Aims. Acquired heterotopic ossification (HO) is a debilitating disease characterized by abnormal extraskeletal bone formation within soft-tissues after injury. The exact pathogenesis of HO remains unknown. It was reported that BRD4 may contribute to osteoblastic differentiation. The current study aims to determine the role of BRD4 in the pathogenesis of HO and whether it could be a potential target for HO therapy. Methods. Achilles tendon puncture (ATP) mouse model was performed on ten-week-old male C57BL/6J mice. One week after ATP procedure, the mice were given different treatments (e.g. JQ1, shMancr). Achilles tendon samples were collected five weeks after treatment for RNA-seq and real-time quantitative polymerase chain reaction (RT-qPCR) analysis; the legs were removed for micro-CT imaging and subsequent histology. Human bone marrow mesenchymal stem cells (hBMSCs) were isolated and purified bone marrow collected during surgeries by using density gradient centrifugation. After a series of interventions such as knockdown or overexpressing BRD4, Alizarin red staining, RT-qPCR, and Western Blot (Runx2, alkaline phosphatase (ALP), Osx) were performed on hBMSCs. Results. Overexpression of BRD4 enhanced while inhibition of Brd4 suppressed the osteogenic differentiation of hBMSCs in vitro. Overexpression of Brd4 increased the expression of mitotically associated long non-coding RNA (Mancr). Downregulation of Mancr suppressed the osteoinductive effect of BRD4. In vivo, inhibition of BRD4 by JQ1 significantly attenuated pathological bone formation in the ATP model (p = 0.001). Conclusion. BRD4 was found to be upregulated in HO and Brd4-Mancr-Runx2 signalling was involved in the modulation of new bone formation in HO. Cite this article: Bone Joint Res 2021;10(10):668–676

Neurogenic heterotopic ossification (NHO) is a disorder of aberrant bone formation affecting one in five patients sustaining a spinal cord injury or traumatic brain injury. Ectopic bone forms around joints in characteristic patterns, causing pain and limiting movement especially around the hip and elbow. Clinical sequelae of neurogenic heterotopic ossification include urinary tract infection, pressure injuries, pneumonia and poor hygiene, making early diagnosis and treatment clinically compelling. However, diagnosis remains difficult with more investigation needed. Our pathophysiological understanding stems from mechanisms of basic bone formation enhanced by evidence of systemic influences from circulating humor factors and perhaps neurological ones. This increasing understanding guides our implementation of current prophylaxis and treatment including the use of non-steroidal anti-inflammatory drugs, bisphosphonates, radiation therapy and surgery and, importantly, should direct future, more effective ones

Lumbar diseases have become a major problem affecting human health worldwide. Conservative treatment of lumbar diseases is difficult to achieve ideal results, and surgical treatment of trauma, complications, it is imperative to develop a new treatment method. This study aims to explore the regulatory mechanism of cartilage endplate ossification caused by abnormal stress, and design intervention targets for this mechanism, so as to provide theoretical reference for the prevention and treatment of lumbar degeneration. In vivo, we constructed spinal instability model in mice. In vitro, we used a mechanical tensile machine to simulate the abnormal stress conditions of the endplate cartilage cells. Through the high-throughput sequencing, we found the enrichment of Hippo signaling pathway. As YAP is a key protein in the Hippo signaling pathway, we then created cartilaginous YAP elimination mice (Col2::YAPfl/fl). The lumbar spine model was constructed again in these mice for H&E, SOFG and immunofluorescence staining. In vitro lentivirus was used to knock out YAP, immunofluorescence staining, WB and qPCR were performed. Finally, we conducted therapeutic experiments by using YAP agonist and AAV5 carrying YAP plasmids. We collected 8w samples from C57/BL6 mice after modeling. We found ossification of the endplate in mice similar to human disc degeneration. High-throughput sequencing of stretched cells demonstrated high enrichment of the Hippo signaling pathway. By immunofluorescence staining, it was confirmed that Col-II decreased and Col-X gradually increased in the endplate cartilage of mice. This was also confirmed at 7 days after an in vitro stretch of 5% and 12%. Meanwhile, we found that cartilaginous YAP elimination mice developed very severe endplate degeneration. However, the endplate was well protected by intraperitoneal injection of YAP agonist or AAV5-YAP endplate injection, and the results in vitro were consistent with that. In the process of cartilaginous ossification, abnormal stress regulates Col10a1 to promote cartilage endplate ossification through Hippo signaling pathway mediated YAP, and we expect to find potential drug targets for treatment through this mechanism

Aims. Heterotopic ossification (HO) is a common complication after elbow trauma and can cause severe upper limb disability. Although multiple prognostic factors have been reported to be associated with the development of post-traumatic HO, no model has yet been able to combine these predictors more succinctly to convey prognostic information and medical measures to patients. Therefore, this study aimed to identify prognostic factors leading to the formation of HO after surgery for elbow trauma, and to establish and validate a nomogram to predict the probability of HO formation in such particular injuries. Methods. This multicentre case-control study comprised 200 patients with post-traumatic elbow HO and 229 patients who had elbow trauma but without HO formation between July 2019 and December 2020. Features possibly associated with HO formation were obtained. The least absolute shrinkage and selection operator regression model was used to optimize feature selection. Multivariable logistic regression analysis was applied to build the new nomogram: the Shanghai post-Traumatic Elbow Heterotopic Ossification Prediction model (STEHOP). STEHOP was validated by concordance index (C-index) and calibration plot. Internal validation was conducted using bootstrapping validation. Results. Male sex, obesity, open wound, dislocations, late definitive surgical treatment, and lack of use of non-steroidal anti-inflammatory drugs were identified as adverse predictors and incorporated to construct the STEHOP model. It displayed good discrimination with a C-index of 0.80 (95% confidence interval 0.75 to 0.84). A high C-index value of 0.77 could still be reached in the internal validation. The calibration plot showed good agreement between nomogram prediction and observed outcomes. Conclusion. The newly developed STEHOP model is a valid and convenient instrument to predict HO formation after surgery for elbow trauma. It could assist clinicians in counselling patients regarding treatment expectations and therapeutic choices. Cite this article: Bone Joint J 2022;104-B(8):963–971

We developed a rat model of limb lengthening to study the basic mechanism of distraction osteogenesis, using a small monolateral external fixator. In 11-week-old male rats we performed a subperiosteal osteotomy in the midshaft of the femur with distraction at 0.25 mm every 12 hours from seven days after operation. Radiological and histological examinations showed a growth zone of constant thickness in the middle of the lengthened segment, with formation of new bone at its proximal and distal ends. Osteogenic cells were arranged longitudinally along the tension vector showing the origin and the fate of individual cells in a single section. Typical endochondral bone formation was prominent in the early stage of distraction, but intramembraneous bone formation became the predominant mechanism of ossification at later stages. We also showed a third mechanism of ossification, ‘transchondroid bone formation’. Chondroid bone, a tissue intermediate between bone and cartilage, was formed directly by chondrocyte-like cells, with transition from fibrous tissue to bone occurring gradually and consecutively without capillary invasion. In situ hybridisation using digoxigenin-11-UTP-labelled complementary RNAs showed that the chondroid bone cells temporarily expressed type-II collagen mRNA. They did not show the classical morphological characteristics of chondrocytes, but were assumed to be young chondrocytes undergoing further differentiation into bone-forming cells. We found at least three different modes of ossification during bone lengthening by distraction osteogenesis. We believe that this is the first report of such a rat model, and have shown the validity of in situ hybridisation techniques for the study of the cellular and molecular mechanisms involved in distraction osteogenesis

Severe heterotopic ossification (grade III and IV) after contemporary total hip arthroplasty (THA) requiring excision is very uncommon. We performed a systematic review of the literature, and report a new case series with operative treatment after primary uncemented THA. A systematic review identified papers describing patients who had excision of heterotopic ossification (HO) after contemporary THA, defined as performed after 1988. Concepts of hip arthroplasty, heterotopic ossification, and surgical excision were searched in MEDLINE, Embase, and Scopus, from database inception to November 2022. Inclusion criteria were: articles that included specific patient data on grade of heterotopic ossification, operative procedure, and prophylaxis. Studies were screened for inclusion by two independent reviewers. Extracted data included demographic data, interval from index surgery to excision, clinical results, and complications. One surgeon performed reoperation for ankylosis of primary THA in three patients with severe pain and deformity. Seven case series or case report studies were included. There were 41 patients, with grade III or IV HO, that had excision, and in five patients, revision of a component was also performed. Perioperative prophylaxis was irradiation alone in 10 patients, irradiation and indomethacin in 10, and indomethacin alone in 21 patients. At a mean follow-up time of 14.8 months, definition of the results was not uniform, and range of motion was improved, but relief of pain was inconsistent. There was one dislocation, one gastrointestinal complication, and two recurrences. Treatment of the three patients, with wide excision of peri-articular bone, selective exchange of components, and peri-operative irradiation prophylaxis, was successful in improving motion and deformity. There is insufficient data on the treatment of severe symptomatic HO after contemporary THA. Prophylaxis with low-dose irradiation was successful to prevent recurrence. Multicenter studies will be needed to determine the optimum timing and prognosis for treatment

Aims. To clarify the asymmetrical ossification of the epiphyseal ring between the convex and concave sides in patients with adolescent idiopathic scoliosis (AIS). Patients and Methods. A total of 29 female patients (mean age, 14.4 years; 11 to 18) who underwent corrective surgery for AIS (Lenke type 1 or 2) were included in our study. In all, 349 vertebrae including 68 apical vertebrae and 87 end vertebrae in the main thoracic (MT) curve and thoracolumbar/lumbar (TL/L) curve were analysed. Coronal sections (anterior, middle and posterior) of the vertebral bodies were reconstructed from pre-operative CT scans (320-row detector; slice thickness, 0.5 mm) and the appearances of the ossification centre in the epiphyseal ring at four corners were evaluated in three groups; all vertebrae excluding end vertebrae, apical vertebrae and end vertebrae. The appearance rates of the ossification centre at the concave and convex sides were calculated and compared. Results. The appearance rates of the ossification centres in all vertebrae excluding end vertebrae and apical vertebrae were significantly lower on the concave side than on the convex side in both MT and TL/L curves irrespective of curve flexibility. There was no significant difference in the rate of appearance of the ossification centres on the concave or convex sides in end vertebrae. Conclusion. The asymmetric bony growth of vertebral body came into existence at both structural and non-structural curves, and was more apparent around the apical vertebrae. Evaluation of the ossification centre in the epiphyseal ring could be a measure of the effectiveness of brace treatment. Take home message: The ossification of the epiphyseal ring in patients with AIS was delayed or absent on the concave side particularly around the apical vertebrae. Cite this article: Bone Joint J 2016;98-B:666–71

We evaluated the incidence of heterotopic ossification following total ankle replacement to determine whether the degree of ossification was associated with the clinical outcome. We evaluated 90 ankles in 81 consecutive patients who underwent total ankle replacement, and heterotopic ossification was assessed according to proportional involvement of the ankle joint. Correlation analysis was used to investigate the association between heterotopic ossification and outcome. . No significant association was found between the formation of heterotopic ossification and the clinical outcome. The degree of heterotopic ossification in the posterior ankle joint was not significantly correlated with posterior ankle pain (p = 0.929), the American Orthopaedic Foot and Ankle Society score (p = 0.454) or range of movement (p = 0.283). . This study indicates that caution should be observed in attributing symptoms and functional limitation to the presence of heterotopic ossification in the posterior ankle joint when considering excision of heterotopic bone after total ankle replacement

Aim. The primary aim of this retrospective study was to identify the incidence of heterotopic ossification (HO) following elective and trauma elbow arthroplasty. The secondary aim was to determine clinical outcomes with respect to the formation of heterotopic ossification. Patients and Methods. A total of 55 total elbow arthroplasties (TEAs) (52 patients) performed between June 2007 and December 2015 were eligible for inclusion in the study (29 TEAs for primary elective arthroplasty and 26 TEAs for trauma). At review, 15 patients (17 total elbow arthroplasties) had died from unrelated causes. There were 14 men and 38 women with a mean age of 70 years (42 to 90). The median clinical follow-up was 3.6 years (1.2 to 6) and the median radiological follow-up was 3.1 years (0.5 to 7.5). Results. The overall incidence of HO was 84% (46/55). This was higher in the trauma group (96%, 25/26) compared with the elective arthroplasty group (72%, 21/29) (p = 0.027, Fisher’s exact test). Patients in the trauma group had HO of higher Brooker class. The presence of HO did not significantly affect elbow range of movement within the trauma or elective groups (elective arthroplasty, Mann–Whitney U test, p = 0.070; trauma arthroplasty, p = 0.370, Mann–Whitney U test). Conclusion. HO after total elbow arthroplasty is seen more commonly than previously reported. We have reported a significantly higher rate of HO in TEAs performed for trauma than those performed electively. Cite this article: Bone Joint J 2018;100-B:767–71

Heterotopic ossification is the formation of lamellar bone in soft tissues and is a common complication of high-energy combat injury. This disabling condition can cause pain, joint ankylosis, and skin ulceration in the residua of amputees. This project is aimed at developing a novel treatment to dissolve hydroxyapatite in heterotopic ossification and prevent the crystallisation of this this mineral at sites of ectopic bone formation. Previously reported results demonstrated that hexametaphosphate could dissolve hydroxyapatite at physiological pH. Further work has been undertaken to investigate the mechanism of this dissolution and establish a means of temporal control of action. In addition, physicochemical analyses of samples of human heterotopic ossification have yielded important insights into the nature of this pathological tissue. Techniques include mapped micro X-ray fluorescence, mapped Raman spectroscopy, scanning electron microscopy, and micro computed tomography. Formulation engineering work has begun in order to develop an appropriate delivery vehicle for this agent. This includes rheological testing and hexametaphosphate elution profiles. Finally, micro CT analysis has shown that hexametaphosphate is able to dissolve human heterotopic ossification tissue. In summary, this work has moved us closer towards our goal of a novel injectable agent for the treatment and prevention of heterotopic ossification

Distal femoral physeal fractures can cause of growth distrurbance which frequently requires further surgical intervention. The aim of this study was to determine if tibial tuberosity ossification at the time of injury can predict further surgery in patients who have sustained a physeal fracture of the distal femur. We retrospectively investigated all patients who had operative treatment for a distal femoral physeal fracture at a paediatric level one trauma center over a 17 year period. Logistic regression analysis was performed investigating associations between the need for further surgery to treat growth disturbance and tibial tuberosity ossification, age, Salter Harris grade, mode of fixation or mechanism of injury. 74 patients met the inclusion criteria. There were 57 boys (77%) and 17 girls (23%). The average age at time of injury was 13.1 years (range 2.-17.1 years). Following fixation, 30 patients (41%) underwent further surgery to treat growth disturbance. Absence of tibial tuberosity fusion to the metaphysis was significantly associated with need for further surgery (p = < 0 .001). Odds of requiring secondary surgery after tibial tuberosity fusion to metaphysis posteriorly (compared with not fused) were 0.12, 95% CI (0.04, 0.34). The estimate of effect of tibial tuberosity ossification on reoperation rates did not vary when adjusted for gender, mechanism, fixation and Salter Harris grade. When accounting for age, the odds of further operation if the tibial tuberosity is fused to the metaphysis posteriorly (compared with not fused) were 0.28, 95% CI (0.08, 0.94). Tibial tuberosity ossification stage at time of injury is a predictor of further surgery to treat growth disturbance in paediatric distal femoral fractures. Children with distal femoral physeal fractures whose tibial tuberosity was not fused to the metaphysis posteriorly were 8.3 times more likely to require further surgery

