Increased advanced glycation endproducts, stiffness, and hardness in iliac crest bone from postmenopausal women with type 2 diabetes mellitus on insulin

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Lekkala, Sashank¹; Sacher, Sara E.¹; Taylor, Erik A.²; Williams, Rebecca M.³; Moseley, Kendall F.⁴; Donnelly, Eve^1,5

Increased advanced glycation endproducts, stiffness, and hardness in iliac crest bone from postmenopausal women with type 2 diabetes mellitus on insulin

J Bone Miner Res. February 2023;38(2):261-277

©2022 American Society for Bone and Mineral Research (ASBMR)

Affiliations

¹Department of Materials Science and Engineering, Cornell University, Ithaca, NY, USA

²Sibley School of Mechanical and Aerospace Engineering Cornell University, Ithaca, NY, USA

³Meinig School of Biomedical Engineering Cornell University, Ithaca, NY, USA

⁴Division of Endocrinology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

⁵Research Division, Hospital for Special Surgery, New York, NY, USA
Abstract and keywords

ndividuals with type 2 diabetes mellitus (T2DM) have a greater risk of bone fracture compared with those with normal glucose tolerance (NGT). In contrast, individuals with impaired glucose tolerance (IGT) have a lower or similar risk of fracture. Our objective was to understand how progressive glycemic derangement affects advanced glycation endproduct (AGE) content, composition, and mechanical properties of iliac bone from postmenopausal women with NGT (n = 35, age = 65 ± 7 years, HbA1c = 5.8% ± 0.3%), IGT (n = 26, age = 64 ± 5 years, HbA1c = 6.0% ± 0.4%), and T2DM on insulin (n = 25, age = 64 ± 6 years, HbA1c = 9.1% ± 2.2%). AGEs were assessed in all samples using high-performance liquid chromatography to measure pentosidine and in NGT/T2DM samples using multiphoton microscopy to spatially resolve the density of fluorescent AGEs (fAGEs). A subset of samples (n = 14 NGT, n = 14 T2DM) was analyzed with nanoindentation and Raman microscopy. Bone tissue from the T2DM group had greater concentrations of (i) pentosidine versus IGT (cortical +24%, p = 0.087; trabecular +35%, p = 0.007) and versus NGT (cortical +40%, p = 0.003; trabecular +35%, p = 0.004) and (ii) fAGE cross-link density versus NGT (cortical +71%, p < 0.001; trabecular +44%, p < 0.001). Bone pentosidine content in the IGT group was lower than in the T2DM group and did not differ from the NGT group, indicating that the greater AGE content observed in T2DM occurs with progressive diabetes. Individuals with T2DM on metformin had lower cortical bone pentosidine compared with individuals not on metformin (−35%, p = 0.017). Cortical bone from the T2DM group was stiffer (+9%, p = 0.021) and harder (+8%, p = 0.039) versus the NGT group. Bone tissue AGEs, which embrittle bone, increased with worsening glycemic control assessed by HbA1c (Pen: R² = 0.28, p < 0.001; fAGE density: R² = 0.30, p < 0.001). These relationships suggest a potential mechanism by which bone fragility may increase despite greater tissue stiffness and hardness in individuals with T2DM; our results suggest that it occurs in the transition from IGT to overt T2DM.

Keywords: bone; glycation; material properties; prediabetes; type 2 diabetes
Links

DOI: 10.1002/jbmr.4757

PubMed: 36478472

WoS: 000905185600001
History

Received: 2022-03-17

Revised: 2022-11-25

Accepted: 2022-12-02

Cited Works (47)

