Skip to main content
Top
Published in: Osteoporosis International 5/2014

01-05-2014 | Original Article

High serum pentosidine but not esRAGE is associated with prevalent fractures in type 1 diabetes independent of bone mineral density and glycaemic control

Authors: T. Neumann, S. Lodes, B. Kästner, S. Franke, M. Kiehntopf, T. Lehmann, U. A. Müller, G. Wolf, A. Sämann

Published in: Osteoporosis International | Issue 5/2014

Login to get access

Abstract

Summary

Fracture risk in type 1 diabetes (T1D) is supposed to be underestimated by bone mineral density (BMD). Individuals with T1D had more prevalent fractures in a cross-sectional study. Serum levels of pentosidine, an advanced glycation end product, and poor glycaemic control were associated with prevalent fractures independent of BMD.

Introduction

Type 1 diabetes (T1D) is associated with increased fracture risk. Bone mineral density (BMD) underestimates the risk of fractures in some individuals. The accumulation of advanced glycation end products (AGEs) impairs bone matrix and reduces bone strength.

Methods

In a cross-sectional study, 128 men and premenopausal women with T1D were evaluated. We compared traditional risk factors for fractures, BMD, parameters of bone metabolism and AGEs in individuals with and without prevalent fractures. An independent association of serum AGE levels with prevalent fractures was investigated.

Results

Individuals with prevalent fractures exhibited a longer duration of T1D, higher HbA1c and more diabetic-related complications. BMD at the femoral neck (z-score −0.76 ± 0.94 vs. −0.23 ± 1.02; p = 0.031) and total hip (z-score −0.54 ± 0.93 vs. 0.11 ± 1.11; p = 0.017) was lower in those with prevalent fractures. Individuals with fractures had higher pentosidine levels (164.1 ± 53.6 vs. 133.2 ± 40.4; p = 0.002). The levels of N-ε-(carboxymethyl)-lysine (CML) and endogenous secretory receptor for AGEs (esRAGE) did not significantly differ. Multivariate logistic regression analysis adjusted for age, BMI, family history of fractures, smoking, vitamin D deficiency, BMD at lumbar spine, femoral neck and total hip identified pentosidine levels and HbA1c as independent factors associated with prevalent fractures (odds ratio 1.02, 95 % CI 1.00–1.03/pmol/ml increase of pentosidine; p = 0.008 and odds ratio 1.93, 95 % CI 1.16–3.20 per percentage increase of HbA1c; p = 0.011).

