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The Journal of Bone & Joint Surgery British Volume
Vol. 34-B, Issue 4 | Pages 646 - 698
1 Nov 1952
Duraiswami PK

1 . The magnitude of the problem of congenital anomalies becomes evident when one takes into consideration the fact that they cause the death of approximately one quarter of the human race either before or shortly after birth, and handicap an appreciable proportion of the survivors throughout their lives. Further, a significant percentage of infants judged to be normal at birth are found in later life to suffer from "disguised" anomalies of the skeleton and soft tissues. Though the study of genetic factors leading to congenital defects has attracted a great deal of attention during the last few decades, the importance of environmental causes of human malformations has received relatively less emphasis. The association of congenital anomalies such as cataract and cardiac septal defects with maternal intercurrent infection of rubella during the early months of pregnancy demonstrates clearly that changes in the germplasm cannot always be invoked as the cause of developmental abnormalities. Congenital malformations that are sometimes genetically determined, such as microphthalmos, cleft palate, and certain skeletal abnormalities, can be caused in the offspring not only by maternal nutritional deficiencies and x-radiation but also, at least in some animals, such as chickens, rats and rabbits, by the introduction of certain substances like insulin into the environment of the embryo during its development. 2. Since very little is known of the detailed histology of the early human embryo, the histological examination of cases of perverted growth is mainly limited to aborted foetuses which, unfortunately, tend to present varying degrees of post-mortem degeneration before accurate histological methods can be applied. It is exactly in this field that animal experiments can offer valuable help. According to Mall and other embryologists the pathological changes that take place in human foetuses and those obtained experimentally in animals are not merely "analogous or similar but identical.". 3. An attempt has been made to review, in some detail, the more important work which has been carried out on experimental teratogenesis, on the epidemiological implications of developmental arrests in humans, and on foetal abnormalities associated with maternal metabolic and hormonal disorders during pregnancy. 4. The technique employed for injection of insulin into the egg yolk has been described. Methods used for the estimation of blood sugar in chick embryos at various stages after injection of insulin and special histochemical techniques for localising polysaccharides in cartilage have been outlined. 5. A few salient experimental results have been tabulated, and some of the insulin-induced abnormalities have been illustrated. 6. The possible mechanism of action of insulin in the causation of the various developmental anomalies has been discussed. Broadly speaking, insulin seems to affect primarily the part or tissue which is in the most active stage of growth or differentiation at the time of the injection. Within the range of 0·05 to 6 units of insulin employed, the incidence, severity and distribution of the deformities appear to increase with the dose of the hormone. It has been observed that the hypoglycaemia caused by insulin injection is not counteracted till about the twelfth day of incubation, presumably because of excessive accumulation of glycogen in the yolk-sac membrane immediately after the injection, and because of lack of glycogen storage in the embryonic liver and the absence of active secretion in the endocrine glands concerned with the carbohydrate metabolism of the embryo. It has been suggested that this unchecked hypoglycaemia may deprive the mesenchyme, pre-cartilage and cartilage of glycogen and mucopolysaccharides (chondroiten-sulphuric acid complexes), depending on the time of injection and the dose of insulin, and thus not only give rise to a variety of single and multiple deformities in the cartilaginous skeleton but also interfere with the normal endochondral ossification, resulting in a generalised developmental disturbance of bone resembling osteogenesis imperfecta in the human. 7. Insulin-induced abnormalities can be prevented to a remarkable extent by injecting nicotinamide and riboflavin into eggs along with insulin. 8. The question of the practical application of the knowledge gained from experimental observations on insulin-induced developmental abnormalities in explaining the possible causation of congenital anomalies in humans by genetic and environmental teratogenic factors, has been discussed. It is suggested that the orderly progression from the mesenchymatous condensation to cartilage, and then through calcified cartilage to bone, may be disturbed by these teratogenic factors at critical phases during the development of the embryo, and a variety of single and multiple skeletal deformities may thus be induced. 9. A plea is made for routine pathological and radiological examination of aborted foetuses and stillborn infants more or less on the lines followed for experimentally induced deformities with a view to applying the knowledge gained from animal experiments to a better understanding of the etiology and pathology of human congenital anomalies. 10. As regards the possible prevention of these deformities, it is not always easy to offer sound eugenic advice in the cases of congenital malformations determined partly or completely by genetic factors, for two important reasons. First, it is often difficult to distinguish between genetically determined congenital anomalies and their phenocopies. Secondly, genetically determined developmental defects sometimes show surprisingly variable expressivity and penetrance. For the conditions in which both genetic and environmental factors are involved, the most profitable immediate line of attack would be on the environmental factors. A relatively simpler problem is presented by the malformations which are, for all practical purposes, entirely caused by environmental factors. Measures to prevent congenital anomalies caused by prenatal rubella, such as exposure of girls to the disease during childhood and protection of pregnant women during the early stages of pregnancy by immune serum, are under active consideration. 11 . Further energetic investigation of the causes of permaturity, stillbirths, monstrosities and congenital malformations is urgently needed, before embarking on a successful programme for prevention. "The day of successful prophylaxis is not yet, but it is much nearer than seemed possible a few years ago."