Year	Entry
2010	Donnelly E, Chen DX, Boskey AL, Baker SP, van der Meulen MCH. Contribution of mineral to bone structural behavior and tissue mechanical properties. Calcif Tiss Int. November 2010;87(5):450-460.
1999	Rho JY, Zioupos P, Currey JD, Pharr GM. Variations in the individual thick lamellar properties within osteons by nanoindentation. Bone. September 1999;25(3):295-300.
2007	Tang SY, Zeenath U, Vashishth D. Effects of non-enzymatic glycation on cancellous bone fragility. Bone. April 2007;40(4):1144-1151.
2020	Arakawa S, Suzuki R, Kurosaka D, Ikeda R, Hayashi H, Kayama T, Ohno R-i, Nagai R, Marumo K, Saito M. Mass spectrometric quantitation of AGEs and enzymatic crosslinks in human cancellous bone. Sci Rep. 2020;10:18774.
2003	Currey JD. Role of collagen and other organics in the mechanical properties of bone. Osteoporos Int. September 2003;14(suppl 5):S29-S36.
2010	Boskey AL, Coleman R. Aging and bone. J Dent Res. December 2010;89(2):1333-1348.
2006	Donnelly E, Williams RM, Downs SA, Dickinson ME, Baker SP, van der Meulen MCH. Quasistatic and dynamic nanomechanical properties of cancellous bone tissue relate to collagen content and organization. J Mater Res. August 2006;21(8):2106-2117.
1997	Bank RA, Beekman B, Verzijl N, de Roos JADM, Nico Sakkee A, TeKoppele JM. Sensitive fluorimetric quantitation of pyridinium and pentosidine crosslinks in biological samples in a single high-performance liquid chromatographic run. J Chromatogr B Biomed Sci Appl. December 5, 1997;703:37.
2017	Nilsson AG, Sundh D, Johansson L, Nilsson M, Mellström D, Rudäng R, Zoulakis M, Wallander M, Darelid A, Lorentzon M. Type 2 diabetes mellitus is associated with better bone microarchitecture but lower bone material strength and poorer physical function in elderly women: a population‐based study. J Bone Miner Res. May 2017;32(5):1062-1071.
2013	Willett TL, Sutty S, Gaspar A, Avery N, Grynpas M. In vitro non-enzymatic ribation reduces post-yield strain accommodation in cortical bone. Bone. February 2013;52(2):611-622.
2016	Furst JR, Bandeira LC, Fan W-W, Agarwal S, Nishiyama KK, McMahon DJ, Dworakowski E, Jiang H, Silverberg SJ, Rubin MR. Advanced glycation endproducts and bone material strength in type 2 diabetes. J Clin Endocrinol Metab. June 2016;101(6):2502-2510.
2016	Farlay D, Armas LAG, Gineyts E, Akhter MP, Recker RR, Boivin G. Nonenzymatic glycation and degree of mineralization are higher in bone from fractured patients with type 1 diabetes mellitus. J Bone Miner Res. January 2016;31(1):190-195.
2005	Strotmeyer ES, Cauley JA, Schwartz AV, Nevitt MC, Resnick HE, Bauer DC, Tylavsky FA, Rekeneire Nd, Harris TB, Newman AB. Nontraumatic fracture risk with diabetes mellitus and impaired fasting glucose in older white and black adults: the health, aging, and body composition study. Arch Intern Med. July 25, 2005;165(14):1612-1617.
2016	Torres AM, Matheny JB, Keaveny TM, Taylor D, Rimnac CM, Hernandez CJ. Material heterogeneity in cancellous bone promotes deformation recovery after mechanical failure. Proc Natl Acad Sci USA. March 15, 2016;113(11):2892-2897.
2007	Janghorbani M, Van Dam RM, Willett WC, Hu FB. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol. September 1, 2007;166(5):495-505.
2011	Tang SY, Vashishth D. The relative contributions of non-enzymatic glycation and cortical porosity on the fracture toughness of aging bone. J Biomech. January 11, 2011;44(2):330-336.