Conclusions

The pentosidine levels but not BMD are independently associated with prevalent fractures. Impaired bone quality in T1D may result from increased AGE formation.
Literature
1.
go back to reference Zhukouskaya VV, Eller-Vainicher C, Vadzianava VV, Shepelkevich AP, Zhurava IV, Korolenko GG, Salko OB, Cairoli E, Beck-Peccoz P, Chiodini I (2013) Prevalence of morphometric vertebral fractures in patients with type 1 diabetes. Diabetes Care 36:1635–1640PubMedCrossRef Zhukouskaya VV, Eller-Vainicher C, Vadzianava VV, Shepelkevich AP, Zhurava IV, Korolenko GG, Salko OB, Cairoli E, Beck-Peccoz P, Chiodini I (2013) Prevalence of morphometric vertebral fractures in patients with type 1 diabetes. Diabetes Care 36:1635–1640PubMedCrossRef
2.
go back to reference Nicodemus KK, Folsom AR (2001) Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women. Diabetes Care 24:1192–1197PubMedCrossRef Nicodemus KK, Folsom AR (2001) Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women. Diabetes Care 24:1192–1197PubMedCrossRef
3.
go back to reference 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 18:427–444PubMedCrossRef 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 18:427–444PubMedCrossRef
4.
go back to reference Neumann T, Samann A, Lodes S et al (2011) Glycaemic control is positively associated with prevalent fractures but not with bone mineral density in patients with type 1 diabetes. Diabet Med 28:872–875PubMedCrossRef Neumann T, Samann A, Lodes S et al (2011) Glycaemic control is positively associated with prevalent fractures but not with bone mineral density in patients with type 1 diabetes. Diabet Med 28:872–875PubMedCrossRef
5.
go back to reference Danielson KK, Elliott ME, LeCaire T, Binkley N, Palta M (2009) Poor glycemic control is associated with low BMD detected in premenopausal women with type 1 diabetes. Osteoporos Int 20:923–933PubMedCentralPubMedCrossRef Danielson KK, Elliott ME, LeCaire T, Binkley N, Palta M (2009) Poor glycemic control is associated with low BMD detected in premenopausal women with type 1 diabetes. Osteoporos Int 20:923–933PubMedCentralPubMedCrossRef
6.
go back to reference Seeman E, Delmas PD (2006) Bone quality–the material and structural basis of bone strength and fragility. N Engl J Med 354:2250–2261PubMedCrossRef Seeman E, Delmas PD (2006) Bone quality–the material and structural basis of bone strength and fragility. N Engl J Med 354:2250–2261PubMedCrossRef
7.
go back to reference Busch M, Franke S, Ruster C, Wolf G (2010) Advanced glycation end-products and the kidney. Eur J Clin Invest 40:742–755PubMedCrossRef Busch M, Franke S, Ruster C, Wolf G (2010) Advanced glycation end-products and the kidney. Eur J Clin Invest 40:742–755PubMedCrossRef
8.
go back to reference Miyata T, Wada Y, Cai Z, Lida Y, Horie K, Yasuda Y, Maeda K, Kurokawa K, van Ypersele de Strihou C (1997) Implication of an increased oxidative stress in the formation of advanced glycation end products in patients with end-stage renal failure. Kidney Int 51:1170–1181PubMedCrossRef Miyata T, Wada Y, Cai Z, Lida Y, Horie K, Yasuda Y, Maeda K, Kurokawa K, van Ypersele de Strihou C (1997) Implication of an increased oxidative stress in the formation of advanced glycation end products in patients with end-stage renal failure. Kidney Int 51:1170–1181PubMedCrossRef
9.
go back to reference Salman AG, Mansour DE, Swelem AH, Al-Zawahary WM, Radwan AA (2009) Pentosidine - a new biochemical marker in diabetic retinopathy. Ophthalmic Res 42:96–98PubMedCrossRef Salman AG, Mansour DE, Swelem AH, Al-Zawahary WM, Radwan AA (2009) Pentosidine - a new biochemical marker in diabetic retinopathy. Ophthalmic Res 42:96–98PubMedCrossRef
10.
go back to reference Dong XN, Qin A, Xu J, Wang X (2011) In situ accumulation of advanced glycation endproducts (AGEs) in bone matrix and its correlation with osteoclastic bone resorption. Bone 49:174–183PubMedCentralPubMedCrossRef Dong XN, Qin A, Xu J, Wang X (2011) In situ accumulation of advanced glycation endproducts (AGEs) in bone matrix and its correlation with osteoclastic bone resorption. Bone 49:174–183PubMedCentralPubMedCrossRef
11.
go back to reference Saito M, Marumo K (2010) Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int 21:195–214PubMedCrossRef Saito M, Marumo K (2010) Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int 21:195–214PubMedCrossRef
12.
go back to reference Vashishth D (2007) The role of the collagen matrix in skeletal fragility. Curr Osteoporos Rep 5:62–66PubMedCrossRef Vashishth D (2007) The role of the collagen matrix in skeletal fragility. Curr Osteoporos Rep 5:62–66PubMedCrossRef
13.
go back to reference Alikhani M, Alikhani Z, Boyd C, MacLellan CM, Raptis M, Liu R, Pischon N, Trackman PC, Gerstenfeld L, Graves DT (2007) Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. Bone 40:345–353PubMedCentralPubMedCrossRef Alikhani M, Alikhani Z, Boyd C, MacLellan CM, Raptis M, Liu R, Pischon N, Trackman PC, Gerstenfeld L, Graves DT (2007) Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. Bone 40:345–353PubMedCentralPubMedCrossRef
