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      The multifactorial aetiology of fracture nonunion and the importance of searching for latent infection

      research-article
      , MBChB, FRCS(Tr&Orth), MD 1 , , , MBChB BSc (Hons) MSc MRCSEd 2 , , MBChB, MSc, MRCS 3 , , MBChB, FRCS(Tr&Orth) 4 , , MA(Cantab), DM (Oxon), FRCS(England & Edinburgh) 4
      Bone & Joint Research
      Delayed union, Infection, Nonunion

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          Abstract

          Objectives

          A successful outcome following treatment of nonunion requires the correct identification of all of the underlying cause(s) and addressing them appropriately. The aim of this study was to assess the distribution and frequency of causative factors in a consecutive cohort of nonunion patients in order to optimise the management strategy for individual patients presenting with nonunion.

          Methods

          Causes of the nonunion were divided into four categories: mechanical; infection; dead bone with a gap; and host. Prospective and retrospective data of 100 consecutive patients who had undergone surgery for long bone fracture nonunion were analysed.

          Results

          A total of 31% of patients had a single attributable cause, 55% had two causes, 14% had three causes and 1% had all four. Of those (31%) with only a single attributable cause, half were due to a mechanical factor and a quarter had dead bone with a gap. Mechanical causation was found in 59% of all patients, dead bone and a gap was present in 47%, host factors in 43% and infection was a causative factor in 38% of patients.

          In all, three of 58 patients (5%) thought to be aseptic and two of nine (22%) suspected of possible infection were found to be infected. A total of 100% of previously treated patients no longer considered to have ongoing infection, had multiple positive microbiology results.

          Conclusion

          Two thirds of patients had multiple contributing factors for their nonunion and 5% had entirely unexpected infection. This study highlights the importance of identifying all of the aetiological factors and routinely testing tissue for infection in treating nonunion. It raises key points regarding the inadequacy of a purely radiographic nonunion classification system and the variety of different definitions for atrophic nonunion in the current mainstream classifications used for nonunion.

          Cite this article: L. Mills, J. Tsang, G. Hopper, G. Keenan, A. H. R. W. Simpson. The multifactorial aetiology of fracture nonunion and the importance of searching for latent infection. Bone Joint Res 2016;5:512–519. DOI: 10.1302/2046-3758.510.BJR-2016-0138.

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          Most cited references29

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          Cyclo-oxygenase 2 function is essential for bone fracture healing.

          Despite the molecular and histological similarities between fetal bone development and fracture healing, inflammation is an early phase of fracture healing that does not occur during development. Cyclo-oxygenase 2 (COX-2) is induced at inflammation sites and produces proinflammatory prostaglandins. To determine if COX-2 functions in fracture healing, rats were treated with COX-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) to stop COX-2-dependent prostaglandin production. Radiographic, histological, and mechanical testing determined that fracture healing failed in rats treated with COX-2-selective NSAIDs (celecoxib and rofecoxib). Normal fracture healing also failed in mice homozygous for a null mutation in the COX-2 gene. This shows that COX-2 activity is necessary for normal fracture healing and confirms that the effects of COX-2-selective NSAIDs on fracture healing is caused by inhibition of COX-2 activity and not from a drug side effect. Histological observations suggest that COX-2 is required for normal endochondral ossification during fracture healing. Because mice lacking Cox2 form normal skeletons, our observations indicate that fetal bone development and fracture healing are different and that COX-2 function is specifically essential for fracture healing.
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            Impact of smoking on fracture healing and risk of complications in limb-threatening open tibia fractures.

