Accepted 27 August 2004

The physiology of fracture healing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364Inflammatory phase of fracture healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364

Hormonal influence on bone healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368

Injury, Int. J. Care Injured (2005) 36, 363368

www.elsevier.com/locate/injury

KEYWORDSBrain injury;Fracture healing;Physiological

restoration

Abstract In patients who have sustained a traumatic brain injury with an associatedextremity fracture there is often a clinical perception that the rate of new boneformation around the fracture site is increased. Whether this rapidly forming newbone is fracture callus or a variant of heterotopic ossification, a common complicationof traumatic brain injury, is the subject of some debate. This review will provide acomprehensive analysis on this topic and will discuss clinical and physiologicalevidence as well as potential areas for future research in this field.* Corresponding author. Tel.: +44 113 2065298; fax: +44 113 2065156.E-mail address: pgiannoudi@aol.com (P.V. Giannoudis).

00201383/$ see front matter # 2004 Elsevier Ltd. All rights reserved.doi:10.1016/j.injury.2004.08.028Research opporutnities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368Growth factors and cytokines involved in bone healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364

Bone healing after traumatic brain injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365Accelerated fracture healing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365Potential mechanisms for accelerated bone healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365Accelerated fracture healing, or purely heterotopic ossification? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367Reparative phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364Remodelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364Factors influencing bone healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364

# 2004 Elsevier Ltd. All rights reserved.REVIEW

Does traumatic brain injury result in acceleratedfracture healing?

John Morleya, Sarah Marsha, Emmanuil Drakoulakisa,Hans-Christoph Papeb, Peter V. Giannoudisa,*

aDepartment of Trauma and Orthopaedic Surgery, St. Jamess University Hospital, University of Leeds,Beckett Street, Leeds LS9 7TF, UKbDepartment of Trauma, Hannover Medical School, Hannover, Germany

from immature osteoid in a matter of weeks.

Reparative phase

Following a fracture the development of primarycallus begins normally at around 2 weeks afterinjury. If the main fragment ends are not in contactwith each other, then bridging (soft) callus develops(a form of enchondral ossification). Medullary (hard)callus augments the bridging callus, but it formslater in the healing process and is slower to develop.

364 J. Morley et al.and fibroblasts. These cells are required to begin thereparative phase fracture healing.

a Check with bauthors that this is agreeable.The alleged link between TBI injury and acceler-ated fracture healing has not been universallyagreed. Controversy reigns with regard to boththe validity of the findings and the process that isoccurring at the fracture site.14 As yet, the questionof whether head injury genuinely results in accel-erated fracture healing, or a form of heterotopicossification, first asked by authors in the late 1980s,still remains unanswered.11,13,14

This review will provide a comprehensive analysisof the previously published work on this topic andwill discuss clinical and physiological evidence, aswell as potential areas for future research in thisfield.

The physiology of fracture healing

The processes involved in fracture healing can beendivided into three overlapping phases. These are aninitial inflammatory phase, followed by a reparativephase and finally a remodelling phase.3 The bonehealing process can be influenced by a variety ofboth local and systemic factors.4

Inflammatory phase of fracture healing

Bleeding from the fractured bone and from theneighbouring soft tissues results in the formationof a fracture site haematoma. This haematoma actsas a reservoir of haemopoietic cells that can secretea variety of cytokines and growth factors. Osteopro-genitor cells and mesenchymal cells are attracted tothis area and result in the proliferation of osteoblastsIntroduction

Fracture healing can be defined as the physiologicalrestoration of bone tissue, structure and functionafter injury. In orthopaedic folklore an acceleratedrate of fracture healing has long been associatedwith traumatic brain injury (TBI). Evidence for thishas come both from clinical practice and laboratorystudies, where a relationship has been observedbetween TBI, the more rapid development of callusand the stimulation of bone forming cells.1,10 Trau-matic brain injury is also associated with the for-mation of heterotopic ossification. Roberts12 first in1968 described heterotopic ossification of the elbowin patients with cerebral injury and a prolongedperiod of coma. The incidence of heterotopic ossi-fication after TBI has been reported to be up to 22%.5

The formation of heterotopic bone can be a veryrapid process, with mineralised bone developingRemodelling

The process by which the healing fracture site isreshaped involves an interaction between osteo-clasts resorbing bone and osteoblasts laying downnew bone. It begins during the reparative phase andcontinues after the fracture has healed. Remodel-ling allows the bone to regain its functional strengthand shape.

