spagnoli A (2009) Increased circulating IL-8 is associated with reduced IGF-1 and related to poor metabolic control in adolescents with type 1 diabetes mellitus. Cytokine 48:290–294

    Article  PubMed  PubMed Central  Google Scholar 

  40. Ekstrom K, Salemyr J, Zachrisson I, Carlsson-Skwirut C, Ortqvist E, Bang P (2007) Normalization of the IGF-IGFBP axis by sustained nightly insulinization in type 1 diabetes. Diabetes Care 30:1357–1363

    Article  PubMed  Google Scholar 

  41. Rubin J, Ackert-Bicknell CL, Zhu L, Fan X, Murphy TC, Nanes MS, Marcus R, Holloway L, Beamer WG, Rosen CJ (2002) IGF-I regulates osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand in vitro and OPG in vivo. J Clin Endocrinol Metab 87:4273–4279

    Article  CAS  PubMed  Google Scholar 

  42. Pascual J, Argente J, Lopez M, Muñoz M, Martinez G, Vazquez M, Jodar E, Perez-Cano R, Hawkins F (1998) Bone mineral density in children and adolescents with diabetes mellitus type 1 of recent onset. Calcif Tissue Int 62:31–35

    Article  CAS  PubMed  Google Scholar 

  43. De Schepper J, Smitz J, Rosseneu S, Bollen P, Louis O (1998) Lumbar spine bone mineral density in diabetic children with recent onset. Horm Res 50:193–196

    PubMed  Google Scholar 

  44. Vázquez Gámez MÁ, Marín Pérez JM, Montoya García MJ, Moruno García RM, Argüelles Martín F, Pérez Cano R (2008) Evolución de la masa ósea durante la infancia y adolescencia en niños con diabetes mellitus tipo 1. Med Clin (Barc) 130:526–530

    Article  Google Scholar 

  45. Liu EY, Wactawski-Wende J, Donahue RP, Dmochowski J, Hovey K, Quattrin T (2003) Does low bone mineral density start in post-teenage years in women with type 1 diabetes? Diabetes Care 26:2365–2369

    Article  PubMed  Google Scholar 

  46. Onder A, Cetinkaya S, Tunc O, Aycan Z (2013) Evaluation of bone mineral density in children with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 26:1077–1081

    Article  CAS  PubMed  Google Scholar 

  47. Salvatoni A, Mancassola G, Biasoli R, Cardani R, Salvatore S, Broggini M, Nespoli L (2004) Bone mineral density in diabetic children and adolescents: a follow-up study. Bone 34:900–904

    Article  PubMed  Google Scholar 

  48. Heilman K, Zilmer M, Zilmer K, Tillmann V (2009) Lower bone mineral density in children with type 1 diabetes is associated with poor glycemic control and higher serum ICAM-1 and urinary isoprostane levels. J Bone Miner Metab 27:598–604

    Article  CAS  PubMed  Google Scholar 

  49. Roma-Giannikou E, Adamidis D, Gianniou M, Nikolara R, Matsaniotis N (1997) Nutritional survey in Greek children: nutrient intake. Eur J Clin Nutr 51:273–285

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Diabetes Clinic, 2nd Department of Pediatrics, Athens University Medical School, “P&A Kyriakou” Children’s Hospital, Thivon & Livadias, 11527, Ampelokipi, Athens, Greece

    C. Tsentidis, L. Kossiva & K. Karavanaki

  2. Laboratory of Clinical Biochemistry—Molecular Diagnostics, 2nd Department of Pediatrics, Athens University Medical School, “P&A Kyriakou” Children’s Hospital, Athens, Greece

    D. Gourgiotis & A. Marmarinos

  3. Department of Bone and Mineral Metabolism, Institute of Child Health, “Aghia Sophia” Children’s Hospital, Athens, Greece

    A. Doulgeraki

  4. Fourth Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece

    A. Galli-Tsinopoulou

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  1. C. Tsentidis
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Correspondence to C. Tsentidis.

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Charalampos Tsentidis, Dimitrios Gourgiotis, Lydia Kossiva, Artemis Doulgeraki, Antonios Marmarinos, Assimina Galli-Tsinopoulou, and Kyriaki Karavanaki declare that they have no conflict of interest.

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Tsentidis, C., Gourgiotis, D., Kossiva, L. et al. 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. Osteoporos Int 27, 1631–1643 (2016). https://doi.org/10.1007/s00198-015-3422-5

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