New horizons for the in vivo assessment of major aspects of bone quality

Summary

The Biomechanically founded individualised osteoporosis Assessment and treatment (BioAsset) consortium pursues experimental and clinical studies in the context of skeletal effects of bisphosphonate treatment. Here, first results using newly developed diagnostic methods in a set of vertebral bone specimen obtained from donors with documented bisphosphonate history ranging from 0 to more than 5 years of treatment are presented. A new thoracolumbar quantitative computed tomography (QCT) protocol covering T6 to L4 plus high-resolution QCT (HRQCT) assessment of T12 were compared with high-resolution peripheral QCT (HRpQCT) and micro-CT scans of excised specimens serving as gold standard techniques. Finite element (FE) modelling was performed. Material, ultrastructural, and micromechanical properties were tested on a set of single trabeculae obtained from the donor specimens. A newly developed quantitative ultrasound (QUS) device for measuring the anisotropy of cortical material properties at the tibia was designed and built. The thoracolumbar QCT protocol permitted in situ imaging with good image quality and automated segmentation of vertebral bodies in the whole range from T6 to L4. The duration of bisphosphonate treatment was significantly associated with increased levels of mineralization and this effect could be measured with HRQCT performed on excised specimens. Microstructural parameters contributed to vertebral bone strength modelled by FE analysis independently of bone mineral density. The new QUS tibia scanner permitted measuring the acoustical anisotropy of reference materials. Taken together, these results document that new methods developed in BioAsset permit a more comprehensive assessment of bone fragility. The set of donor specimens with a documented history of bisphosphonate treatment allows for the assessment of the effects of long-term treatment from the organ down to the tissue and material level. These results will ultimately be linked to the parallel clinical study to provide guidance for determining the optimum duration of bisphosphonate treatment to reduce the incidence of osteoporotic fractures.

Zusammenfassung

Das Biomechanically founded individualised osteoporosis Assessment and treatment (Bio-Asset)-Konsortium führt experimentelle und klinische Studien zu skelettalen Effekten von Bisphosphonaten durch. Neue diagnostische Verfahren zur Analyse von Wirbelkörper – proben von Spendern mit dokumentierter Bisphosphonateinnahme über 0 bis > 5 Jahre Uniwurden entwickelt. Mittels thorakolumbaler Quantitativer Computertomografie (QCT) und hochauflösender QCT (HRQCT) wurden Knochenmineraldichte (BMD), Mikrostrukturvariablen und Materialeigenschaften, ins – besondere Mineralisierung, untersucht. Finite Element (FE)-Modellierung dient der Bestimmung der Wirbelkörperbruchlast. Ein neues Quantitatives-Ultraschall (QUS)-Gerät zur Mes sung anisotroper kortikaler Materialeigenschaften der Tibia wurde konstruiert. Ein signifikanter Zusammenhang von Mineralisierung und (Dauer der) Bisphosphonattherapie konnte mit Mikro-CT und HRQCT nachgewiesen werden. Das thorakolumbale QCT-Protokoll ermöglichte eine Dosisreduktion von 60 % gegenüber Standardprotokollen. Eine Finite-Elemente-Analyse zeigte BMD und Trabek elanzahl als unabhängige Determinanten der Bruchlast. Mit dem neuen QUS-Tibia-Gerät konnte die akustische Anisotropie von Referenzmaterialien bestimmt werden. Die Daten dokumentieren erweiterte Dia gnosemöglichkeiten zur Abschätzung von Knochenfragilität durch die neuen Verfahren. Parallel durchgeführte klinische Studien sollen die Frage der optimalen Dauer von Bisphosphonattherapie klären.

Keywords

Osteoporosis - bone quality - mineralization - high resolution quantitative computed tomography - quantitative ultrasound - finite element analysis

Schlüsselwörter

Osteoporose - Knochenqualität - Mineralisierung - hochauflösende Quantitative Computertomografie - Quantitativer Ultraschall - Finite Elemente Analyse

