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

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

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

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 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

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

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

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

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

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

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

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

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

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.

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.

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

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

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

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

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.

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

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.

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

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

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

1. Two boys complaining of pain in the ankle were shown to have centres of separate ossification for the medial malleoli. These were present bilaterally, but discomfort was unilateral. 2. In one, followed for fifteen months, the extra centre became wholly incorporated into the normal lower tibial epiphysis. 3. in a series of 100 children between the ages of six and twelve, without any known disease or injury of the ankles, radiographs showed that 20 per cent had a separate medial malleolar centre on one side. In 13 per cent this finding was present bilaterally. In one child a separate lateral malleolar centre was also found. 4. The significance of this finding is discussed, and it is considered to be a normal variant. 5. Occasionally one of these centres may remain unfused into adult life. Attention is drawn to the possible implications of this persistence

We report a 72-year-old patient with thoracic myelopathy due to isolated ossification of the ligamentum flavum at T9-T10. Severe paraparesis had developed before the lesion was identified when thinning of a segment of the lower thoracic spinal cord was suspected on a second MRI examination. The diagnosis was then established by CT

Old calcified fibrin coagula are frequently found in simple bone cysts. They provide a scaffold on which new bone is laid down, in a process analogous to endochondral ossification. It is suggested that these coagula are derived in substantial part from the plasma-like contents of the cyst, after the release of plasma-clotting factors as the result of injury. Major haemorrhage is not involved and in many cases there is no antecedent fracture. The phenomenon is not seen in other common cystic conditions of bone and its recognition is thus helpful in the histological diagnosis of simple bone cyst. Cystic bone infarcts and their possible confusion with simple bone cysts are also briefly discussed

We studied radiographs of 125 children (105 boys, 20 girls) with unilateral Legg-Calvé-Perthes’ disease to examine the epiphyseal development of the femoral head in the contralateral (unaffected) hip. The epiphyseal height (EH) and width (EW) of the unaffected hip were measured on the initial anteroposterior pelvic radiograph. In 109 of the patients (87.2%) the EH was below the mean for normal Japanese children and a significantly small EH (below −2 . sd. s) was observed in 23 patients (18.4%). By contrast, the EW of most patients (95.2%) lay within ± 2 SDs of normal values except for six with a significantly small EW. A strong positive linear correlation (R = 0.87) was observed in the EH:EW ratio in the patients. A smaller EH than expected for EW in our series indicated epiphyseal flattening of the femoral head in Legg-Calvé-Perthes’ disease. Our findings support the hypothesis that a delay in endochondral ossification in the proximal capital femoral epiphysis may be associated with the onset of Perthes’ disease

We report 14 cases of symptomatic ossification of the posterior longitudinal ligament (OPLL) diagnosed in non-oriental men between 1978 and 1985. All 14 patients had incomplete spinal cord syndromes due to OPLL in the cervical spine and had been referred undiagnosed from other institutions. Twelve had severe myelopathy and seven were wheelchair-bound before OPLL was diagnosed, while six patients had had operations elsewhere for their neurological dysfunction. There was a close association between OPLL and diffuse idiopathic skeletal hyperostosis (Forestier's disease) on plain radiographs, seven patients having both disorders. Enhanced CT scans proved to be the best diagnostic method for the localisation of cord compression, and magnetic resonance imaging, used on four recent cases, provided the best visualisation of the extent of involvement in the sagittal plane. We aim to heighten awareness of OPLL in non-orientals, in whom the clinical features, histological characteristics, and radiographic patterns are very similar to those of oriental patients

1. Serial radiographs of fifty-two normal children's feet, taken at six-monthly intervals between two and five years, have been reviewed. 2. Twenty-one naviculars have been injected post-mortem and the vascularisation of the growing bone investigated. 3. The records of sixty-two children with a diagnosis of Köhler's disease have been studied. 4. It is submitted that abnormal ossification results from compression of the bony nucleus at a critical phase during growth of a navicular bone whose appearance is delayed. 5. Symptoms in Köhler's disease are related to further compression which produces vascular changes in the bony nucleus. Consequent ischaemia is followed by hyperaemia which produces local pain, tenderness and swelling. 6. Two radiographic types of Köhler's disease are described and attributed to variations in the basic vascular pattern of the affected bone. 7. The usual complete recovery of the navicular is ascribed in part to the basic arrangement of numerous radially penetrating vessels