Background. The pattern of appearance of secondary ossification centers in the elbow has been based on historical studies and is popularly referred to with the mnemonic CRITOL. However the six secondary ossification centers can be variable in their presentation and pose a challenge in assessment of children with elbow injuries. Furthermore limited studies available in the current literature have reported an aberration to the sequence of appearance especially with the ossification centers of trochlea and olecranon. Aims. The aim of the study was to evaluate the relative sequence of appearance of secondary ossification centers for the trochlea and olecranon. Methods. Children between 8 and 10 years of age who had radiographs of elbow following trivial trauma between July 2013 and Feb 2015 were identified using the hospital PACS database. Cases with radiographic markers of significant trauma ie. fat pad sign, displaced fracture were excluded. Anteroposterior and lateral views of elbow were reviewed for the presence of the six ossification centers. Results. A total of 114 radiographs were reviewed of which 51 were boys and 63 were girls with a mean age of 9.03 years (±0.59). 60 radiographs were of right elbow and 54 were of the left elbow. The capitulum, radial head and medial epicondyle ossification centers were present in all patients. Both trochlea and olecranon ossification centers were noted in 51/114 (44.7%) children. 12/114 (10.5%) of the children were noted to have trochlea ossification center with no olecranon ossification center. Of these 12 children 7 were boys and 5 were girls. On the other hand 19/114 (16.7%) of the children had an olecranon ossification center but without a trochlea ossification center. Amongst these 7 were boys and 12 were girls. Discussion and Conclusions. The results of this limited cross sectional study demonstrate that the CRITOL sequence may not followed in 16.7% of cases and more so in girls. Historical studies were based on conventional radiographs. However the current digital radiographs with image enhancement tools help in accurate identification of relatively small ossification centers which may not be apparent on conventional radiographs. The current study has helped to quantify the violators to CRITOL sequence. Level of Evidence. Level III (Cross-sectional study among non-consecutive patients)

Aims. Heterotopic ossification (HO) is a potentially devastating complication of the surgical treatment of a proximal humeral fracture. The literature on the rate and risk factors for the development of HO under these circumstances is lacking. The aim of this study was to determine the incidence and risk factors for the development of HO in these patients. Methods. A retrospective analysis of 170 patients who underwent operative treatment for a proximal humeral fracture between 2005 and 2016, in a single institution, was undertaken. The mean follow-up was 18.2 months (1.5 to 140). The presence of HO was identified on follow-up radiographs. Results. The incidence of HO was 15% (n = 26). Our multivariate model revealed that male sex (odds ratio (OR) 3.57, 95% confidence interval (CI) 1.30 to 9.80 compared to female) and dislocation as the initial injury (OR 5.01, 95% CI 1.31 to 19.22) were significantly associated with the formation of HO (p < 0.05) while no significant associations were seen for the age of the patient, the characteristics of the injury, or the type of operative treatment. Conclusion. This retrospective radiological study is the first to investigate the association between the method of surgical treatment for a proximal humeral fracture and the formation of HO postoperatively. We found that male sex and dislocation as the initial injury were risk factors for HO formation, whereas the method of surgical treatment, the age of the patient, and the pattern of the fracture were not predictive of HO formation. While additional studies are needed, these findings can help to identify those at an increased risk for HO formation under these circumstances. Cite this article: Bone Joint J 2020;102-B(4):539–544

Heterotopic ossification (HO) is a well-known complication of traumatic elbow injuries. The reported rates of post-traumatic HO formation vary from less than 5% with simple elbow dislocations, to greater than 50% in complex fracture-dislocations. Previous studies have identified fracture-dislocations, delayed surgical intervention, and terrible triad injuries as risk factors for HO formation. There is, however, a paucity of literature regarding the accuracy of diagnosing post-traumatic elbow HO. Therefore, the purpose of our study was to determine the inter-rater reliability of HO diagnosis using standard radiographs of the elbow at 52 weeks post-injury, as well as to report on the rate of mature compared with immature HO. We hypothesized inter-rater reliability would be poor among raters for HO formation. Prospectively collected data from a large clinical trial was reviewed by three independent reviewers (one senior orthopedic resident, one senior radiology resident, and one expert upper extremity orthopedic surgeon). Each reviewer examined anonymized 52-week post-injury radiographs of the elbow and recorded: 1. the presence or absence of HO, 2. the location of HO, 3. the size of the HO (in cm, if present), and 4. the maturity of the HO formation. Maturity was defined by consensus prior to image review and defined as an area of well-defined cortical and medullary bone outside the cortical borders of the humerus, ulna, or radius. Immature lesions were defined as an area of punctate calcification with an ill-defined cloud-like density outside the cortical borders of the humerus, ulna or radius. Data were collected using a standardized online data collection form (CognizantMD, Toronto, ON, CA). Inter-rater reliability was calculated using Fleiss’ Kappa statistic and a multivariate logistic regression analysis was performed to identify risk factors for HO formation in general, as well as mature HO at 52 weeks post injury. Statistical analysis was performed using RStudio (version1.4, RStudio, Boston, MA, USA). A total of 79 radiographs at the 52-week follow-up were reviewed (54% male, mean age 50, age SD 14, 52% operatively treated). Inter-rater reliability using Fleiss’ Kappa was k= 0.571 (p = 0.0004) indicating moderate inter-rater reliability among the three reviewers. The rate of immature HO at 52 weeks was 56%. The multivariate logistic regression analysis identified male sex as a significant risk factor for HO development (OR 5.29, 1.55-20.59 CI, p = 0.011), but not for HO maturity at 52 weeks. Age, time to surgery, and operative intervention were not found to be significant predictors for either HO formation or maturity of the lesion in this cohort. Our study demonstrates moderate inter-rater reliability in determining the presence of HO at 52 weeks post-elbow injury. There was a high rate (56%) of immature HO at 52-week follow-up. We also report the finding of male sex as a significant risk factor for post traumatic HO development. Future research directions could include investigation into possible male predominance for traumatic HO formation, as well as improving inter-rater reliability through developing a standardized and validated classification system for reporting the radiographic features of HO formation around the elbow

Introduction and Objective. Heterotopic ossification is the formation of extraskeletal mineralized tissue commonly associated with either trauma or surgery. While several mouse models have been developed to better characterize the pathologic progression of HO, no model currently exists to study HO of the hip, the most common location of acquired HO in patients. Owing to the unique biological mechanisms underpinning the formation of HO in different tissues, we sought to develop a model to study the post-surgical HO of the hip. Materials and Methods. Wild-type mice C57BL/6J mice were used to study the procedure outcomes, while Pdgfra-CreERT2;mT/mG and Scx-GFP reporter animals were used for the lineage tracing experiments (total n=16 animals, male, 12 weeks old). An anterolateral approach to the hip was performed. Briefly, a 2 cm incision was made centered on the great trochanter and directed proximal to the iliac crest and distally over the lateral shaft of the femur. The joint was then reached following the intermuscular plane between the rectus femoris and gluteus medius muscles. After the joint was exposed, the articular cartilage was removed using a micropower drill with a 1.2 mm reamer. The medius gluteus and superficial fascia were then re-approximated with Vicryl 5-0 suture (Ethicon Inc, Somerville, NJ) and skin was then closed with Ethilon 5-0 suture (Ethicon Inc). Live high resolution XR imaging was performed every 2 wks to assess the skeletal tissues (Faxitron Bioptics, Tucson, AZ). The images were then scored using the Brooker classification. Ex-vivo microCT was conducted using a Skyscan 1275 scanner (Bruker-MicroCT, Kontich, Belgium). 3D reconstruction and analysis was performed using Dragonfly (ORS Inc., Montreal, Canada). For the histological analysis of specimens, Hematoxylin and Eosin (H&E), modified Goldner's Trichrome (GMT) stainings were performed. Reporter activity was assessed using fluorescent imaging. Results. Substantial periarticular heterotopic bone was seen in all cases. A periosteal reaction and an initial formation of calcified tissue within the soft tissue was apparent starting from 4 wks after surgery. By XR, progressive bone formation was observed within the periosteum and intermuscular planes during the subsequent 8 weeks. Stage 1 HO was observed in 12.5% of cases, stage 2 in 62.5% of cases, and stage 3 HO in 25% of cases. 3D microCT reconstructions of the treated hip joints demonstrated significant de novo heterotopic bone in several location which phenocopy human disease. Heterotopic bone was observed in an intracapsular location, periosteal location involving the iliac bone and proximal femur, and intermuscular locations. Histological analyses further confirmed these findings. To assess the cells which gave rise to HO in this model, an inducible PDGFRα and constitutive Scx-GFP reporter mice were used. A dramatic increase in mGFP reporter activity was noted PDGFRα within the HO injury site, including in areas of new cartilage and bone formation. Scx-associated reporter activity increased in the soft tissue and periosteal periacetabular areas of injured hips. Conclusions. HO has a diverse set of pathologies, of which joint associated HO after elective surgery is the most common. Here, we present the first mouse model of hip dislocation and acetabular reaming that mimics elements of human periarticular HO. The diverse locations of HO after acetabular reaming (intracapsular, intermuscular and periosteal) suggests the activation of different and specific HO program after surgery. Such a field effect would be consistent with local trauma and inflammation, which is a well-studied contributor to HO genesis. Not surprisingly, joint-associated HO significantly derives from PDGFRα-expressing cells, which has been shown to similarly give rise to intramuscular and intratendinous HO

Heterotopic ossification following joint replacement in the lower limb occurs in 3% to 90% of cases. Higher grades of heterotopic ossification can result in significant limitation of function and can negate the benefits of joint replacement. The understanding of the pathophysiology of this condition has improved in recent years. It would appear to be related to a combination of systemic and local factors, including over-expression of bone morphogenetic protein-4. There is currently little evidence to support the routine use of prophylaxis for heterotopic ossification in arthroplasty patients, but prophylaxis is recommended by some for high-risk patients. Radiotherapy given as one dose of 7 Gy to 8 Gy, either pre-operatively (< four hours before) or post-operatively (within 72 hours of surgery), appears to be more effective than indometacin therapy (75 mg daily for six weeks). In cases of prophylaxis against recurrent heterotopic ossification following excision, recent work has suggested that a combination of radiotherapy and indometacin is effective. Advances in our understanding of this condition may permit the development of newer, safer treatment modalities

Abstract. Objectives. The term heterotopic ossification (HO) describes lamellar bone formation within soft tissues following injury. A genome-wide scan of patients after hip arthroplasty has identified that variation within the lncRNA CASC20 is associated with HO susceptibility. Previous findings in our lab have demonstrated upregulation of CASC20 during BMP2-induced osteodifferentiation of adipose-derived stem cells (hMAD) alongside osteodifferentiation markers, RUNX2 and OSX. We hypothesize that CASC20 is a novel regulator of bone formation and aim to investigate CASC20 function in bone formation. Methods. 1) We used miRanda prediction algorithm and the ENCORI database to respectively predict which miRNAs CASC20 interacts with and to select for experimentally validated miRNAs. 2) We characterized the expression and functional role of CASC20-interacting miRNAs by respectively analyzing publicly available datasets (GSE107279 and pubmed.ncbi.nlm.nih.gov/26175215/) and by using Gene Ontology (GO) analysis. 3) We overexpressed CASC20 in hMAD using a lentiviral system and tested the effect of CASC20 overexpression in osteodifferentiation and expression of putative CASC20-interacting miRNAs. Results. 1) We identified 64 experimentally validated miRNAs that are predicted to interact with CASC20. 2) GO analysis revealed that the most frequently targeted molecular functions included SMADs, MAPKK and other kinase activities known to play a central role in osteo and chondrogenesis. We found 10 miRNAs including hsa-miR-485-3p that demonstrated down-regulation in both osteo- and chondrogenesis. 3) We found that CASC20-overexpression augmented the osteodifferentiation of hMAD measured in mineralization using Alizarin Red S. CASC20 overexpression increased the expression of osteogenic marker ALP and decreased the expression of hsa-miR-485-3p. Conclusion. Here we show how CASC20 may regulate bone formation by acting as a competitive endogenous RNA (ceRNA). We are currently using CASC20 overexpression model in osteo- and chondrogenesis, and testing CASC20-miRNA interaction to establish the underlying mechanism for the observed associations

Aims. We aimed to assess the influence of ethnicity on the incidence of heterotopic ossification (HO) after total hip arthroplasty (THA). . Patients and Methods. We studied the six-month post-operative anteroposterior radiographs of 1449 consecutive primary THAs (1324 patients) and retrospectively graded them for the presence of HO, using the Brooker Classification. . Results. Based on multivariate analysis, African-American ethnicity was an independent risk factor for HO formation following THA with an adjusted odds ratio (OR) of 2.6 (95% confidence interval (CI) 1.3 to 5.2, p = 0.007) for severe HO and 1.9 (95% CI 1.3 to 2.7, p < 0.001) for any grade of HO. . Conclusion. Given the increased risk of HO formation, particularly high grade HO, and the potentially poorer outcomes associated with HO, it is important to consider using prophylaxis against HO in patients of African-American ethnicity undergoing THA. Take home message: African Americans are at an increased risk for developing heterotopic ossification and thus may benefit from HO prophylaxis. . Cite this article: Bone Joint J 2016;98-B:761–6

Introduction. Osteogenesis imperfect (OI) is a geno- and phenotypically heterogeneous group of congenital collagen disorders characterized by fragility and microfractures resulting in long bone deformities. OI can lead to progressive femoral coxa vara from bone and muscular imbalance and continuous microfracture about the proximal femur. If left untreated, patients develop Trendelenburg gait, leg length discrepancy, further stress fracture and acute fracture at the apex of the deformity, impingement and hip joint degeneration. In the OI patient, femoral coxa vara cannot be treated in isolation and consideration must be given to protecting the whole bone with the primary goal of verticalization and improved biomechanical stability to allow early loading, safe standing, re-orientation of the physis and avoidance of untreated sequelae. Implant constructs should therefore be designed to accommodate and protect the whole bone. The normal paediatric femoral neck shaft angle (FNSA) ranges from 135 to 145 degrees. In OI the progressive pathomechanical changes result in FNSA of significantly less than 120 degrees and decreased Hilgenreiner epiphyseal angles (HEA). Proximal femoral valgus osteotomy is considered the standard surgical treatment for coxa vara and multiple surgical techniques have been described, each with their associated complications. In this paper we present the novel technique of controlling femoral version and coronal alignment using a tubular plate and long bone protection with the use of teleoscoping rods. Methodology. After the decision to operate had been made, a CT scan of the femur was performed. A 1:1 scale 3D printed model (AXIAL3D, Belfast, UK) was made from the CT scan to allow for accurate implant templating and osteotomy planning. In all cases a subtrochanteric osteotomy was performed and fixed using a pre-bent 3.5 mm 1/3 tubular plate. The plate was bent to allow one end to be inserted into the proximal femur to act as a blade. A channel into the femoral neck was opened using a flat osteotome. The plate was then tapped into the femoral neck to the predetermined position. The final position needed to allow one of the plate holes to accommodate the growing rod. This had to be determined pre operatively using the 3D printed model and the implants. The femoral canal was reamed, and the growing rod was placed in the femur, passing through the hole in the plate to create a construct that could effectively protect both the femoral neck and the full length of the shaft. The distal part of the plate was then fixed to the shaft using eccentric screws around the nail to complete the construct. Results. Three children ages 5,8 and 13 underwent the procedure. Five coxa vara femurs have undergone this technique with follow-up out to 62 months (41–85 months) from surgery. Improvements in the femoral neck shaft angle (FNSA) were av. 18. o. (10–38. o. ) with pre-op coxa vara FNSA av. 99. o. (range 87–114. o. ) and final FNSA 117. o. (105–125. o. ). Hilgenreiner's epiphyseal angle was improved by av. 29. o. (2–58. o. ). However only one hip was restored to <25. o. In the initial technique employed for 3 hips, the plates were left short in the neck to avoid damaging the physis. This resulted in 2 of 3 hips fracturing through the femoral neck above the plate at approximately 1 year. There were revisions of the 3 hips to longer plates to prevent intra-capsular stress riser. All osteotomies united and both intracapsular fractures healed. No further fractures have occurred within the protected femurs and no other repeat operations have been required. Conclusions. Surgical correction of the OI coxa vara hip is complex. Bone mineral density, multiplanar deformity, a desire to maintain physeal growth and protection of the whole bone all play a role in the surgeon's decision making process. Following modifications, this technique demonstrates a novel method in planning and control of multiplanar proximal femoral deformity, resulting in restoration of the FNSA to a more appropriate anatomical alignment, preventing long bone fracture and improved femoral verticalization in the medium term follow-up