Factors influencing bone healing

There are many factors that can influence bonehealing, including systemic factors such as hor-mones and local factors such as cytokines. A fullsummary of those factors involved is in Table 1.

Hormonal influences on bone healing

There are six principal hormoneswith an influence onfracture healing. Corticosteroids have an inhibitoryeffect on bone healing by reducing callus formation.Calcitonin, thyroxine, parathyroid hormone, growthhormone and androgens all have a stimulatory effecton bone healing, acting by a variety of mechanisms.The various hormonal actions and mechanisms aresummarised in Table 2.

Growth factors and cytokines involved inbone healing

A wide variety of growth factors and cytokines isinvolved in the process of bone healing. Theseinclude bone morphogenic proteins (BMP), trans-

Table 1 Factors influencing bone healing4.

Systemic Local

Age Degree of local traumaHormones Degree of bone lossFunctional Activity Vascular injuryNerve function Type of bone fracturedNutrition Degree of immobilisationDrugs (e.g. NSAID) InfectionSmokinga Local pathological condition

reference was made to the established fracturehealing rates in the general population. Three stu-

finding was replicated by Perkins et al. in a similarcohort of head-injured patients with an associatedfemoral shaft fracture, treated by intramedullarynailing. This study had the useful addition of a non-head-injured control group with similar femoralinjuries.11 A significant difference was demon-strated in the time to fracture healing betweenthe two groups of patients, with the mean timeto union being 89 days in the head-injured group

Does traumatic brain injury result in accelerated fracture healing? 365

Table 2 Hormonal influences on bone healing4.

Hormone Effect Mechanism

Cortisone Decrease Decreased callusformation

Calcitonin Increased UnknownThyroxine/parathyroidhormone

Increased Promotes boneremodelling

Growth hormone Increased Increased callus volumeAndrogens Increased Increased callus volumedies by different authors claim to have shown accel-erated fracture healing after TBI.10,11,14

Newman et al.10 reported an increased rate offracture healing in a small series of 11 patients whoforming growth factor- (TGF-)), insulin-likegrowth factor II, platelet derived growth factorand the cytokines interleukin 1 and 6. These factorsand their actions are summarised in Table 3.

Bone healing after traumatic brain injury

In patients who have sustained a TBI, with an asso-ciated extremity fracture, there is often a clinicalperception that the rate and volume of new boneformation around the fracture site are increased.Whether this rapidly forming new bone is fracturecallus, or a variant of heterotopic ossification, acommon complication after TBI, is the subject ofcontinued debate. A detailed analysis of the pub-lished clinical studies specifically addressing thistopic is summarised in Table 4.

Accelerated fracture healing

The studies published to date on this topic havebeen either retrospective, or analyses of case serieswith relatively small numbers of patients. In somestudies control groups were included and in othershad sustained a TBI and an associated long bonefracture, either of the femur or the tibia. This

Table 3 Important growth factors and cytokines in bone h

Growth factor/Cytokine Effect on bone he

Bone morphogenic proteins Osteoinductive: inTransforming growth factor- Induces osteoblasPlatelet derived growth factor Attracts inflammaInsulin like growth factor-II Stimulates type 1Fibroblast growth factor Stimulates fibroblInterleukin 1- Attracts inflammaInterleukin 6 Attracts inflammaand 110 days in the control group (p < 0.01). Anadditional radiological observation was made ofexcessive and exuberant fracture site callus forma-tion. (Editorone of the problems with such studiesis the definition of time to bony union and itsrelationship to the intervals at which the patientswere reviewed to assess this. A difference in theaverage time to union of only 21 days may bemathematically significant but does it have meaningif the patients are reviewed at 28 day intervals?)