• References

• 1 Siris ES, Chen YT, Abbott TA. et al. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 2004; 164 (10) 1108-1112.
• 2 Krause M, Anschütz W, Vettorazzi E. et al. Vitamin D deficiency intensifies deterioration of risk factors, such as male sex and absence of vision, leading to increased postural body sway. Gait and Posture. 2013 accepted for publication.
• 3 Li Z, Chines AA, Meredith MP. Statistical validation of surrogate endpoints: is bone density a valid surrogate for fracture?. J Musculoskelet Neuronal Interact 2004; 4 (1) 64-74.
• 4 S3-guidelines osteoporosis of the Dachverband Osteologie (DVO). 2009 Available from: http://www.dv-osteologie.de
• 5 Barkmann R, Dencks S, Laugier P. et al. Femur ultrasound (FemUS) – first clinical results on hip fracture discrimination and estimation of femoral BMD. Osteoporos Int 2010; 21 (6) 969-976.
• 6 Rohde K, Rohrbach D, Glüer C. et al. Influence of porosity, pore size and cortical thickness on the propagation of ultrasonic waves guided through the femoral neck cortex: a simulation study. IEEE Transactions on Ultrasonics Ferroelectrics and Frequency Control. 2012 in revision.
• 7 Mastmeyer A, Engelke K, Fuchs C, Kalender WA. A hierarchical 3D segmentation method and the definition of vertebral body coordinate systems for QCT of the lumbar spine. Med Image Anal 2006; 10 (4) 560-577.
• 8 Scheitacker J. Segmentierung der Bandscheiben in Datensätzen der dreidimensionalen Computertomographie [Diploma Thesis]: Hochschule Coburg. 2013
• 9 Krebs A, Graeff C, Frieling I. et al. High resolution computed tomography of the vertebrae yields accurate information on trabecular distances if processed by 3D fuzzy segmentation approaches. Bone 2009; 44 (1) 145-152.
• 10 Graeff C, Chevalier Y, Charlebois M. et al. Improvements in vertebral body strength under teriparatide treatment assessed in vivo by finite element analysis: results from the EUROFORS study. J Bone Miner Res 2009; 24 (10) 1672-1680.
• 11 Schwiedrzik JJ, Zysset PK. An anisotropic elastic-viscoplastic damage model for bone tissue. Biomech Model Mechanobiol. 2012 Apr 18.
• 12 Moramarco V, Perez del Palomar A, Pappalettere C, Doblare M. An accurate validation of a computational model of a human lumbosacral segment. J Biomech 2010; 43 (2) 334-342.
• 13 Busse B, Hahn M, Soltau M. et al. Increased calcium content and inhomogeneity of mineralization render bone toughness in osteoporosis: mineralization, morphology and biomechanics of human single trabeculae. Bone 2009; 45 (6) 1034-1043.
• 14 Daugschies M, Rohde K, Glüer CC, Barkmann R. A new ultrasound probe for the acoustical measurement of elastic anisotropy at the human tibia shaft. Ultrasonics. 2013 in revision.
• 15 Grampp S, Genant HK, Mathur A. et al. Comparisons of noninvasive bone mineral measurements in assessing age-related loss, fracture discrimination, and diagnostic classification. J Bone Miner Res 1997; 12 (5) 697-711.
• 16 Eckstein F, Lochmuller EM, Lill CA. et al. Bone strength at clinically relevant sites displays substantial heterogeneity and is best predicted from site-specific bone densitometry. J Bone Miner Res 2002; 17 (1) 162-171.
• 17 McCloskey EV, Vasireddy S, Threlkeld J. et al. Vertebral fracture assessment (VFA) with a densitometer predicts future fractures in elderly women unselected for osteoporosis. J Bone Miner Res 2008; 23 (10) 1561-1568.
• 18 Cootes T, Taylor C, Cooper D, Graham J. Active shape models – their training and application. Comp Vis Image Underst 1995; 61 (1) 38-59.
• 19 Roschger P, Rinnerthaler S, Yates J. et al. Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women. Bone 2001; 29 (2) 185-191.
• 20 Agarwal S, Gupta P, Agarwal PK. et al. Risk of atypical femoral fracture with long-term use of alendronate (bisphosphonates): a systemic review of literature. Acta Orthop Belg 2010; 76 (5) 567-571.
• 21 Bala Y, Depalle B, Farlay D. et al. Bone micromechanical properties are compromised during long-term alendronate therapy independently of mineralization. J Bone Miner Res 2012; 27 (4) 825-834.
• 22 Bilezikian JP. Efficacy of bisphosphonates in reducing fracture risk in postmenopausal osteoporosis. Am J Med 2009; 122 (2 Suppl) S14-S21.
• 23 Mashiba T, Turner CH, Hirano T. et al. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone 2001; 28 (5) 524-531.
• 24 Allen MR, Burr DB. Three years of alendronate treatment results in similar levels of vertebral microdamage as after one year of treatment. J Bone Miner Res 2007; 22 (11) 1759-1765.
• 25 Turner CH. Bone strength: current concepts. Ann N Y Acad Sci 2006; 1068: 429-446.
• 26 Burr DB. Bone material properties and mineral matrix contributions to fracture risk or age in women and men. J Musculoskelet Neuronal Interact 2002; 2 (3) 201-204.
• 27 Graeff C, Marin F, Petto H. et al. High resolution quantitative computed tomography-based assessment of trabecular microstructure and strength estimates by finite-element analysis of the spine, but not DXA, reflects vertebral fracture status in men with glucocorticoid-induced osteoporosis. Bone 2013; 52 (2) 568-577.
• 28 Glüer CC, Marin F, Ringe JD. et al. Comparative effects of teriparatide and risedronate in glucocorticoid-induced osteoporosis in men: 18-month results of the EuroGIOPs trial. J Bone Miner Res. 2013 Jan 15.
• 29 Bossy E, Talmant M, Peyrin F. et al. An in vitro study of the ultrasonic axial transmission technique at the radius: 1-MHz velocity measurements are sensitive to both mineralization and intracortical porosity. J Bone Miner Res 2004; 19 (9) 1548-1556.
• 30 Rudy DJ, Deuerling JM, Espinoza Orias AA, Roeder RK. Anatomic variation in the elastic inhomogeneity and anisotropy of human femoral cortical bone tissue is consistent across multiple donors. J Biomech 2011; 44 (9) 1817-1820.
• 31 Diez-Perez A, Guerri R, Nogues X. et al. Microindentation for in vivo measurement of bone tissue mechanical properties in humans. J Bone Miner Res 2010; 25 (8) 1877-1885.