The Role of Cortical and Cancellous Bone Quality on Vertebral Fragility

A serious health concern of aging populations is the increased risk of non-traumatic fracture caused by age-related changes in bone's structure and morphology. Thinning bone caused by asymmetric bone resorption, diagnosed as osteoporosis, is commonly the focal point for age-related fracture risk. Although the majority of orthopedic research is conducted on decreased bone quantity, changes in bone's quality are as equally impactful on the fracture mechanics of bone and are largely overlooked. One of the most prevalent modifications in aging bone is the accumulation of advanced glycation end-products (AGEs) caused by nonenzymatic glycation (NEG). AGE content in bone increases with age and has a deleterious effect on bone's material properties.

Vertebral fractures account for more than half of all osteoporotic fractures and correlate to increased mortality and morbidity. In order to define an objective fracture risk indicator, interactions between cortical and cancellous constituents of vertebrae have been widely studied. Notwithstanding, some disparity remains over the exact fracture modality within the vertebrae. Despite known limitations, bone mineral density (BMD) remains the standard for assessing vertebral fragility. As alterations in bone's organic matrix have a marked impact on the tissue's material properties, it is imperative to elucidate the effects of nonenzymatic glycation on load bearing ability of the vertebrae's constituent parts.

Therefore, the objective of this doctoral research is to combine biochemical, mechanical, and computational methods to: a) better characterize the load sharing role of cortical and cancellous bone within the vertebrae, b) determine the effect of AGE accumulation on load sharing within the vertebrae, and c) validate the feasibility of reversing the effects of NEG-mediated AGE crosslinking using n-Phenacylthiazolium Bromide.

The results presented herein provide a better understanding of load sharing and fracture within the vertebrae. They also reinforce the degenerative nature of age-related changes within bone's organic matrix, stressing the importance of considering quality as well as quantity of bone when defining fracture risk. To reverse the effects of NEG, a novel compound is proposed and verified as a possible therapy for the accumulation of AGEs within bone's structure. Finally, a computational model encompassing a damaged-plasticity material definition is vetted as a predictive tool for assigning fracture risk. When combined, this work may provide a baseline for the development of much-needed fracture risk assessment tools to diagnose and prescribe necessary treatments for the aging skeleton.

