Mechanical Induction of Bone Formation: Comparison Between Rat and Mouse Forelimb Models

To investigate the effects of mechanical loading on the rat and mouse forelimb, male Sprague Dawley rats and male C57/BL-6 mice forelimbs were cyclically loaded in axial compression. Two studies were performed, one to examine woven bone formation in both the rat and mouse forelimb, and one to examine lamellar bone formation in the rat forelimb. Both types of bone formation were induced through an acute loading event.

Repeatable levels of fatigue damage were induced in both the rat and mouse ulna, yielding a consistent woven bone response. Rats formed more woven bone than mice. Woven bone formed by the rats was evenly distributed along the medial cortex versus woven bone formed by the mice was more abundant towards the posterior side of the medial surface.

150 cycles of rest inserted loading to a peak load of 30 N was found to induce lamellar bone formation with the greatest apposition rate. Apposition rate was more strongly influenced by peak loading rather than number of loading cycles. At the 30 N loading level, 300 loading cycles induced woven bone formation in two of the five animals.

Finite element models were created to examine the mechanical environment of both the rat and mouse ulna during compressive forelimb loading. Stress distribution in the rat ulna was found to be distributed along the medial surface of the rat ulna. Stress distribution was biased to the posterior side of the medial surface on the mouse ulna. These stress distributions supported the bone formation observed. Maximal stress occurred in both the rat and mouse ulna at the same location failure occurred during monotonic and fatigue to failure tests conducted on both rat and mouse ulnas.

Year	Entry
2008	Ritchie RO, Koester KJ, Ionova S, Yao W, Lane NE, Ager JW III. Measurement of the toughness of bone: a tutorial with special reference to small animal studies. Bone. November 2008;43(5):798-812.
1994	Torrance AG, Mosley JR, Suswillo RFL, Lanyon LE. Noninvasive loading of the rat ulna in vivo induces a strain-related modeling response uncomplicated by trauma or periostal pressure. Calcif Tiss Int. March 1994;54(3):241-247.
1998	Martin RB, Burr DB, Sharkey NA. Skeletal Tissue Mechanics. New York, NY: Springer-Verlag; 1998.
1992	Gross TS, McLeod KJ, Rubin CT. Characterizing bone strain distributions in vivo using three triple rosette strain gages. J Biomech. September 1992;25(9):1081-1087.
2002	Martin RB. Is all cortical bone remodeling initiated by microdamage? Bone. January 2002;30(1):8-13.
1996	Forwood MR, Owan I, Takano Y, Turner CH. Increased bone formation in rat tibiae after a single short period of dynamic loading in vivo. Am J Physiol Endocrinol Metab. March 1996;270(3):E419-E423.
2008	Bacabac RG, Mizuno D, Schmidt CF, MacKintosh FC, Van Loon JJWA, Klein-Nulend J, Smit TH. Round versus flat: bone cell morphology, elasticity, and mechanosensing. J Biomech. 2008;41(7):1590-1598.
1998	Carter DR, Beaupré GS, Giori NJ, Helms JA. Mechanobiology of skeletal regeneration. Clin Orthop Relat Res. October 1998;355(suppl):S41-S55.
2002	Ohashi N, Robling AG, Burr DB, Turner CH. The effects of dynamic axial loading on the rat growth plate. J Bone Miner Res. February 2002;17(2):284-292.
1984	Lanyon LE, Rubin CT. Static vs dynamic loads as an influence on bone remodelling. J Biomech. 1984;17(12):897-905.
2008	Vatsa A, Breuls RG, Semeins CM, Salmon PL, Smit TH, Klein-Nulend J. Osteocyte morphology in fibula and calvaria: is there a role for mechanosensing? Bone. September 2008;43(3):452-458.
2009	van Hove RP, Nolte PA, Vatsa A, Semeins CM, Salmon PL, Smit TH, Klein-Nulend J. Osteocyte morphology in human tibiae of different bone pathologies with different bone mineral density: is there a role for mechanosensing? Bone. August 2009;45(2):321-329.
1993	Turner CH, Burr DB. Basic biomechanical measurements of bone: a tutorial. Bone. 1993;14(4):595-608.
1994	Turner CH, Forwood MR, Rho J, Yoshikawa T. Mechanical loading thresholds for lamellar and woven bone formation. J Bone Miner Res. January 1994;9(1):87-97.
2004	Kotha SP, Hsieh Y-F, Strigel RM, Müller R, Silva MJ. Experimental and finite element analysis of the rat ulnar loading model: correlations between strain and bone formation following fatigue loading. J Biomech. April 2004;37(4):541-548.
1982	Rubin CT, Lanyon LE. Limb mechanics as a function of speed and gait: a study of functional strains in the radius and tibia of horse and dog. J Exp Biol. December 1982;101:187-211.
1985	Rubin CT, Lanyon LE. Regulation of bone mass by mechanical strain magnitude. Calcif Tiss Int. 1985;37(4):411-417.
2002	Burr DB. Targeted and nontargeted remodeling. Bone. January 2002;30(1):2-4.
2005	Shefelbine SJ, Simon U, Claes L, Gold A, Gabet Y, Bab I, Müller R, Augat P. Prediction of fracture callus mechanical properties using micro-CT images and voxel-based finite element analysis. Bone. March 2005;36(3):480-488.
1998	Guldberg RE, Hollister SJ, Charras GT. The accuracy of digital image-based finite element models. J Biomech Eng. 1998;120(2):289-295.
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.
2001	Hsieh Y, Robling AG, Ambrosius WT, Burr DB, Turner CH. Mechanical loading of diaphyseal bone in vivo: the strain threshold for an osteogenic response varies with location. J Bone Miner Res. December 2001;16(10):2291-2297.
2002	Srinivasan S, Weimer DA, Agans SC, Bain SD, Gross TS. Low‐magnitude mechanical loading becomes osteogenic when rest is inserted between each load cycle. J Bone Miner Res. September 2002;17(9):1613-1620.
2003	Srinivasan S, Agans SC, King KA, Moy NY, Poliachik SL, Gross TS. Enabling bone formation in the aged skeleton via rest-inserted mechanical loading. Bone. December 2003;33(6):946-955.
1989	Martin RB, Burr DB. Structure, Function, and Adaptation of Compact Bone. New York, NY: Raven Press; 1989.
2002	Hsieh Y-F, Silva MJ. In vivo fatigue loading of the rat ulna induces both bone formation and resorption and leads to time-related changes in bone mechanical properties and density. J Orthop Res. July 2002;20(4):764-771.
2001	Robling AG, Burr DB, Turner CH. Recovery periods restore mechanosensitivity to dynamically loaded bone. J Exp Biol. 2001;204(19):3389-3399.
2001	Cowin SC, ed. Bone Mechanics Handbook. 2nd ed. Boca Raton, FL: CRC Press; 2001.
2002	Robling AG, Turner CH. Mechanotransduction in bone: genetic effects on mechanosensitivity in mice. Bone. November 2002;31(5):562-569.

