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Bone & Joint Research
Vol. 6, Issue 3 | Pages 144 - 153
1 Mar 2017
Kharwadkar N Mayne B Lawrence JE Khanduja V

Objectives. Bisphosphonates are widely used as first-line treatment for primary and secondary prevention of fragility fractures. Whilst they have proved effective in this role, there is growing concern over their long-term use, with much evidence linking bisphosphonate-related suppression of bone remodelling to an increased risk of atypical subtrochanteric fractures of the femur (AFFs). The objective of this article is to review this evidence, while presenting the current available strategies for the management of AFFs. Methods. We present an evaluation of current literature relating to the pathogenesis and treatment of AFFs in the context of bisphosphonate use. Results. Six broad themes relating to the pathogenesis and management of bisphosphonate-related AFFs are presented. The key themes in fracture pathogenesis are: bone microdamage accumulation; altered bone mineralisation and altered collagen formation. The key themes in fracture management are: medical therapy and surgical therapy. In addition, primary prevention strategies for AFFs are discussed. Conclusions. This article presents current knowledge about the relationship between bisphosphonates and the development of AFFs, and highlights key areas for future research. In particular, studies aimed at identifying at-risk subpopulations and organising surveillance for those on long-term therapy will be crucial in both increasing our understanding of the condition, and improving population outcomes. Cite this article: N. Kharwadkar, B. Mayne, J. E. Lawrence, V. Khanduja. Bisphosphonates and atypical subtrochanteric fractures of the femur. Bone Joint Res 2017;6:144–153. DOI: 10.1302/2046-3758.63.BJR-2016-0125.R1


Orthopaedic Proceedings
Vol. 101-B, Issue SUPP_1 | Pages 14 - 14
1 Jan 2019
Martin J Murphy C Gregory J Aspden R Riemen A Saunders F
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An increased prevalence of osteoarthritis (OA) in post-menopausal women has led to the suggestion that hormonal factors may play a role in the pathogenesis. This study aims to examine if undergoing a hysterectomy, both with retention and removal of ovaries, predisposes women to OA and secondly if the development is influenced by hormone replacement therapy (HRT). Statistical shape modelling (SSM) is a method of image analysis allowing for detection of subtle shape variation described by landmark points. Through the generation of linearly independent modes of variation, each image can be described in terms of numerical scores. 149 radiographs from female participants of the Osteoarthritis Initiative (OAI) were examined to compare hip morphology in those who had undergone hysterectomies compared to controls. No differences were observed in BMI, age, height or weight between groups. ANOVA and Games-Howell post-hoc analysis showed that modes 3 and 5 were statistically significant. Lower mode 3 scores were associated with hysterectomy (p=0.019), with narrowing of the femoral neck and increased acetabular coverage. Lower mode 5 scores were associated with hysterectomy and oophorectomy (p=0.049), displaying reduced coverage of the femoral head, superolateral migration of the femoral head and larger greater trochanter. No associations were observed between HRT use and OA. The subtle morphologic features of hip OA present in only hysterectomised women suggests undergoing a hysterectomy may be a predisposing factor and a clinical consideration. The use of HRT was not observed to influence the development of OA and thus cannot be suggested as a protective measure


The Bone & Joint Journal
Vol. 97-B, Issue 8 | Pages 1144 - 1151
1 Aug 2015
Waki T Lee SY Niikura T Iwakura T Dogaki Y Okumachi E Kuroda R Kurosaka M