The Bone & Joint Journal
Vol. 106-B, Issue 10 | Pages 1074 - 1083
1 Oct 2024
Sørensen RR Timm S Rasmussen LE Brasen CL Varnum C

Aims

The influence of metabolic syndrome (MetS) on the outcome after hip and knee arthroplasty is debated. We aimed to investigate the change in patient-reported outcome measure (PROM) scores after hip and knee arthroplasty, comparing patients with and without MetS.

Methods

From 1 May 2017 to 30 November 2019, a prospective cohort of 2,586 patients undergoing elective unilateral hip and knee arthroplasty was established in Denmark. Data from national registries and a local database were used to determine the presence of MetS. Patients’ scores on Oxford Hip Score (OHS) or Oxford Knee Score (OKS), EuroQol five-dimension five-level questionnaire (EQ-5D-5L), University of California, Los Angeles (UCLA) Activity Scale, and Forgotten Joint Score (FJS) at baseline, three, 12, and 24 months after surgery were collected. Primary outcome was the difference between groups from baseline to 12 months in OHS and OKS. Secondary outcomes were scores of OHS and OKS at three and 24 months and EQ-5D-5L, UCLA Activity Scale, and FJS at three, 12, and 24 months after surgery. Generalized linear mixed model was applied, adjusting for age, sex, Charlson Comorbidity Index, and smoking to present marginal mean and associated 95% CIs.


The Bone & Joint Journal
Vol. 104-B, Issue 12 | Pages 1323 - 1328
1 Dec 2022
Cochrane NH Kim B Seyler TM Bolognesi MP Wellman SS Ryan SP

Aims

In the last decade, perioperative advancements have expanded the use of outpatient primary total knee arthroplasty (TKA). Despite this, there remains limited data on expedited discharge after revision TKA. This study compared 30-day readmissions and reoperations in patients undergoing revision TKA with a hospital stay greater or less than 24 hours. The authors hypothesized that expedited discharge in select patients would not be associated with increased 30-day readmissions and reoperations.

Methods

Aseptic revision TKAs in the National Surgical Quality Improvement Program database were reviewed from 2013 to 2020. TKAs were stratified by length of hospital stay (greater or less than 24 hours). Patient demographic details, medical comorbidities, American Society of Anesthesiologists (ASA) grade, operating time, components revised, 30-day readmissions, and reoperations were compared. Multivariate analysis evaluated predictors of discharge prior to 24 hours, 30-day readmission, and reoperation.


The Bone & Joint Journal
Vol. 105-B, Issue 4 | Pages 439 - 448
15 Mar 2023
Hong H Pan X Song J Fang N Yang R Xiang L Wang X Huang C

Aims

The prevalence of scoliosis is not known in patients with idiopathic short stature, and the impact of treatment with recombinant human growth hormone on those with scoliosis remains controversial. We investigated the prevalence of scoliosis radiologically in children with idiopathic short stature, and the impact of treatment with growth hormone in a cross-sectional and retrospective cohort study.

Methods

A total of 2,053 children with idiopathic short stature and 4,106 age- and sex-matched (1:2) children without short stature with available whole-spine radiographs were enrolled in the cross-sectional study. Among them, 1,056 with idiopathic short stature and 790 controls who had radiographs more than twice were recruited to assess the development and progression of scoliosis, and the need for bracing and surgery.