The largest single study showing an increasedrate of fracture healing after TBI, by Spenceret al.14 analysed a variety of long bone fractures,including those of the femur, tibia and humerus. Astatistically significant reduction in the time to bonyunion was shown for fractures of the tibia(p = 0.001) and humerus (p = 0.011), but not forthe femur (p = 0.93), when compared to the controlgroup. As well as assessing the time to union of thefractures, the authors studied the nature of thecallus formed. The observation was made histolo-gically that callus formed at the fracture site inhead-injured patients differed significantly fromnormal callus formation.

Potential mechanisms for accelerated bonehealing

The authors of the studies that showed acceleratedfracture healing all proposed hypotheses to explaintheir findings. One hypothesis was developed fromthe fact that many patients with TBI are hyperven-tilated in an attempt to lower intracranial pressureby reducing pCO2. As a secondary result, their bloodpH may become more alkalotic. In experimentalmodels, an alkaline pH has been shown to promote

ealing4.

aling

duce metaplasia of mesenchymal cells into osteoblaststs production of collagentory cells to fracture sitecollagen productionast proliferationtory cells to fracture sitetory cells to fracture site

366J.

Morle

yetal.

Table 4 Published clinical research studying the relationship between traumatic brain injury and accelerated bone healing.

Study Evidence ofacceleratedbone healing

Bone studied(n = no of #s)

No. ofpatients

Treatment Operativetreatmentmethod

Controlgroupa

Head injury,Mean timeto Union(days)

Control, Meantime toUnion (days)

p value Suggestedmechanism

Newman et al.10 Yes Femur, tibia 11 Non-operative No 38 Publishednormalhealing rates

Notcalculated

? # site pHchanges

Perkins et al.11 Yes Femur 22 Operative IM nail Yes (n = 22) 89 110 p < 0.01 ? Centralmechanism, ?heterotopicossification

Spencer et al.14 Yes Femur (n = 15),tibia (n = 19),humerus(n = 11)

53 Operative(n = 8),non-operative

Internalfixation

Yes, Femur(n = 8),tibia (n = 9),humerus(n = 10)

Femur 87,tibia 91,humerus 47

107, 104, 51 p = 0.93,p = 0.001,p = 0.011

? Systemic andlocal factors, ?heterotopicossification

Garland et al.8 No Tibia (n = 47) 41 Operative andnon-operative

IM nail& ORIF

No 157 Publishednormalhealing rates

Notcalculated

? Heterotopicossification

Garland et al.7 No Femur (n = 68) 65 Operative (n = 25),non-operative(n = 43)

IM nail& ORIF

No 112 Publishednormalhealing rates

Notcalculated

? Heterotopicossification

Garland et al.6 No Radius andulna (n = 50)

47 Operative (n = 18),non-operative (n = 32)

ORIF No 81 Publishednormalhealing rates

Notcalculated

? Heterotopicossification

a Control group refers to a matched population with similar injuries receiving similar treatment to head injured group.

Does traumatic brain injury result in accelerated fracture healing? 367calcium precipitation.2 Newman et al. found themean arterial pH of patients studied to be 7.49(normal range 7.357.45), which is mildly alkalotic.They hypothesised that this mildly alkaline systemicenvironment may predispose to calcium depositionand, as a result, a more rapid formation of callus andaccelerated fracture healing.10 To date, there hasbeen no further published work to test this hypoth-esis.

In the other studies showing accelerated fracturehealing, no specific hypothesis was proposed for thefindings seen, although it was speculated that therecould be a central hormonal, or a combination oflocal and systemic factors, involved.11,14 Some evi-dence for a potential humoral mechanism forenhanced bone formation after head injury has beenpublished. Research, using a rat osteoblast cellculture model, has studied the effects of the serumfrom head injured patients on rates of cellularproliferation.1 A statistically significant increase(p < 0.03) in cellular proliferation was seen in thecells treated with the test serum when compared toserum from an healthy control group. This led theauthors to hypothesise that a circulating growthfactor was present after head injury that promotedosteogenic activity, and that it could be autocrine,or paracrine, in its release.