14.
go back to reference Karim L, Tang SY, Sroga GE, Vashishth D (2013) Differences in non-enzymatic glycation and collagen cross-links between human cortical and cancellous bone. Osteoporos Int 24:2441–2447PubMedCrossRef Karim L, Tang SY, Sroga GE, Vashishth D (2013) Differences in non-enzymatic glycation and collagen cross-links between human cortical and cancellous bone. Osteoporos Int 24:2441–2447PubMedCrossRef
15.
go back to reference Tanaka S, Kuroda T, Saito M, Shiraki M (2011) Urinary pentosidine improves risk classification using fracture risk assessment tools for postmenopausal women. J Bone Miner Res 26:2778–2784PubMedCrossRef Tanaka S, Kuroda T, Saito M, Shiraki M (2011) Urinary pentosidine improves risk classification using fracture risk assessment tools for postmenopausal women. J Bone Miner Res 26:2778–2784PubMedCrossRef
16.
go back to reference Yamamoto M, Yamaguchi T, Yamauchi M, Yano S, Sugimoto T (2008) Serum pentosidine levels are positively associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab 93:1013–1019PubMedCrossRef Yamamoto M, Yamaguchi T, Yamauchi M, Yano S, Sugimoto T (2008) Serum pentosidine levels are positively associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab 93:1013–1019PubMedCrossRef
17.
go back to reference Schwartz AV, Garnero P, Hillier TA et al (2009) Pentosidine and increased fracture risk in older adults with type 2 diabetes. J Clin Endocrinol Metab 94:2380–2386PubMedCentralPubMedCrossRef Schwartz AV, Garnero P, Hillier TA et al (2009) Pentosidine and increased fracture risk in older adults with type 2 diabetes. J Clin Endocrinol Metab 94:2380–2386PubMedCentralPubMedCrossRef
18.
go back to reference Kislinger T, Fu C, Huber B et al (1999) N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem 274:31740–31749PubMedCrossRef Kislinger T, Fu C, Huber B et al (1999) N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem 274:31740–31749PubMedCrossRef
19.
go back to reference Yonekura H, Yamamoto Y, Sakurai S et al (2003) Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. Biochem J 370:1097–1109PubMedCentralPubMedCrossRef Yonekura H, Yamamoto Y, Sakurai S et al (2003) Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. Biochem J 370:1097–1109PubMedCentralPubMedCrossRef
20.
go back to reference Yamamoto M, Yamaguchi T, Yamauchi M, Sugimoto T (2009) Low serum level of the endogenous secretory receptor for advanced glycation end products (esRAGE) is a risk factor for prevalent vertebral fractures independent of bone mineral density in patients with type 2 diabetes. Diabetes care 32:2263–2268PubMedCentralPubMedCrossRef Yamamoto M, Yamaguchi T, Yamauchi M, Sugimoto T (2009) Low serum level of the endogenous secretory receptor for advanced glycation end products (esRAGE) is a risk factor for prevalent vertebral fractures independent of bone mineral density in patients with type 2 diabetes. Diabetes care 32:2263–2268PubMedCentralPubMedCrossRef
21.
go back to reference Mackey DC, Lui LY, Cawthon PM, Bauer DC, Nevitt MC, Cauley JA, Hillier TA, Lewis CE, Barrett-Connor E, Cummings SR (2007) High-trauma fractures and low bone mineral density in older women and men. JAMA 298:2381–2388PubMedCrossRef Mackey DC, Lui LY, Cawthon PM, Bauer DC, Nevitt MC, Cauley JA, Hillier TA, Lewis CE, Barrett-Connor E, Cummings SR (2007) High-trauma fractures and low bone mineral density in older women and men. JAMA 298:2381–2388PubMedCrossRef
22.
go back to reference Franke S, Muller A, Sommer M, Busch M, Kientsch-Engel R, Stein G (2003) Serum levels of total homocysteine, homocysteine metabolites and of advanced glycation end-products (AGEs) in patients after renal transplantation. Clin Nephrol 59:88–97PubMedCrossRef Franke S, Muller A, Sommer M, Busch M, Kientsch-Engel R, Stein G (2003) Serum levels of total homocysteine, homocysteine metabolites and of advanced glycation end-products (AGEs) in patients after renal transplantation. Clin Nephrol 59:88–97PubMedCrossRef
23.
go back to reference Sun JK, Keenan HA, Cavallerano JD et al (2011) Protection from retinopathy and other complications in patients with type 1 diabetes of extreme duration: the Joslin 50-year medalist study. Diabetes Care 34:968–974PubMedCentralPubMedCrossRef Sun JK, Keenan HA, Cavallerano JD et al (2011) Protection from retinopathy and other complications in patients with type 1 diabetes of extreme duration: the Joslin 50-year medalist study. Diabetes Care 34:968–974PubMedCentralPubMedCrossRef
24.
go back to reference Vashishth D, Gibson GJ, Khoury JI, Schaffler MB, Kimura J, Fyhrie DP (2001) Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone 28:195–201PubMedCrossRef Vashishth D, Gibson GJ, Khoury JI, Schaffler MB, Kimura J, Fyhrie DP (2001) Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone 28:195–201PubMedCrossRef