1. Ectopic ossification is commonest in, but not confined to, traumatic paraplegia. It occurs also in many other neurological disorders which have in common a gross disturbance of spinal cord reflex activity. It is a true ossification and must be distinguished from calcification. 2. The neurological lesion may lie anywhere from the cerebral cortex to the mixed peripheral nerve. It may involve motor tracts, sensory tracts or a mixture of both. 3. The ossification is localised and self-limiting. It occurs mainly in the lower limbs and is restricted to certain muscles or muscle groups, the nerve supply of which is always below the level of the central neurological lesion. 4. The blood chemistry is usually normal. 5. A true arthropathy is rare except as part of a secondary suppurative arthritis. 6. The resemblance to myositis ossificans progressiva or to ossifying haematoma is only superficial, although the pathological process at cellular level may be the same. 7. The period of onset after paraplegia is variable. The earliest recorded example is in one of our own cases in which ossification occurred nineteen days after injury. Other patients have developed ossification after several years. 8. The condition is commonest in acquired nervous disease rather than in congenital disorders, and so far as we know it has not been described in the myopathies. The presence of muscular spasticity or flaccidity is relevant only in that it indicates a disturbance of reflex activity. 9. Soft-tissue ulceration appears to be frequently associated with ectopic ossification. The type of new bone formation associated with large chronic ulcers is not to be compared with the new bone formation in the muscles of a paraplegic patient in otherwise good general condition. 10. The occurrence of urinary tract infections with calculi and generalised sepsis is not specifically related to the onset of new bone formation. 11. Localised soft-tissue oedema often precedes the formation of new bone. Its appearance is undoubtedly important, but the mechanism of its origin is obscure. 12. It is not yet known what initiates ectopic ossification, what limits its spread and what finally causes it to stop. 13. We have described 100 examples of ectopic ossification in 603 paraplegic patients. 14. Surgery has been required in only eight patients. The only indication for surgery is bony ankylosis of the hip in an unacceptable position

Our study was designed to compare the effect of indometacin with that of a placebo in reducing the incidence of heterotopic ossification in a prospective, randomised trial. A total of 121 patients with displaced fractures of the acetabulum treated by operation through a Kocher-Langenbeck approach was randomised to receive either indometacin (75 mg) sustained release, or a placebo once daily for six weeks. The extent of heterotopic ossification was evaluated on plain radiographs three months after operation. Significant ossification of Brooker grade III to IV occurred in nine of 59 patients (15.2%) in the indometacin group and 12 of 62 (19.4%) receiving the placebo. We were unable to demonstrate a statistically significant reduction in the incidence of severe heterotopic ossification with the use of indometacin when compared with a placebo (p = 0.722). Based on these results we cannot recommend the routine use of indometacin for prophylaxis against heterotopic ossification after isolated fractures of the acetabulum

Seven men with a mean age of 63.9 years (59 to 67) developed dysphagia because of oesophageal compression with ossification of the anterior longitudinal ligament (OALL) and radiculomyelopathy due to associated stenosis of the cervical spine. The diagnosis of OALL was made by plain lateral radiography and classified into three types; segmental, continuous and mixed. Five patients had associated OALL in the thoracic and lumbar spine without ossification of the ligamentum flavum. All underwent removal of the OALL and six had simultaneous decompression by removal of ossification of the posterior longitudinal ligament or a bony spur. All had improvement of their dysphagia. Because symptomatic OALL may be associated with spinal stenosis, precise neurological examination is critical. A simultaneous microsurgical operation for patients with OALL and spinal stenosis gives good results without serious complications

Heterotopic Ossification (HO) is a known complication that can arise after total elbow arthroplasty (TEA). In most cases it is asymptomatic, however, in some patients it can limit range of motion and lead to poor outcomes. The objective of this review was to assess and report incidence, risk factors, prophylaxis, and management of HO after TEA. A systematic search was conducted using MEDLINE, EMBASE, and PubMed to retrieve all relevant studies evaluating occurrence of HO after TEA. The search was performed in duplicate and a quality assessment was performed of all included studies. A total of 1907 studies were retrieved of which 45 studies were included involving 2256 TEA patients. HO was radiographically present in 10% of patients and was symptomatic in 3%. Less than 1% of patients went on to surgical excision of HO, with outcomes following surgery reported as good or excellent as assessed by range of motion and Mayo Elbow Performance Scores (MEPS). TEA due to ankylosis, primary osteoarthritis, and posttraumatic arthritis are more likely to develop symptomatic HO. HO is an uncommon complication following TEA with the majority of patients developing HO being asymptomatic and requiring no surgical management. Routine HO prophylaxis for TEA is not supported by the literature. The effectiveness of prophylaxis in high risk patients is uncertain and future studies are required to clarify its usefulness. The strength of these conclusions are limited by inconsistent reporting in the available literature

Aims. After the initial correction of congenital talipes equinovarus (CTEV) using the Ponseti method, a subsequent dynamic deformity is often managed by transfer of the tendon of tibialis anterior (TATT) to the lateral cuneiform. Many surgeons believe the lateral cuneiform should be ossified before surgery is undertaken. This study quantifies the ossification process of the lateral cuneiform in children with CTEV between one and three years of age. . Patients and Methods. The length, width and height of the lateral cuneiform were measured in 43 consecutive patients with unilateral CTEV who had been treated using the Ponseti method. Measurements were taken by two independent observers on standardised anteroposterior and lateral radiographs of both feet taken at one, two and three years of age. Results. All dimensions of the lateral cuneiform on the affected side increased annually but remained smaller than the corresponding dimensions of the unaffected foot (p < 0.01). The lateral cuneiform resembled a 9 mm cube at two years and an 11 mm cube at three years. Conclusion. At one and two years, the ossification centre of the lateral cuneiform may not be large enough to accommodate a drill hole for tendon transfer. However, by three years, it has undergone sufficient ossification to do so. Cite this article: Bone Joint J 2017;99-B:1109–14

We report the case of an 82-year-old man who underwent fasciectomy for a severe Dupuytren’s contracture, during which an ossified lesion was encountered within the contracture and surrounding the neurovascular bundle. The abnormal tissue was removed with difficulty and heterotopic ossification was confirmed histologically. We believe this is the first report of heterotopic ossification in Dupuytren’s disease

Aims. The optimal procedure for the treatment of ossification of the posterior longitudinal ligament (OPLL) remains controversial. The aim of this study was to compare the outcome of anterior cervical ossified posterior longitudinal ligament en bloc resection (ACOE) with posterior laminectomy and fusion with bone graft and internal fixation (PTLF) for the surgical management of patients with this condition. Methods. Between July 2017 and July 2019, 40 patients with cervical OPLL were equally randomized to undergo surgery with an ACOE or a PTLF. The clinical and radiological results were compared between the two groups. Results. The Japanese Orthopaedic Association (JOA) score and recovery rate in the ACOE group were significantly higher than those in the PTLF group during two years postoperatively, provided that the canal occupying ratio (COR) was > 50%, or the K-line was negative. There was no significant difference in JOA scores and rate of recovery between the two groups in those in whom the COR was < 50%, or the K-line was positive. There was no significant difference in the Cobb angle between C2 and C7, sagittal vertical axis, cervical range of motion (ROM), and complications between the two groups. Conclusion. Compared with PTLF, ACOE is a preferred surgical approach for the surgical management of patients with cervical OPLL in that it offers a better therapeutic outcome when the COR is > 50%, or the K-line is negative, and it also preserves better cervical curvature and sagittal balance. The prognosis of ACOE is similar to that of PTLE when the COR is < 50%, or the K-line is positive. Cite this article: Bone Joint J 2023;105-B(4):412–421

Introduction:. The incidence of heterotrophic ossification after primary total hip arthoplasty (THA) has been reported to be between 8 to 90%. The incidence is higher in lateral approach because of extensive muscular trauma associated with it. There exists limited data on the incidence of heterotrophic ossification after direct anterior approach (DAA) THA. The purpose of this study was to assess the incidence of heterotrophic ossification after THA via the direct anterior approach and the influence of surgical technique and chemoprophylaxis. Method:. A consecutive series of four hundred two primary uncemented direct anterior approach total hip arthoplasties in 378 patients were reviewed for incidence of heterotrophic ossification. In the first 200 total hip arthoplasties an anterior capsulectomy (Group 1) was done for exposure while in the subsequent 202 total hip arthoplasties a capsulotomy (Group 2) followed by complete release of supero-lateral flap of from its attachement to the gluteus minimus muscle and trochanter was performed (Figure 1). Group 1 received warfarin for thromboprophylaxis; while aspirin (thromboprophylaxis) and celecoxib (pain) was used in group 2. Heterotrophic ossification was classified according to Brooker's classification on plain radiographs. Results:. Heterotrophic ossification was significantly less in group 2 (4/202, 1.98%) as compared to group 1 (29/200, 14.5%). No severe heterotrophic ossification was found in group 2. Conclusion:. Release of the superior-lateral capsular flap from the gluteus minimus muscle allows the femoral mobilization required during the femoral preparation and exposes the trochanter for easier retractor placement and thereby minimizes the muscular traumatic insult. When combined with aspirin and celecoxib chemoprophylaxis, this technique may diminish heterotrophic ossification

Aim. The aim of the study was to define the peculiarities of bone remodeling and identify specific parameters to development to heterotopic ossification. Materials and methods. Markers of bone formation (Osteocalcin, serum type 1 procollagen (N-terminal) (tP1NP)) and bone resorption (serum collagen type 1 cross-linked C-telopeptide (β-CTx)) were determined by the electrochemiluminiscence immunoassay “ECLIA” for Elecsys user cobas immunoassay analyser. In the study were included 23 patients with spinal cord injury – first group (average age 26.8 ± 3.9, duration of spinal cord injury from 3 to 12 months) and 23 healthy people's appropriate age and gender (average age 30.6 ± 6.0, years). In the first group included 11 patients with spinal cord injury with the presence of heterotopic ossification – subgroup I and 12 patients with spinal cord injury without heterotopic ossification – subgroup II. Results. The results of examination showed that patients of first group had significantly higher bone markers than control group: P1NP (256.7±48.2 ng/ml vs 49.3±5.1 ng/ml, p<0.001), serum β-CTx (1.47±0.23 ng/ml vs 0.45±0.04 ng/ml, p<0.0001), osteocalcin (52.2±9.8 ng/ml vs 24.9±2.08 ng/ml, p<0.001). There were obtained that levels of bone remodeling markers in patients with HO were significantly higher in comparison with patients without HO: P1NP (404.9±84.9 ng/ml vs 133.2±15.7 ng/ml, p<0.001), serum β-CTx (1.75±0.23 ng/ml vs 0.28±0.14 ng/ml, p<0.0001), osteocalcin (87.1±18.9 ng/ml vs 29.4±3.7 ng/ml, p<0.001). Conclusion. The bone formation and bone resorption markers in patient of first group were significantly higher than in healthy individuals of appropriate age. The rate of bone turnover markers in patient with HO was considerably higher than in patient without HO and the process of formation dominated over the resorption in patient with HO

Purpose: Periprosthetic ossification is a frequent complication of total hip arthroplasty and can have a major functional impact. Non-steroidal anti-inflammatory drugs (NSAID) can provide effective prevention but with a risk of morbidity. The purpose of this work was to evaluate the efficacy of an anti-Cox2 agent, cele-coxib, for this indication. Material and methods: Total hip arthroplasty was performed in 42 patients with a relative (gastrointestinal) contraindication for the use of NSAID. These patients were given celecoxib (Celebrxy(r)) 200 mg bid starting the day before the operation and continuing for at least five days. A control group of 42 age- (±3 yr) and sex-matched patients who underwent surgery for the same indication performed by a surgeon with equivalent experience was also established. The control patients were given ketoprofen (Profénidy(r)) 50 mg qid for two days then 150 mg bid for five days. The approach, implant, and other adjuvant treatments were equivalent between the two groups. Ossifications were analysed on the follow-up films taken at least three months after surgery. The Brooker classification was used. The exact Fisher test was used for the statistical analysis. Results: The two groups each included 31 women and eleven men, mean age being the same in the two groups (67.12 yrs). Mean follow-up was very similar (8.44 vs 8.6 months). Aetiologies were: primary degenerative hip (n=30), degenerative hip disease after dysplasia (n=9), sequela of infantile arthritis (n=1), revision total hip prosthesis (n=2). Two patients in each group interrupted their treatment between day 2 and 4 because of intolerance. There were no cases of significant haematoma in either group. No ossification > grade 2 was observed. The overall rate of ossification was 42.5% in the control group versus 48.6% in the celecoxib group. The rate of grade 2 ossifications was 8% in the cele-coxib group versus 12% in the control group. These rates were not significantly different (Fisher’s exact test= 0.6). Discussion: In this study, celecoxib and ketoprofen were found to have equivalent efficacy for the prevention periprosthetic ossification. This is an interesting perspective in the probable hypothesis of less morbidity with anti-Cox 2 antiinflammatory drugs used in combination with an antalgesia protocol

The study of the chondrocyte maturation cycle and endochondral ossification showed that the developing vascular supply has appeared to play a key role in determining the cortical or trabecular structure of the long bones. The chondrocyte maturation cycle and endochondral ossification were studied in human, foetal cartilage anlagen and in postnatal meta-epiphyses. The relationship between the lacunar area, the inter territorial fibril network variations and CaP nucleation in primary and secondary ossification centres were assessed using light microscopy and SEM morphometry. The anlage topographic, zonal classification derived from the anatomical nomenclature of the completely developed long bone (diaphysis, metaphyses and epiphyses) allowed to follow the development of long bones cartilage model. A significant increase in chondrocyte lacunar area (p<0.001) was documented from the anlage epiphyseal zone 4 and 3 to zone 2 (metaphysis) and zone 1 (diaphysis), with the highest variation from zone 2 to zone 1. An inverse reduction in the intercellular matrix area (p<0.001) and matrix interfibrillar empty space (p<0.001) was also documented. These findings are consistent with the osmotic passage of free cartilage water from the interfibrillar space into the swelling chondrocytes, raising ion concentrations up to the critical threshold for mineral precipitation in the matrix. The mineralised cartilage served as a scaffold for osteoblasts apposition both in primary and secondary ossification centres and in the metaphyseal growth plate cartilage, but at different periods of bone anlage development and with distinct patterns for each zone. They all shared a common initial pathway, but it progressed with different times, modes and organisation in diaphysis, metaphysis and epiphysis. In the ossification phase the developing vascular supply has appeared to play a key role in determining the cortical or trabecular structure of the long bones

Harnessing the potential of mesenchymal stem cell (MSC) mediated endochondral ossification for the repair of large bone defects represents a promising avenue of investigation as an alternative option to autologous bone transplantation. To date, it has been shown that undifferentiated MSCs are somewhat immune-privileged. In order to induce bone formation from MSCs by endochondral ossification it is usually necessary to first differentiate these cells chondrogenically. However, the status of differentiated cells is less clear than that of undifferentiated MSCs. Furthermore, the fate of implanted bone forming constructs in an allogeneic setting is not known. The potential to use allogeneic MSCs for large bone defect repair would offer opportunities to researchers to develop new therapies using more potent MSC sources and in a more readily available manner with regard to the patient. I will present our research investigating the interactions between chondrogenically primed MSCs and immune cell subsets, namely T cells and dendritic cells. Furthermore, I will discuss the ability of human paediatric MSCs to form bone in the in vivo allogeneic setting

Purpose: The aim of the study was to establish normal reference standards for the appearance of the femoral head ossification center according to age, sex and gestational age. Material and Methods: Sonographic examination of the hip was performed in 1800 healthy Indian and Israeli infants (900 each) aged 2 to 24 weeks. There was an equal number of males and females. A single physician performed all examinations in each country. For each infant, we recorded sex, date of birth, gestational age at birth (weeks), date of ultrasound examination, age at examination (weeks), and presence or absence of the femoral head ossification center on sonographic examination. All data were collected in a Microsoft Excell file and submitted for independent statistical analysis using paired Fisher exact test, chi-square test, and a NOVA test. Results: The ossification center was noted in the second week of life in the Israeli infants and at 8 weeks in the Indian infants. By 20 weeks, however, it was noted in 81% or more of the Indian infants but only 22–74% of the Israeli ones. In both groups between 20 to 24 weeks of age the ossification center was noted in more than 90% of the infants. Conclusions: Knowledge of the normal sonographic appearance of the femoral head ossification center by age and ethnicity will help clinicians in the diagnosis and treatment of hip disorders

