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EDITORIAL

The Effect Of Head Injury On Fracture Healing

Raju Karuppal*
 
*Senior Lecturer, Dept. of Orthopaedics, Medical College, Calicut

Address for Correspondence

Dr. Raju K,
Karuppal House, PO Mukkam-673602
Calicut, Kerala, India.
Phone:+91 9447330002
E-Mail:drrajuortho@rediffmail.com

 

 

J.Orthopaedics 2007;4(1)e7

Introduction:

The rate of fracture healing is accelerated and abundant callus develops in patients who have a head injury and fractures. There are several clinical phenomena that present with an enhancement of bone formation. Clinical presentation of up regulated bone formation, like heterotopic ossification is either acquired, which occur with incidents such as brain injury, spinal cord injury, blunt trauma, burns, infection, neurologic disease and post surgical complications, or inherited, such as fibrodysplasia ossificans progressiva and progressive osseous heteroplasia. There is a well-established relationship between brain injury and heterotopic ossification.  Patients with brain injury are known to have an increased tendency to form ectopic bone and are given corticosteroids, nonsteroidal anti-inflammatory drugs, disphosphonates, and radiotherapy as a preventative measure. There is a reported 10--86% incidence of heterotopic ossification associated with brain injury. Early clinical reports were inconclusive or demonstrated no evidence of accelerated union or increased formation of callus. Histologic analysis of the callus revealed findings characteristic of mature woven bone at the periphery.

There is evidence to suggest that fractures heal more rapidly in patients with a head injury as a result of systemic factors released from the site of this injury. The mechanism underlying this is unclear. Patients sustaining severe head injury and fractures of long bones or large joints often show enhanced osteogenesis, with hypertrophic callus formation and/or heterotopic ossification. Nervous tissue produces a great number of neuropeptides and neurotransmitters, which are known to affect osteoblasts metabolism, possibly through receptors on osteoblastic cell lines. These mediators would also likely play a critical role in the internal homeostatic switch relating to bone formation.

Several studies have addressed the issue of released mediators, in addition to BMP, in brain-injured patients in relation to increased bone growth. Trauma to the CNS may increase the release of, or decrease uptake of, bone formation mediators that can enter the systemic circulation. Alternatively, other chemicals may be released from the brain, which act to stimulate local production of BMP or other mediators. Investigators hypothesized that the BMPs and their receptors are involved in neuronal plasticity that occurs after traumatic brain injury (TBI). Both scenarios would result in altered bone formation.

Review:

Perkins and Skirving1 compared two groups of patients with and without head injury, in whom fractures of the femoral shaft had been fixed by inter medullary nailing. They concluded that the callus was significantly greater in the group with head injury and the mean time to radiological union was reduced.

Spencer2 compared fractures of the long bones at different sites in surviving adults with severe head injury with those in an age and gender matched control group without head injury. They concluded that the greatest healing response was found in the patients with the most head injury and this directly correlated with an accelerated time of union of the fracture.

Renfree KJ et al 3 inferred the release of circulating osteogenic factor from the site of head injury is a possible explanation for the connection between CNS injury and the formation of new bone at a distant location. Studies in vitro showing that both the proliferation of osteoblast and the production of alkaline phosphatase are stimulated by serum from patients with head injury have provided evidence for this hypothesis. Other possible factors affecting the repair of fractures after head injury include altered neuronal activity and drug intervention.

Beeton, C A et al4 concluded that they had measured the circulating level of insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) in serum because of their known involvement in the stimulation of the activity of osteoblasts and the healing of fractures. The serum level of IGF-1 was significantly lower in patients with both head injury and fracture, and fracture only compared with that in healthy volunteers.Their findings showed, however, that the level of IGF-1 and IGFBP-3 varied from week to week in both the patients and healthy control subjects. These results indicate that the levels of circulating IGF-1 and IGFBP-3 are unlikely to be responsible for the altered healing of fractures seen in conjunction with head injury.

Spencer RF5 stated using a simple method of quantifying fracture healing, 53 patients who had limb fractures and also severe head injuries were studied; they were compared with 30 patients who had limb fractures but no head injury. Those with head injuries had a greater healing response and united more rapidly. Radiological and histological analysis revealed that the terms "myositis ossificans" and "heterotopic bone" might be more appropriate than "fracture callus" to describe the healing response in these patients.

Beeton, C A et al 6  inferred that IL-6 may be involved in altered healing of a fracture after head injury.They measured the circulating level of interleukin-6 (IL-6) and its soluble receptor (sIL-6R) and soluble glycoprotein 130 (sgp130) in serum from patients who had sustained a head injury with and without fracture and compared these with levels found in control subjects.Within 12 hours of injury the serum level of IL-6 was significantly higher in patients with head injury and fracture compared with the control group. Levels of IL-6 were also significantly higher in patients with head injury and fracture compared with fracture only. While there was no significant difference in circulating levels of sIL-6R in the initial samples they were increased one week after surgery in patients with head injury and fracture and with head injury only. In addition, reduced levels of sgp130 in patients with head injury with and without fracture indicated a possible reduction of the inhibitory effect of this protein on the activity of IL-6.