The Journal of Bone & Joint Surgery British Volume
Vol. 82-B, Issue 1 | Pages 131 - 137
1 Jan 2000
Menetrey J Kasemkijwattana C Day CS Bosch P Vogt M Fu FH Moreland MS Huard J

Injury to muscles is very common. We have previously observed that basic fibroblast growth factor (b-FGF), insulin growth factor type 1 (IGF-1) and nerve growth factor (NGF) are potent stimulators of the proliferation and fusion of myoblasts in vitro. We therefore injected these growth factors into mice with lacerations of the gastrocnemius muscle. The muscle regeneration was evaluated at one week by histological staining and quantitative histology. Muscle healing was assessed histologically and the contractile properties were measured one month after injury. Our findings showed that b-FGF, IGF and to a less extent NGF enhanced muscle regeneration in vivo compared with control muscle. At one month, muscles treated with IGF-1 and b-FGF showed improved healing and significantly increased fast-twitch and tetanus strengths. Our results suggest that b-FGF and IGF-1 stimulated muscle healing and may have a considerable effect on the treatment of muscle injuries


The Bone & Joint Journal
Vol. 103-B, Issue 9 | Pages 1497 - 1504
1 Sep 2021
Rotman D Ariel G Rojas Lievano J Schermann H Trabelsi N Salai M Yosibash Z Sternheim A

Aims

Type 2 diabetes mellitus (T2DM) impairs bone strength and is a significant risk factor for hip fracture, yet currently there is no reliable tool to assess this risk. Most risk stratification methods rely on bone mineral density, which is not impaired by diabetes, rendering current tests ineffective. CT-based finite element analysis (CTFEA) calculates the mechanical response of bone to load and uses the yield strain, which is reduced in T2DM patients, to measure bone strength. The purpose of this feasibility study was to examine whether CTFEA could be used to assess the hip fracture risk for T2DM patients.

Methods

A retrospective cohort study was undertaken using autonomous CTFEA performed on existing abdominal or pelvic CT data comparing two groups of T2DM patients: a study group of 27 patients who had sustained a hip fracture within the year following the CT scan and a control group of 24 patients who did not have a hip fracture within one year. The main outcome of the CTFEA is a novel measure of hip bone strength termed the Hip Strength Score (HSS).


The Bone & Joint Journal
Vol. 104-B, Issue 6 | Pages 696 - 702
1 Jun 2022
Kvarda P Puelacher C Clauss M Kuehl R Gerhard H Mueller C Morgenstern M

Aims

Periprosthetic joint infections (PJIs) and fracture-related infections (FRIs) are associated with a significant risk of adverse events. However, there is a paucity of data on cardiac complications following revision surgery for PJI and FRI and how they impact overall mortality. Therefore, this study aimed to investigate the risk of perioperative myocardial injury (PMI) and mortality in this patient cohort.

Methods

We prospectively included consecutive patients at high cardiovascular risk (defined as age ≥ 45 years with pre-existing coronary, peripheral, or cerebrovascular artery disease, or any patient aged ≥ 65 years, plus a postoperative hospital stay of > 24 hours) undergoing septic or aseptic major orthopaedic surgery between July 2014 and October 2016. All patients received a systematic screening to reliably detect PMI, using serial measurements of high-sensitivity cardiac troponin T. All-cause mortality was assessed at one year. Multivariable logistic regression models were applied to compare incidence of PMI and mortality between patients undergoing septic revision surgery for PJI or FRI, and patients receiving aseptic major bone and joint surgery.


The Bone & Joint Journal
Vol. 103-B, Issue 6 Supple A | Pages 45 - 50
1 Jun 2021
Kerbel YE Johnson MA Barchick SR Cohen JS Stevenson KL Israelite CL Nelson CL

Aims

It has been shown that the preoperative modification of risk factors associated with obesity may reduce complications after total knee arthroplasty (TKA). However, the optimal method of doing so remains unclear. The aim of this study was to investigate whether a preoperative Risk Stratification Tool (RST) devised in our institution could reduce unexpected intensive care unit (ICU) transfers and 90-day emergency department (ED) visits, readmissions, and reoperations after TKA in obese patients.