Aims. Heterotopic ossification (HO) occurs after arthroplasty, especially total hip arthroplasty. In this study we describe the incidence, evolution, morphology and clinical consequences of HO following reverse shoulder arthroplasty. Patients and Methods. This is a single-centre retrospective study of 132 consecutive patients who received a Delta III or Delta Xtend reverse total shoulder arthroplasty between 2006 and 2013 for the treatment of cuff tear arthropathy. There were 96 women and 36 men. Their mean age at the time of surgery was 69 years (49 to 89) and the mean follow-up was 36 months (12 to 84). The incidence, evolution, morphology and clinical consequences of HO using the Constant-Murley score (CS) were analysed. A modified Brooker classification of HO of the hip was used. Results. HO was seen in 39 patients (29.5%). A total of 31 of these patients (81.6%) began to develop HO by three months post-operatively. According to the Hamada classification, 11 patients had grade 1a, eight had grade 1b, six had grade 1c and 14 had grade 2 HO. The HO evolved over a mean of 8.3 months (3 to 21). Patients with HO had a lower mean CS at three (p = 0.017), six (p < 0.001) and 12 months (p < 0.001) post-operatively. HO was not associated with notching (p = 0.675). Conclusion. HO after reverse shoulder arthroplasty is a non-progressive condition without long-term clinical consequences. Only grade 2 HO is clinically relevant with a negative effect on the function of the shoulder during its development. Cite this article: Bone Joint J 2016;98-B:1215–21

Aims. The aim of this study was to assess the efficacy of non-selective and selective non-steroidal anti-inflammatory drugs (NSAIDs) in preventing heterotopic ossification (HO) after total hip arthroplasty (THA). Methods. A thorough and systematic literature search was conducted and 29 studies were found that met inclusion criteria. Data were extracted and statistical analysis was carried out generating forest plots. Results. Non-selective NSAIDs showed a significant decrease in the odds for forming HO after THA (odds ratio (OR) -1.35, confidence interval (CI) -1.83 to -0.86) when compared with placebo. Selective NSAIDs also showed a significant decrease in the odds for forming HO after THA when compared with placebo (OR -1.58, CI -2.41 to -0.75). When comparing non-selective NSAIDs with selective NSAIDs, there was no significant change in the odds for forming HO after THA (OR 0.22, CI -0.36 to 0.79). Conclusion. Our meta-analyses of all available data suggest that both non-selective and selective NSAIDs are effective HO prophylaxis and can be used routinely after THA for pain control as well as prevention of HO. Indomethacin may serve as the benchmark among non-selective NSAIDs and celecoxib among selective NSAIDs. There was no difference in the incidence of HO between non-selective and selective NSAIDs, allowing physicians to choose either based on the clinical scenario and patient-specific factors. Cite this article: Bone Joint J 2018;100-B:915–22

We examined whether a selective cyclooxygenase-2 (COX-2) inhibitor (celecoxib) was as effective as a non-selective inhibitor (ibuprofen) for the prevention of heterotopic ossification following total hip replacement. A total of 250 patients were randomised to receive celecoxib (200 mg b/d) or ibuprofen (400 mg t.d.s) for ten days after surgery. Anteroposterior radiographs of the pelvis were examined for heterotopic ossification three months after surgery. Of the 250 patients, 240 were available for assessment. Heterotopic ossification was more common in the ibuprofen group (none 40.7% (50), Brooker class I 46.3% (57), classes II and III 13.0% (16)) than in the celecoxib group (none 59.0% (69), Brooker class I 35.9% (42), classes II and III 5.1% (6), p = 0.002). Celecoxib was more effective than ibuprofen in preventing heterotopic bone formation after total hip replacement

Introduction: The x-ray test, introduced at the beginning of the XX century, originated a succession of descriptions of alterations in the different secondary ossification nuclei of the long bones, systematically considered as osteocondrosis cases. Osteocondrosis is a wide concept including etiological, pathological, histological, clinical and radiological data, there being no unique criterium about the concept in the literarure. There are no clear data in the literature about the prevalence of radiological alterations in the forefoot ossification nuclei. In most cases such ‘alterations’ are rather anatomical variants in the development and growth of the ossification nuclei. The aim of the present study was to determine the different radiological alterations observed in our series and their possible relation with other variables (sex, foot pathology and forefoot morphology). Material and Methods: A serie of 971 dorso-plantar radiographs from 225 patients were retrospectively analysed. The presence, or lack, of each nucleus and its radiological aspect were observed. The different alterations of the nuclei were classified as: normal, sclerotic, sclerotic and notch, sclerotic and flattened, sclerotic and fragmented, and fragmented. Likewise, a statistical analysis was performed relating the alterations of each nucleus with the forefoot morphology (digital and metatarsal formulae) and the main pathologies motivating the x-ray examination (traumatism, our control group; flatfoot; hallux valgus; clubfoot). Results: We could not find any asymmetry or dimorphism in our series. The prevalence of different alterations of each nucleus was higher in younger children, excepting in the ossification nucleus of the proximal phalanx. In the 46.3% of the cases there are radiological alterations in the ossification nucleus of the proximal phalanx. In such cases, the 79.2% were sclerotic. In the flatfoot patients a higher frequency regarding the apperance of radiological alterations was shown significant (p< 0.05) for first cuneiform, proximal metatarsal, and proximal phalanx nuclei. In the cases with evident alterations of the proximal or distal metatarsal nuclei, the 100% of the cases was related to egyptian digital formula. The retrospective study did not provide us with additional clinical information about symptoms that could define osteocondrosis in each case. Conclusions: There is a higher prevalence regarding to radiological alterations of the ossification nuclei of the first radio of the foot. The biomechanical alterations of the gait in the flat-foot patients, or its treatment (insole), could be related to radiological alterations of such nuclei

Background: Heterotopic ossification is a common feature that follows total hip arthroplasty, and affects up to 70% of patients with clinical implications, such as pain and restricted hip movements. Previous clinical observation showed negligible heterotopic ossification in our patients who underwent total hip arthroplasty due to familial Mediterranean fever, and received colchicines on a daily basis. Aims: To evaluate in vitro, in vivo and during clinical studies whether colchicines, given on a prophylactic daily basis to all total hip arthroplasty patients, was responsible for the negligible heterotopic ossification. Methods: In vitro: cell lines of fibroblasts and osteoblasts were cultured with increasing concentrations of colchicines. Direct cell counts [3H]thymidine uptake, and mineralization were measure. In vivo: heterotopic ossification was induced in the thigh muscle of rabbits by injecting bone marrow. Animals were given colchicines, and X-ray radiographs, ultrasound the histological studies measured its effect on heterotopic ossification. Clinical study: Fifty-two patients admitted for total hip arthroplasty were randomly selected to receive colchicines on a daily basis, starting 10 days pre-operatively, and 6 weeks postoperatively. Clinical evaluation was made according to Harris Hip Score and heterotopic ossification according to Brooker classification. Results: In vitro: colchicines was found to be a strong, nonselective inhibitor of cell proliferation, and an even greater inhibitor of tissue mineralization. In vivo: statistically significant reduction in the amount of hetero-topic ossification induced in the thigh muscle of rabbits was measured in the groups that received colchicines. Clinical study: Patients who received colchicines pre-operatively developed a negligible amount of hetero-topic ossification after total hip arthroplasty at 1-year follow-up without adversely affecting the Harris Hip Score. Conclusions: Colchicine is a strong inhibitor of cell proliferation and tissue mineralization, and an effective means of reducing heterotopic ossification after total hip arthroplasty. These effects may be used in other bone-forming processes: after hip/pelvic trauma, head injury, and possibly in other bone-forming conditions

Heterotopic ossi?cation is the abnormal formation of bone in soft tissues and is a frequent complication of hip replacement surgery. Heterotopic ossi?cations are described to develop via endochondral ossification and standard treatment is administration of indomethacin. It is currently unknown how indomethacin influences heterotopic ossi?cation on a molecular level, therefore we aimed to determine whether indomethacin might influence heterotopic ossi?cation via impairing the chondrogenic phase of endochondral ossification. ATDC5, human bone marrow stem cells (hBMSCs) and rabbit periosteal agarose cultures were employed as progenitor cell models; SW1353, human articular chondrocytes and differentiated ATDC5 cells were used as matured chondrocyte cell models. All cells were cultured in the presence of (increasing) concentrations of indomethacin. The action of indomethacin was confirmed by decreased PGE2 levels in all experiments, and was determined by specific PGE2 ELISA. Gene- and protein expression analyses were employed to determine chondrogenic outcome. Progenitor cell models differentiating in the chondrogenic lineage (ATDC5, primary human bone marrow stem cells and ex vivo periosteal agarose cultures) were treated with increasing concentrations of indomethacin and a dose-dependent decrease in gene- and protein expression of chondrogenic and hypertrophic markers as well as decreased glycosaminoglycan content was observed. Even when hypertrophic differentiation was provoked the addition of indomethacin resulted in decreased hypertrophic marker expression. Interestingly, when mature chondrocytes were treated with indomethacin, a clear increase in collagen type 2 expression was observed. Similarly, when ATDC5 cells and bone marrow stem cells were pre-differentiated to obtain a chondrocyte phenotype and indomethacin was added from this time point onwards, low concentrations of indomethacin also resulted in increased chondrogenic differentiation. Indomethacin induces differential effects on in vitro endochondral ossification, depending on the chondrocyte's differentiation stage, with complete inhibition of chondrogenic differentiation as the most pronounced action. This observation may provide a rationale behind the elusive mode of action of indomethacin in the treatment of heterotopic ossifications

The purpose of this study was to determine if the incidence of heterotopic ossification following total hip replacement decreases with increasing experience of the surgeon. A comparison of the incidence of heterotopic ossification between 196 patients having primary total hip replacement in 1989–1990 and a second group of 180 patients between 1999–2000 was performed. The surgery was done by one surgeon. Radiographs taken at least six months post operatively were assessed, and graded using both the Hamblen and Brooker classification systems. No patients were given specific prophylaxis. The groups were well matched. There was a statistically significant reduction in the incidence of Grade 2 and 3 heterotopic ossification in the 1999–2000 patient group. There did not appear to be any identifiable reason for this except increased surgeon experience. The incidence in the 1999–2000 group was well below reported figures from other studies. The incidence of heterotopic ossification following total hip replacement is falling and the fall may be related to improved surgical technique

Heterotopic ossification is a recognised complication of surgery on the hip joint that can adversely affect the outcome. The aim of this study was to determine the incidence of heterotopic ossification following surgical hip dislocation and debridement for femoro-acetabular impingement using Ganz trochanteric flip osteotomy approach. We also compared the incidence of heterotopic ossification between two subgroups of patients; in the first group, a shaver burr was used to reshape the femoral head and in the second group, an osteotome was used. Methods: We reviewed postoperative radiographs of all patients who underwent surgical hip dislocation and debridement during the period between March 2003 and July 2007. We excluded patients with radiographic follow-up of less than one year. Brooker classification was used to grade heterotopic ossifications. Results: Ninety eight patients (mean age 35 years, range 12–65 years) were included with a mean radiological follow-up of 23 months (range 12–61 months). The overall incidence of heterotopic ossification was 31%. None of the patients developed Brooker grade III or IV heterotopic ossifications. The incidence of heterotopic ossifications in the shaver burr group (n=57) and in the osteotome group (n=41) was 30% and 32%, respectively. Conclusions: Heterotopic ossification of minor grade is a common complication of surgical hip dislocation using trochanteric flip osteotomy approach. The use of a shaver burr did not result in higher rates of heterotopic ossifications despite the formation of large amounts bone debris

Background. Heterotopic ossification (HO) is lamellar bone formation in the soft tissues following trauma or joint replacement for osteoarthritis (OA). A genome wide association study of HO patients after total hip arthroplasty for OA has identified Kinesin Family Member 26B (KIF26B) as a gene associated with HO severity. KIF26B has previously been associated with HO in mice. Hypothesis and aims: We hypothesised that Kif26b regulates the osteogenic trans-differentiation of myoblasts; a possible mechanism of HO. Using an in vitro model, we wished to establish whether Kif26b is involved in HO formation and to explore the molecular mechanism. Methods. We developed CRISPR/Cas9 mediated Kif26b knockout (KO) C2C12 myoblasts. Wild type (WT) and KO cells were transdifferentiated towards an osteogenic lineage using BMP-2 for 24 days. The effect of Kif26b KO on mineralisation was quantified by calcium staining. The mean difference (±SEM) in gene expression between WT and KO lines was compared with ANOVA. Results. qPCR and western blotting confirmed Kif26b knockout. Kif26b deficient cells produced substantially less mineral versus WT in response to BMP-2 (34.71% ±3.62%, n=12, P<0.0001). At day 8 of osteogenic differentiation, loss of Kif26b abrogated Osterix (113.6 ±6.781 n=5, P<0.0001), Osteocalcin (737.9 ±84.25, n=5, P<0.0001) and Alkaline phosphatase (6989 ±365.7, n=5, P<0.0001) expression, and down regulated Runx2 (2.725 ±0.7724, n=5, P<0.0052) and Collagen type I (7.25 ±1.154, n=5, P<0.0001) expression relative to WT. The knockout cells also appeared morphologically different. Compared to WT, the Kif26b KO cells displayed a less osteoblast-like morphology during transdifferentiation. Conclusion. Our findings demonstrate an undescribed function for Kif26b as a critical regulator of pathological ossification, with a putative role in HO pathogenesis after THA

Heterotopic ossification which may develop around the elbow in patients with burns may lead to severe functional impairment. We describe the outcome of early excision of such heterotopic ossification in 28 patients (35 elbows), undertaken as soon as the patient’s general and local condition allowed. The mean age at operation was 42 years. The mean area of burnt body surface was 49%. The mean pre-operative range of movement was 22° in flexion/extension and 94° in pronation/supination. The mean time between the burn and operation was 12 months with the median being 9.5. The mean follow-up period was for 21 months. At the last review, the mean range of movement was 123° in flexion/extension and 160° in pronation/supination. Clinical evidence of recurrence was seen in four patients, occurring within the first two months after operation. Nevertheless, three of these elbows gained 60° or more in flexion/extension and in pronation/supination. Based on this experience, we recommend early surgical treatment of heterotopic ossification of the elbow in patients with severe burns

Heterotopic ossification occurring after the use of commercially available bone morphogenetic proteins has not been widely reported. We describe four cases of heterotopic ossification in patients treated with either recombinant bone morphogenetic protein 2 or recombinant bone morphogenetic protein 7. We found that while some patients were asymptomatic, heterotopic ossification which had occurred around a joint often required operative excision with good results

Introduction. Ectopic ossification (EO) at the acetabular rim has been suggested to be associated with pincer impingement and to lead to ossification of the labrum. However, this has never been substantiated with histological, radiographic and MRI findings in large cohorts of patients. We hypothesized that it is more a bone apposition of the acetabular rim and that it occurs more frequently in coxa profunda (CP) hips. Materials and Methods. In the first part, a cohort of 20 hips with this suspected ectopic rim ossification (EO) pattern were identified. The radiographic features that could be associated with this ossification pattern were described and evaluated by a histologic examination of intra-operative samples taken from the rim trimming. In the second part, we assessed the prevalence of this ectopic ossification process in a cohort of 203 patients treated for FAI. Results. Histologic examination revealed that new acetabular bone formation was either overgrowing the non-ossified labrum or moving it away from the native rim. Radiologically, this was associated with an “indentation sign” and/or a “double line sign”. There were no specimens that had shown any evidence of labral ossification. EO was found in 26 hips (18%) of the second cohort. Twenty of 26 hips (77%) with EO had CP morphology and 29% of CP hips had EO signs. In contrast, only 6 non-profunda hips (8%) were associated with EO. There was a high correlation between XR and MRI findings as >80% of XR findings were confirmed on MRI. Sixty-nine hips had CP morphology. The double line sign (N = 13), the indentation sign (N = 12) and a prominent lateral rim (N = 11) were found. Hips with an EO pattern were found in patients that were significantly older than those without EO (p = 0.01). The acetabular characteristics of the EO groups were not significantly different from the CP hips without EO. The femoral characteristics were significantly different between groups with lower neck shaft angles (128° vs 134°;p = 0,0002) and shorter femoral necks lengths (62mm vs 65mm; p = 0,04)) in the EO group. The mean Tonnis classification was not significantly different (p = 0,18). In addition, the mean acetabular cartilage degeneration status was not different between both groups (p = 0,9). Rim trimming down to the native acetabular bone was done in all cases either by arthroscopy (N = 40) or open surgical dislocation (N = 17). Discussion. Ectopic ossification of the acetabular rim predominantly occurs in CP and is associated with specific anatomic features of the proximal femur. This type of impingement seems to be different and less aggressive than other described impingement processes. The double line sign and indentation sign are highly indicative for this EO process and are indicative for a longstanding impingement problem. Trimming of the acetabular rim should be conducted