MicroRNAs (miRNAs ) are small non-coding RNAs that regulate gene expression. We hypothesised that the functions of certain miRNAs and changes to their patterns of expression may be crucial in the pathogenesis of nonunion. Healing fractures and atrophic nonunions produced by periosteal cauterisation were created in the femora of 94 rats, with 1:1 group allocation. At post-fracture days three, seven, ten, 14, 21 and 28, miRNAs were extracted from the newly generated tissue at the fracture site. Microarray and real-time polymerase chain reaction (PCR) analyses of day 14 samples revealed that five miRNAs, miR-31a-3p, miR-31a-5p, miR-146a-5p, miR-146b-5p and miR-223-3p, were highly upregulated in nonunion. Real-time PCR analysis further revealed that, in nonunion, the expression levels of all five of these miRNAs peaked on day 14 and declined thereafter. . Our results suggest that miR-31a-3p, miR-31a-5p, miR-146a-5p, miR-146b-5p and miR-223-3p may play an important role in the development of nonunion. These findings add to the understanding of the molecular mechanism for nonunion formation and may lead to the development of novel therapeutic strategies for its treatment. Cite this article: Bone Joint J 2015; 97-B:1144–51


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXXVII | Pages 417 - 417
1 Sep 2012
Chaudhury S Xia Z Hulley P Carr A
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INTRODUCTION. There is increasing evidence for a multi-stage model of rotator cuff (RC) tendon tears, wherein healing is affected by tear size. The underlying pathophysiology however is not fully understood. Changes in the production and remodeling of the RC extracellular matrix (ECM) are likely to be important determinants of RC tendinopathy as they affect healing and the ability to bear loads. This study aimed to gain greater insight into size related tear pathogenesis by analyzing gene expression profiles from normal, small and massive RC tears. METHODS. The genetic profiles of 28 human RC tendons were analyzed using microarrays representing the entire genome. 11 massive and 5 small torn RC tendon specimens were obtained from tear edges intraoperatively, and compared to 12 age matched normal controls. Semiquantitative real-time polymerase chain reaction (RT-PCR) and immunohistochemistry were performed for validation. RESULTS. Numerous insightful gene changes were detected. Key changes included upregulation of aggrecan in massive tendon tears compared to normal controls, but not in small tears (p < 0.05 and > 2-fold change). Matrix metallopeptidases (MMP)-3,-10,-12,-13,-15,-21,-25 and a disintegrin and metallopeptidase (ADAMs)-12,-15,-22 were significantly upregulated in tears. Aggrecan was upregulated in massive tendon tears but not in small tears. Amyloid was downregulated in the small and massive tear groups when compared to normals. BMP-5 was upregulated in small tears only when compared to normals. As part of the chemotaxis pathway, IL-3,-10,-13,-15,-18 were upregulated in tears, whereas downregulation of IL-1,-8,-11,-27, was seen. RT-PCR and immunohistochemistry confirmed altered gene expression. CONCLUSION. The gene profiles of normal, small and massive RC tear groups suggested they are biologically distinct groups. In addition to confirming altered gene expression in pathways reported in previous studies, this study has identified a number of novel pathways which are affected between the different tendon tear and normal groups. This study identified that RC tear pathogenesis is contributed to by ECM remodeling genes, chemotaxis genes, aggrecan and amyloid. Further investigation is required to determine whether some of these genes may potentially have a role as biomarkers of failure. Modulating these ECM pathways may be a useful treatment strategy for improving clinical outcomes