Uwe Scherbel et al 7 inferred a possible link between brain injury and bone formation is through the bone morphogenic proteins (BMPs). Their study was to test this phenomenon at the histologic and molecular level by using a well-established head injury model in rats. The lateral fluid percussion model is the most widely used and characterized method of inducing brain injury in rats. Rats were subjected to severe experimental lateral fluid percussion (FP) injury (3.0--3.6 atm) as described by McIntosh et al. [18]. They utilized a reliable tibia fracture model described by Bourque et al. [2] and Otto et al. [23] for rats. One group (n=5) of rats traumatic brain injury (TBI), another group (n=5) of rats was exposed to TBI and an experimental fracture, the third group was only exposed to experimental fracture (n=5) and sham animals (n=5) were subjected to anesthesia without injury. Muscle specimens from around the hip as well as the entire area of the fractured tibia were taken and processed. Rt-PCR showed an up regulation of BMP 2 and 4 (2/4) in muscle around the hip of all brain-injured animals and also in the soft tissue around the tibia. BMP 2/4 was up regulated in the fractured tibia and the surrounding soft tissue in all animals with a fractured tibia. BMP 2/4 was not up regulated in muscle tissue around the hip in these animals (fractured tibia group).

Their study revealed differences at the tissue level in animals with head injury with or without tibia fracture when compared to their controls. There was differential expression of several genes including BMP 2/4 that was activated by head injury, perhaps by a circulating factor or direct nerve-signaling pathway. This might be a possible mechanism by which head injury induces ectopic ossification.

The brain injured animals showed an up regulation of BMP 2/4 in muscle specimen around the hip. Their studies correspondent to the results of TBI may lead to an up regulation of bone growth via BMP or similar chemical mediators, directly or indirectly, released from the brain. In support of this, Groot et al. (1994) recently demonstrated the differentiation of fetal mouse chondrocytes into functional osteoid producing osteoblasts when co-cultured with brain tissue.

Bidner-SM et al 8 studied the possibility that increased circulating growth factors or circulating factors that stimulate local release of growth factors mediate the increased osteogenesis. Samples of serum were obtained from thirty-two subjects: patients who had a head injury alone, those who had a head injury and fractures of the lower extremities, those who had only fractures, and control subjects who had neither a head injury nor a fracture. Severe head injury was defined as that producing coma of at least three days' duration. Growth-factor activity was determined by assessing the effect of serum on the incorporation of thymidine and on cell counts in primary cultures of osteoblastic cells from the calvaria of fetal rats. Samples of serum from the two groups of patients who had a head injury had higher mitogenic activity and produced a greater increase in the number of cells than did the samples from the other two groups. The mean levels of activity were not statistically different between the first two groups or between the patients who had fractures only and the control subjects. Dilution studies showed that increased mitogenic activity in the serum from the patients who had a head injury was dose-dependent. In three patients in whom it was studied, the mitogenic activity peaked approximately thirty-seven days after the head injury was sustained.

Khare GN et al9 proposed a new hypothesis to explain excessive callus formation seen after injury to brain or spinal cord. Nervous tissue is very active metabolically and when damaged or inflamed it extracts, utilizes and inactivates most of the corticosteroids and other anti-inflammatory substances present in the blood. Therefore now very little active corticosteroids are left to exhibit the inhibitory effect on callus formation. This leads to faster fracture healing with excessive callus formation in head or spinal cord injured patients.

C.A. Beeton and N. Rushton10  concluded that there is evidence that fractures heal more rapidly in patients with co-existing head injury and that this may be due a factor or factors released into the blood from the head injury site acting to promote fracture repair. We aim to identify the factor/s involved by comparing the effect of serum from patients with head injury with that of control subjects on the proliferative and osteogenic responses of human osteoblasts and periosteal cells. We will then remove known cytokines using inhibitory antibodies and ultrafiltration to assess their involvement in any differential response observed. If we are unable to identify the factor/s we will carry out size fractionation prior to further purification and characterisation.

Nakase and Yaoita11, 12 both found mRNA of BMP 2/4 up regulated at the fracture site 48 hours post injury after rats and mice had been exposed to an experimental femur fracture.

