A Preclinical Assessment of Lithium to Enhance Fracture Healing

Delayed or impaired bone healing occurs in 5-10% of all fractures, yet cost effective solutions to enhance the healing process are limited. Lithium, a current treatment for bipolar disorder, is not clinically indicated for use in fracture management, but has been reported to positively influence bone biology. The objective of this study was to identify lithium administration parameters that maximize bone healing in a preclinical, rodent femur fracture model. Using a three factor, two level, design of experiments (DOE) approach, bone healing was assessed through mechanical testing and µCT-image analysis. Significant improvements in healing were found at a low dose, later onset, longer duration treatment combination, with onset identified as the most influential parameter. The positive results from this DOE screening focuses the optimization phase towards further investigation of the onset component of treatment, and forms a crucial foundation for future studies evaluating the role of lithium in fracture healing

Year	Entry
1974	Reilly DT, Burstein AH, Frankel VH. The elastic modulus for bone. J Biomech. May 1974;7(3):271-275.
1998	Einhorn TA. The cell and molecular biology of fracture healing. Clin Orthop Relat Res. October 1998;355(suppl):S7-S21.
2010	Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Müller R. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res. July 2010;25(7):1468-1486.
1985	Wronski TJ, Lowry PL, Walsh CC, Ignaszewski LA. Skeletal alterations in ovariectomized rats. Calcif Tiss Int. May 1985;37(3):324-328.
2001	Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GCM, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Jüppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard M-J, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. November 16, 2001;107(4):513-523.
2009	Morgan EF, Mason ZD, Chien KB, Pfeiffer AJ, Barnes GL, Einhorn TA, Gerstenfeld LC. Micro-computed tomography assessment of fracture healing: relationships among callus structure, composition, and mechanical function. Bone. February 2009;44(2):335-344.
2002	Cho T-J, Gerstenfeld LC, Einhorn TA. Differential temporal expression of members of the transforming growth factor β superfamily during murine fracture healing. J Bone Miner Res. March 2002;17(3):513-520.
2009	Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y, Shalhoub V, Tipton B, Haldankar R, Chen Q, Winters A, Boone T, Geng Z, Niu Q-T, Ke HZ, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res. April 2009;24(4):578-588.
2006	Viguet-Carrin S, Garnero P, Delmas PD. The role of collagen in bone strength. Osteoporos Int. March 2006;17(3):319-336.
2002	Vahle JL, Sato M, Long GG, Young JK, Francis PC, Engelhardt JA, Westmore MS, Ma YL, Nold JB. Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety. Toxicol Pathol. May 1, 2002;30(3):312-321.
1971	Burstein AH, Frankel VH. A standard test for laboratory animal bone. J Biomech. March 1971;4(2):155-158.
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.
2011	Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single‐dose, placebo‐controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res. January 2011;26(1):19-26.
1991	Kalu DN. The ovariectomized rat model of postmenopausal bone loss. Bone Miner. December 1991;15(3):175-191.
2011	Marsell R, Einhorn TA. The biology of fracture healing. Injury. June 2011;42(6):551-555.
2006	Krishnan V, Bryant HU, MacDougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest. May 2006;116(5):1202-1209.
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.
2002	Rogers KD, Daniels P. An X-ray diffraction study of the effects of heat treatment on bone mineral microstructure. Biomaterials. June 2002;23(12):2577-2585.

Year

Entry

1974

Reilly DT, Burstein AH, Frankel VH. The elastic modulus for bone. J Biomech. May 1974;7(3):271-275.

1998

Einhorn TA. The cell and molecular biology of fracture healing. Clin Orthop Relat Res. October 1998;355(suppl):S7-S21.

2010

Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Müller R. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res. July 2010;25(7):1468-1486.

1985

Wronski TJ, Lowry PL, Walsh CC, Ignaszewski LA. Skeletal alterations in ovariectomized rats. Calcif Tiss Int. May 1985;37(3):324-328.

2001

Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GCM, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Jüppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard M-J, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. November 16, 2001;107(4):513-523.

2009

Morgan EF, Mason ZD, Chien KB, Pfeiffer AJ, Barnes GL, Einhorn TA, Gerstenfeld LC. Micro-computed tomography assessment of fracture healing: relationships among callus structure, composition, and mechanical function. Bone. February 2009;44(2):335-344.

2002

Cho T-J, Gerstenfeld LC, Einhorn TA. Differential temporal expression of members of the transforming growth factor β superfamily during murine fracture healing. J Bone Miner Res. March 2002;17(3):513-520.

2009

Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y, Shalhoub V, Tipton B, Haldankar R, Chen Q, Winters A, Boone T, Geng Z, Niu Q-T, Ke HZ, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res. April 2009;24(4):578-588.

2006

Viguet-Carrin S, Garnero P, Delmas PD. The role of collagen in bone strength. Osteoporos Int. March 2006;17(3):319-336.

2002

Vahle JL, Sato M, Long GG, Young JK, Francis PC, Engelhardt JA, Westmore MS, Ma YL, Nold JB. Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety. Toxicol Pathol. May 1, 2002;30(3):312-321.

1971

Burstein AH, Frankel VH. A standard test for laboratory animal bone. J Biomech. March 1971;4(2):155-158.

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.

2011

Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single‐dose, placebo‐controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res. January 2011;26(1):19-26.

1991

Kalu DN. The ovariectomized rat model of postmenopausal bone loss. Bone Miner. December 1991;15(3):175-191.

2011

Marsell R, Einhorn TA. The biology of fracture healing. Injury. June 2011;42(6):551-555.

2006

Krishnan V, Bryant HU, MacDougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest. May 2006;116(5):1202-1209.

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.

2002

Rogers KD, Daniels P. An X-ray diffraction study of the effects of heat treatment on bone mineral microstructure. Biomaterials. June 2002;23(12):2577-2585.

Year	Entry
2016	Vachhani KJ. A Pre-Clinical Assessment of Lithium to Enhance Fracture Healing in Healthy and Impaired Bone Rat Model [Master's thesis]. University of Toronto; 2016.

Year

Entry

2016

Vachhani KJ. A Pre-Clinical Assessment of Lithium to Enhance Fracture Healing in Healthy and Impaired Bone Rat Model [Master's thesis]. University of Toronto; 2016.