Methods

We retrospectively reviewed 1,614 consecutive patients undergoing primary unilateral TKA. Their mean age was 65.1 years (17.9 to 87.7) and the mean BMI was 34.2 kg/m2 (SD 7.7). All patients underwent perioperative optimization and monitoring using the RST, which is a validated calculation tool that provides a recommendation for postoperative ICU care or increased nursing support. Patients were divided into three groups: non-obese (BMI < 30 kg/m2, n = 512); obese (BMI 30 kg/m2 to 39.9 kg/m2, n = 748); and morbidly obese (BMI > 40 kg/m2, n = 354). Logistic regression analysis was used to evaluate the outcomes among the groups adjusted for age, sex, smoking, and diabetes.


The Bone & Joint Journal
Vol. 102-B, Issue 3 | Pages 345 - 351
1 Mar 2020
Pitts C Alexander B Washington J Barranco H Patel R McGwin G Shah AB

Aims

Tibiotalocalcaneal (TTC) fusion is used to treat a variety of conditions affecting the ankle and subtalar joint, including osteoarthritis (OA), Charcot arthropathy, avascular necrosis (AVN) of the talus, failed total ankle arthroplasty, and severe deformity. The prevalence of postoperative complications remains high due to the complexity of hindfoot disease seen in these patients. The aim of this study was to analyze the relationship between preoperative conditions and postoperative complications in order to predict the outcome following primary TTC fusion.

Methods

We retrospectively reviewed the medical records of 101 patients who underwent TTC fusion at the same institution between 2011 and 2019. Risk ratios (RRs) associated with age, sex, diabetes, cardiovascular disease, smoking, preoperative ankle deformity, and the use of bone graft during surgery were related to the postoperative complications. We determined from these data which pre- and perioperative factors significantly affected the outcome.


The Bone & Joint Journal
Vol. 100-B, Issue 8 | Pages 1125 - 1132
1 Aug 2018
Shohat N Foltz C Restrepo C Goswami K Tan T Parvizi J

Aims

The aim of this study was to examine the association between postoperative glycaemic variability and adverse outcomes following orthopaedic surgery.

Patients and Methods

This retrospective study analyzed data on 12 978 patients (1361 with two operations) who underwent orthopaedic surgery at a single institution between 2001 and 2017. Patients with a minimum of either two postoperative measurements of blood glucose levels per day, or more than three measurements overall, were included in the study. Glycaemic variability was assessed using a coefficient of variation (CV). The length of stay (LOS), in-hospital complications, and 90-day readmission and mortality rates were examined. Data were analyzed with linear and generalized linear mixed models for linear and binary outcomes, adjusting for various covariates.


The Bone & Joint Journal
Vol. 101-B, Issue 1_Supple_A | Pages 3 - 9
1 Jan 2019
Alamanda VK Springer BD

Aims

Prosthetic joint infection (PJI) remains a serious complication that is associated with high morbidity and costs. The aim of this study was to prepare a systematic review to examine patient-related and perioperative risk factors that can be modified in an attempt to reduce the rate of PJI.

Materials and Methods

A search of PubMed and MEDLINE was conducted for articles published between January 1990 and February 2018 with a combination of search terms to identify studies that dealt with modifiable risk factors for reducing the rate of PJI. An evidence-based review was performed on 12 specific risk factors: glycaemic control, obesity, malnutrition, smoking, vitamin D levels, preoperative Staphylococcus aureus screening, the management of anti-rheumatic medication, perioperative antibiotic prophylaxis, presurgical skin preparation, the operating room environment, irrigant options, and anticoagulation.


The Bone & Joint Journal
Vol. 99-B, Issue 11 | Pages 1526 - 1532
1 Nov 2017
Tarride JE Hopkins RB Blackhouse G Burke N Bhandari M Johal H Guyatt GH Busse JW

Aims

This 501-patient, multi-centre, randomised controlled trial sought to establish the effect of low-intensity, pulsed, ultrasound (LIPUS) on tibial shaft fractures managed with intramedullary nailing. We conducted an economic evaluation as part of this trial.

Patients and Methods

Data for patients’ use of post-operative healthcare resources and time taken to return to work were collected and costed using publicly available sources. Health-related quality of life, assessed using the Health Utilities Index Mark-3 (HUI-3), was used to derive quality-adjusted life years (QALYs). Costs and QALYs were compared between LIPUS and control (a placebo device) from a payer and societal perspective using non-parametric bootstrapping. All costs are reported in 2015 Canadian dollars unless otherwise stated.