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXXVII | Pages 520 - 520
1 Sep 2012
Xu Y Rudkjoebing V Simonsen O Pedersen C Schoenheyder H Nielsen P Thomsen T
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Prosthetic joint infection is one of the most challenging complications of joint alloplasty and the diagnosis remains difficult. The aim of the study was to investigate the bacterial flora in surgical samples from 22 prosthetic patients using a panel of culture-independent molecular methods including broad range 16S rRNA gene PCR, cloning, sequencing, phylogeny, quantitative PCR (qPCR), and fluorescence in situ hybridization (FISH). Concomitant samples were cultured by standard methods. Molecular methods detected presence of bacteria in samples from 12 of 22 patients. Using clone libraries a total of 40 different bacterial species were identified including known pathogens and species not previously described in association with prosthetic joint infections. The predominant species were Propionibacterium acnes and Staphylococcus epidermidis; polymicrobial infections were found in 9 patients. Culture-based methods showed bacterial growth in 8 cases with the predominant species being S. epidermidis. Neither anaerobic bacteria (including P. acnes) nor any of the species not previously described in implant infections were isolated. Additionally, 7 of the 8 culture positive cases were monomicrobial. Overall, the results of culture-based and molecular methods showed concordance in 11 cases (hereof 9 negative by both methods) and discrepancy in 6 cases. In the remaining 5 cases, culture-based methods identified only one species or a group of bacteria (e.g., coagulase negative staphylococci or coryneform rods), while culture-independent molecular methods were able to detect several distinct bacterial species including a species within the group identified by culture. A qPCR assay was developed to assess the abundance of Propionibacterium while S. aureus was quantified by a published S. aureus qPCR assay. These quantifications confirmed the findings from the clone library approach and showed the potential of qPCR for fast detection of bacteria in orthopedic samples. Additionally, both single cells and microcolonies were visualized using FISH and confocal scanning laser microscopy. In conclusion, the molecular methods detected a more diverse bacterial flora in prosthetic joint infections than revealed by standard culture-based methods, and polymicrobial infections were more frequently observed. The pathogenesis of these microorganisms and their role in implant-associated infections needs to be determined


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXXVII | Pages 467 - 467
1 Sep 2012
Ding M Overgaard S
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Introduction. Osteoporosis (OP), osteoarthrosis (OA), and rheumatoid arthritis (RA) are the most common age-related degenerative bone diseases, and major public health problems in terms of enormous amount of economic cost. RA is considered as a major cause of secondary osteoporosis. At late stage, OP often leads to skeletal fractures, and OA and RA result in severe joint disability. Over the last a few decades, much significant research on the properties has been carried out on these diseases, however, a detailed comparison of the microarchitecture of cancellous bones of these diseases is not available. In this study, we investigated three-dimensional (3-D) microarchitectural properties of OP, OA and RA cancellous bone. We hypothesized that there were significant differences in microarchitecture among OP, OA and RA bone tissues that might lead to different bone quality. Materials and Method. Twenty OP, fifty OA, and twelve RA femur heads were harvested from patients undergone total hip replacement surgery. Cubic cancellous bone samples (8∗8∗8 mm3) were prepared and scanned with a high resolution microtomographic system (vivaCT 40, Scanco Medical AG., Brüttisellen, Switzerland). Then micro-CT images were segmented using individual thresholds to obtain accurate 3-D data sets. Detailed microarchitectural properties were evaluated based on novel unbiased, model-free 3-D methods. For statistical analysis, one-way ANOVA was used, and a p<0.05 was considered significant. Results. Significant differences in the microarchitecture of cancellous bone were observed among the OP, OA and RA groups. Compared with the other groups, OP cancellous bone had lowest density, thinner, typical rod-like structure and less connectivity (all p<0.01). Interestingly, there were no significant differences in the microarchitectural properties measured between the OA and RA cancellous bones. Both OA and RA cancellous bones had significant higher bone volume fraction and were thicker, typical plate-like structure compared with the OP group (all p<0.01), even though there was clearly bone erosion observed in RA cancellous bone. Discussion. Quantification of the alterations in bone properties and quality will help to gain more insights into the pathogenesis of degenerative bone diseases and to target and develop novel approaches for the intervention and treatment, and for the design, fixation and durability of total joint prosthesis. Our study demonstrated that there were significant differences in the microarchitecture of the OP, OA and RA femur head cancellous bone. The OA and RA cancellous bone had similar bone density and microarchitecture despite apparent bone erosion in the RA cancellous bone. These results from femur head did not support the traditional notion that RA and OP had similar low bone density. Thus, whether femur head bone tissues from these diseases have similar bone collagen, mineral and mechanical properties, more importantly bone quality, should be clarified in the future