2010	Gamsjaeger S, Masic A, Roschger P, Kazanci M, Dunlop JWC, Klaushofer K, Paschalis EP, Fratzl P. Cortical bone composition and orientation as a function of animal and tissue age in mice by raman spectroscopy. Bone. August 2010;47(2):392-399.
2007	Mulder L, Koolstra JH, den Toonder JMJ, van Eijden TMGJ. Intratrabecular distribution of tissue stiffness and mineralization in developing trabecular bone. Bone. August 2007;41(2):256-265.
2005	de Liefde II, van der Klift M, de Laet CEDH, van Daele PLA, Hofman A, Pols HAP. Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study. Osteoporos Int. December 2005;16(12):1713-1720.
2005	Hoffler CE, Guo XE, Zysset PK, Goldstein SA. An application of nanoindentation technique to measure bone tissue lamellae properties. J Biomech Eng. January 2005;127(7):1046-1053.
2014	Farr JN, Drake MT, Amin S, Melton LJ III, McCready LK, Khosla S. In vivo assessment of bone quality in postmenopausal women with type 2 diabetes. J Bone Miner Res. April 2014;29(4):787-795.
2006	Saito M, Fujii K, Mori Y, Marumo K. Role of collagen enzymatic and glycation induced cross-links as a determinant of bone quality in spontaneously diabetic WBN/Kob rats. Osteoporos Int. October 2006;17(10):1514-1523.
2015	Poundarik AA, Wu P-C, Evis Z, Sroga GE, Ural A, Rubin M, Vashishth D. A direct role of collagen glycation in bone fracture. J Mech Behav Biomed Mater. December 2015;52:120-130.
2010	Donnelly E, Boskey AL, Baker SP, van der Meulen MCH. Effects of tissue age on bone tissue material compositionand nanomechanical properties in the rat cortex. J Biomed Mater Res. March 1, 2010;A92(3):1048-1056.
2020	Piccoli A, Cannata F, Strollo R, Pedone C, Leanza G, Russo F, Greto V, Isgrò C, Quattrocchi CC, Massaroni C, Silvestri S, Vadalà G, Bisogno T, Denaro V, Pozzilli P, Tang SY, Silva MJ, Conte C, Papalia R, Maccarrone M, Napoli N. Sclerostin regulation, microarchitecture, and advanced glycation end‐products in the bone of elderly women with type 2 diabetes. J Bone Miner Res. December 2020;35(12):2415-2422.
2021	Hunt HB, Miller NA, Hemmerling KJ, Koga M, Lopez KA, Taylor EA, Sellmeyer DE, Moseley KF, Donnelly E. Bone tissue composition in postmenopausal women varies with glycemic control from normal glucose tolerance to type 2 diabetes mellitus. J Bone Miner Res. February 2021;36(2):334-346.
2017	Lloyd AA, Gludovatz B, Riedel C, Luengo EA, Saiyed R, Marty E, Lorich DG, Lane JM, Ritchie RO, Busse B, Donnelly E. Atypical fracture with long-term bisphosphonate therapy is associated with altered cortical composition and reduced fracture resistance. Proc Natl Acad Sci USA. August 15, 2017;114(33):8722-8727.
1992	Oliver WC, Pharr GM. An improved technique for determining hardness and elastic modulus using load and displacement sensing indentation experiments. J Mater Res. 1992;7(6):1564-1583.
2003	Boskey A. Bone mineral crystal size. Osteoporos Int. September 2003;14(suppl 5):S16-S20.
2020	Taylor EA, Donnelly E. Raman and Fourier transform infrared imaging for characterization of bone material properties. Bone. October 2020;139:115490.
2007	Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes: a meta-analysis. Osteoporos Int. April 2007;18(4):427-444.
2013	Karim L, Tang SY, Sroga GE, Vashishth D. Differences in non-enzymatic glycation and collagen cross-links between human cortical and cancellous bone. Osteoporos Int. September 2013;24(9):2441-2447.
2017	Napoli N, Chandran M, Pierroz DD, Abrahamsen B, Schwartz AV, Ferrari SL; IOF Bone and Diabetes Working Group. Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol. April 2017;13(4):208-219.