1. Osteogenesis in the osteoarthritic femoral head has been examined with radioactive . 32. P and tetracycline bone markers. 2. In advanced osteoarthritis considerable osteogenic activity was observed, particularly in osteophytes, around cysts and in some areas of bone sclerosis. 3. Two forms of osteogenesis were seen: a form of enchondral ossification, and apposition of new bone to existing bone trabeculae. 4. The findings support previous studies suggesting that rapid turnover of bone tissues occurs in advanced osteoarthritis

Purpose. The ideal timing for a Total Hip Arthroplasty (THA) remains a highly controversial topic in the treatment of displaced acetabular fractures in the elderly with damage to the articular surface of the acetabulum or femoral head. Acute THA offers early rehabilitation but a high incidence of heterotopic ossification has been reported. Its incidence and consequences on the patient's function are not clear. The goal of this study is to compare the incidence of heterotopic ossification following acute THA of acetabular fractures compared to delayed THA, and to evaluate its functional effects on the patient. Method. In this retrospective consecutive case series of acetabular fractures; 20 patients were treated with acute THA and 20 patients were treated with delayed THA after failed conservative or surgical treatment. The incidence of heterotopic ossification (using Brooker's classification) was obtained and functional outcomes were evaluated using SF-12, WOMAC, Harris Hip Score surveys. Results. Heterotopic ossification (HO) was found in 55% (13/20) in the acute THR group compared to 25% (5/20) in the delayed THA group. The relative risk of having significant HO (grades 2–3-4) when the prosthesis was done acutely was 3.4 times higher then when it was delayed. (p=0.01). Furthermore, significant difference in functional outcome was noted in the acute THA group. In fact, seven of eight (7/8) patients in the first subgroup of patients with no HO or grade 1 HO had excellent or good HHS scores. However, only three of eight (3/8) patients with grade 2 or 3 HO showed excellent or good HHS scores. The specific heterotopic ossification grade did not correlate with function. Conclusion. The incidence of HO was significantly higher in patients with acute THA compared to delayed THA for acetabular fractures. Interestingly, in the acute THA group, patients with grades 2 and 3 HO seem to have worst functional outcomes than patients with no HO or grade 1 HO

1. A clinical study has been made of heterotopic ossification in 273 patients with paraplegia of traumatic and non-traumatic origin treated at the Liverpool Paraplegic Centre over a period of twelve and a half years. 2. The literature is reviewed and theories of etiology are discussed. 3. Etiological factors have been studied. Prominent among these is inadequacy of early treatment leading to urinary infection and to the formation of pressure sores. 4. It is concluded that there is no effective treatment for established heterotopic ossification. 5. The importance of prophylactic treatment is stressed. Special emphasis is placed on adequate primary treatment, correction of hypoproteinaemia and early mobilisation

Heterotopic ossification (HO) is lamellar bone formation that occurs within tissues that do not normally have properties of ossification. The pathoaetiology of HO is poorly understood. We conducted a genome wide association study to better understand the genetic architecture of HO. 891 patients of European descent (410 HO cases) following THA for primary osteoarthritis were recruited from the UK. HO was assessed from plain AP radiographs of the pelvis. Genomic DNA was extracted, genotyped using the Illumina 610 beadchip and referenced using the 1000 Genome Project panel. HO susceptibility case-control analysis and an evaluation of disease severity in those with HO was undertaken using SNPTESTv2.3.0 on>10 million variants. We tested variants most strongly associated with HO in an independent UK THA replication cohort comprising 209 cases and 211 controls. The datasets were meta-analysed using PLINK. In the discovery cohort 70 signals with an index variant at p<9×10–5 were suggestively associated with HO susceptibility. The strongest signal lay just downstream of the gene ARHGAP18 (rs59084763, effect allele frequency (EAF) 0.19, OR1.87 [1.48–2.38], p=2.48×10–8), the second strongest signal lay within the long non-coding (LNC) RNA gene CASC20 (rs11699612, EAF 0.25, OR1.73 [1.1.40–2.16, p=9.3×10–8). In the discovery cohort 73 signals with an index variant at p<9×10–5 were associated with HO severity. At replication, 12 of the leading 14 susceptibility signals showed a concordant direction of allelic effect and 5 replicated at nominal significance. Following meta-analysis, the lead replicating susceptibility signal was the CASC20 variant rs11699612 (p=2.71×10–11). We identify consistent replicating association of variation within the LNC RNA CASC20 with HO susceptibility after THA. Although the function of CASC20 is currently unknown, possible mechanisms include transcriptional, post-transcriptional and epigenetic regulation of downstream target genes. The work presented here provides new avenues for the development of novel predictive and therapeutic approaches towards HO

Introduction. The hematoma occurring at a fracture site is known to play an important role in fracture healing. Previously, we demonstrated that fracture hematoma contained multilineage mesenchymal progenitor cells. On the other hand, the process of fracture healing is associated by two different mechanisms, intramembranous and endochondral. However, there are no reports proving the details about cellular analysis in the process of endochondoral ossification. Hypothesis. We hypothesized that one of the cell origins for endochondral ossification after fracture was hematoma. Materials & Methods. Fracture hematoma was obtained during osteosynthesis. Hematoma-derived cells were isolated and cultured for 5-weeks of chondrogenic induction followed by 2-weeks hypertrophic induction using pellet culture system. The pellets were analyzed histologically and immunohistochemically. The gene expression levels of chondrogenic, hypertrophic, osteogenic and angiogenic markers were measured by real-time PCR. Results. The histological and immunohistochemical analysis revealed that the Hematoma-derived cells differentiated into hypertrophic chondrocytes through chondrocytes, and finally differentiate into calcifying chondrocytes. The same trend was seen in the gene expression using real-time PCR analysis. Discussion & Conclusions. Our results suggest that fracture hematoma may be an origin of cells which play key roles in the process of endochondoral ossification during fracture healing

Introduction: Children with clubfoot treated by the Ponseti method of clubfoot management require anterior tibialis tendon transfer if there is persistent varus and supination deformity. However the size of bone is a determining factor in whether this transfer can be carried out. We have assesses the difference in the age at which the lateral cuneiform ossifies in normal feet compare with clubfeet. Methods: Foot x-rays of children less than 4 years old (AP view) carried out between 2003 and 2005 were obtained from the Radiology department Booth Hall Children’s Hospital. A total of 341 radiographs were analyzed. Exclusion criteria included: any condition affecting foot anatomy or weight bearing or any previous surgery (including surgery for clubfoot). The lateral cuneiform was measured with 1mm accuracy in the longest diameter. Results: We analysed the size of the lateral cuneiform in patients with and without clubfoot in relation to age. In children without clubfoot there was a R2 value of 0.517, showing a positive correlation between age and size of the bone. In children with clubfoot, R2 value was 0.207 showing no correlation between age and ossification rate of the lateral cuneiform. In addition, we compare the size of the lateral cuneiform between patients with and without clubfoot at different ages. There was a significance difference in the level of ossification of the lateral cuneiform in all age groups. In addition, a greater number of patients with no ossification of the lateral cuneiform were found amongst the clubfoot group in all age groups up to the age of 36 months. Conclusions: We have identified a delayed ossification in the lateral cuneiform in children with clubfoot when compared with normal feet. This delayed ossification should be taken into account when considering anterior tibialis tendon transfer for correction of clubfoot

Bone regeneration is an area of acute medical need, but its clinical success is hampered by the need to ensure rapid vascularization of osteogenic grafts. Vascular Endothelial Growth Factor (VEGF) is the master regulator of vascular growth and during bone development angiogenesis and osteogenesis are physiologically coupled through so-called angiocrine factors produced by blood vessels. However, how to exploit this process for therapeutic bone regeneration remains a challenge (1).

Here we will describe recent work aiming at understanding the cross-talk between vascular growth and osteogenesis under conditions relevant for therapeutic bone regeneration. To this end we take advantage of a unique platform to generate controlled signalling microenvironments, by the covalent decoration of fibrin matrices with tunable doses and combinations of engineered growth factors. The combination of human osteoprogenitors and hydroxyapatite in these engineered fibrin matrices provides a controlled model to investigate how specific molecular signals regulate vascular invasion and bone formation in vivo. In particular, we found that:

In conclusion, vascularization of osteogenic grafts is not simply necessary in order to enable progenitor survival. Rather, blood vessels can actively stimulate bone regeneration in engineered grafts through specific molecular signals that can be harnessed for therapeutic purposes.

Acknowledgements: This work was supported in part by the European Union Horizon 2020 Program (Grant agreement 874790 – cmRNAbone).

For any figures and tables, please contact the authors directly.

1. The occurrence of multiple centres of ossification in the epiphyses of the long bones of the hand and foot is shown to be frequent, and in the first metatarsal and first proximal phalanx of both hand and foot in both sexes the normal pattern of epiphysial ossification must be regarded as taking place in this way. 2. Multiple centres of ossification are shown to occur simultaneously in several epiphyses of the same hand or foot. 3. There seems to be a relationship between the shape of an epiphysial area and the pattern of ossification occurring within it. 4. Care should be taken to avoid confusing these normal patterns of ossification with radiological appearances caused by pathological changes

Heterotopic ossification (HO) is perhaps the single most significant obstacle to independence, functional mobility, and return to duty for combat-injured veterans of Operation Enduring Freedom and Operation Iraqi Freedom. Recent research into the cause(s) of HO has been driven by a markedly higher prevalence seen in these wounded warriors than encountered in previous wars or following civilian trauma. To that end, research in both civilian and military laboratories continues to shed light onto the complex mechanisms behind HO formation, including systemic and wound specific factors, cell lineage, and neurogenic inflammation. Of particular interest, non-invasive in vivo testing using Raman spectroscopy may become a feasible modality for early detection, and a wound-specific model designed to detect the early gene transcript signatures associated with HO is being tested. Through a combined effort, the goals of early detection, risk stratification, and development of novel systemic and local prophylaxis may soon be attainable.

The use of intramedullary implants in Osteogenesis Imperfecta (OI) patients to treat and prevent fractures, non-unions and limb deformities has been well established. To serve this purpose different implants are available from non-telescoping rods such as Rush rods and Kirschner wires, to telescoping rods such as the Dubow-Bailey rod, the Sheffield rod and the Fassier-Duval (FD) rod (Pega Medical, Laval, Quebec, Canada). The purpose of this study is to report on the long-term results of the femoral Fassier-Duval rod. A retrospective chart review of all patients with OI who underwent a femoral intramedullary Fassier-Duval rodding between 2002 and 2017 and followed for an average of 12 years at the Shriner's Hospital, Montreal, Quebec, Canada was performed. A total of 81 patients underwent femoral FD rodding between 2002 and 2017. Twenty-seven children undergoing 83 procedures had completed a minimum 10-year follow up with complete charts and these were included here. The average follow up time was 12 years (10–15 years). Fifty procedures were initial rodding surgeries and 30 (36.1%) were revision surgeries. A total of 69 complications were reported in the medical record and confirmed on x-ray. The 3 most common complications were a bent rod 24 (34.8%), femur fracture 16 (23.2%) and loss of telescoping in 12 (17.4%) of patients. The 3 most common cause of revision were femur fracture 16 (53.3%), broken rod 5 (16.7%) and coxa vara in 3 (10%) of patients. The average time from initial surgery to the first revision was 5.9 years. Long term performance of femoral FD rodding shows that despite improved functioning with these rods, certain complications are to be expected, most commonly a risk of femoral fracture requiring revision surgery

Introduction: Heterotopic ossification around the tip of intramedullary nail is a well-known complication of the nailing technique, since the time of Kuntscher. Nevertheless, little attention has been given to it in the current literature. Aim: The evaluation of the incidence, clinical significance and possible risk factors of this complication after intramedullary nailing of femur with reaming. Material – Method: For this purpose we studied the X-rays and medical charts of 30 patients who had undergone the above procedure at the Orthopaedic Departments of both Institutions mentioned above, between 2000 and 2002. The preoperative diagnoses were diaphyseal fracture: 13 patients, subtrochanteric fracture: 7 patients, refracture of femur: 1 patient, non-union: 5 patients, imminent fracture (due to intraosseous lesion): 2 patients, failure of previous fixation: 2 patients. In 18 cases the G.K. nail was used, whereas, in the remaining twelve, the long gamma nail was used. The patients’ follow-up ranged from 6 to 18 months (mean: 11 months). The presence of heterotopic bone around the proximal tip of the nail was graded according to the grading system of Brumback et al. Results: In 12 patients (40%) there was no development of heterotopic bone around the proximal tip of the nail. In 14 patients (47%) minimal and moderate grade of heterotopic ossification was developed (grade I and II). Finally, in 4 patients (13%) there was significant heterotopic bone formation (grade III). None of the above patients presented with any significant limitation of ipsilateral hip joint motion. There was no correlation between type of fracture, type of nail fixation, presence of concomitant injuries, nail prominence above the tip of greater trochanter and the formation of heterotopic bone. The only positive correlation was between male sex and the presence of heterotopic ossification. Conclusion: Heterotopic ossification of minimal and moderate grade is a common complication of the technique of intramedullary nailing of femur, without any further clinical significance. The formation of heterotopic bone of significant degree in the hip region, though it does not results in serious clinical problems for the patient, it will surely make future extraction of the nail difficult

Aims

Several artificial bone grafts have been developed but fail to achieve anticipated osteogenesis due to their insufficient neovascularization capacity and periosteum support. This study aimed to develop a vascularized bone-periosteum construct (VBPC) to provide better angiogenesis and osteogenesis for bone regeneration.

