Low-intensity pulsed ultrasound accelerated callus formation, angiogenesis and callus remodeling in osteoporotic fracture healing.

Osteoporotic fracture is a critical medico-social challenge leading to burdens in health care costs and hospital bed stays. Low-intensity pulsed ultrasound (LIPUS) was reported to accelerate normal fracture; however, its effect on osteoporotic fracture has not been previously addressed. We hypothesize that LIPUS can accelerate osteoporotic fracture healing and up-regulate the expression in the osteogenesis-, remodeling- and angiogenesis-related genes. Ovariectomy-induced osteoporotic fracture rat model was used to investigate the effects of LIPUS. Fractured rats were assigned to LIPUS or control group and healing was assessed by gene expression quantification, radiographic callus morphometry and histomorphometry. In the LIPUS group, Col-1 and bone morphogenetic protein-2 were up-regulated at earlier time points of week 2 to week 4 post-fracture; vascular endothelial growth factor was found to be up-regulated at week 4 to week 8; osteoprotegerin was up-regulated at week 2 post-fracture, followed by the surge of RANKL expression. Callus width and area measurements showed higher callus formation at weeks 2-4 in the LIPUS group and more rapid drop at weeks 6-8. Histomorphometry showed enhanced endochondral ossification in the callus at weeks 2-4, and lower at week 8. We conclude that LIPUS can accelerate osteoporotic fracture healing by enhancing callus formation, angiogenesis and callus remodeling.

[1]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[2]  Engin Ozcivici,et al.  Mechanical signals as anabolic agents in bone , 2010, Nature Reviews Rheumatology.

[3]  L. Hofbauer,et al.  The OPG/RANKL/RANK system in metabolic bone diseases. , 2004, Journal of musculoskeletal & neuronal interactions.

[4]  R. Huiskes,et al.  Additional Weight Bearing during Exercise and Estrogen in the Rat: The Effect on Bone Mass, Turnover, and Structure , 2006, Calcified Tissue International.

[5]  E Y Chao,et al.  Enhancement of fracture healing by mechanical and surgical intervention. , 1998, Clinical orthopaedics and related research.

[6]  Cato T Laurencin,et al.  Fracture repair with ultrasound: clinical and cell-based evaluation. , 2008, The Journal of bone and joint surgery. American volume.

[7]  C. Colnot,et al.  Immunolocalization of BMPs, BMP antagonists, receptors, and effectors during fracture repair. , 2010, Bone.

[8]  Dohyung Lim,et al.  Low‐intensity ultrasound stimulation prevents osteoporotic bone loss in young adult ovariectomized mice , 2011, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[9]  A. S. Stephens,et al.  Temporal pattern of gene expression and histology of stress fracture healing. , 2010, Bone.

[10]  T. Einhorn,et al.  Production of a standard closed fracture in laboratory animal bone , 1984, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[11]  L. Qin,et al.  Dose‐dependent effect of low‐intensity pulsed ultrasound on callus formation during rapid distraction osteogenesis , 2006, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[12]  S. Bloomfield Cellular and molecular mechanisms for the bone response to mechanical loading. , 2001, International journal of sport nutrition and exercise metabolism.

[13]  L. R. Duarte The stimulation of bone growth by ultrasound , 2004, Archives of orthopaedic and traumatic surgery.

[14]  W. Kohrt Aging and the osteogenic response to mechanical loading. , 2001, International journal of sport nutrition and exercise metabolism.

[15]  Pekka Kannus,et al.  Correction: Pathogenesis of Age-Related Osteoporosis: Impaired Mechano-Responsiveness of Bone Is Not the Culprit , 2008, PLoS ONE.

[16]  M. Goumans,et al.  BMP signaling components are expressed in human fracture callus. , 2003, Bone.

[17]  S. Cummings,et al.  Epidemiology and outcomes of osteoporotic fractures , 2002, The Lancet.

[18]  R Huiskes,et al.  Osteocyte density changes in aging and osteoporosis. , 1996, Bone.

[19]  A. Maddi,et al.  Long wave ultrasound may enhance bone regeneration by altering OPG/RANKL ratio in human osteoblast-like cells. , 2006, Bone.

[20]  Neill M Pounder,et al.  Low intensity pulsed ultrasound for fracture healing: a review of the clinical evidence and the associated biological mechanism of action. , 2008, Ultrasonics.

[21]  L. Qin,et al.  Osteogenic effects of low-intensity pulsed ultrasound, extracorporeal shockwaves and their combination - an in vitro comparative study on human periosteal cells. , 2008, Ultrasound in medicine & biology.

[22]  Kwok-Sui Leung,et al.  Complex tibial fracture outcomes following treatment with low-intensity pulsed ultrasound. , 2004, Ultrasound in medicine & biology.

[23]  D. Woo,et al.  Evaluation of the Potential Clinical Application of Low-Intensity Ultrasound Stimulation for Preventing Osteoporotic Bone Fracture , 2010, Annals of Biomedical Engineering.

[24]  C. Rubin,et al.  Low-magnitude mechanical signals that stimulate bone formation in the ovariectomized rat are dependent on the applied frequency but not on the strain magnitude. , 2007, Journal of biomechanics.

[25]  S Meghji,et al.  Effect of ultrasound on the production of IL-8, basic FGF and VEGF. , 1999, Cytokine.

[26]  L. Qin,et al.  Low-magnitude high-frequency vibration treatment augments fracture healing in ovariectomy-induced osteoporotic bone. , 2010, Bone.

[27]  J. A. Baart,et al.  Donor Age and Mechanosensitivity of Human Bone Cells , 2002, Osteoporosis International.

[28]  S. Vukicevic,et al.  Biological mechanisms of bone and cartilage remodelling—genomic perspective , 2007, International Orthopaedics.

[29]  K. Ikeda Osteocytes in the pathogenesis of osteoporosis , 2008, Geriatrics & gerontology international.

[30]  T A Einhorn,et al.  The cell and molecular biology of fracture healing. , 1998, Clinical orthopaedics and related research.

[31]  G. Marotti,et al.  Ovariectomy Sensitizes Rat Cortical Bone to Whole-Body Vibration , 2008, Calcified Tissue International.

[32]  C. Hettrich,et al.  Vascular Endothelial Growth Factor: An Essential Component of Angiogenesis and Fracture Healing , 2010, HSS Journal.

[33]  A. Tosteson,et al.  Incidence and Economic Burden of Osteoporosis‐Related Fractures in the United States, 2005–2025 , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[34]  L. Qin,et al.  Low intensity pulsed ultrasound accelerated bone remodeling during consolidation stage of distraction osteogenesis , 2006, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.