Year	Entry
1990	Beaupré GS, Orr TE, Carter DR. An approach for time‐dependent bone modeling and remodeling: theoretical development. J Orthop Res. September 1990;8(5):651-661.
1970	Merz WA, Schenk RK. A quantitative histological study on bone formation in human cancellous bone. Acta Anat. 1970;76(1):1-15.
2002	Currey JD. Bones: Structure and Mechanics. Princeton, NJ: Princeton University Press; 2002.
2010	Gourion-Arsiquaud S, Allen MR, Burr DB, Vashishth D, Tang SY, Boskey AL. Bisphosphonate treatment modifies canine bone mineral and matrix properties and their heterogeneity. Bone. March 2010;46(3):666-672.
1970	Abendschein W, Hyatt GW. Ultrasonics and selected physical properties of bone. Clin Orthop Relat Res. March–April 1970;69:294-301.
2006	Eswaran SK, Gupta A, Adams MF, Keaveny TM. Cortical and trabecular load sharing in the human vertebral body. J Bone Miner Res. February 2006;21(2):307-314.
2001	Keyak JH. Improved prediction of proximal femoral fracture load using nonlinear finite element models. Med Eng Phys. April 2001;23(3):165-173.
1988	Fondrk M, Bahniuk E, Davy DT, Michaels C. Some viscoplastic characteristics of bovine and human cortical bone. J Biomech. 1988;21(8):623-630.
2011	Kanis JA, Hans D, Cooper C, Baim S, Bilezikian JP, Binkley N, Cauley JA, Compston JE, Dawson-Hughes B, El-Hajj Fuleihan G, Johansson H, Leslie WD, Lewiecki EM, Luckey M, Oden A, Papapoulos SE, Poiana C, Rizzoli R, Wahl DA, McCloskey EV. Interpretation and use of FRAX in clinical practice. Osteoporos Int. September 2011;22(9):2395-2411.
2012	Hambli R, Bettamer A, Allaoui S. Finite element prediction of proximal femur fracture pattern based on orthotropic behaviour law coupled to quasi-brittle damage. Med Eng Phys. March 2012;34(2):202-210.
2013	Hambli R. Micro-CT finite element model and experimental validation of trabecular bone damage and fracture. Bone. October 2013;56(2):363-374.
2011	Dragomir-Daescu D, Op Den Buijs J, McEligot S, Dai Y, Entwistle RC, Salas C, Melton LJ III, Bennet KE, Khosla S, Amin S. Robust QCT/FEA models of proximal femur stiffness and fracture load during a sideways fall on the hip. Ann Biomed Eng. February 2011;39(2):742-755.
2011	Burghardt AJ, Link TM, Majumdar S. High-resolution computed tomography for clinical imaging of bone microarchitecture. Clin Orthop Relat Res. August 2011;469:2179-2193.
2002	Cummings SR, Melton LJ III. Epidemiology and outcomes of osteoporotic fractures. Lancet. May 18, 2002;359(9319):1761-1767.
1995	Duncan RL, Turner CH. Mechanotransduction and the functional response of bone to mechanical strain. Calcif Tiss Int. December 1995;57(5):344-358.
2000	Haapasalo H, Kontulainen S, Sievänen H, Kannus P, Järvinen M, Vuori I. Exercise-induced bone gain is due to enlargement in bone size without a change in volumetric bone density: a peripheral quantitative computed tomography study of the upper arms of male tennis players. Bone. September 2000;27(3):351-357.
2008	Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. NEJM. March 20, 2008;358(12):1304-1306.
1997	Cheng XG, Nicholson PHF, Boonen S, Lowet G, Brys P, Aerssens J, van der Perre G, Dequeker J. Prediction of vertebral strength in vitro by spinal bone densitometry and calcaneal ultrasound. J Bone Miner Res. October 1997;12(10):1721-1728.
2007	Canalis E, Giustina A, Bilezikian JP. Mechanisms of anabolic therapies for osteoporosis. NEJM. August 30, 2007;357(9):905-916.
2008	Zioupos P, Cook RB, Hutchinson JR. Some basic relationships between density values in cancellous and cortical bone. J Biomech. 2008;41(9):1961-1968.
1993	Mosekilde L. Vertebral structure and strength in vivo and in vitro. Calcif Tiss Int. February 1993;53(suppl 1):S121-S126.
1990	Jensen KS, Mosekilde L, Mosekilde L. A model of vertebral trabecular bone architecture and its mechanical properties. Bone. 1990;11(6):417-423.
2003	Crawford RP, Cann CE, Keaveny TM. Finite element models predict in vitro vertebral body compressive strength better than quantitative computed tomography. Bone. 2003;33(4):744-750.
1998	Singer BR, McLauchlan GJ, Robinson CM, Christie J. Epidemiology of fractures in 15 000 adults: the influence of age and gender. J Bone Joint Surg. March 1998;80B(2):243-248.
1969	Rockoff SD, Sweet E, Bleustein J. The relative contribution of trabecular and cortical bone to the strength of human lumbar vertebrae. Calcif Tiss Res. December 1969;3(1):163-175.
2007	Bessho M, Ohnishi I, Matsuyama J, Matsumoto T, Imai K, Nakamura K. Prediction of strength and strain of the proximal femur by a CT-based finite element method. J Biomech. 2007;40(8):1745-1753.
