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Osteogenic Effects of Traumatic Brain Injury on Experimental Fracture-Healing
Matthew Boes, MD1; Michael Kain, MD1; Sanjeev Kakar, MD1; Fred Nicholls, MA2; Dennis Cullinane, PhD2; Louis Gerstenfeld, PhD2; Thomas A. Einhorn, MD3; Paul TornettaIII, MD1
1 Department of Orthopaedics, Boston Medical Center, Dowling 2 North, 850 Harrison Avenue, Boston, MA 02118. E-mail address for M. Boes: mattboes@hotmail.com. E-mail address for M. Kain: mikain@bmc.org. E-mail address for S. Kakar: sanjeev.kakar@bmc.org. E-mail address for P. Tornetta III: ptornetta@pol.net
2 Orthopaedic Research Laboratory, Boston University School of Medicine, 715 Albany Street, R-205, Boston, MA 02118
3 Department of Orthopaedics, Boston Medical Center, 720 Harrison Avenue, Suite 808, Boston, MA 02118. E-mail address for T. Einhorn: thomas.einhorn@bmc.org
View Disclosures and Other Information
In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from the Orthopaedic Trauma Association and the Orthopaedic Research and Education Foundation. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
Investigation performed at the Department of Orthopaedics, Boston Medical Center, and the Orthopaedic Research Laboratory, Boston University School of Medicine, Boston, Massachusetts

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2006 Apr 01;88(4):738-743. doi: 10.2106/JBJS.D.02648
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Background: Heterotopic bone formation has been observed in patients with traumatic brain injury; however, an association between such an injury and enhanced fracture-healing remains unclear. To test the hypothesis that traumatic brain injury causes a systemic response that enhances fracture-healing, we established a reproducible model of traumatic brain injury in association with a standard closed fracture and measured the osteogenic response with an in vitro cell assay and assessed bone-healing with biomechanical testing.

Methods: A standard closed femoral fracture was produced in forty-three Sprague-Dawley rats. Twenty-three of the rats were subjected to additional closed head trauma that produced diffuse axonal injury similar to that observed in patients with a traumatic brain injury. Twenty-one days after the procedure, all animals were killed and fracture-healing was assessed by measuring callus size and by mechanical testing. Sera from the animals were used in subsequent in vitro experiments to measure mitogenic effects on established cell lines of committed osteoblasts, fibroblasts, and mesenchymal stem cells.

Results: Biomechanical assessment demonstrated that the brain-injury group had increased stiffness (p = 0.02) compared with the fracture-only group. There was no significant difference in torsional strength between the two groups. Cell culture studies showed a significant increase in the proliferative response of mesenchymal stem cells after exposure to sera from the brain-injury group compared with the response after exposure to sera from the fracture-only group (p = 0.0002). This effect was not observed in fibroblasts or committed osteoblasts.

Conclusions: These results support data from previous studies that have suggested an increased osteogenic potential and an enhancement of fracture-healing secondary to traumatic brain injury. Our results further suggest that the mechanism for this enhancement is related to the presence of factors in the serum that have a mitogenic effect on undifferentiated mesenchymal stem cells.

Clinical Relevance: Fracture-healing may be enhanced by an associated traumatic brain injury. Further understanding of this systemic response could lead to important insights about systemic therapeutic strategies for the enhancement of skeletal repair.

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    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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    Michael S. Kain, M.D.
    Posted on June 14, 2006
    Dr. Kain responds to Dr. Garland
    Boston University Medical Center, Boston, MA

    I thank Dr Garland for his interest in our article and would respond to his comment that we “dismissed” the finding of a smaller fracture callus. The results of our study demonstrated that the animals with traumatic brain injury had a smaller callus, a stiffer callus, and mesenchymal stem cells proliferated in their serum in vitro. As stated in the papeer, we felt this was unexpected because large exuberant callus formation has been associated with TBI and fracture healing from clinical observations. From our past experience with the fracture model in our study, we felt the smaller callus in combination with stiffer callus, represented faster healing as a result of head trauma.

    As to the exact mechanism that controls this and how they are related is a matter of speculation, and it may involve the proliferation of mesenchymal stem cells. Dr. Garland proposes other possibilities as to the relationship that exists and our model may help to elicit some of the relationships in the lab over time, but there is not enough science to prove or disprove these theories at this time. Furthermore, the clinical scenario we are trying to emulate usually has many variables involved and are difficult to account for in clinical trials.