Indomethacin is commonly administered for the prophylaxis of heterotopic ossification (HO) after the surgical treatment of acetabular fractures. Non-steroidal anti-inflammatory drugs such as indomethacin, have been associated with delayed healing of fractures and mechanically weaker callus. Our aim was to determine if patients with an acetabular fracture, who received indomethacin for prophylaxis against HO, were at risk of delayed healing or nonunion of any associated fractures of long bones. We reviewed 282 patients who had had open reduction and internal fixation of an acetabular fracture. Patients at risk of HO were randomised to receive either radiation therapy (XRT) or indomethacin. Of these patients, 112 had sustained at least one concomitant fracture of a long bone; 36 needed no prophylaxis, 38 received focal radiation and 38 received indomethacin. Fifteen patients developed 16 nonunions. When comparing patients who received indomethacin with those who did not, a significant difference was noted in the rate of nonunion (26% v 7%; p = 0.004). Patients with concurrent fractures of the acetabulum and long bones who receive indomethacin have a significantly greater risk of nonunion of the fractures of the long bones when compared with those who receive XRT or no prophylaxis

We report a prospective, randomised, blinded clinical comparison of the use of indomethacin or radiation therapy for the prevention of heterotopic ossification (HO) in 75 adults who had open reduction and internal fixation of acetabular fractures through either a Kocher-Langenbeck, a combined ilioinguinal and Kocher-Langenbeck, or an extended iliofemoral approach. Indomethacin, 25 mg, was given three times daily for six weeks. Radiation with 800 cGy was delivered within three days of operation. Plain radiographs were reviewed and given Brooker classification scores by three independent observers who were unaware of the method of prophylaxis. One patient died from unrelated causes and two were lost to follow-up, leaving 72, 33 in the radiation group and 39 in the indomethacin group, available for evaluation at a mean of 12 months (6 to 48). There was no significant difference in the two groups in terms of age, gender, injury severity score, estimated blood loss, delay to surgery, head injury, presence of femoral head dislocation, or operating time, and no complications due to either method of treatment. The final extent of HO was already present by six weeks in all patients who were followed up. Three patients in the radiation group and five who received indomethacin developed HO of Brooker grade III. Two patients in the indomethacin group developed Brooker IV changes; both had failed to receive proper doses of the drug. Cochran-Armitage analysis showed no significant difference between the two treatment groups as regards the formation of HO. Indomethacin and single-dose radiation therapy are both safe and effective for the prevention of HO after operation for acetabular fractures. Radiation therapy is, however, approximately 200 times more expensive than indomethacin therapy at our institution and has other risks

An eight-year-old boy presented with massive pseudomalignant heterotopic ossification around the upper femur. The mass was completely excised because of severe pain, systemic illness and a flexion contracture at the hip. Symptomatic improvement was swift, but two weeks later the mass had recurred and was even more extensive. During the subsequent 18 months of conservative management he has been free of pain and there has been progressive resorption and remodelling of the heterotopic bone. There is now no limitation of physical activity and movement at the hip is full

Aims

LY3023414 is a novel oral phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor designed for advanced cancers, for which a phase II clinical study was completed in March 2020; however, little is known about its effect on bone modelling/remodelling. In this study, we aimed to explore the function of LY3023414 in bone modelling/remodelling.

Objectives

Up to 10% of fractures result in undesirable outcomes, for which female sex is a risk factor. Cellular sex differences have been implicated in these different healing processes. Better understanding of the mechanisms underlying bone healing and sex differences in this process is key to improved clinical outcomes. This study utilized a macrophage–mesenchymal stem cell (MSC) coculture system to determine: 1) the precise timing of proinflammatory (M1) to anti-inflammatory (M2) macrophage transition for optimal bone formation; and 2) how such immunomodulation was affected by male versus female cocultures.

Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides with limited coding potential, which have emerged as novel regulators in many biological and pathological processes, including growth, development, and oncogenesis. Accumulating evidence suggests that lncRNAs have a special role in the osteogenic differentiation of various types of cell, including stem cells from different sources such as embryo, bone marrow, adipose tissue and periodontal ligaments, and induced pluripotent stem cells. Involved in complex mechanisms, lncRNAs regulate osteogenic markers and key regulators and pathways in osteogenic differentiation. In this review, we provide insights into the functions and molecular mechanisms of lncRNAs in osteogenesis and highlight their emerging roles and clinical value in regenerative medicine and osteogenesis-related diseases.

Cite this article: J. Zhang, X. Hao, M. Yin, T. Xu, F. Guo. Long non-coding RNA in osteogenesis: A new world to be explored. Bone Joint Res 2019;8:73–80. DOI: 10.1302/2046-3758.82.BJR-2018-0074.R1.

Early total hip replacement (THR) for acetabular fractures offers accelerated rehabilitation, but a high risk of heterotopic ossification (HO) has been reported. The purpose of this study was to evaluate the incidence of HO, its associated risk factors and functional impact. A total of 40 patients with acetabular fractures treated with a THR weres retrospectively reviewed. The incidence and severity of HO were evaluated using the modified Brooker classification, and the functional outcome assessed. The overall incidence of HO was 38% (n = 15), with nine severe grade III cases. Patients who underwent surgery early after injury had a fourfold increased chance of developing HO. The mean blood loss and operating time were more than twice that of those whose surgery was delayed (p = 0.002 and p < 0.001, respectively). In those undergoing early THR, the incidence of grade III HO was eight times higher than in those in whom THR was delayed (p = 0.01). Only three of the seven patients with severe HO showed good or excellent Harris hip scores compared with eight of nine with class 0, I or II HO (p = 0.049). Associated musculoskeletal injuries, high-energy trauma and head injuries were associated with the development of grade III HO.