1985	McBroom RJ, Hayes WC, Edwards WT, Goldberg RP, White AA III. Prediction of vertebral body compressive fracture using quantitative computed tomography. J Bone Joint Surg. 1985;67A(8):1206-1214.
1988	Yoganandan N, Myklebust JB, Cusick JF, Wilson CR, Sances A Jr. Functional biomechanics of the thoracolumbar vertebral cortex. Clin Biomech (Bristol, Avon). February 1988;3(1):11-18.
1996	Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. May 18, 1996;312(7041):1254-1259.
1993	Lanyon LE. Osteocytes, strain detection, bone modeling and remodeling. Calcif Tiss Int. February 1993;53(suppl 1):S102-S107.
2004	Chesnut CH III, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A, Felsenberg D, Huss H, Gilbride J, Schimmer RC, Delmas PD; Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE). Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. August 2004;19(8):1241-1249.
1992	Ettinger B, Black DM, Nevitt MC, Rundle AC, Cauley JA, Cummings SR, Genant HK; The Study of Osteoporotic Fractures Research Group. Contribution of vertebral deformities to chronic back pain and disability. J Bone Miner Res. April 1992;7(4):449-456.
1994	Kanis JA; WHO Study Group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. Osteoporos Int. November 1994;4(6):368-381.
2000	Vashishth D, Koontz J, Qiu SJ, Lundin-Cannon D, Yeni YN, Schaffler MB, Fyhrie DP. In vivo diffuse damage in human vertebral trabecular bone. Bone. February 2000;26(2):147-152.
1992	Cooper C, Atkinson EJ, O'Fallon WM, Melton JL III. Incidence of clinically diagnosed vertebral fractures: a population‐based study in Rochester, Minnesota, 1985‐1989. J Bone Miner Res. February 1992;7(2):221-227.
2011	Wolfram U, Wilke H-J, Zysset PK. Damage accumulation in vertebral trabecular bone depends on loading mode and direction. J Biomech. April 7, 2011;44(7):1164-1169.
1999	Keaveny TM, Wachtel EF, Kopperdahl DL. Mechanical behavior of human trabecular bone after overloading. J Orthop Res. May 1999;17(3):346-353.
1993	Cooper C. The epidemiology of fragility fractures: is there a role for bone quality? Calcif Tiss Int. February 1993;53(suppl 1):S23-S26.
1992	Cooper C, Campion G, Melton LJ III. Hip fractures in the elderly: a world-wide projection. Osteoporos Int. November 1992;2(6):285-289.
2003	Keyak JH, Falkinstein Y. Comparison of in situ and in vitro CT scan-based finite element model predictions of proximal femoral fracture load. Med Eng Phys. November 2003;25(9):781-787.
2003	Ammann P, Rizzoli R. Bone strength and its determinants. Osteoporos Int. March 2003;14(suppl 3):S13-S18.
2011	Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. NEJM. May 5, 2011;364(18):1728-1737.
2002	Wang X, Shen X, Li X, Agrawal CM. Age-related changes in the collagen network and toughness of bone [published correction appears in Bone. 2003;32(1):107]. Bone. 2002;31(1):1-7.
2001	Wang X, Bank RA, Tekoppele JM, Agrawal CM. The role of collagen in determining bone mechanical properties. J Orthop Res. 2001;19(6):1021-1026.
2000	Fyhrie DP, Vashishth D. Bone stiffness predicts strength similarly for human vertebral cancellous bone in compression and for cortical bone in tension. Bone. February 2000;26(2):169-173.
1998	Bailey AJ, Paul RG, Knott L. Mechanisms of maturation and ageing of collagen. Mech Ageing Dev. December 1, 1998;106(1-2):1-56.
2001	Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster J-Y, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mellström D, Oefjord ES, Marcinowska-Suchowierska E, Salmi J, Mulder H, Halse J, Sawicki AZ, Mitlak BH. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. NEJM. May 10, 2001;344(19):1434-1441.
1999	Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH III, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD; Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA. October 13, 1999;282(14):1344-1352.
1987	Parfitt AM. Trabecular bone architecture in the pathogenesis and prevention of fracture. Am J Med. January 26, 1987;82(suppl 1B):68-72.
2009	Boskey AL, Spevak L, Weinstein RS. Spectroscopic markers of bone quality in alendronate-treated postmenopausal women. Osteoporos Int. May 2009;20(5):793-800.
2012	Sroga GE, Vashishth D. Effects of bone matrix proteins on fracture and fragility in osteoporosis. Curr Osteoporos Rep. June 2012;10(2):141-150.
1995	McCubbrey DA, Cody DD, Peterson EL, Kuhn JL, Flynn MJ, Goldstein SA. Static and fatigue failure properties of thoracic and lumbar vertebral bodies and their relation to regional density. J Biomech. August 1995;28(8):891-899.
2006	Hadjidakis DJ, Androulakis II. Bone remodeling. Annals NY Acad Sci. December 2006;1092(1):385-396.