The work of Sloof, Ling and Gie has established allografting as a modern technique in revision total hip arthroplasty. The use of allograft enhances the local bone stock and provides a secure fixation for cemented components. Its association with the problem of heterotopic ossification has not been previously considered. The records and x-rays of 114 patients after revision hip surgery were reviewed. All had been operated upon by three Consultant Orthopaedic Surgeons using standard techniques. 35 patients had undergone revision with impaction allografting of both the femur and acetabulum, 29 had allografting of the femur only, 18 of the acetabulum alone and the final 32 patients (acting as controls) had cemented revision arthroplasty without impaction allografting. Fresh frozen allograft was used in all cases and prepared using a bone mill. No patient was given radiation or Indomethacin after their revision surgery, even if they had pre-existing heterotopic ossification. The immediate pre-operative x-rays and x-rays at least a year post-revision were assessed independently by a musculoskeletal radiologist. He was blinded to the type of revision procedure and graded the heterotopic ossification according to the Brooker Classification. Our results report the incidence of heterotopic ossification after revision hip arthroplasty with fresh frozen allograft when compared with cemented revision arthroplasty from our unit and other studies

Osteogenesis Imperfecta (OI) is a heritable bone disorder characterized by bone fragility and often caused by mutations in the Type I collagen-encoding genes COL1A1 and COL1A2. The pathophysiology of OI, particularly at the cellular level, is still not well understood. This contributes to the lack of a cure for this disorder as well as an effective preventive or management options of its complications. In the bone environment, mesenchymal stem cells (MSCs) and osteoblasts (Ob) exert their function, at least partially, through the secretion of extracellular vesicles (EV). EV is a heterogeneous group of nanosized membrane-enclosed vesicles that carry/transfer a cargo of proteins, lipid and nucleic acids from the secreting cell to its target cells. Our objective is to characterize EVs secreted by human control (HC)- and OI-MSCs and their derived Obs, with focus on their protein content. We hypothesize that there will be differences in the protein content of EVs secreted by OI-Obs compared to HC-Ob, which may indicate a deviation from healthy Ob behavior and, thus, a role in OI pathophysiology. MSCs were harvested from the adipose tissue of four COL1A1-OI and two HC patients. They were proliferated in an EV-depleted media, then induced to differentiate to extracellular matrix (ECM)-producing osteoblasts, which then gets mineralized. EVs secreted by MSCs (MSC-EV) and Obs (Ob-EV) were then purified and concentrated. Using liquid chromatography- tandem mass spectrometry, proteomic analysis of the EV groups was done. A total of 384 unique proteins were identified in all EVs, 373 were found in Vesiclepedia indicating a good enrichment of our samples with EV proteins. 67 proteins of the total 384 were exclusively or significantly upregulated (p-value < 0 .05) in OI-Ob-EV and 28 proteins in the HC-Ob-EVs, relative to each other. These two groups of differentially expressed proteins were compared by Gene Ontology (GO) analysis of their cellular compartment, molecular functions and biological processes. We observed that there were differences in the cellular origin of EV-proteins, which may indicate heterogeneity of the isolated EVs. Molecular function and biological process analyses of the HC-Ob-EV proteins showed, as expected, predominantly calcium-related activities such as extracellular matrix (ECM) mineralization. OI-Ob-EV proteins were still predominantly exhibiting ECM organization and formation functions. Annexins A1,2,4,5 and 6 were differentially and significantly upregulated by the HC-Ob-EVs. Fibronectin (FN), Fibulin-1 and −2, and Laminins (α4 & γ1), which are amongst the early non-collagenous proteins to form the ECM, were differentially and significantly upregulated in the OI-Ob-EVs. We concluded that the persistent expression of Fibronectin (FN), Fibulin-1 and −2, and Laminins in OI-Ob-EVs might indicate the presence of an immature ECM that the OI-Obs are trying to organize. ECM mineralization is largely dependent on the presence of an organized mature ECM, and this being compromised in OI bone environment, may be a contributor to the bone fragility seen in these patients. Annexins, which are calcium-binders that are vital for ECM mineralization, were significantly downregulated in the OI-Ob-EVs and this may be a further contributor to ECM mineralization impairment and bone fragility

Background. Heterotopic ossification (HO) is a known complication following total hip arthroplasty, with increased incidence in certain patient populations. Current prophylaxis options include oral non-steroidal anti-inflammatory drugs (NSAIDs) and radiation therapy, but an optimal radiation protocol has yet to be clearly defined. We performed a randomized, double-blinded clinical trial in high-risk total hip arthroplasty patients to determine the efficacy of 400 cGy versus 700 cGy doses of radiation. Methods. 147 patients at high risk for HO undergoing total hip arthroplasty (THA) at Rush-St. Luke's- Presbyterian medical center were randomized to either a single 400 cGy or 700 cGy dose of radiation. High risk was defined as diagnosis of diffuse idiopathic skeletal hyperostosis (DISH), hypertrophic osteoarthritis, ankylosing spondylitis, or history of previous heterotopic ossification. Radiation was administered over a 14 × 6 cm area of soft tissue and given on the first or second post-operative day. A blinded reviewer graded anterior-posterior (AP) and lateral radiographs taken immediately post-operatively and at a minimum of 6 months post-operatively. Progression was defined as an increase in Brooker classification from the immediate post-operative to the long-term post-operative radiograph. Operative data including surgical approach, use of cemented implants, revision surgery, and post-operative range of motion data were also collected. Results. A significantly greater portion of patients who received the 400 cGy dose demonstrated progression of HO than patients who received the 700 cGy dose. No pre-operative factors were associated with a higher rate of progression. Patients who progressed had less flexion on physical exam than patients who did not progress, but this was not clinically significant. Conclusion. To the authors' knowledge this is the largest randomized prospective study to date comparing two single-dosages of radiation treatment. 700 cGy demonstrates superiority over 400 cGy in preventing HO formation following total hip arthroplasty in high-risk patients and may be the more effective treatment in this population

Ossification of the posterior longitudinal ligament in the cervical region is generally regarded as a rare disease, though a Japanese series of 185 cases has been reported. The main symptoms arise from a myelopathy, the degree of which varies from moderate to severe, due to stenosis of the spinal canal. In order to clarify the relationship between the severity of symptoms and the cross-sectional area of ossification, axial transverse tomography of the cervical spine has been carried out on twenty-six patients at intervals of 5 millimetres over the full extent of the ossification. In this way the cross-sectional areas of the ossified tissue and of the spinal canal were calculated. The former varied from a minimum of 0.8 to a maximum of 1.8 square centimetres. In cases of severe myelopathy the ossification was mainly at the fourth and fifth cervical levels and the stenosis ration exceeded 30 per cent

Currently, there is no animal model in which to evaluate the underlying physiological processes leading to the heterotopic ossification (HO) which forms in most combat-related and blast wounds. We sought to reproduce the ossification that forms under these circumstances in a rat by emulating patterns of injury seen in patients with severe injuries resulting from blasts. We investigated whether exposure to blast overpressure increased the prevalence of HO after transfemoral amputation performed within the zone of injury. We exposed rats to a blast overpressure alone (BOP-CTL), crush injury and femoral fracture followed by amputation through the zone of injury (AMP-CTL) or a combination of these (BOP-AMP). The presence of HO was evaluated using radiographs, micro-CT and histology. HO developed in none of nine BOP-CTL, six of nine AMP-CTL, and in all 20 BOP-AMP rats. Exposure to blast overpressure increased the prevalence of HO. This model may thus be used to elucidate cellular and molecular pathways of HO, the effect of varying intensities of blast overpressure, and to evaluate new means of prophylaxis and treatment of heterotopic ossification. Cite this article: Bone Joint J 2015;97-B:572–6

PURPOSE OF THE STUDY. To assess if prolonged use of Bisphosphonates in Osteogenesis Imperfecta alters the pattern of femoral fractures. Osteogenesis Imperfecta (OI) has been treated with Bisphosphonates for many years with some clear clinical benefits. In adult cohorts there are reports of a new pattern of atraumatic subtrochanteric fractures seen with Bisphosphonate treatment. SUMMARY OF METHODS. This study assesses the location of femoral fractures in a cohort of 176 OI patients treated with Bisphosphonates over a two year period and compares it to a historical control group of 45 managed prior to the advent of this specific treatment. SUMMARY OF RESULTS. review of the radiological digital archive identified 16 femoral fractures in this time period in the Bisphosphonate treated group. All but 2 were within 5cm of the lesser trochanter, and 50% within 3cm. In comparison, the historical group, composed of 26 femoral fractures had a more widespread fracture pattern with the most frequent location being the mid-diaphysis. Many of the sub-trochanteric fractures in the treatment group occurred with minimal trauma, and in some cases without any injury. CONCLUSION. It appears that concerns in the adult osteoporotic population treated with Bisphosphonates are mirrored in Osteogenesis Imperfecta. It is possible that the high bending moments in the proximal femur together with altered mechanical properties of cortical bone secondary to the use of this group of drugs, mediated by abnormal osteoclast and osteoblast function, increase the risk of this type of injury and warrants further investigation

From 1981 to 1986 we treated 413 patients for acute spinal-cord injuries. We reviewed 356 patients followed for a minimum of two years of whom 71 (20%) developed heterotopic ossification around one or more joints. Heterotopic ossification occurred more often in male patients (23%) than in female (10%), and was most frequent in the 20- to 30-year age group. It was also more common after injuries of the lower cervical or thoracic spine than after those of the lumbar spine. Patients with severe neurological deficits (Frankel grades A and B) showed significantly more heterotopic ossification but there was no correlation with the number or severity of associated head and limb injuries. Serum calcium levels did not change significantly in either group for 30 weeks after injury, but the erythrocyte sedimentation rate and the alkaline phosphatase level were significantly increased at six weeks in patients with heterotopic ossification

We retrospectively reviewed 89 consecutive patients (45 men and 44 women) with a mean age at the time of injury of 58 years (18 to 97) who had undergone external fixation after sustaining a unilateral fracture of the distal humerus. Our objectives were to determine the incidence of heterotopic ossification (HO); identify risk factors associated with the development of HO; and characterise the location, severity and resultant functional impairment attributable to the presence of HO. . HO was identified in 37 elbows (42%), mostly around the humerus and along the course of the medial collateral ligament. HO was hazy immature in five elbows (13.5%), mature discrete in 20 (54%), extensive mature in 10 (27%), and complete bone bridges were present in two elbows (5.5%). Mild functional impairment occurred in eight patients, moderate in 27 and severe in two. HO was associated with less extension (p = 0.032) and less overall flexion-to-extension movement (p = 0.022); the flexion-to-extension arc was < 100º in 21 elbows (57%) with HO compared with 18 elbows (35%) without HO (p = 0.03). HO was removed surgically in seven elbows. . The development of HO was significantly associated with sustaining a head injury (p = 0.015), delayed internal fixation (p = 0.027), the method of fracture fixation (p = 0.039) and the use of bone graft or substitute (p = 0.02).HO continues to be a substantial complication after internal fixation for distal humerus fractures. Cite this article: Bone Joint J 2014;96-B:1681–7

We present nine patients (five men and four women) who underwent surgical excision of clinically significant heterotopic ossification at the elbow. They also received perioperative radiation therapy using total doses between 600 and 1000 cGy. Five received fractionated radiotherapy, with two fractions of 500 cGy applied on the first two postoperative days, and the remaining four were irradiated with single doses of 600 and 700 cGy. After a mean period of observation of 7.7 months (6 to 13) none had radiological recurrence of heterotopic ossification and eight showed clinical improvement. Assessment of the functional outcome showed a mean improvement in the Morrey score from 33.3 to 84.5 points indicating a high therapeutic efficacy of prophylactic irradiation

1. The epiphyses of the metatarsal heads of 250-gramme rabbits were separated at the zone of cell columns, stripped of perichondrium, labelled with tritiated thymidine and transplanted into the back muscles of the same animals. 2. Endochondral ossification started in the grafts at four days, was well established by seven days and progressed until fourteen days, the end of the study. 3. Progressive passage of the label down the zone of cell columns and into the hypertrophic zone was observed. 4. The tritiated-. 3. H thymidine label had disappeared from the cartilage cells by ten days. No labelling was observed in the bone cells at any stage. 5. It was not possible to demonstrate from the experiment that growth plate chondrocytes are precursors of osteoblasts in the process of endochondral ossification in rabbits

Purpose of Study. To see if the addition of a locking plate to FD rod fixation of osteogenesis imperfecta confers extra strength and allows earlier mobilisation. Introduction. Osteogenesis imperfecta is a heterogeneous group of disorders with congenital osseous fragility. The goal of surgery is to minimise the incidence of fracture and correct deformity. The concept of multilevel osteotomies and intramedullary fixation with a non-extendable nail was popularised by Sofield and Millar in 1959. The Bailey Dubow telescoping nail was introduced in 1963. The Fassier-Duval (FD) telescoping nail is a more recent design inserted via smaller incisions, in conjunction with percutaneous osteotomies. However there are still problems. Often the medullary canal may be too narrow to harbour a nail of adequate size for the body. Furthermore they do not give significant rotational control, which is compounded by the elasticity of the soft tissues. Methods. We treated two patients with Osteogenesis imperfecta with supplementary unicortical locked plating in addition to intramedullary fixation with FD rods. Results. The patients both underwent femoral fixation. Both had deformity and previous femoral stress fractures treated non operatively. One patient, aged 24, was non ambulant pre-operatively. She was allowed to transfer without a brace immediately post operatively. The other patient, aged 64 years and ambulant indoors, initially had additional fixation with a non- locking semitubular plate that went onto fail, therefore had revision fixation with a locking plate. She was asked to bear weight as tolerated in a brace immediately post-op. Conclusion. Classically, plates and screws have been avoided in Osteogenesis imperfecta due to the predisposition to fracture at the ends of the plate. We have found that the extra fixation enables extra strength where the nail size is small, and helps control rotation in the post-operative period, allowing earlier mobility

1. A case of ossification and partial rupture of the tendo calcaneus is reported. 2. The possible etiology of the ossification and its relationship to the rupture is discussed

We have developed an animal model to examine the formation of heterotopic ossification using standardised muscular damage and implantation of a beta-tricalcium phosphate block into a hip capsulotomy wound in Wistar rats. The aim was to investigate how cells originating from drilled femoral canals and damaged muscles influence the formation of heterotopic bone. The femoral canal was either drilled or left untouched and a tricalcium phosphate block, immersed either in saline or a rhBMP-2 solution, was implanted. These implants were removed at three and 21 days after the operation and examined histologically, histomorphometrically and immunohistochemically. Bone formation was seen in all implants in rhBMP-2-immersed, whereas in those immersed in saline the process was minimal, irrespective of drilling of the femoral canals. Bone mineralisation was somewhat greater in the absence of drilling with a mean mineralised volume to mean total volume of 18.2% (. sd. 4.5) versus 12.7% (. sd. 2.9, p < 0.019), respectively. Our findings suggest that osteoinductive signalling is an early event in the formation of ectopic bone. If applicable to man the results indicate that careful tissue handling is more important than the prevention of the dissemination of bone cells in order to avoid heterotopic ossification

Introduction: The study of appearance and development of the different ossification nuclei of the skeleton in the diverse segments of the locomotor apparatus is relevant for fields of medicine, such as Human Anatomy, Paediatry, Endocrinology, Forensic Medicine, Traumatology and Orthopaedic Surgery, among others. A number of studies show significant differences regarding their results due to the heterogeneity of methods and scientific and geographic fields originating each series. The present study is intended to show the age of appearance and complete fusion of the different ossification nuclei of the first radio of the foot in a present Mediterranean sample of children and its relation with several morphometric and clinical parameters. Material and Methods: We report a retrospective study where 971 x-ray dorso-plantar images from 225 patients were analysed. A descriptive and qualitative assessment allowed us to determine the existence or lack of each ossification nucleus of the first radio of the foot. Risser’s scale, adapted by us, was applied in the following way: 0, lack; I, rudimentary nucleus; II, well formed nucleus; III, partial fusion to diaphysis; IV, complete fusion. Likewise, a statistical analysis was performed relating the ages of appearance and fusion of each nucleus with the forefoot morphology (digital and metatarsal formulae) and the main pathologies motivating the x-ray examination (traumatism, our control group; flatfoot; hallux valgus; clubfoot). Results: Data about the age of appearance and fusion of each nucleus of the first radio of the foot were quantified. As a general rule, the age of appearance of each nucleus was earlier in girls. A delay in the age of appearance of the proximal metatarsal epiphysis in clubfoot patients (3.33 years) was observed in comparison with the control group (1.96 years). In general, there was no relation between sex and the fusion (partial and total) of each nucleus of the first radio of the foot. The exception was the age of appearance of the distal metatarsal epiphysis (when this incostant nucleus was present), earlier in boys (9.49 years) than girls (11.21 years). A delay in the age of fusion of the proximal and distal metatarsal epiphyses and the proximal phalanx epiphysis was observed in hallux valgus patients. In patients with egyptian foot, there seems to be a delay in the age of fusion of the distal metatarsal and distal phalanx epiphyses. Conclusions: The different ages of appearance and partial and total fusion of each ossification secondary nucleus of the first radio of the foot are detailed in the present comunication. A delay in the age of fusion of the secondary nucleus of the first radio of the foot would contribute to determine significantly forefoot morphology (egyptian formula) and even its pathology (hallux valgus)

We have carried out a prospective, randomised study of prophylaxis for heterotopic ossification (HO) comparing indomethacin for 7 and 14 days, acetylsalicylic acid, and fractional (4 × 3 Gy) or single exposure of 5 or 7 Gy irradiation after operation. We initially had 723 patients (733 hip replacements), but after withdrawals there were 685 hips of which 18.4% developed HO; 14% were grade I, 2.9% grade II and 1.5% grade III of the Brooker classification. We compared the results between these groups with those of a matched control series and found that indomethacin, 2 × 50 mg for 7 and 14 days, and postoperative irradiation of 4 × 3 Gy or 1 × 7 Gy, significantly reduced the development of HO compared with the control group. Patients in the acetylsalicylic acid group and those with a single irradiation of 5 Gy after operation developed significantly more ossification than those in the indomethacin and other irradiation groups. We suggest the use of 2 × 50 mg of indomethacin with mucoprotection for seven days as prophylaxis against HO after total hip replacement for all patients. A single irradiation of 7 Gy is recommended for patients who have developed HO after previous operations or to whom administration of indomethacin is contraindicated

