Human tibial cortical bone with high porosity in type 2 diabetes mellitus is accompanied by distinctive bone material properties

Wölfel, Eva M.<sup>1</sup>; Fiedler, Imke A. K.<sup>1,2</sup>; Dragoun Kolibova, Sofie<sup>1</sup>; Krug, Johannes<sup>1</sup>; Lin, Mei-Chun<sup>1</sup>; Yazigi, Bashar<sup>1</sup>; Siebels, Anna K.<sup>1</sup>; Mushumba, Herbert<sup>3</sup>; Wulff, Birgit<sup>3</sup>; Ondruschka, Benjamin<sup>3</sup>; Püschel, Klaus<sup>3</sup>; Glüer, Claus C.<sup>4</sup>; Jähn-Rickert, Katharina<sup>1,5</sup>; Busse, Björn<sup>1,2</sup>

Affiliations

¹Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 22529 Hamburg, Germany

²Interdisciplinary Competence Center for Interface Research (ICCIR), University Medical Center Hamburg-Eppendorf, 22529 Hamburg, Germany

³Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, 22529 Hamburg, Germany

⁴Sektion Biomedizinische Bildgebung, Klinik für Radiologie und Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Christian-Albrechts-Universitat zu Kiel, MOIN CC, 24118 Kiel, Germany

⁵Mildred Scheel Cancer Career Center Hamburg, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany

Abstract and keywords

Diabetes mellitus is a metabolic disease affecting bone tissue at different length-scales. Higher fracture risk in diabetic patients is difficult to detect with common clinical fracture risk assessment due to normal or high bone mineral density in diabetic patients. The observed higher fracture risk despite normal to high areal bone mineral density in diabetic patients points towards impaired bone material quality. Here, we analyze tibial bone from individuals with type 2 diabetes mellitus using a multiscale-approach, which includes clinical and laboratory-based bone quality measures.

Tibial cortical bone tissue from individuals with type 2 diabetes mellitus (T2DM) and age-matched healthy controls (n = 15 each) was analyzed with in situ impact indentation, dual energy X-ray absorptiometry (DXA), high resolution peripheral microcomputed tomography (HR-pQCT), micro-computed tomography (microCT), cyclic indentation, quantitative backscattered electron microscopy (qBEI), vibrational spectroscopy (Raman), nanoindentation, and fluorescence spectroscopy. With this approach, a high cortical porosity subgroup of individuals with T2DM was discriminated from two study groups: individuals with T2DM and individuals without T2DM, while both groups were associated with similar cortical porosity quantified by means of microCT.

The high porosity T2DM group, but not the T2DM group, showed compromised bone quality expressed by altered cyclic indentation properties (transversal direction) in combination with a higher carbonate-to-amide I ratio in endocortical bone. In addition, in the T2DM group with high cortical porosity group, greater cortical pore diameter was identified with HR-pQCT and lower tissue mineral density using microCT, both compared to T2DM group. Micromechanical analyses of cross-sectioned osteons (longitudinal direction) with cyclic indentation, qBEI, and nanoindentation showed no differences between the three groups.

High tibial cortical porosity in T2DM can be linked to locally altered bone material composition. As the tibia is an accessible skeletal site for fracture risk assessment in the clinics (CT, indentation), our findings may contribute to further understanding the site-specific structural and compositional factors forming the basis of bone quality in diabetes mellitus. Refined diagnostic strategies are needed for a comprehensive fracture risk assessment in diabetic bone disease.

Keywords: Diabetic bone disease; Cortical bone; Tibia; Impact indentation; Advanced glycation end-products

Links

DOI: 10.1016/j.bone.2022.116546

PubMed: 36113843

WoS: 000864791800003

History

Received: 2022-05-1

Revised: 2022-09-09

Accepted: 2022-09-11

Online: 2022-09-14

Cited Works (22)

Year	Entry
2010	Burghardt AJ, Issever AS, Schwartz AV, Davis KA, Masharani U, Majumdar S, Link TM. High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2010;95(11):5045-5055.
2003	Roschger P, Gupta HS, Berzlanovich A, Ittner G, Dempster DW, Fratzl P, Cosman F, Parisien M, Lindsay R, Nieves JW, Klaushofer K. Constant mineralization density distribution in cancellous human bone. Bone. March 2003;32(3):316-323.
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.
2013	Patsch JM, Burghardt AJ, Yap SP, Baum T, Schwartz AV, Joseph GB, Link TM. Increased cortical porosity in type 2 diabetic postmenopausal women with fragility fractures. J Bone Miner Res. February 2013;28(2):313-324.
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.
2013	Gallant MA, Brown DM, Organ JM, Allen MR, Burr DB. Reference-point indentation correlates with bone toughness assessed using whole-bone traditional mechanical testing. Bone. March 2013;53(1):301-305.
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.
2017	Paschalis EP, Gamsjaeger S, Klaushofer K. Vibrational spectroscopic techniques to assess bone quality. Osteoporos Int. August 2017;28(8):2275-2291.
2010	Burghardt AJ, Buie HR, Laib A, Majumdar S, Boyd SK. Reproducibility of direct quantitative measures of cortical bone microarchitecture of the distal radius and tibia by HR-pQCT. Bone. September 2010;47(3):519-528.
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.
2009	Schwartz AV, Garnero P, Hillier TA, Sellmeyer DE, Strotmeyer ES, Feingold KR, Resnick HE, Tylavsky FA, Black DM, Cummings SR, Harris TB, Bauer DC; Health, Aging, and Body Composition Study. Pentosidine and increased fracture risk in older adults with type 2 diabetes. J Clin Endocrinol Metab. July 2009;94(7):2380-2386.
2018	Samelson EJ, Demissie S, Cupples LA, Zhang X, Xu H, Liu C-T, Boyd SK, McLean RR, Broe KE, Kiel DP, Bouxsein ML. Diabetes and deficits in cortical bone density, microarchitecture, and bone size: Framingham HR-pQCT study. J Bone Miner Res. January 2018;33(1):54-62.
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.
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.
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.
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.
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.
2015	Milovanovic P, Zimmermann EA, Riedel C, vom Scheidt A, Herzog L, Krause M, Djonic D, Djuric M, Püschel K, Amling M, Ritchie RO, Busse B. Multi-level characterization of human femoral cortices and their underlying osteocyte network reveal trends in quality of young, aged, osteoporotic and antiresorptive-treated bone. Biomaterials. March 2015;45:46-55.
2011	Morris MD, Mandair GS. Raman assessment of bone quality. Clin Orthop Relat Res. August 2011;469:2160-2169.
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.
1995	Currey JD, Brear K, Zioupos P, Reilly GC. Effect of formaldehyde fixation on some mechanical properties of bovine bone. Biomaterials. 1995;16(16):1267-1271.
2022	Dhaliwal R, Ewing SK, Vashishth D, Semba RD, Schwartz AV. Greater carboxy-methyl-lysine is associated with increased fracture risk in type 2 diabetes. J Bone Miner Res. February 2022;37(2):265-272.

Cited By (1)

Year	Entry
2023	Jerban S, Ma Y, Alenezi S, Moazamian D, Athertya J, Jang H, Dorthe E, Dlima D, Woods G, Chung CB, Chang EY, Du J. Ultrashort echo time (UTE) MRI porosity index (PI) and suppression ratio (SR) correlate with the cortical bone microstructural and mechanical properties: ex vivo study. Bone. April 2023;169:116676.