1990	Frost HM. Skeletal structural adaptations to mechanical usage (SATMU), I: redefining Wolff's law: the bone modeling problem. Anat Rec. 1990;226(4):403-413.
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.
1997	De Laet CEDH, van Hout BA, Burger H, Hofman A, Pols HAP. Bone density and risk of hip fracture in men and women: cross sectional analysis. BMJ. July 26, 1997;315(7102):221-225.
1994	Silva MJ, Wang C, Keaveny TM, Hayes WC. Direct and computed tomography thickness measurements of the human, lumbar vertebral shell and endplate. Bone. July 8, 1994;15(4):409-414.
2004	Lang T, LeBlanc A, Evans H, Lu Y, Genant H, Yu A. Cortical and trabecular bone mineral loss from the spine and hip in long‐duration spaceflight. J Bone Miner Res. June 2004;19(6):1006-1012.
2003	Crawford RP, Rosenberg WS, Keaveny TM. Quantitative computed tomography-based finite element models of the human lumbar vertebral body: effect of element size on stiffness, damage, and fracture strength predictions. J Biomech Eng. August 2003;125(4):434-438.
1989	Mosekilde L, Bentzen SM, Ørtoft G, Jørgensen J. The predictive value of quantitative computed tomography for vertebral body compressive strength and ash density. Bone. 1989;10(6):465-470.
1999	Fondrk MT, Bahniuk EH, Davy DT. Inelastic strain accumulation in cortical bone during rapid transient tensile loading. J Biomech Eng. December 1999;121(6):616-621.
2008	Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol. November 2008;3(suppl 3):S131-S139.
1998	Nevitt MC, Ettinger B, Black DM, Stone K, Jamal SA, Ensrud K, Segal M, Genant HK, Cummings SR. The association of radiographically detected vertebral fractures with back pain and function: a prospective study. Ann Intern Med. May 15, 1998;128(10):793-800.
2010	Tang SY, Vashishth D. Non-enzymatic glycation alters microdamage formation in human cancellous bone. Bone. January 2010;46(1):148-154.
1999	Ebbesen EN, Thomsen JS, Beck-Nielsen H, Nepper-Rasmussen HJ, Mosekilde L. Lumbar vertebral body compressive strength evaluated by dual-energy X-ray absorptiometry, quantitative computed tomography, and ashing. Bone. December 1999;25(6):713-724.
2004	Homminga J, Van-Rietbergen B, Lochmüller EM, Weinans H, Eckstein F, Huiskes R. The osteoporotic vertebral structure is well adapted to the loads of daily life, but not to infrequent “error” loads. Bone. March 2004;34(3):510-516.
1988	Melton LJ III, Kan SH, Wahner HW, Riggs BL. Lifetime fracture risk: an approach to hip fracture risk assessment based on bone mineral density and age. J Clin Epidemiol. 1988;41(10):985-994.
2006	Teo JCM, Si-Hoe KM, Keh JEL, Teoh SH. Relationship between CT intensity, micro-architecture and mechanical properties of porcine vertebral cancellous bone. Clin Biomech (Bristol, Avon). March 2006;21(3):235-244.
1997	Ray NF, Chan JK, Thamer M, Melton LJ III. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res. January 1997;12(1):24-35.
2005	Gibson LJ. Biomechanics of cellular solids. J Biomech. 2005;38(3):377-399.
1977	Kazarian L, Graves GA Jr. Compressive strength characteristics of the human vertebral centrum. Spine. March 1977;2(1):1-14.
1997	Saito M, Marumo K, Fujii K, Ishioka N. Single-column high-performance liquid chromatographic-fluorescence detection of immature, mature, and senescent cross-links of collagen. Anal Ciochem. November 1, 1997;253(1):26-32.
2003	Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ; PaTH Study Investigators. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. NEJM. September 25, 2003;349(13):1207-1215.
1994	Turner CH, Forwood MR, Otter MW. Mechanotransduction in bone: do bone cells act as sensors of fluid flow? FASEB J. August 1994;8(11):875-878.
2005	Kanis JA, Borgstrom F, De Laet C, Johansson H, Johnell O, Jonsson B, Oden A, Zethraeus N, Pfleger B, Khaltaev N. Assessment of fracture risk. Osteoporos Int. June 2005;16(6):581-589.
2013	Chen H, Zhou X, Fujita H, Onozuka M, Kubo K-Y. Age-related changes in trabecular and cortical bone microstructure. Int J Endocrinol. March 18, 2013;2013:213234.
2003	Kim CH, Takai E, Zhou H, Von Stechow D, Müller R, Dempster DW, Guo XE. Trabecular bone response to mechanical and parathyroid hormone stimulation: the role of mechanical microenvironment. J Bone Miner Res. December 2003;18(12):2116-2125.
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.
1997	Burr DB, Forwood MR, Fyhrie DP, Martin RB, Schaffler MB, Turner CH. Bone microdamage and skeletal fragility in osteoporotic and stress fractures. J Bone Miner Res. January 1997;12(1):6-15.
1999	Kothari M, Keaveny TM, Lin JC, Newitt DC, Majumdar S. Measurement of intraspecimen variations in vertebral cancellous bone architecture. Bone. August 1999;25(2):245-250.