2020	Wölfel EM, Jähn-Rickert K, Schmidt FN, Wulff B, Mushumba H, Sroga GE, Püschel K, Milovanovic P, Amling M, Campbell GM, Vashishth D, Busse B. Individuals with type 2 diabetes mellitus show dimorphic and heterogeneous patterns of loss in femoral bone quality. Bone. November 2020;140:115556.
2017	Hygum K, Starup-Linde J, Harsløf1 T, Vestergaard P, Langdahl BL. Diabetes mellitus, a state of low bone turnover: a systematic review and meta-analysis. Eur J Endocrinol. March 2017;176(3):R137-R157.
2016	Paschalis EP, Gamsjaeger S, Fratzl-Zelman N, Roschger P, Masic A, Brozek W, Hassler N, Glorieux FH, Rauch F, Klaushofer K, Fratzl P. Evidence for a role for nanoporosity and pyridinoline content in human mild osteogenesis imperfecta. J Bone Miner Res. May 2016;31(5):1050-1059.
2006	Bonds DE, Larson JC, Schwartz AV, Strotmeyer ES, Robbins J, Rodriguez BL, Johnson KC, Margolis KL. Risk of fracture in women with type 2 diabetes: the Women’s Health Initiative Observational Study. J Clin Endocrinol Metab. September 2006;91(9):3404-3410.
1997	Han Z-H, Palnitkar S, Rao DS, Nelson D, Parfitt AM. Effects of ethnicity and age or menopause on the remodeling and turnover of iliac bone: implications for mechanisms of bone loss. J Bone Miner Res. April 1997;12(4):498-508.
2006	Donnelly E, Baker SP, Boskey AL, van der Meulen MC. Effects of surface roughness and maximum load on the mechanical properties of cancellous bone measured by nanoindentation. J Biomed Mater Res. May 2006;A77(2):426-435.
2001	Vashishth D, Gibson GJ, Khoury JI, Schaffler MB, Kimura J, Fyhrie DP. Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone. February 2001;28(2):195-201.
2018	Karim L, Moulton J, Van Vliet M, Velie K, Robbins A, Malekipour F, Abdeen A, Ayres D, Bouxsein ML. Bone microarchitecture, biomechanical properties, and advanced glycation end-products in the proximal femur of adults with type 2 diabetes. Bone. September 2018;114:32-39.
2018	Hunt HB. Characterization of Material Properties, Microarchitecture, and Mechanics of Bone from Subjects With Type 2 Diabetes Mellitus [PhD thesis]. Ithaca, NY: Cornell University; December 2018.
2019	Hunt HB, Torres AM, Palomino PM, Marty E, Saiyed R, Cohn M, Jo J, Warner S, Sroga GE, King KB, Lane JM, Vashishth D, Hernandez CJ, Donnelly E. Altered tissue composition, microarchitecture, and mechanical performance in cancellous bone from men with type 2 diabetes mellitus. J Bone Miner Res. July 2019;34(7):1191-1206.
2011	Schwartz AV, Vittinghoff E, Bauer DC, Hillier TA, Strotmeyer ES, Ensrud KE, Donaldson MG, Cauley JA, Harris TB, Koster A, Womack CR, Palermo L, Black DM; Study of Osteoporotic Fractures (SOF); Osteoporotic Fractures in Men (MrOS); Health, Aging, and Body Composition (Health ABC) Research Groups. Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes. JAMA. June 1, 2011;305(21):2184-2192.
2006	Saito M, Fujii K, Marumo K. Degree of mineralization-related collagen crosslinking in the femoral neck cancellous bone in cases of hip fracture and controls. Calcif Tiss Int. September 2006;79(3):160-168.
2010	Saito M, Marumo K. Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int. 2010;21(2):195-214.
2018	Thomas CJ, Cleland TP, Sroga GE, Vashishth D. Accumulation of carboxymethyl-lysine (CML) in human cortical bone. Bone. May 2018;110:128-133.

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