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXXVII | Pages 263 - 263
1 Sep 2012
Monk A Grammatopoulos G Chen M Gibbons M Beard D Gill H Murray D
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Introduction. Osteoarthritis (OA) of the hip is an important cause of pain and morbidity. The mechanisms and pathogenesis of OA'sdevelopment remain unknown. Minor acetabular dysplasia and subtle variations in proximal femoral morphology are increasingly being recognized as factors that potentially compromise the joint biomechanically and lead to OA. Previous studies have shown that risk of hip OA increased as the femoral head to femoral neck ratio (HNR) decreased. Previous work has described the evolutionary change in inferior femoral neck trabecular density and geometry associated with upright stance, but no study has highlighted the evolutionary change in HNR. The aim of this study was to examine evolutionary evidence that the hominin bipedal stance has lead to alterations in HNR that would predispose humans to hip OA. Methods. A collaboration with The Natural History Museums of London, Oxford and the Department of Zoology, University of Oxford provided specimens from the Devonian, Jurassic, Cretaceous, Miocene, Palaeolithic and Pleistocene periods to modern day. Specimens included amphibious reptiles, dinosaurs, shrews, tupaiae, lemurs, African ground apes, Lucy (A. Afarensis), H. Erectus, H. Neaderthalis and humans. Species were grouped according to gait pattern; HAKF (hip and knee flexed), Arboreal (ability to stand with hip and knee joints extended) and hominin/bi-pedal. Imaging of specimens was performed using a 64 slice CT scanner. Three-dimensional skeletal geometries were segmented using MIMICS software. Anatomical measurements from bony landmarks were performed to describe changes in HNR, in the coronal plane of the different specimens over time using custom software. Measurements of HNR from the specimens were compared with HNR measurements made from AP pelvic radiographs of 119 normal subjects and 210 patients with known hip OA listed for hip arthroplasty. Results. Species from the HAKF group that ambulate via sprawling had the smallest HNR (1.10, SD: 0.09) (p<0.001). Species of the arboreal group (tree dwelling) had the biggest HNR (1.63, SD: 0.15) (p=0.006). The earliest bipedal species (1.41, SD: 0.04) had significantly bigger HNR (p=0.04) in comparison to the normal human subjects (1.33, SD: 0.08). Lower HNR was observed in the OA group (1.3, SD: 0.09). Discussion. The adoption of an upright stance during evolution has created an associated change in the femoral neck bone stock to adapt to the altered loading environment. These data would suggest that the HNR peaked in the Miocene period (10–15 million years ago). The trade-off between mobility and the bony density required to support gait has lead to a decreasing HNR throughout hominid evolution. Evolutionary theory would suggest that modern environmental pressures might pre-dispose future hominid evolution to an increased risk of hip OA