25.
go back to reference Hein G, Weiss C, Lehmann G, Niwa T, Stein G, Franke S (2006) Advanced glycation end product modification of bone proteins and bone remodelling: hypothesis and preliminary immunohistochemical findings. Ann Rheum Dis 65:101–104PubMedCentralPubMedCrossRef Hein G, Weiss C, Lehmann G, Niwa T, Stein G, Franke S (2006) Advanced glycation end product modification of bone proteins and bone remodelling: hypothesis and preliminary immunohistochemical findings. Ann Rheum Dis 65:101–104PubMedCentralPubMedCrossRef
26.
go back to reference Hein G, Wiegand R, Lehmann G, Stein G, Franke S (2003) Advanced glycation end-products pentosidine and N epsilon-carboxymethyllysine are elevated in serum of patients with osteoporosis. Rheumatology (Oxford) 42:1242–1246CrossRef Hein G, Wiegand R, Lehmann G, Stein G, Franke S (2003) Advanced glycation end-products pentosidine and N epsilon-carboxymethyllysine are elevated in serum of patients with osteoporosis. Rheumatology (Oxford) 42:1242–1246CrossRef
27.
go back to reference Valcourt U, Merle B, Gineyts E, Viguet-Carrin S, Delmas PD, Garnero P (2007) Non-enzymatic glycation of bone collagen modifies osteoclastic activity and differentiation. J Biol Chem 282:5691–5703PubMedCrossRef Valcourt U, Merle B, Gineyts E, Viguet-Carrin S, Delmas PD, Garnero P (2007) Non-enzymatic glycation of bone collagen modifies osteoclastic activity and differentiation. J Biol Chem 282:5691–5703PubMedCrossRef
28.
go back to reference Raucci A, Cugusi S, Antonelli A, Barabino SM, Monti L, Bierhaus A, Reiss K, Saftig P, Bianchi ME (2008) A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10). FASEB J 22:3716–3727PubMedCrossRef Raucci A, Cugusi S, Antonelli A, Barabino SM, Monti L, Bierhaus A, Reiss K, Saftig P, Bianchi ME (2008) A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10). FASEB J 22:3716–3727PubMedCrossRef
29.
go back to reference Miura J, Yamagishi S, Uchigata Y, Takeuchi M, Yamamoto H, Makita Z, Iwamoto Y (2003) Serum levels of non-carboxymethyllysine advanced glycation endproducts are correlated to severity of microvascular complications in patients with type 1 diabetes. J Diabetes Complicat 17:16–21PubMedCrossRef Miura J, Yamagishi S, Uchigata Y, Takeuchi M, Yamamoto H, Makita Z, Iwamoto Y (2003) Serum levels of non-carboxymethyllysine advanced glycation endproducts are correlated to severity of microvascular complications in patients with type 1 diabetes. J Diabetes Complicat 17:16–21PubMedCrossRef
30.
go back to reference Lapolla A, Reitano R, Baccarin L, Sartore G, Plebani M, Fedele D (2005) Pentosidine plasma levels and relation with metabolic control in diabetic patients. Horm Metab Res 37:252–256PubMedCrossRef Lapolla A, Reitano R, Baccarin L, Sartore G, Plebani M, Fedele D (2005) Pentosidine plasma levels and relation with metabolic control in diabetic patients. Horm Metab Res 37:252–256PubMedCrossRef
31.
go back to reference Nyman JS, Even JL, Jo CH et al (2011) Increasing duration of type 1 diabetes perturbs the strength-structure relationship and increases brittleness of bone. Bone 48:733–740PubMedCentralPubMedCrossRef Nyman JS, Even JL, Jo CH et al (2011) Increasing duration of type 1 diabetes perturbs the strength-structure relationship and increases brittleness of bone. Bone 48:733–740PubMedCentralPubMedCrossRef
32.
go back to reference Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Yano S, Sugimoto T (2008) Combination of obesity with hyperglycemia is a risk factor for the presence of vertebral fractures in type 2 diabetic men. Calcif Tissue Int 83:324–331PubMedCrossRef Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Yano S, Sugimoto T (2008) Combination of obesity with hyperglycemia is a risk factor for the presence of vertebral fractures in type 2 diabetic men. Calcif Tissue Int 83:324–331PubMedCrossRef
33.
go back to reference Honkanen K, Honkanen R, Heikkinen L, Kroger H, Saarikoski S (1999) Validity of self-reports of fractures in perimenopausal women. Am J Epidemiol 150:511–516PubMedCrossRef Honkanen K, Honkanen R, Heikkinen L, Kroger H, Saarikoski S (1999) Validity of self-reports of fractures in perimenopausal women. Am J Epidemiol 150:511–516PubMedCrossRef
Metadata
Title
High serum pentosidine but not esRAGE is associated with prevalent fractures in type 1 diabetes independent of bone mineral density and glycaemic control
Authors
T. Neumann
S. Lodes
B. Kästner
S. Franke
M. Kiehntopf
T. Lehmann
U. A. Müller
G. Wolf
A. Sämann
Publication date
01-05-2014
Publisher
Springer London
Published in
Osteoporosis International / Issue 5/2014
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-014-2631-7

Other articles of this Issue 5/2014

Osteoporosis International 5/2014 Go to the issue