220 consecutive hip resurfacing procedures were reviewed at a minimum of two years follow up to assess the incidence of heterotopic ossification and its effect on function and clinical outcome. We also reviewed the pre-operative diagnosis, gender and previous surgery. The overall percentage of heterotopic ossification was 58.63%. The incidence of Brooker 1 was 37.27%, Brooker 2 was 13.18% and Brooker 3 was 8.18%. Male osteoarthritics had the highest incidence of heterotopic bone formation. Three males underwent excision of heterotopic bone, two for pain and stiffness and one for decreased range of movement. Both antero-posterior and lateral radiographs were reviewed for evidence of heterotopic bone formation. 12.7% had no evidence of heterotopic bone formation on one view but clearly had on the second view. Overall we found no evidence that heterotopic bone formation affected the clinical or functional outcome of the hip resurfacing at a mean of 3 years follow up

Wear debris from implant interfaces is the major factor leading to periprosthetic osteolysis. Fibroblast-like synoviocytes (FLSs) populate the intimal lining of the synovium and are in direct contact with wear debris. This study aimed to elucidate the effect of Ti particles as wear debris on human FLSs and the mechanism by which they might participate in the bone remodeling process during periprosthetic osteolysis. FLSs were isolated from synovial tissue from patients, and the condition medium (CM) was collected after treating FLSs with sterilized Ti particles. The effect of CM was analyzed for the induction of osteoclastogenesis or any effect on osteogenesis and signaling pathways. The results demonstrated that Ti particles could induce activation of the NFκB signaling pathway and induction of COX-2 and inflammatory cytokines in FLSs. The amount of RANL in the conditioned medium collected from Ti particle-stimulated FLSs (Ti CM) showed the ability to stimulate osteoclast formation. The Ti CM also suppressed the osteogenic initial and terminal differentiation markers for osteoprogenitors, such as alkaline phosphate activity, matrix mineralization, collagen synthesis, and expression levels of Osterix, Runx2, collagen 1α, and bone sialoprotein. Inhibition of the WNT and BMP signaling pathways was observed in osteoprogenitors after the treatment with the Ti CM. In the presence of the Ti CM, exogenous stimulation by WNT and BMP signaling pathways failed to stimulate osteogenic activity in osteoprogenitors. Induced expression of sclerostin (SOST: an antagonist of WNT and BMP signaling) in Ti particletreated FLSs and secretion of SOST in the Ti CM were detected. Neutralization of SOST in the Ti CM partially restored the suppressed WNT and BMP signaling activity as well as the osteogenic activity in osteoprogenitors. Our results reveal that wear debris-stimulated FLSs might affect bone loss by not only stimulating osteoclastogenesis but also suppressing the bone-forming ability of osteoprogenitors. In the clinical setting, targeting FLSs for the secretion of antagonists like SOST might be a novel therapeutic approach for preventing bone loss during inflammatory osteolysis.

Electron Microscopy and Synchrotron analysis of Heterotopic Ossification (HO) from blast-related amputees' has shown that HO is bone with a disorganised structure and altered remodelling. This research performs mechanical testing of HO to understand its biomechanical properties in an attempt to create an accurate model to predict its morphological appearance. The hypothesis of this work is that HO is mechanically mediated in its formation. Synchrotron mechanical analysis of HO samples was performed to measure Young's modulus, ultimate strength and density distribution. A novel algorithm based on Wolf's law was implemented in a Finite Element (FE) analysis model of HO to take into account the differing mechanical and biological properties measured and the presence of HO outside the skeletal system. An HO modeling factor, which considers boundary conditions, and regulates recruitment of the soft tissue into bone formation, results in a re-creatable formation of HO within the soft tissues, comparable to the appearance of HO seen in military amputees. The results and model demonstrates that certain types of HO are under the control of endogenous and exogenous mechanical stimulus. HO can thus be mechanically exploited in the casualty management and rehabilitation process to achieve better clinical outcomes

From 1987 to 1991, we treated 53 patients with 54 fractures of the acetabulum by reconstruction through a posterior or an extended iliofemoral surgical approach. For prophylaxis against heterotopic ossification we used perioperative irradiation and indomethacin. Indomethacin was given as daily doses of 25 mg started within 24 hours of operation and continued for four weeks. Irradiation was by either 1200 cGy in three daily doses or by a single 700 cGy dose on the first postoperative day. All patients were followed for at least one year postoperatively and the severity of heterotopic ossification was recorded using the Brooker classification and correlated with hip mobility. The combination therapy proved very effective; 44 fractures showed no heterotopic ossification and ten showed Brooker class I. The functional results were good and there were no complications of this therapy. Irradiation with 1200 cGy did not appear to offer any therapeutic advantage over the 700 cGy dose

Aims

Alcoholism is a well-known detrimental factor in fracture healing. However, the underlying mechanism of alcohol-inhibited fracture healing remains poorly understood.

Aims

Transcription factor nuclear factor kappa B (NF-κB) plays a major role in the pathogenesis of chronic inflammatory diseases in all organ systems. Despite its importance, NF-κB targeted drug therapy to mitigate chronic inflammation has had limited success in preclinical studies. We hypothesized that sex differences affect the response to NF-κB treatment during chronic inflammation in bone. This study investigated the therapeutic effects of NF-κB decoy oligodeoxynucleotides (ODN) during chronic inflammation in male and female mice.

Children with osteogenesis imperfecta (OI) frequently present with coxa vara (CV). Skeletal fragility, severe deformity and limited fixation options make this a challenging condition to correct surgically. Our study aimed to determine the efficacy of the Fassier technique to correct CV and determine the complication rate.

Retrospective, descriptive case series from a tertiary hospital. We retrospectively reviewed records of a cohort of eight children (four females, 12 hips) with OI (6/8 Sillence type III, 2/8 type IV) who had surgical treatment with Fassier technique for CV between 2014 and 2020.

Inclusion Criteria: All patients with CV secondary to OI treated surgically with Fassier technique.

Exclusion Criteria: Patients older than 18 years; Patients with CV treated non-operatively or by surgical technique different to Fassier technique.

Data relating to the following parameters was collected and analyzed: demographic data, pre- and postoperative neck shaft angle (NSA), complications and NSA at final follow-up.

The mean age at operation was 5.8 years (range 2–10). The mean NSA was corrected from 96.8° preoperatively to 137º postoperatively. At a mean follow-up of 38.6 months, the mean NSA was maintained at 133°, and 83% (10/12) of hips had an NSA that remained greater than 120°. There was a 42% (5/12) complication rate: three Fassier–Duval rods failed to expand after distal epiphyseal fixation was lost during growth; one Rush rod migrated through the lateral proximal femur cortex with recurrent coxa vara; and one Rush rod migrated proximally and required rod revision.

The Fassier technique effectively corrected CV in children with moderate and progressively deforming OI. The deformity correction was maintained in the short term. The complication rate was high, but mainly related to the failed expansion of the Fassier–Duval rods.

Bone morphogenetic proteins (BMPs) have been widely investigated for treating non-healing fractures. They participate in bone reconstruction by inducing osteoblast differentiation, and osteoid matrix production.¹ The human recombinant protein of BMP-7 was among the first growth factors approved for clinical use. Despite achieving comparable results to autologous bone grafting, severe side effects have been associated with its use.² Furthermore, BMP-7 was removed from the market.³ These complications are related to the high doses used (1.5-40 miligrams per surgery)² compared to the physiological concentration of BMP in fracture healing (in the nanogram to picogram per milliliter range).⁴ In this study, we use transcript therapy to deliver chemically modified mRNA (cmRNA) encoding BMP-7. Compared to direct use of proteins, transcript therapy allows the sustained synthesis of proteins with native conformation and true post-translational modifications using doses comparable to the physiological ones.⁵ Moreover, cmRNA technology overcomes the safety and affordability limitations of standard gene therapy i.e. pDNA.⁶ BMP-7 cmRNA was delivered using Lipofectamine™ MessengerMAX™ to human mesenchymal stromal cells (hMSCs). We assessed protein expression and osteogenic capacity of hMSCs in monolayer culture and in a house-made, collagen hydroxyapatite scaffold. Using fluorescently-labelled cmRNA we observed an even distribution after loading complexes into the scaffold and a complete release after 3 days. For both monolayer and 3D culture, BMP-7 production peaked at 24 hours post-transfection, however cells transfected in scaffolds showed a sustained expression. BMP-7 transfected hMSCs yielded significantly higher ALP activity and Alizarin red staining at later timepoints compared to the untransfected group. Interestingly, BMP-7 cmRNA treatment triggered expression of osteogenic genes like OSX, RUNX-2 and OPN, which was also reflected in immunostainings. This work highlights the relevance of cmRNA technology that may overcome the shortcomings of protein delivery while circumventing issues of traditional pDNA-based gene therapy for bone regeneration.

Acknowledgement: This work has been performed as part of the cmRNAbone project and has received funding from the European Union's Horizon 2020 research and innovation programme under the Grant Agreement No 874790.

Extensive bone defects, caused by severe trauma or resection of large bone tumors, are difficult to treat. Regenerative medicine, including stem cell transplantation, may provide a novel solution for these intractable problems and improve the quality of life in affected patients. Adipose-derived stromal/stem cells (ASCs) have been extensively studied as cell sources for regenerative medicine due to their excellent proliferative capacity and the ability to obtain a large number of cells with minimal donor morbidity. However, the osteogenic potential of ASCs is lower than that of bone marrow-derived stromal/stem cells. To address this disadvantage, our group has employed various methods to enhance osteogenic differentiation of ASCs, including factors such as bone morphogenetic protein or Vitamin D, coculture with bone marrow stem cells, VEGF transfection, and gene transfer of Runx-2 and osterix. Recently, we mined a marker that can predict the osteogenic potential of ASC clones and also investigated the usefulness of the molecule as the enhancer of osteogenic differentiation of ASCs as well as its mechanism of action. Through RNA-seq gene analysis, we discovered that GSTT1 was the most distinguished gene marker between highly osteogenic and poorly osteogenic ASC clones. Knockdown of GSTT1 in high osteogenic ASCs by siGSTT1 treatment reduced mineralized matrix formation while GSTT1 overexpression by GSTT1 transfection or GSTT1 recombinant protein treatment enhanced osteogenic differentiation of low osteogenic ASCs. Metabolomic analysis confirmed significant changes of metabolites related to bone differentiation in ASCs transfected with GSTT1. A high total antioxidant capacity, low levels of cellular reactive oxygen species and increased GSH/GSSG ratios were also detected in GSTT1- transfected ASCs. GSTT1 can be a useful marker to screen the highly osteogenic ASC clones and also a therapeutic factor to enhance the osteogenic differentiation of poorly osteogenic ASC clones.

Critical size bone defects are frequently caused by accidental trauma, oncologic surgery, and infection. Distraction osteogenesis (DO) is a useful technique to promote the repair of critical size bone defects. However, DO is usually a lengthy treatment, therefore accompanied with increased risks of complications such as infections and delayed union.

Herein, we developed an innovative intramedullary biodegradable magnesium (Mg) nail to accelerate bone regeneration in critical size bone defect repair during DO.

We observed that Mg nail induced almost 4-fold increase of new bone formation and over 5-fold of new vessel formation at 2 weeks after distraction. Mg nail upregulated the expression of calcitonin gene-related peptide (CGRP) in the new bone as compared with the DO alone group. We further revealed that blockade of the sensory nerve by overdose capsaicin blunted Mg nail enhanced critical size bone defect repair during the DO process. Moreover, inhibitors/antagonist of CGRP receptor, FAK, and VEGF receptor blocked the Mg nail stimulated vessel and bone formation.

In summary, we revealed, for the first time, a CGRP-FAK-VEGF signaling axis linking sensory nerve and endothelial cells, which may be the main mechanism underlying Mg-enhanced critical size bone defect repair when combined with DO, suggesting a great potential of Mg implants in reducing DO treatment time for clinical applications.

Estimations of serum alkaline phosphatase were carried out prospectively on a series of patients having a total hip replacement. The levels of serum alkaline phosphatase before operation indicated a group of patients who subsequently developed heterotopic ossification. Levels of this enzyme after operation did not indicate those patients who were developing heterotopic ossification

Endochondral ossification involves a well ordered sequence of cellular events. Chondrocytes change their morphology and functions and are ultimately removed by the process of apoptosis. A variety of apoptotic-related signals have been characterised. These include Fas receptor (FasR)/Fas ligand (FasL), p53 and Bcl family. However, there is little known regarding the activity of these signals in the process of fracture healing. The purpose of this study was to investigate mRNA expression of apoptotic signals using RNase protection assay (RPA) and immunohistochemistry in endochondral bone formation. BALB/C mice aged 8 to 10 weeks were used for this study. First, a transverse fracture was made in the right tibia. Mice were euthanised at 1, 2 and 3 weeks postfracture. The calluses were harvested and studied for the expression of caspase-8, a key enzyme of apoptosis, and apoptosis inducers: tumour necrosis factor-alpha (TNF-α) and its receptor p55, FasL and Fas receptor (FasR), and TNF-related apoptosis-inducing ligand (TRAIL). Four mice at each timepoint were used for immunostaining of fracture callus. Sections were incubated with primary antibody then labelled by avi-din-biotin complex method. Another four to ten tibiae were used for RPA. Fracture callus were harvested and snap frozen in liquid nitrogen. RNA was isolated by TRI reagent and BCP, and mRNAs expression of apoptotic signals were detected. At each timepoint, mRNA of caspase-8, TNF-α, p55, FasL,FasR and TRAIL were detected by RPA. Immunostainings clearly showed that those apoptotic-related proteins were expressed by callus chondrocytes. Cartilaginous callus is replaced by woven bone in endochondral ossification. In this process, chondrocytes should be removed by the process of apoptosis in which death factors are elaborated directly in both an autocrine and paracrine manner

1. Osteogenesis imperfecta is characterised by osseous fragility. Patients with the "congenita" form have multiple fractures before birth; those with the "tarda" form have osteoporosis, and develop multiple fractures and milder deformities of long bones at varying times after birth. 2. The frequency of blue sclera, dentinogenesis imperfecta, bruising, ligamentous laxity, and deafness are recorded in sixty patients seen at the Hospital for Sick Children, Toronto, from 1949 to 1969. The major orthopaedic deformities of long bones were antero-lateral bowing of femur and anterior bowing (sabre shin) of tibia. 3. The incidence of scoliosis (40 per cent) is high in osteogenesis imperfecta. Two patients, one in Toronto and one in Seattle, have had Harrington instrumentation and fusion for this. 4. Fractures were commonest in the femur and tibia and few in the cervical spine and femoral neck. There were four cases of disturbing hyperplastic callus formation. 5. Twenty-one patients were operated on for long bone deformities and recurrent fractures by the Sofield technique. Despite extensive subperiosteal dissection non-union is rare (four cases). Fourteen of twenty-one patients so treated are able to walk, with or without assistance. Surgical intervention to both correct and prevent deformities is justified. 6. Patients with osteogenesis imperfecta compensated for their disability by reasonable academic achievement and by choosing a sedentary occupation

This study evaluates factors related to myelopathic symptoms in patients with ossification of the posterior longitudinal ligament (OPLL). A total of 87 patients with OPLL were included. Of these, 53 (Group I) had no symptoms or presented with neck pain and radiculopathy and 34 (Group II) had myelopathic symptoms. Gender, age, and history of trauma were evaluated in the two groups. The range of movement of the cervical spine was measured using plain radiographs. The number of involved segments, type of OPLL, and maximal compression ratio were analysed using CT and signal change in the spinal cord was evaluated using MRI. The patients’ age was found to be significant (p = 0.001). No difference was found between gender and the range of movement in the two groups. The maximum compression of the spinal canal showed a difference (p = 0.03). The signal change of the spinal cord was different between the two groups. In patients with OPLL of the cervical spine, myelopathic symptoms are not related to the range of movement or the number of involved segments.