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXXVII | Pages 579 - 579
1 Sep 2012
Grammatopoulos G Pandit H Backer K Gundle R Mclardy-Smith P Desmet K Murray D Gill H
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INTRODUCTION. Femoral neck narrowing (NN) following Metal-on-Metal Hip Resurfacing Arthroplasty (MoMHRA) is a well-recognised clinical phenomenon. The incidence of resurfaced hips with NN > 10% is reported to be up to 27%. Its pathogenesis is thought to be multi-factorial secondary to stress shielding, impingement, osteolysis secondary to wear/ion particles and as a result of reduced vascularity and pressure effect on cancellous bone secondary to the presence of a soft-tissue mass around the resurfaced hip. Recognised risk factors for its development include: female gender and the presence of a pseudotumour. Serum Chromium (Cr) and Cobalt (Co) are recognised surrogate markers of in-vivo wear of MoMHRA. The aims of this study were to establish whether NN is associated with increased wear. METHODS. A cohort of 214 patients with unilateral MoMHRA (139M: 75F) was included in this study. Primary osteoarthritis was the diagnosis leading to surgery for the majority of patients (208). The average age at surgery was 54.1 years old (13–73). Six different implants were used; BHR (116), Conserve plus (92), Recap (2), ASR (2), Adept (1) and Cormet (1). The average femoral component size was 49.2mm (range: 38–59). The average follow up was 4.3 years (range: 2–10). Patients were subdivided into 3 groups as per implant size. Small size component group had implants <45mm, average size group had components 45–51mm and large component size group had components >51mm. All patients had Prosthesis-Junction-Ratio (PJR) measured from postoperative (PJRpost) and at latest follow up (PJRfollow) radiographs. Measurements were made using the method described by Lilikakis1. Metal ion levels (Cr/Co) were measured at last follow-up for all patients. Cr level >5.1g/ml and Co levels >4.4 g/ml were considered high2 and patients with such levels formed the high ion group. RESULTS. For the whole cohort, mean NN was 3.2% (range: 0–32%, SD:4.3). Females (4.7%, range: 0–32%, SD: 5.8) had significantly greater NN than males (2.4%, range: 0–23%, SD: 2.9) (p=0.001). Patients in the large component group had less NN (2.1%, SD: 2.3) in comparison to the average (3.2%, SD: 3.7%) (p=0.046) and the small (5.9%, SD: 7.9) (p=0.007) component size groups. There was no difference in NN between small and average sized components (p=0.1). Patients in the high ion group (25 patients) had significantly greater NN than patients with low ions (10.1%, range: 1%–32%, SD: 8.3 Vs 2.3%, range: 0–11, SD 2.3) (p<0.0001). NN >10% was seen in 16 hips (7.5%). The odds ratio of having high ions if NN >10% was 125 (p<0.001). DISCUSSION. The findings of this study showed that greater NN occurs in females and patients with small components and in patients with high ions. Furthermore, hips with NN >10% should be investigated further as they are more likely to have increased wear


The Bone & Joint Journal
Vol. 97-B, Issue 9 | Pages 1279 - 1283
1 Sep 2015
Mahale YJ Aga N

In this retrospective observational cohort study, we describe 17 patients out of 1775 treated for various fractures who developed mycobacterium tuberculosis (MTB) infection after surgery. The cohort comprised 15 men and two women with a mean age of 40 years (24 to 70). A total of ten fractures were open and seven were closed. Of these, seven patients underwent intramedullary nailing of a fracture of the long bone, seven had fractures fixed with plates, two with Kirschner-wires and screws, and one had a hemiarthroplasty of the hip with an Austin Moore prosthesis. All patients were followed-up for two years. In all patients, the infection resolved, and in 14 the fractures united. Nonunion was seen in two patients one of whom underwent two-stage total hip arthroplasty (THA) and the other patient was treated using excision arthoplasty. Another patient was treated using two-stage THA. With only sporadic case reports in the literature, MTB infection is rarely clinically suspected, even in underdeveloped and developing countries, where pulmonary and other forms of TB are endemic. In developed countries there is also an increased incidence among immunocompromised patients. In this paper we discuss the pathogenesis and incidence of MTB infection after surgical management of fractures and suggest protocols for early diagnosis and management.

Cite this article: Bone Joint J 2015;97-B:1279–83.


The Bone & Joint Journal
Vol. 98-B, Issue 7 | Pages 884 - 891
1 Jul 2016
Elliott DS Newman KJH Forward DP Hahn DM Ollivere B Kojima K Handley R Rossiter ND Wixted JJ Smith RM Moran CG