The Bone & Joint Journal
Vol. 96-B, Issue 12 | Pages 1674 - 1680
1 Dec 2014
Choi WJ Lee JS Lee M Park JH Lee JW

We compared the clinical and radiographic results of total ankle replacement (TAR) performed in non-diabetic and diabetic patients. We identified 173 patients who underwent unilateral TAR between 2004 and 2011 with a minimum of two years’ follow-up. There were 88 male (50.9%) and 85 female (49.1%) patients with a mean age of 66 years (sd 7.9, 43 to 84). There were 43 diabetic patients, including 25 with controlled diabetes and 18 with uncontrolled diabetes, and 130 non-diabetic patients. The clinical data which were analysed included the Ankle Osteoarthritis Scale (AOS) and the American Orthopaedic Foot and Ankle Society (AOFAS) scores, as well the incidence of peri-operative complications.

The mean AOS and AOFAS scores were significantly better in the non-diabetic group (p = 0.018 and p = 0.038, respectively). In all, nine TARs (21%) in the diabetic group had clinical failure at a mean follow-up of five years (24 to 109), which was significantly higher than the rate of failure of 15 (11.6%) in the non-diabetic group (p = 0.004). The uncontrolled diabetic subgroup had a significantly poorer outcome than the non-diabetic group (p = 0.02), and a higher rate of delayed wound healing.

The incidence of early-onset osteolysis was higher in the diabetic group than in the non-diabetic group (p = 0.02). These results suggest that diabetes mellitus, especially with poor glycaemic control, negatively affects the short- to mid-term outcome after TAR.

Cite this article: Bone Joint J 2014;96-B:1674–80.


The Bone & Joint Journal
Vol. 99-B, Issue 4_Supple_B | Pages 3 - 10
1 Apr 2017
Parvizi J Shohat N Gehrke T

The World Health Organization (WHO) and the Centre for Disease Control and Prevention (CDC) recently published guidelines for the prevention of surgical site infection. The WHO guidelines, if implemented worldwide, could have an immense impact on our practices and those of the CDC have implications for healthcare policy in the United States.

Our aim was to review the strategies for prevention of periprosthetic joint infection in light of these and other recent guidelines.

Cite this article: Bone Joint J 2017;99-B(4 Supple B):3–10.


The Bone & Joint Journal
Vol. 97-B, Issue 11 | Pages 1512 - 1518
1 Nov 2015
Courtney PM Melnic CM Gutsche J Hume EL Lee G

Older patients with multiple medical co-morbidities are increasingly being offered and undergoing total joint arthroplasty (TJA). These patients are more likely to require intensive care support, following surgery. We prospectively evaluated the need for intensive care admission and intervention in a consecutive series of 738 patients undergoing elective hip and knee arthroplasty procedures. The mean age was 60.6 years (18 to 91; 440 women, 298 men. Risk factors, correlating with the need for critical care intervention, according to published guidelines, were analysed to identify high-risk patients who would benefit from post-operative critical care monitoring. A total of 50 patients (6.7%) in our series required critical care level interventions during their hospital stay. Six independent multivariate clinical predictors were identified (p < 0.001) including a history of congestive heart failure (odds ratio (OR) 24.26, 95% confidence interval (CI) 9.51 to 61.91), estimated blood loss >  1000 mL (OR 17.36, 95% CI 5.36 to 56.19), chronic obstructive pulmonary disease (13.90, 95% CI 4.78 to 40.36), intra-operative use of vasopressors (OR 8.10, 95% CI 3.23 to 20.27), revision hip arthroplasty (OR 2.71, 95% CI 1.04 to 7.04) and body mass index > 35 kg/m2 (OR 2.70, 95% CI 123 to 5.94). The model was then validated against an independent, previously published data set of 1594 consecutive patients. The use of this risk stratification model can be helpful in predicting which high-risk patients would benefit from a higher level of monitoring and care after elective TJA and aid hospitals in allocating precious critical care resources.

Cite this article: Bone Joint J 2015;97-B:1512–18.