Elongating rods have been used in the management of Osteogenesis Imperfecta (OI) for the last 50 years; complication rates have been high in many reviews of available techniques. The functional outcomes and complications of a cohort of 22 Osteogenesis Imperfecta patients treated with 66 Sheffield Telescopic Intramedullary Rods at an average of 19 years post-initial surgery are analysed. The revision rate was 35% for any reason, 20% excluding revisions for rods separating due to growth. Re-operation other than revisions occurred in 10 rods (15%). Mobility was significantly better in the initial post-operative period (p=0.0015), this difference maintained in adulthood (p=0.0077). Back pain was the most frequent symptom. Symptoms related to the insertion technique across the knee and ankle were rare but those related to femoral trochanteric entry were common. Physeal damage following surgery was not experienced and all rods elongated. All patients were satisfied with the outcome of their surgeries. SF-36 scores were significantly different for physical functioning domains, social functioning and vitality in comparison to normal population values, but comparable to other studies of OI. The outcomes of this technique are satisfactory in adulthood; re-operation rates are high but related mainly to outgrowing the rods. Concerns regarding insertion with this fixed device at the knee and ankle are not founded, although proximal femoral fixation remains a problem

Throughout this work data have been gathered favouring the concept that the metaphysial vascular arrangement is primarily related to the process of enchondral ossification, and has very limited, if any, responsibility for the nourishment of the growth cartilage. The present evidence favours the suggestion that when the chondrocytes of the column have become too far separated from their source of nourishment (the epiphysial vessels) they and their surrounding matrix suffer changes which prepare them for the process of calcification. At least calcium and phosphate ions will be required for this to take place. The proximity of the vessel and also the fact that it is not isolated by a membrane at its very end suggests a profuse interchange of fluids with the surrounding area

In this work the role of the blood vessels surrounding the epiphysial growth plate has been studied. The nutritional dependence of the proliferative cells on the epiphysial vessels has been established whereas the metaphysial vessels were seen to take part in calcification and ossification at the metaphysis. As it does not seem likely that the blood circulating in the two systems of vessels had a different constitution, particularly in hormones and vitamins, it seems permissible to assume that it is the characteristics, particularly in shape and number, of such vessels that make growth the orderly process it is, with the repeated birth of a cell at the top of a column and burial at the bottom end. But, despite this undeniable role of the vessels, growth depends on the ability of the cartilage cell to form a matrix which, in due course, will be avid for apatite crystals

In this series, 15 patients with ossification of the posterior longitudinal ligament underwent anterior decompression to relieve moderate or severe myelopathy, which in 11 included urinary disturbance. The operation consisted of partial resection of the vertebrae, release of the ossified plaque from the surrounding tissue and the insertion of an iliac bone graft. The extent of ossification was confirmed by computerised tomography before and after operation. The plaque was completely detached and moved forward in half of the patients, but only partially moved in the remainder. Symptoms improved considerably. Urinary disturbance disappeared in all patients, but sensory disturbance was left in most. Two patients had prolonged symptoms which were not relieved despite the complete release of the ossified defect

Purpose: Heterotopic ossification is a recognised complication after total hip arthroplasty. Prevalence can reach 53%, particularly if prophylaxis is not given, leading to postoperative pain and limiting the functional prognosis. Non-steroidal antiinflammatory drugs have proven efficacy but also present the risk of gastroduodenal toxicity making postoperative administration hasardous. Recently, selective COX-2 inhibitors have been shown to have a similar antiinflammatory activity with a clear reduction in gastrointestinal disorders. We hypothesised that selective COX-2 inhibitors could be as effective as classical NSAID for the prevention of heterotopic ossifications. Material and methods: This clinical trial was conducted according to a prospective randomised protocol comparing a group of patients given prophylaxis with Celecoxib (Celebrex®) and another group of patients given ibuprofen (Brufen®). All patients scheduled for total elective prostheses were radomised in a prospective manner to one of the two groups, either Celecoxib 200mg b.i.d. or ibuprofen 400mg t.i.d. for ten immediate postoperative days. Radiological assessment was performed by two independent investigators blinded to the study (an orthopaedic surgeon and a radiologist) who scored calcifications according to the Brooker classification (type I to IV) at three months after surgery. Reproducibility of radiogram reading was tested and analysed with a kappa test K=0.74). Results: Two hundred ten patients were randomised and 73 have had their three-month radiograms. The Cele-coxib group included 37 patients: 24 with Brooker stage 0, eleven with stage 1, two with stage 2. The ibuprofren group included 42 patients, 15 with Brooker 0, 16 with Brooker 1; nine with Brooker 2 and two with Brooker 3. The statistical analysis will be performed at the end of this study (June 2002). Discussion: The preliminary results show that Celecoxib appears to have the same efficacy as ipubrofen for the prevention of heterotopic ossification after total hip arthroplasty. There was a clear trend in favour of Celecoxib

Previous reports of the prevalence of Heterotopic Ossification (HO) in limbs from UK blast-related amputees from Afghanistan, is demonstrated to be 57.1%. With the end of UK military operations in Afghanistan in 2014 the aim of this study is establish the rate of HO, assess causality demographics and ascertain risk factors for the formation of HO during the entire period of operations in Afghanistan. Military databases, case notes and radiographs were scrutinised to quantify and qualify the prevalence and risk factors for the formation of HO. 256 servicemen sustained 398 military trauma related amputations. The overall prevalence of HO was 65.9%. Significant (p<0.05) risks identified for the formation of HO included a blast mechanism of injury, a zone of injury the same as the subsequent amputation, and an increased number of debridements prior to closure. Positive correlation existed between the number of amputations and the presence and grade of HO (p=0.04). HO presents clinical problems to military blast injury patient populations. This study demonstrates that both a blast mechanism of injury and an increased injury load are key factors in the increased prevalence of HO seen in military trauma

Heterotopic ossification (HO) is the formation of bone in extraskeletal sites. It is a major problem for combat-related casualties with 64% of such patients showing radiological evidence of the disease. Of these, 19% require surgical excision. Current prophylaxis is problematic due to poor efficacy and unsuitability in a military setting. Our novel anti-HO strategy is to use an inorganic reagent to inhibit the deposition of HA and disperse any pre-formed mineral. Literature review identified several potentially effective agents. These were tested for their ability to disperse solid monoliths of HA. In addition, a standard HA synthetic reaction was performed in the presence of each agent to establish their inhibiting activity. One reagent (a condensed phosphate) dispersed a solid monolith of HA by 38% (mass loss) over 30 days. This reagent was also shown to inhibit HA crystal synthesis yield by 28%. Early work on a hydrogel delivery system has produced favourable results. These preliminary data demonstrate proof of concept that HA may be dispersed and its formation inhibited by a non-toxic polyphosphate. This work will form the justification for development into in vitro osteogenic cell culture models and animal HO models

The objective of this study was to evaluate the functional outcome of the elbow joint in patients with heterotopic ossification of the elbow joint who underwent surgical excision of pathologic bone. From 5/1994 to 12/2006, 24 patients (33 joints) with heterotopic ossification of the elbow joint were evaluated. All patients were attended in the Intensive Care Unit (ICU). The patient\’s age ranged from 19–48 years (mean; 32 years) The median ICU hospitalization was 3 weeks. In nine patients both elbows were affected. Unilateral involvement was equally noticed to the right (seven cases) and the left elbow (eight cases). The DASH SCORE and the range of motion were used for the evaluation of the results. All patients underwent surgical treatment in order to extract heterotopic bone and to improve the range of motion of the affected elbow joint. Postoperatively 18 out of 33 operated elbow joints (54.54%) demonstrated improvement of the range of motion, whereas no improvement was observed in the remaining 15 elbow joints (45.45%). Higher DASH SCORE was obtained in 19 out of 24 patients (79.17%). Surgical excision of the ectopic bone around the affected elbow significantly improves the range of motion of the joint providing better use of the upper extremity and therefore a superior quality of life in these patients

Ossification of the ligamentum flavum and secondary spinal-cord compression were produced experimentally in mice by implanting bone morphogenetic protein (BMP) in the lumbar extradural space. The ligamentum flavum became hypertrophied and ossified, and protruded into the spinal canal. The thickness of the ossified ligament increased gradually with time, leading to compression and deformation of the spinal cord which showed various degrees of degeneration. Demyelination occurred in the posterior and lateral white columns and neuronal loss or chromatolysis in the grey matter. The pathological findings in the experimental animals closely resemble those found in the human disease and suggest that BMP may be a causative factor of ossification of the ligamentum flavum in man. This experimental model may be useful for the study of myelopathy caused by gradual spinal-cord compression

Osteogenesis is key to fracture healing and osteointegration of implanted material. Modification of surfaces on a nanoscale has been shown to affect cell interaction with the material and can lead to preferential osteogenesis. We hypothesised that osteogenesis could be induced in a heterogeneous population of osteoprogenitor cells by circular nanopits on a material surface. Furthermore, we intended to assess any correlation between nanopit depth and osteoinductive potential. The desired topographies were embossed onto polycaprolactone (PCL) discs using pre-fabricated nickel shims. All pits had a diameter of 30μm and investigated pit depths were 80nm, 220nm and 333nm. Scanning electron microscopy confirmed successful embossing and planar controls were shown to be flat. A bone marrow aspirate was obtained from the femoral neck of a healthy adult undergoing a hip replacement. After establishing a culture, cells were seeded onto the PCL discs, suspended in basal media and incubated. Samples were fixed and stained after three and 28 days. Cells were stained for the adhesion molecule vinculin after three days. Lowest concentrations of vinculin were seen in the planar control group. Osteoprogenitor cells on the shallowest pits, 80nm, had larger and brighter adhesion complexes. After 28 days, osteocalcin and osteopontin expression were used as markers of cell differentiation into an osteoblastic phenotype. 220nm deep pits consistently produced cells with the highest concentrations of osteopontin (p = 0.017) with a similar trend of osteocalcin expression. Cells on all topographies had higher expression levels than the planar controls. We demonstrated stimulation of osteogenesis in a heterogeneous population of osteoprogenitor cells. This cell mix is similar to that present in fracture healing and after reaming for intramedullary devices or uncemented implants. All nanopit depths gave promising results with an optimum depth of 220nm after 28 days

Two men, aged 21 and 50 years, were seen with ossification of the patellar tendon after injury to the knee in adolescence. They complained of pain and had patella alta. Large bony masses were excised from below the affected patellae. The patellar tendon was then reconstructed using a Leeds-Keio ligament. The results at six and ten years, respectively, were good, with neither patient having pain or an extension lag

Heterotopic ossification (HO) of the hip after injury to the central nervous system can lead to joint ankylosis. Surgery is usually delayed to avoid recurrence, even if the functional status is affected. We report a consecutive series of patients with HO of the hip after injury to the central nervous system who required surgery in a single, specialised tertiary referral unit. As was usual practice, they all underwent CT to determine the location of the HO and to evaluate the density of the femoral head and articular surface. The outcome of surgery was correlated with the pre-, peri- and post-operative findings. In all, 183 hips (143 patients) were included of which 70 were ankylosed. A total of 25 peri-operative fractures of the femoral neck occurred, all of which arose in patients with ankylosed hips and were associated with intra-articular lesions in 18 and severe osteopenia of the femoral head in seven. All the intra-articular lesions were predicted by CT and strongly associated with post-operative complications. The loss of the range of movement before ankylosis is a more important factor than the maturity of the HO in deciding the timing of surgery. Early surgical intervention minimises the development of intra-articular pathology, osteoporosis and the resultant complications without increasing the risk of recurrence of HO

Purpose: The purpose is to evaluate the clinical outcome of patients who underwent excision of motion-limiting radioulnar heterotopic ossification (HO) as a complication of a distal biceps tendon repair. The hypothesis is that there are no measurable clinical losses that persist after excision. Method: Between 1996 and 2005, eight consecutive patients were identified. All were treated with heterotopic ossification excision using a standard surgical technique, a single dose of postoperative radiation, four weeks of indomethacin, and a standard rehabilitation protocol. These individuals were studied and compared to a matched cohort of eight patients who underwent a distal biceps tendon repair with a similar surgical technique that was uncomplicated. At minimum follow-up of one year, all patients in both groups completed the Disabilities of the Arm, Shoulder and Hand (DASH) outcomes questionnaire, were tested for range of motion in elbow flexion/extension and forearm supination/pronation, and underwent biceps isokinetic dynamometry strength testing including elbow flexion and forearm supination. Both peak strength as well as muscle fatigue were quantified. Range of motion and strength comparisons were made both between groups and side-to-side within each group. Results: There were no patients lost to follow-up. At mean follow-up of 56 months, there were no cases of nerve palsy, recurrence, or other complications. All patients in the HO group returned to their original occupation without restrictions. Mean arc of forearm rotation in this group increased from 19 to 151 degrees (p=0.01), but pronation (65 degrees) was less than the unaffected arm (p=0.01). There were no side-to-side differences in motion within the control group, or differences in peak strength or fatigue within either group. When comparing the two groups, there was a trend towards worse functional outcomes on DASH in the HO group than the controls (p=0.09). No differences were identified between the HO and control groups with respect to isokinetic torque, endurance strength or range of motion. Conclusion: When patients develop motion-limiting heterotopic ossification after distal biceps tendon repair, surgical resection can safely lead to a functional recovery of elbow and forearm strength and motion. Level III Evidence, Case-control

The purpose of this study was to investigate the outcome after surgical therapy of patients suffering from HO of the hip after treatment in ICU. We retrospectively examined 39 patients with heterotopic ossification of the hip (18 bilateral and 21 unilateral). All patients have had history of ICU treatment for several reasons, such as craniocerebral injury (35 patients-90%), 2 patients with Guillain-Barre syndrome (5%), 1 patient with pulmonary druse (2.5%), and 1 patient with inflammatory bowel disease (2.5%). They all underwent surgical removal of HO and postoperative irradiation therapy. On the basis of plain radiographic findings, we evaluated the recurrent ossification after an 18-month follow-up period. The evaluation of the average 18-months follow-up period showed relief of pain and clear improvement of range of motion in most of our patients. Specifically, improvement in the range of movement was observed in 41 hip joints (71.93%) in contrast to 16 hip joints (28.07%) that did not show any alteration post-operatively. No lesion re-occurrence was observed. There was only one complication of peroneal nerve paresis following HO excision. The majority of our patients that were treated with surgical excision of the ectopic bone around the hip joint significantly improved their range of joint movement and were relieved from pain. Surgical excision seems to provide a superior quality of life in these patients, as they have a high risk for major complications due to their poor level of mobility

Background: A 9- year-old child with osteogenesis imperfecta and severe cervical kyphosis associated with wedged vertebrae and progressive neurological deterioration is presented. There is no report of upper cervical kyphosis associated with wedged vertebrae in osteogenesis imperfecta in the literature. We discuss the methods and difficulties in the surgical management of this condition and to highlight the appropriate surgical approach. Methods: Methods:A 9-year-old girl presented with progressive cervical kyphosis and quadriparesis. At the age of 3 years she underwent posterior cervical fusion (C1–C6) for instability and deformity. Radiological and laboratory investigations confirmed the diagnosis of osteogenesis imperfecta. Radiographs of the cervical spine revealed a kyphotic deformity of 120° Magnetic Resonance Imaging (MRI) and Computerised Tomography (CT) scans showed anterior cord compression due to wedged vertebrae at C3 and C4. MRI-Angiography was performed pre-operatively to identify the anatomical position of the vertebral arteries. A modified anterolateral approach to the upper cervical spine was performed. Anterior C3 and C4 corpectomies with interbody fusion with cage and plate fixation was carried out. Results: Postoperatively the patient made a full neurological recovery and significant correction of the deformity was achieved and correction was maintained at final follow-up. Conclusion: Cervical kyphotic deformity in Osteogenesis Imperfecta is uncommon. Association of this condition with wedged vertebrae is rare. Surgical decompression of the upper cervical spine with severe kyphosis is a challenging problem. Which surgical approach should be used is controversial? There are difficulties exposing wedged vertebrae by a standard anterior or chin split approach to perform vertebrectomy. Costo-transversectomy has been used successfully in patients with Gibbous deformity in the thoracic spine but due the presence of vertebral artery in the cervical spine posterolateral approach is impossible. We have used a modified anterolateral approach to overcome this problem. Spinal stabilisation in children with Osteogenesis Imperfecta and poor bone quality is another challenge. We have used a small diameter MOSS cage with maxillofacial plate and screws to achieve stabilisation and fusion. The purpose of this report is to highlight the importance of diagnosis of progressive cervical kyphotic deformity in children with osteogenesis imperfecta and also to describe the difficulties encountered with surgical management of this condition