This article presents a unified clinical theory that links established facts about the physiology of bone and homeostasis, with those involved in the healing of fractures and the development of nonunion. The key to this theory is the concept that the tissue that forms in and around a fracture should be considered a specific functional entity. This ‘bone-healing unit’ produces a physiological response to its biological and mechanical environment, which leads to the normal healing of bone. This tissue responds to mechanical forces and functions according to Wolff’s law, Perren’s strain theory and Frost’s concept of the “mechanostat”. In response to the local mechanical environment, the bone-healing unit normally changes with time, producing different tissues that can tolerate various levels of strain. The normal result is the formation of bone that bridges the fracture – healing by callus. Nonunion occurs when the bone-healing unit fails either due to mechanical or biological problems or a combination of both. In clinical practice, the majority of nonunions are due to mechanical problems with instability, resulting in too much strain at the fracture site. In most nonunions, there is an intact bone-healing unit. We suggest that this maintains its biological potential to heal, but fails to function due to the mechanical conditions. The theory predicts the healing pattern of multifragmentary fractures and the observed morphological characteristics of different nonunions. It suggests that the majority of nonunions will heal if the correct mechanical environment is produced by surgery, without the need for biological adjuncts such as autologous bone graft.

Cite this article: Bone Joint J 2016;98-B:884–91.


The Bone & Joint Journal
Vol. 97-B, Issue 4 | Pages 539 - 543
1 Apr 2015
Lawendy A Bihari A Sanders DW McGarr G Badhwar A Cepinskas G

Compartment syndrome, a devastating consequence of limb trauma, is characterised by severe tissue injury and microvascular perfusion deficits. We hypothesised that leucopenia might provide significant protection against microvascular dysfunction and preserve tissue viability. Using our clinically relevant rat model of compartment syndrome, microvascular perfusion and tissue injury were directly visualised by intravital video microscopy in leucopenic animals. We found that while the tissue perfusion was similar in both groups (38.8% (standard error of the mean (sem) 7.1), 36.4% (sem 5.7), 32.0% (sem 1.7), and 30.5% (sem 5.35) continuously-perfused capillaries at 45, 90, 120 and 180 minutes compartment syndrome, respectively versus 39.2% (sem 8.6), 43.5% (sem 8.5), 36.6% (sem 1.4) and 50.8% (sem 4.8) at 45, 90, 120 and 180 minutes compartment syndrome, respectively in leucopenia), compartment syndrome-associated muscle injury was significantly decreased in leucopenic animals (7.0% (sem 2.0), 7.0%, (sem 1.0), 9.0% (sem 1.0) and 5.0% (sem 2.0) at 45, 90, 120 and 180 minutes of compartment syndrome, respectively in leucopenia group versus 18.0% (sem 4.0), 23.0% (sem 4.0), 32.0% (sem 7.0), and 20.0% (sem 5.0) at 45, 90, 120 and 180 minutes of compartment syndrome in control, p = 0.0005). This study demonstrates that the inflammatory process should be considered central to the understanding of the pathogenesis of cellular injury in compartment syndrome.

Cite this article: Bone Joint J 2015;97-B:539–43


The Bone & Joint Journal
Vol. 96-B, Issue 2 | Pages 259 - 262
1 Feb 2014
Guo KJ Zhao FC Guo Y Li FL Zhu L Zheng W

Corticosteroid use has been implicated in the development of osteonecrosis of the femoral head (ONFH). The exact mechanism and predisposing factors such as age, gender, dosage, type and combination of steroid treatment remain controversial. Between March and July 2003, a total of 539 patients with severe acute respiratory syndrome (SARS) were treated with five different types of steroid. There were 129 men (24%) and 410 women (76%) with a mean age of 33.7 years (21 to 59). Routine screening was undertaken with radiographs, MRI and/or CT to determine the incidence of ONFH.

Of the 129 male patients with SARS, 51 (39.5%) were diagnosed as suffering from ONFH, compared with only 79 of 410 female patients (19.3%). The incidence of ONFH in the patients aged between 20 and 49 years was much higher than that of the group aged between 50 and 59 years (25.9% (127 of 491) versus 6.3% (3 of 48); p = 0.018). The incidence of ONFH in patients receiving one type of steroid was 12.5% (21 of 168), which was much lower than patients receiving two different types (28.6%; 96 of 336) or three different types of steroid (37.1%; 13 of 35).

Cite this article: Bone Joint J 2014;96-B:259–62.