The Bone & Joint Journal
Vol. 95-B, Issue 5 | Pages 673 - 677
1 May 2013
Menakaya CU Pennington N Muthukumar N Joel J Ramirez Jimenez AJ Shaw CJ Mohsen A

This paper reports the cost of outpatient venous thromboembolism (VTE) prophylaxis following 388 injuries of the lower limb requiring immobilisation in our institution, from a total of 7408 new patients presenting between May and November 2011. Prophylaxis was by either self-administered subcutaneous dalteparin (n = 128) or oral dabigatran (n = 260). The mean duration of prophylaxis per patient was 46 days (6 to 168). The total cost (pay and non-pay) for prophylaxis with dalteparin was £107.54 and with dabigatran was £143.99. However, five patients in the dalteparin group required nurse administration (£23 per home visit), increasing the cost of dalteparin to £1142.54 per patient. The annual cost of VTE prophylaxis in a busy trauma clinic treating 12 700 new patients (2010/11), would be £92 526.33 in the context of an income for trauma of £1.82 million, which represents 5.3% of the outpatient tariff.

Outpatient prophylaxis in a busy trauma clinic is achievable and affordable in the context of the clinical and financial risks involved.

Cite this article: Bone Joint J 2013;95-B:673–7.


The Bone & Joint Journal
Vol. 98-B, Issue 7 | Pages 984 - 989
1 Jul 2016
Zijlmans JL Buis DR Verbaan D Vandertop WP

Aims

Our aim was to perform a systematic review of the literature to assess the incidence of post-operative epidural haematomas and wound infections after one-, or two-level, non-complex, lumbar surgery for degenerative disease in patients with, or without post-operative wound drainage.

Patients and Methods

Studies were identified from PubMed and EMBASE, up to and including 27 August 2015, for papers describing one- or two-level lumbar discectomy and/or laminectomy for degenerative disease in adults which reported any form of subcutaneous or subfascial drainage.


The Journal of Bone & Joint Surgery British Volume
Vol. 87-B, Issue 4 | Pages 489 - 495
1 Apr 2005
Jones KB Maiers-Yelden KA Marsh JL Zimmerman MB Estin M Saltzman CL

Diabetes mellitus is considered an indicator of poor prognosis for acute ankle fractures, but this risk may be specific to an identifiable subpopulation. We retrospectively reviewed 42 patients with both diabetes mellitus and an acute, closed, rotational ankle fracture. Patients were individually matched to controls by age, gender, fracture type, and surgical vs non-surgical treatment. Outcomes were major complications during the first six months of treatment. We contrasted secondarily 21 diabetic patients with and 21 without diabetic comorbidities. Diabetic patients and controls did not differ significantly in total complication rates. More diabetic patients required long-term bracing. Diabetic patients without comorbidities had complication rates equal to their controls. Diabetic patients with comorbidities had complications at a higher rate (ten patients; 47%) than matched controls (three patients; 14%, p = 0.034). A history of Charcot neuroarthropathy led to the highest rates of complication. An increased risk of complications in diabetic patients with closed rotational fractures of the ankle are specific to a subpopulation with identifiable related comorbidities.


The Journal of Bone & Joint Surgery British Volume
Vol. 92-B, Issue 8 | Pages 1112 - 1117
1 Aug 2010
Clement ND Hallett A MacDonald D Howie C McBirnie J

We compared the outcome of arthroscopic repair of the rotator cuff in 32 diabetic patients with the outcome in 32 non-diabetic patients matched for age, gender, size of tear and comorbidities. The Constant-Murley score improved from a mean of 49.2 (24 to 80) pre-operatively to 60.8 (34 to 95) post-operatively (p = 0.0006) in the diabetic patients, and from 46.4 (23 to 90) pre-operatively to 65.2 (25 to 100) post-operatively (p = 0.0003) in the non-diabetic patients at six months. This was significantly greater (p = 0.0002) in non-diabetic patients (18.8) than in diabetics (11.6). There was no significant change in the mean mental component of the Short-Form 12, but the mean physical component increased from 35 to 41 in non-diabetics (p = 0.0001), and from 37 to 39 (p = 0.15) in diabetics. These trends were observed at one year.

Patients with diabetes showed improvement of pain and function following arthroscopic rotator cuff repair in the short term, but less than their non-diabetic counterparts.


The Journal of Bone & Joint Surgery British Volume
Vol. 89-B, Issue 12 | Pages 1553 - 1560
1 Dec 2007
Gaston MS Simpson AHRW

This paper reviews the current literature concerning the main clinical factors which can impair the healing of fractures and makes recommendations on avoiding or minimising these in order to optimise the outcome for patients. The clinical implications are described.