Conclusion:

The increased rate of fracture healing and abundant callus formation in patients who have a head injury and fractures is well known all over the world. In spite of numerous efforts aimed at clarifying the way in which severe head injury can influence osteogenesis at a distant site, this phenomenon is still not understood. There is a well-established clinical relationship between brain injury and heterotopic ossification. Though various studies stating certain factors as a reasonable cause to the phenomenon of the increased rate of fracture healing and abundant callus formation in patients who have a head injury and fractures. It may be either due to humoral or neural mechanism. There are many studies stating certain factors are not being responsible for this phenomenon. Both accelerated fracture healing and excess formation of callus are associated with increased osteoblastic activity and, almost certainly with proliferation of increased number of osteoblast, whether by stimulation of so called determined osteoblastic progenitor cell or by induction of non-committed mesenchymal cell.

BMP 2/4 is up regulated in all brain-injured animals in the bone and soft tissue (muscle). During development, members of the BMP family of proteins have been shown to induce mesenchymal migration, proliferation and differentiation, leading to cartilage and bone formation. Histopathological studies of pre-osseous lesions in fibrodysplasia ossificans progressiva patients reveal a pattern of lymphocytic infiltration and muscle-cell degeneration followed by the appearance of highly vascular, fibroproliferative tissue and then endochondral ossification with mature lamellar bone and marrow elements. These same patients were found to overexpress BMP-4 in their lymphocytes.

Identification of the stimulator molecule/s may lead to improvements in the treatment of patients with poor rates of fracture healing and bone formation. And it will be possible to synthesize stimulator molecule by genetic engineering technique once the real factor being discovered. It remains unclear if the response of traumatic brain injury is mediated by a circulating factor or direct nerve-signaling pathway. Further studies have to be conducted to characterize the interaction of TBI and bone formation; the results of such studies will aid understanding of the functional roles of growth factors as part of a systemic response to TBI in various morphogenic processes during bone formation. It is clear that the search for a circulating factor responsible for the altered healing of fractures after head injury continues.

References:

  1. Perkins R,Skirving AP.Callus formation and the rate of healing of femoral fractures in patients with head injuries, Journal of Bone & Joint Surgery - British Volume 1987;69-B:521-4.

  2. Spencer RF.the effect of head injury on fracture healing:a quantitative assessment. Journal of Bone & Joint Surgery(B) 1987; 69-B: 493.

  3. Renfree KJ,Banovack,Hornicek FJ,et al. Evaluation of serum osteoblast mitogenic activity in spinal cord and head injury patients with acute heterotopic ossification. Spine 1994; 19; 740-6.

  4. Beeton, C A,  Brooks, R A,  Chatfield, D,  Human, M,  Rushton, N . Circulating levels of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in patients with severe head injury. Journal of Bone and Joint Surgery,  2002 ;84-B:434-9.

  5. Spencer RF. The effect of head injury on fracture healing. A quantitative assessment. Journal of Bone & Joint Surgery British Volume [JC:hk7]1987; 69(4):525-8,

  6. Beeton, C A,  Chatfield, D,  Brooks, R A,  Rushton, N. Circulating levels of interleukin-6 and its soluble receptor in patients with head injury and fracture;Journal of Bone and Joint Surgery,  2004

  7. Uwe Scherbel, M.D,Peter Riess, M.D. Jasvir Khurana, M.D., Christopher Born, M.D., and William DeLong, M.D. Expression of Bone Morphogenic Proteins in Rats with and without Brain Injury and a Tibia Fracture; University of Pennsylvania, 1Department of Orthopaedic Surgery, 2Department of Neurosurgery, 3Department of Pathology

  8. Bidner-SM; Rubins-IM; Desjardins-JV; Zukor-DJ; Goltzman-D; Evidence for a humoral mechanism for enhanced osteogenesis after head injury; J-Bone-Joint-Surg-Am. 1990 Sep; 72(8): 1144-9

  9. Khare GN, Gautam VK, Gupta LN, Gupta AK. A new hypothesis for faster healing of fractures in head injured patients; Department of Orthopaedics Institute of Medical Sciences Banaras Hindu University Varanasi,

  10. C.A. Beeton and N. Rushton; The role of serum components in altered fracture healing following head injury, Orthopaedic Research Unit, Department of Surgery, University of Cambridge.

  11. Nakase T, Nomura S, Yoshikawa H, et al: Transient and Lokalized Expression of Bone Morphogenic Protein4 Messenger RNA during fracture healing. J Bone Mineral Research  1994;9:651--659,.

  12. Yaoita H, Orimo H, Shirai Y, Shimada T. Expression of bone morphogenic proteins less homolog genes following rat femoral fracture. J Bone Miner Metab 2000;18:63--70, .

 

This is a peer reviewed paper 

Please cite as : Raju Karuppal:The Effect Of Head Injury On Fracture Healing

J.Orthopaedics 2007;4(1)e7

URL: http://www.jortho.org/2007/4/1/e7

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