An Investigation of Trabecular Bone Morphology

Osteoporosis and other age-associated diseases are proving to have complex etiologies stemming from the fact that most are multifactorial in nature and are largely attributed to the combined effects of many genes and gene-environment interactions. Osteoporosis results in low bone mass and microarchitectural deterioration of bone tissue, especially of trabecular bone. In this work we located quantitative trait loci (QTL) associated with many properties of tibial trabecular bone in two ages of laboratory mice. Interesting trends were evident in the QTL identified at 500 and 800 days of age. Some QTL were found in both age groups. These QTL may prove to be important across the lifespan in building and maintaining bone tissue. Other QTL were only identified at one age point. These may indicate genetic influences that occur at specific times in development. Several loci were identified in both sexes while others appear to be sex-specific.

Through examination of recombinant inbred strains of mice, we have also been able to measure age-related changes in the microarchitecture of trabecular bone and identify QTL related to the age-related changes. Analyzing the QTL specifically related to the changes seen with age has provided several additional sites likely harbouring important genes effecting how bone is lost or gained with age.

Accurate research results of the architecture and density of trabecular bone depend on reliable, consistent data collection. Microcomputed tomography (µCT) has become a valuable and widely available tool that is often used as a dependable replacement for traditional histological measurements of trabecular bone microstructure, but questions still exist about the reproducibility and reliability of data collected using µCT. It was determined that increasing the number of operators involved in data collection increases the variability and reduces the reliability of data collected with µCT and that using methylmethacrylate as an embedding material does not appear to affect the results collected from µCT. We recommend using as few operators as possible to ensure reliable data, ideally with one individual being responsible for all identification of the volume of interest. These findings will inform future study designs leading to better and more reliable data collection.