Year

Entry

2008

Ritchie RO, Koester KJ, Ionova S, Yao W, Lane NE, Ager JW III. Measurement of the toughness of bone: a tutorial with special reference to small animal studies. Bone. November 2008;43(5):798-812.

1994

Torrance AG, Mosley JR, Suswillo RFL, Lanyon LE. Noninvasive loading of the rat ulna in vivo induces a strain-related modeling response uncomplicated by trauma or periostal pressure. Calcif Tiss Int. March 1994;54(3):241-247.

1998

Martin RB, Burr DB, Sharkey NA. Skeletal Tissue Mechanics. New York, NY: Springer-Verlag; 1998.

1992

Gross TS, McLeod KJ, Rubin CT. Characterizing bone strain distributions in vivo using three triple rosette strain gages. J Biomech. September 1992;25(9):1081-1087.

2002

Martin RB. Is all cortical bone remodeling initiated by microdamage? Bone. January 2002;30(1):8-13.

1996

Forwood MR, Owan I, Takano Y, Turner CH. Increased bone formation in rat tibiae after a single short period of dynamic loading in vivo. Am J Physiol Endocrinol Metab. March 1996;270(3):E419-E423.

2008

Bacabac RG, Mizuno D, Schmidt CF, MacKintosh FC, Van Loon JJWA, Klein-Nulend J, Smit TH. Round versus flat: bone cell morphology, elasticity, and mechanosensing. J Biomech. 2008;41(7):1590-1598.

1998

Carter DR, Beaupré GS, Giori NJ, Helms JA. Mechanobiology of skeletal regeneration. Clin Orthop Relat Res. October 1998;355(suppl):S41-S55.

2002

Ohashi N, Robling AG, Burr DB, Turner CH. The effects of dynamic axial loading on the rat growth plate. J Bone Miner Res. February 2002;17(2):284-292.

1984

Lanyon LE, Rubin CT. Static vs dynamic loads as an influence on bone remodelling. J Biomech. 1984;17(12):897-905.