            Current data show smoking is associated with a number of complications of the fracture healing process. A concern, however, is the potential confounding effect of covariates associated with smoking. The present study is the first to prospectively examine time to union, as well as major complications of the fracture healing process, while adjusting for potential confounders. Eight Level I trauma centers. Patients with unilateral open tibia fractures were divided into 3 baseline smoking categories: never smoked (n = 81), previous smoker (n = 82), and current smoker (n = 105). Time to fracture healing, diagnosis of infection, and osteomyelitis. Survival and logistic analyses were used to study differences in time to fracture healing and the likelihood of developing complications, respectively. Multivariate models were used to adjust for injury severity, treatment variations, and patient characteristics. After adjusting for covariates, current and previous smokers were 37% (P = 0.01) and 32% (P = 0.04) less likely to achieve union than nonsmokers, respectively. Current smokers were more than twice as likely to develop an infection (P = 0.05) and 3.7 times as likely to develop osteomyelitis (P = 0.01). Previous smokers were 2.8 times as likely to develop osteomyelitis (P = 0.07), but were at no greater risk for other types of infection. Smoking places the patient at risk for increased time to union and complications. Previous smoking history also appears to increase the risk of osteomyelitis and increased time to union. The results highlight the need for orthopaedic surgeons to encourage their patients to enter a smoking cessation programs.
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              Path analysis of factors for delayed healing and nonunion in 416 operatively treated tibial shaft fractures.

              A prospective observational study was done in 41 trauma centers. Four hundred sixteen patients with tibial shaft fractures were treated operatively and followed up for at least 6 months. Fifty-two (13%) cases of delayed healing or nonunion were reported. In such nonrandomized observational studies, multiple interrelationships exist between prognostic factors and patient outcomes. We used path analyses to investigate prognostic factors associated with the occurrence of delayed healing or nonunion. The most important factors were identified using multivariate regression analyses, and interrelationships between factors were illustrated using a path diagram. Fractures with open injuries less than and greater than 5 cm were 3.6 and 5.7 times as likely, respectively, to have delayed healing or nonunion as fractures with no skin injuries. The Müller-AO classification of fractures did not provide additional prognostic information. The risk of healing problems was doubled for fractures of the distal shaft and for fractures showing a postoperative diastasis. Treatment options showed an indirect effect on outcome with the occurrence of diastasis. A model for predicting delayed healing or nonunion is proposed. We encourage the use of path analysis in orthopaedics as a powerful visual technique to interpret data from observational studies. Prognostic study, Level II-1 (retrospective study). See the Guidelines for Authors for a complete description of levels of evidence.
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                Author and article information

                Contributors
                Role: Consultant Orthopaedic Surgeon
                Role: Clinical Research Fellow
                Role: Surgical Trainee in Orthopaedics and Trauma
                Role: Consultant Orthopaedic Surgeon
                Role: George Harrison Law Professor of Orthopaedic Surgery
                Journal
                Bone Joint Res
                Bone & Joint Research
                2046-3758
                October 2016
                9 November 2016
                : 5
                : 10
                : 512-519
                Affiliations
                [1 ]Royal Aberdeen Children’s Hospital, Aberdeen, UK
                [2 ]Department of Orthopaedic Surgery, University of Edinburgh, Chancellor’s building, 49 Little France Crescent, Edinburgh, EH16 4SB
                [3 ]West of Scotland, Glasgow Royal Infirmary, Glasgow, UK
                [4 ]Department of Orthopaedic Surgery, Royal Infirmary of Edinburgh, 51 Little France Crescent, Old Dalkeith Road, Edinburgh, EH16 4SA, UK
                Author notes
                [*]Ms L. Mills; email: leanora.mills@ 123456nhs.net
                Article
                10.1302_2046-3758.510.BJR-2016-0138
                10.1302/2046-3758.510.BJR-2016-0138
                5108351
                27784669
                dffd7b8b-bd7c-4d91-b85c-9c9e4faf7942
                © 2016 Mills et al.

                This is an open-access article distributed under the terms of the Creative Commons Attributions licence (CC-BY-NC), which permits unrestricted use, distribution, and reproduction in any medium, but not for commercial gain, provided the original author and source are credited.

                History
                Categories
                Trauma
                6
                Delayed Union
                Infection
                Nonunion

                delayed union,infection,nonunion
                delayed union, infection, nonunion

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