Year	Entry
1999	Ding M, Odgaard A, Hvid I. Accuracy of cancellous bone volume fraction measured by micro-CT scanning. J Biomech. 1999;32(3):323-326.
1996	Rüegsegger P, Koller B, Müller R. A microtomographic system for the nondestructive evaluation of bone architecture. Calcif Tiss Int. 1996;58(1):24-29.
1997	Silva MJ, Gibson LJ. Modeling the mechanical behavior of vertebral trabecular bone: effects of age-related changes in microstructure. Bone. 1997;21(2):191-199.
2000	Ciarelli TE, Fyhrie DP, Schaffler MB, Goldstein SA. Variations in three‐dimensional cancellous bone architecture of the proximal femur in female hip fractures and in controls. J Bone Miner Res. 2000;15(1):32-40.
2001	Borah B, Gross GJ, Dufresne TE, Smith TS, Cockman MD, Chmielewski PA, Lundy MW, Hartke JR, Sod EW. Three‐dimensional microimaging (MRμI and μCT), finite element modeling, and rapid prototyping provide unique insights into bone architecture in osteoporosis. Anat Rec. April 15, 2001;265(2):101-110.
2000	Day JS, Ding M, Odgaard A, Sumner DR, Hvid I, Weinans H. Parallel plate model for trabecular bone exhibits volume fraction-dependent bias. Bone. November 2000;27(5):715-720.
1997	Aerssens J, Boonen S, Joly J, Dequeker J. Variations in trabecular bone composition with anatomical site and age: potential implications for bone quality assessment. J Endocrinol. December 1997;155(3):411-421.
2007	Perilli E, Baruffaldi F, Visentin M, Bordini B, Traina F, Cappello A, Viceconti M. MicroCT examination of human bone specimens: effects of polymethylmethacrylate embedding on structural parameters. J Microsc (Oxford). 2007;225(pt 2):192-200.
2000	Turner CH, Hsieh Y, Müller R, Bouxsein ML, Baylink DJ, Rosen CJ, Grynpas MD, Donahue LR, Beamer WG. Genetic regulation of cortical and trabecular bone strength and microstructure in inbred strains of mice. J Bone Miner Res. June 2000;15(6):1126-1131.
1998	Klein RF, Mitchell SR, Phillips TJ, Belknap JK, Orwoll ES. Quantitative trait loci affecting peak bone mineral density in mice. J Bone Miner Res. November 1998;13(11):1648-1656.
1997	Hildebrand T, Rüegsegger P. Quantification of bone microarchitecture with the structure model index. Comput Methods Prog Biomed. 1997;1(1):15-23.
1993	Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med. June 1993;94(6):646-650.
1998	Müller R, Van Campenhout H, Van Damme B, Van der Perre G, Dequeker J, Hildebrand T, Rüegsegger P. Morphometric analysis of human bone biopsies: a quantitative structural comparison of histological sections and micro-computed tomography. Bone. July 1998;23(1):59-66.
1997	Uchiyama T, Tanizawa T, Muramatsu H, Endo N, Takahashi HE, Hara T. A morphometric comparison of trabecular structure of human ilium between microcomputed tomography and conventional histomorphometry. Calcif Tiss Int. December 1997;61(6):493-498.
2002	Guo XE, Kim CH. Mechanical consequence of trabecular bone loss and its treatment: a three-dimensional model simulation. Bone. February 2002;30(2):404-411.
2000	Ding M, Hvid I. Quantification of age-related changes in the structure model type and trabecular thickness of human tibial cancellous bone. Bone. March 2000;26(3):291-295.
2002	Hara T, Tanck E, Homminga J, Huiskes R. The influence of microcomputed tomography threshold variations on the assessment of structural and mechanical trabecular bone properties. Bone. July 2002;31(1):107-109.
2005	Tommasini SM, Morgan TG, van der Meulen MCH, Jepsen KJ. Genetic variation in structure‐function relationships for the inbred mouse lumbar vertebral body. J Bone Miner Res. May 2005;20(5):817-827.
1997	Burr DB. Muscle strength, bone mass, and age‐related bone loss. J Bone Miner Res. 1997;12(10):1547-1551.
1983	Recker RR, ed. Bone Histomorphometry: Techniques and Interpretation. Boca Raton, FL: Inc., CRC Press; 1983.
1989	Feldkamp LA, Goldstein SA, Parfitt MA, Jesion G, Kleerekoper M. The direct examination of three‐dimensional bone architecture in vitro by computed tomography. J Bone Miner Res. 1989;4(1):3-11.
1999	Hildebrand T, Laib A, Müller R, Dequeker J, Rüegsegger P. Direct three-dimensional morphometric analysis of human cancellous bone: microstructural data from spine, femur, iliac crest, and calcaneus. J Bone Miner Res. July 1999;14(7):1167-1174.
2000	Akhter MP, Iwaniec UT, Covey MA, Cullen DM, Kimmel DB, Recker RR. Genetic variations in bone density, histomorphometry, and strength in mice. Calcif Tiss Int. October 2000;67(4):337-344.
2002	Halloran BP, Ferguson VL, Simske SJ, Burghardt A, Venton LL, Majumdar S. Changes in bone structure and mass with advancing age in the male C57BL/6J mouse. J Bone Miner Res. June 2002;17(6):1044-1050.
1990	Kuhn JL, Goldstein SA, Feldkamp LA, Goulet RW, Jesion G. Evaluation of a microcomputed tomography system to study trabecular bone structure. J Orthop Res. 1990;8(6):833-842.
2001	van der Linden JC, Birkenhäger-Frenkel DH, Verhaar JAN, Weinans H. Trabecular bone's mechanical properties are affected by its non-uniform mineral distribution. J Biomech. December 2001;34(12):1573-1580.
2007	Burge R, Dawson‐Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis‐related fractures in the United States, 2005–2025. J Bone Miner Res. March 2007;22(3):465-475.

Year

Entry

1999

Ding M, Odgaard A, Hvid I. Accuracy of cancellous bone volume fraction measured by micro-CT scanning. J Biomech. 1999;32(3):323-326.

1996

Rüegsegger P, Koller B, Müller R. A microtomographic system for the nondestructive evaluation of bone architecture. Calcif Tiss Int. 1996;58(1):24-29.

1997

Silva MJ, Gibson LJ. Modeling the mechanical behavior of vertebral trabecular bone: effects of age-related changes in microstructure. Bone. 1997;21(2):191-199.

2000

Ciarelli TE, Fyhrie DP, Schaffler MB, Goldstein SA. Variations in three‐dimensional cancellous bone architecture of the proximal femur in female hip fractures and in controls. J Bone Miner Res. 2000;15(1):32-40.

2001

Borah B, Gross GJ, Dufresne TE, Smith TS, Cockman MD, Chmielewski PA, Lundy MW, Hartke JR, Sod EW. Three‐dimensional microimaging (MRμI and μCT), finite element modeling, and rapid prototyping provide unique insights into bone architecture in osteoporosis. Anat Rec. April 15, 2001;265(2):101-110.