    The aim of our study was to create a model removing the multiple variables typically associated with polytrauma, in an attempt to begin the arduous process of eliciting the biological relationship between traumatic brain injuries and fracture healing. This model could also be used to assess the biological relationship between spinal cord injuries and fracture healing. I appreciate Dr. Garland’s interest in our study and his contributions to this area of research and invite him and others to continue to look for answers to a very complicated and interesting area of research.

    Douglas E. Garland
    Posted on April 26, 2006
    Fracture Healing in Traumatic Brain or Spinal Cord Injury
    Rancho Los Amigos Rehabilitation Center

    To the Editor: I read with interest the article by Boes et al, “Osteogenic Effects of Traumatic Brain Injury on Experimental Fracture-Healing.” The emphasis of the article was on the presence of an osteogenic factor in the serum. Only a single paragraph was devoted to the finding of a “smaller callus size” of the femur in traumatic brain injured (TBI) rats compared to controls at three weeks. The authors stated that this finding was “unexpected” and seemingly dismissed it.

    However, I found this finding most informative since it could confirm or at least be consistent with our clinical observations on standard fracture healing in this population (1,2). Why is a smaller callus an unexpected finding? Multiple explanations could be proposed: immobility; decreased weight bearing; poor nutrition; metabolic and neurologic instability; and negative nitrogen balance, to name a few. Contradictory findings of circulating osteogenic factors with a normal or delayed fracture response are not mutually exclusive. Some TBI and spinal cord injured (SCI) individuals initially cling to life on support systems and fracture healing might well be downstream in the metabolic food chain. One could even speculate that without the additional osteogenic factors, non unions would be more common. We too believe there are factors which could potentiate fracture healing in TBI and (SCI) populations simply on the basis of heterotopic ossification (HO) (3). Recently HO has been detected in patients with chemically induced paralysis for adult respiratory distress syndrome (ARDS) – no neurologic insult or spasticity (4). The sites of HO are similar to SCI and TBI but the knee appears to the most common site (as opposed to the hip). The proposed mechanism for HO formation in this entity is similar to the mechanism proposed for fracture healing by the authors. Complete SCI individuals develop rapid and severe lower extremity osteoporosis. Although circulating osteogenic factors may be present, we believe neurogenic osteoporosis predominates and extremity fractures must be treated aggressively to achieve union. “Benign neglect” is not consistent with union. Non-unions and delayed unions are at least as common, if not more common, than rapid unions and are problematic when they occur both in the acute and chronic state (5). We still have not observed, in our 30 year clinical experience, rapid long bone fracture union in the TBI population. As the authors correctly noted HO plus fracture callus especially in the more central locations may be misinterpreted as exuberant fracture callus (6,7). Ingredients (circulating osteogenic factors) may be assembled at the “bench” but confirmation or “proof in the clinical pudding” may only occur with documentations of rapid union in a survey of long bone fractures, especially the tibia, in either population. REFERENCES 1) Garland DE. Clinical observations on fractures and heterotopic ossification in the spinal cord and traumatic brain injured populations. Clin Orthop Relat Res. 1988;233:86-101. 2) Kushwaha VP, Garland D. Extremity fractures in patients with a traumatic brain injury. J Am Acad Orthop Surg. 1988;6:298-307. 3) Garland DE. A clinical perspective on common forms of acquired heterotopic ossification. Clin Orthop Relat Res. 1991;263:13-29. 4) Hewitt MS, Garland DE, Ayyoub Z. Heterotopic Ossification complicating prolonged intubation: Case report and review of the literature. J Spinal Cord Med. 2002;25:46-49. 5) Garland DE, Adkins RA, Co-Editors. Extremity fractures and their treatment. Top in Spinal Cord Inj Rehab. 2005;11:1-78. 6) Garland DE, Miller G. Fractures and dislocations about the hip in head injured adults. Clin Orthop Relat Res. 1984;186:154-158. 7) Garland DE, O’Halleren RM. Fractures and dislocations about the elbow in the head-injured adult. Clin Orthop Rel Res. 1982;168:38-41.

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