Further work to identify possible circulating andlocal factors involved in this process has beenundertaken. Basic fibroblast growth factor is knownto stimulate fibroblast activity and is involved inthe normal fracture healing process.4 The levels ofbasic fibroblast growth factor have been shown toundergo a three-fold rise after a fracture, and inhead injured patients with an associated fracturethis level has been shown to rise by up to seventimes normal.16 The authors of this study hypothe-sised that the increased levels of basic fibroblastgrowth factor could be involved in the acceleratedfracture healing process. This hypothesis wastested in an experiment using a fibroblast cell line.Serum from patients with head injury and asso-ciated fractures and also serum from patients withlimb fractures without head injury, were added tothe cell line and the effect on cellular activityobserved.15 No causative relationship was estab-lished from the results, but the authors did postu-late that systemic changes, as yet unknown, inhead injured patients could cause enhanced osteo-genesis.

Another suggested potential mechanism was thatthe exuberant callus formed at the fracture was aform of heterotopic ossification, known to occurwith regularity after TBI.5,12 Further evidence forheterotopic ossifications being a contributory fac-

tor came from the histological analysis of fracturesite callus in head injured patients, which moreclosely resembled heterotopic bone than normalfracture callus.14 The possible mechanisms for theobserved accelerated bone healing remain to bestudied fully and are poorly understood with manyof the suggested mechanisms being no more thanspeculation.

Accelerated fracture healing, or purelyheterotopic ossification?

Although some authors have shown an increasedrate of new bone formation in patients with TBI,earlier authors have published quite differentresults. In three studies published by Garlandet al., of patients with TBI and diaphyseal tibial,femoral or forearm fractures, no evidence of aincreased rate of bone healing was shown.68 Infact, there was almost evidence to the contrary,namely of delayed fracture union. The mean timeto union for fractures of the femur was 122 days,and 157 days for the tibia. There was no matchedcontrol group for any of these studies, with theauthors using previously published union rates forcomparison. Despite this, the authors were unequi-vocal in their conclusion that TBI did not result inan increased rate of fracture healing, a conclusionthat they have since reiterated in a more recentreview article on the topic of extremity fracturesin head injured patients.9 On the basis of thisevidence, Garland et al. proposed the hypothesisthat the new bone seen at fracture sites in suchpatients is a form of heterotopic ossification. Thissuggestion corresponds with the observation madein all three of these studies of a high rate ofheterotopic ossification, occurring in up to 52% ofpatients.7

Despite the conflicting evidence regarding theexact nature of the callus formed at fracture sitesafter TBI, there is still a consensus of enhancedosteogenesis. Whether it takes the form of accel-erated fracture healing, or heterotopic ossification,TBI seems to promote new bone formation.

Research opportunities

From a research perspective, in the field of TBI andosteogenesis, some preliminary work has been donesome years ago, but little has been undertakensince. The first question that needs to be addressedfully isdoes TBI result in accelerated fracturehealing? A prospective clinical study with significantnumbers of patients and a matched control group isrequired to answer this simple question.

After this has been answered, then scientific

studies using the myriad techniques available to

todays researchers would be invaluable to deline-ate further the mechanisms involved.

The potential clinical and therapeutic benefitsthat could be derived from an enhanced understand-ing of osteogenesis, and how it could be acceler-ated, could prove invaluable in the future for the

the risks of complications, such as mal-union and9

timely surgical management is of paramount impor-tance. An awareness that fractures may heal morerapidly should be ever present in the surgeonsmind, so that windows of opportunity for definitivestabilisation are not lost.

368 J. Morley et al.troublesome heterotopic ossification. The currentconcept for surgeons involved in the care of extre-mity fractures in head-injured patients is be thatmanagement of head-injured patients and also inthe treatment of common orthopaedic problemssuch as fracture non-union.

Conclusion

Does traumatic brain injury result in acceleratedfracture union? This is a question not yet answered,as there is a relative lack of sound information onthe topic. There exists a consensus from all of thepublished studies that TBI results in increased osteo-genesis. The exact form of the product of thisosteogenic tendency is the subject of much debate,but it would seem that the majority of authorspropose that the new bone seen around fracturesites in patients with TBI could be a form of hetero-topic ossification. Whether this heterotopic ossifica-tion goes on to form fracture callus and lead to bonyunion is a further debate and the rate at which thisoccurs causes most contention.