2008

Vatsa A, Breuls RG, Semeins CM, Salmon PL, Smit TH, Klein-Nulend J. Osteocyte morphology in fibula and calvaria: is there a role for mechanosensing? Bone. September 2008;43(3):452-458.

2009

van Hove RP, Nolte PA, Vatsa A, Semeins CM, Salmon PL, Smit TH, Klein-Nulend J. Osteocyte morphology in human tibiae of different bone pathologies with different bone mineral density: is there a role for mechanosensing? Bone. August 2009;45(2):321-329.

1993

Turner CH, Burr DB. Basic biomechanical measurements of bone: a tutorial. Bone. 1993;14(4):595-608.

1994

Turner CH, Forwood MR, Rho J, Yoshikawa T. Mechanical loading thresholds for lamellar and woven bone formation. J Bone Miner Res. January 1994;9(1):87-97.

2004

Kotha SP, Hsieh Y-F, Strigel RM, Müller R, Silva MJ. Experimental and finite element analysis of the rat ulnar loading model: correlations between strain and bone formation following fatigue loading. J Biomech. April 2004;37(4):541-548.

1982

Rubin CT, Lanyon LE. Limb mechanics as a function of speed and gait: a study of functional strains in the radius and tibia of horse and dog. J Exp Biol. December 1982;101:187-211.

1985

Rubin CT, Lanyon LE. Regulation of bone mass by mechanical strain magnitude. Calcif Tiss Int. 1985;37(4):411-417.

2002

Burr DB. Targeted and nontargeted remodeling. Bone. January 2002;30(1):2-4.

2005

Shefelbine SJ, Simon U, Claes L, Gold A, Gabet Y, Bab I, Müller R, Augat P. Prediction of fracture callus mechanical properties using micro-CT images and voxel-based finite element analysis. Bone. March 2005;36(3):480-488.

1998

Guldberg RE, Hollister SJ, Charras GT. The accuracy of digital image-based finite element models. J Biomech Eng. 1998;120(2):289-295.

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.

2001

Hsieh Y, Robling AG, Ambrosius WT, Burr DB, Turner CH. Mechanical loading of diaphyseal bone in vivo: the strain threshold for an osteogenic response varies with location. J Bone Miner Res. December 2001;16(10):2291-2297.

2002

Srinivasan S, Weimer DA, Agans SC, Bain SD, Gross TS. Low‐magnitude mechanical loading becomes osteogenic when rest is inserted between each load cycle. J Bone Miner Res. September 2002;17(9):1613-1620.

2003

Srinivasan S, Agans SC, King KA, Moy NY, Poliachik SL, Gross TS. Enabling bone formation in the aged skeleton via rest-inserted mechanical loading. Bone. December 2003;33(6):946-955.

1989

Martin RB, Burr DB. Structure, Function, and Adaptation of Compact Bone. New York, NY: Raven Press; 1989.

2002

Hsieh Y-F, Silva MJ. In vivo fatigue loading of the rat ulna induces both bone formation and resorption and leads to time-related changes in bone mechanical properties and density. J Orthop Res. July 2002;20(4):764-771.

2001

Robling AG, Burr DB, Turner CH. Recovery periods restore mechanosensitivity to dynamically loaded bone. J Exp Biol. 2001;204(19):3389-3399.

2001

Cowin SC, ed. Bone Mechanics Handbook. 2nd ed. Boca Raton, FL: CRC Press; 2001.

2002

Robling AG, Turner CH. Mechanotransduction in bone: genetic effects on mechanosensitivity in mice. Bone. November 2002;31(5):562-569.

Year	Entry
2012	Druchok C. The Effect of a High-Fat Diet on Bone Strain in Adult Rat Femurs [Master's thesis]. Hamilton, ON: McMaster University; October 2012.
2016	Druchok C. Temporal Influence of NSAIDs on Mechanically Induced Bone Formation and Fluid Flow Stimulated Cellular PGE₂ Production [PhD thesis]. Hamilton, ON: McMaster University; August 2016.

Year

Entry

2012

Druchok C. The Effect of a High-Fat Diet on Bone Strain in Adult Rat Femurs [Master's thesis]. Hamilton, ON: McMaster University; October 2012.

2016

Druchok C. Temporal Influence of NSAIDs on Mechanically Induced Bone Formation and Fluid Flow Stimulated Cellular PGE₂ Production [PhD thesis]. Hamilton, ON: McMaster University; August 2016.