1993	Rho JY, Ashman RB, Turner CH. Young's modulus of trabecular and cortical bone material: ultrasonic and microtensile measurements. J Biomech. February 1993;26(2):111-119.
2002	Thomsen JS, Ebbesen EN, Mosekilde L. Age-related differences between thinning of horizontal and vertical trabeculae in human lumbar bone as assessed by a new computerized method. Bone. July 2002;31(1):136-142.
2009	Vashishth D. Advanced glycation end-products and bone fractures. IBMS Bonekey. August 2009;6(8):268-278.
1998	Rho J-Y, Kuhn-Spearing L, Zioupos P. Mechanical properties and the hierarchical structure of bone. Med Eng Phys. 1998;20(2):92-102.
2007	Tang SY, Zeenath U, Vashishth D. Effects of non-enzymatic glycation on cancellous bone fragility. Bone. April 2007;40(4):1144-1151.
2001	Banse X, Devogelaer JP, Munting E, Delloye C, Cornu O, Grynpas M. Inhomogeneity of human vertebral cancellous bone: systematic density and structure patterns inside the vertebral body. Bone. 2001;28(5):563-571.
1999	Roy ME, Rho J-Y, Tsui TY, Evans ND, Pharr GM. Mechanical and morphological variation of the human lumbar vertebral cortical and trabecular bone. J Biomed Mater Res. February 1999;A44(2):191-197.
1996	Rodan GA, Fleisch HA. Bisphosphonates: mechanisms of action. J Clin Invest. June 15, 1996;97(12):2692-2696.
2007	Valcourt U, Merle B, Gineyts E, Viguet-Carrin S, Delmas PD, Garnero P. Non-enzymatic glycation of bone collagen modifies osteoclastic activity and differentiation. J Biol Chem. February 23, 2007;282(8):5691-5703.
2007	Bolotin HH. DXA in vivo BMD methodology: an erroneous and misleading research and clinical gauge of bone mineral status, bone fragility, and bone remodelling. Bone. July 2007;41(1):138-154.
1999	Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. June 1999;20(3):345-357.
1998	Bank RA, Bayliss MT, Lafeber FPJG, Maroudas A, Tekoppele JM. Ageing and zonal variation in post-translational modification of collagen in normal human articular cartilage: the age-related increase in non-enzymatic glycation affects biomechanical properties of cartilage. Biochem J. February 15, 1998;3301(1):345-351.
1989	Brinckmann P, Biggemann M, Hilweg D. Prediction of the compressive strength of human lumbar vertebrae. Spine. June 1989;14(6):606-610.
2012	Tjong W, Kazakia GJ, Burghardt AJ, Majumdar S. The effect of voxel size on high-resolution peripheral computed tomography measurements of trabecular and cortical bone microstructure. Med Phys. April 2012;39(4):1893-1903.
1988	Hui SL, Slemenda CW, Johnston CC Jr. Age and bone mass as predictors of fracture in a prospective study. J Clin Invest. June 1988;81(6):1804-1809.
1997	Noble BS, Stevens H, Loveridge N, Reeve J. Identification of apoptotic changes in osteocytes in normal and pathological human bone. Bone. March 1997;20(3):273-282.
2000	Klotzbuecher CM, Ross PD, Landsman PB, Abbott TA III, Berger M. Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res. April 2000;15(4):721-739.
1995	Black DM, Palermo L, Nevitt MC, Genant HK, Epstein R, San Valentin R, Cummings SR; Study of Osteoporotic Fractures Research Group. Comparison of methods for defining prevalent vertebral deformities: the study of osteoporotic fractures. J Bone Miner Res. June 1995;10(6):890-902.
1991	Lotz JC, Gerhart TN, Hayes WC. Mechanical properties of metaphyseal bone in the proximal femur. J Biomech. 1991;24(5):317-329.
1990	Leblanc AD, Schneider VS, Evans HJ, Engelbretson DA, Krebs JM. Bone mineral loss and recovery after 17 weeks of bed rest. J Bone Miner Res. August 1990;5(8):843-850.
2012	Dall’Ara E, Pahr D, Varga P, Kainberger F, Zysset P. QCT-based finite element models predict human vertebral strength in vitro significantly better than simulated DEXA. Osteoporos Int. February 2012;23(2):563-572.

Year

Entry

1990

Beaupré GS, Orr TE, Carter DR. An approach for time‐dependent bone modeling and remodeling: theoretical development. J Orthop Res. September 1990;8(5):651-661.

1970

Merz WA, Schenk RK. A quantitative histological study on bone formation in human cancellous bone. Acta Anat. 1970;76(1):1-15.

2002

Currey JD. Bones: Structure and Mechanics. Princeton, NJ: Princeton University Press; 2002.

2010

Gourion-Arsiquaud S, Allen MR, Burr DB, Vashishth D, Tang SY, Boskey AL. Bisphosphonate treatment modifies canine bone mineral and matrix properties and their heterogeneity. Bone. March 2010;46(3):666-672.

1970

Abendschein W, Hyatt GW. Ultrasonics and selected physical properties of bone. Clin Orthop Relat Res. March–April 1970;69:294-301.