Of the published evidence available, only twoclinical studies involve matched control groups.Interestingly they both show statistically significantincreases in the rates of fracture union in head-injured patients. None of the other studies used anyvalid statistical analyses, a deficiency to be levelledagainst them when analysing them critically, as wellas their lack of control groups. One other difficultywith all these studies is the relatively small numbersof patients involved, too small for conclusive anddefinitive answers to be derived.

From a clinical perspective there is agreementfrom the authors on the appropriateness of reduc-tion and surgical stabilisation of long bone fracturesin head-injured patients. Treatment strategies thatallow for easy nursing and early mobilisation ofjoints are to be encouraged, in order to reduceReferences

1. Bidner SM, Rubins IM, Desjardins JV, Zukor DJ, Goltzman D.Evidence for a humoral mechanism for enhanced osteogen-esis after head injury. J Bone Joint Surg Am 1990;72:11449.

2. Boulet M, Marier JR. Precipitation of calcium phosphatesfrom solution at near physiological concentration. Arch Bio-chem 1961;93:157.

3. Brighton CT, Hunt RM. Early histological and ultrastructuralchanges in medullary fracture callus. J Bone Joint Surg Am1991;73:83247.

4. Brinker MR, Miller MD. Basic sciences: bone injury and repair.In: Miller M, editor. Review of Orthopaedics. 3rd ed. SaundersWB; 2000. p. 1922.

5. Citta-Pietrolungo TJ, Alexander MA, Steg NL. Early detectionof heterotopic ossification in young patients with traumaticbrain injury. Arch Phys Med Rehabil 1992;73:25862.

6. Garland DE, Dowling V. Forearm fractures in the head-injuredadult. Clin Orthop 1983;176:1906.

7. Garland DE, Rothi B, Waters RL. Femoral fractures in head-injuries adults. Clin Orthop 1982;21925.

8. Garland DE, Toder L. Fractures of the tibial diaphysis in adultswith head injuries. Clin Orthop 1980;198202.

9. Kushwaha VP, Garland DG. Extremity fractures in the patientwith a traumatic brain injury. J Am Acad Orthop Surg1998;6:298307.

10. Newman RJ, Stone MH, Mukherjee SK. Accelerated fractureunion in association with severe head injury. Injury1987;18:2416.

11. Perkins R, Skirving AP. Callus formation and the rate ofhealing of femoral fractures in patients with head injuries.J Bone Joint Surg Br 1987;69:5214.

12. Roberts P. Heterotopic ossification complicating paralysis ofintracranial origin. J Bone Joint Surg Br 1968;50-B:707.

13. Smith R. Head injury, fracture healing and callus. J Bone JointSurg Br 1987;69:51820.

14. Spencer RF. The effect of head injury on fracture healing. Aquantitative assessment. J Bone Joint Surg Br 1987;69:5258.

15. Wildburger R, Zarkovic N, Egger G, et al. Comparison of thevalues of basic fibroblast growth factor determined by animmunoassay in the sera of patients with traumatic braininjury and enhanced osteogenesis and the effects of the samesera on the fibroblast growth in vitro. Eur J Clin Chem ClinBiochem 1995;33:6938.

16. Wildburger R, Zarkovic N, Egger G, PetekW, Zarkovic K, HoferHP. Basic fibroblast growth factor (BFGF) immunoreactivity asa possible link between head injury and impaired bonefracture healing. Bone Miner 1994;27:18392.

Does traumatic brain injury result in accelerated fracture healing?IntroductionThe physiology of fracture healingInflammatory phase of fracture healingReparative phaseRemodellingFactors influencing bone healingHormonal influences on bone healingGrowth factors and cytokines involved in bone healing

Bone healing after traumatic brain injuryAccelerated fracture healingPotential mechanisms for accelerated bone healingAccelerated fracture healing, or purely heterotopic ossification?Research opportunities

ConclusionReferences