The incidence of HO was significantly higher in patients with a displaced acetabular fracture undergoing THR early compared with those undergoing THR later and this had an adverse effect on the functional outcome.

Cite this article: Bone Joint J 2013;95-B:95–100.

Objectives

Bone tissue engineering is one of the fastest growing branches in modern bioscience. New methods are being developed to achieve higher grades of mineral deposition by osteogenically inducted mesenchymal stem cells. In addition to well established monolayer cell culture models, 3D cell cultures for stem cell-based osteogenic differentiation have become increasingly attractive to promote in vivo bone formation. One of the main problems of scaffold-based osteogenic cell cultures is the difficulty in quantifying the amount of newly produced extracellular mineral deposition, as a marker for new bone formation, without destroying the scaffold. In recent studies, we were able to show that ^99mTc-methylene diphosphonate (^99mTc-MDP), a gamma radiation-emitting radionuclide, can successfully be applied as a reliable quantitative marker for mineral deposition as this tracer binds with high affinity to newly produced hydroxyapatite (HA).

Objectives

Many in vitro studies have investigated the mechanism by which mechanical signals are transduced into biological signals that regulate bone homeostasis via periodontal ligament fibroblasts during orthodontic treatment, but the results have not been systematically reviewed. This review aims to do this, considering the parameters of various in vitro mechanical loading approaches and their effects on osteogenic and osteoclastogenic properties of periodontal ligament fibroblasts.

The continual cycle of bone formation and resorption is carried out by osteoblasts, osteocytes, and osteoclasts under the direction of the bone-signaling pathway. In certain situations the host cycle of bone repair is insufficient and requires the assistance of bone grafts and their substitutes. The fundamental properties of a bone graft are osteoconduction, osteoinduction, osteogenesis, and structural support. Options for bone grafting include autogenous and allograft bone and the various isolated or combined substitutes of calcium sulphate, calcium phosphate, tricalcium phosphate, and coralline hydroxyapatite. Not all bone grafts will have the same properties. As a result, understanding the requirements of the clinical situation and specific properties of the various types of bone grafts is necessary to identify the ideal graft. We present a review of the bone repair process and properties of bone grafts and their substitutes to help guide the clinician in the decision making process.

Cite this article: Bone Joint J 2016;98-B(1 Suppl A):6–9.

Objectives

To assess the structure and extracellular matrix molecule expression of osteogenic cell sheets created via culture in medium with both dexamethasone (Dex) and ascorbic acid phosphate (AscP) compared either Dex or AscP alone.

We have attempted to summarise in a short space investigations that have occupied several years, and we realise that whatever the merits of such an effort the results can only be modest. Many important aspects of the osteogenetic process still remain a mystery and thus are subjected to theory and controversy. Such is the case with this constant attendant at osteogenesis which is alkaline phosphatase. But of one thing we are certain, namely that bone is an organised "soft" tissue of which only part has been made rigid by the deposit of calcium salts. The organiser is the osteogenetic vessel from which springs the syncytial frame of cells and their connections on which the bone architecture is established. Endothelial cell, intermediate cell, osteoblast, osteocyte, osteoclast; these constitute the normal sequence of cellular phylogeny in the constant elaboration and removal of the bone substance. The initial cells on which the whole process rests are those of the capillary-sinusoid vessel which is responsible for providing the transudates on which the life and health of the whole syncytium depends.

If our findings were confirmed, a better understanding of the nature and characteristics of primitive malignant bone tumours would be possible. Each type of tumour from endothelioma to malignant osteoclastoma, including reticulum-cell sarcoma and osteogenic sarcoma, would be initiated by a different cell of the syncytium, but in its monstrous deviation from the normal would still preserve most of the characteristics of its healthy ancestor. Thus the endothelioma causes bone expansion, bone reaction and even bone necrosis, but not proper bone formation, whereas the osteogenic sarcoma or osteoblastoma forms bone; and with the same fidelity to their origin osteoclasts are seen in the malignant osteolytic tumour.

Over thirty years ago the late Sir Arthur Keith (1927) expressed his suspicion that the cells which assume a bone-forming role are derived from the endothelium of the capillary system. We hope we have contributed to show that his suspicion was right.

From this work it may be concluded that persistent compression affects the growth plate by interference with the blood flow on one or both sides of the growth cartilage.

Despite exertion of the same pressure upon both sides of the growth plate, only the metaphysial side was readily affected in the early stages, for, as long as no damage was caused to the epiphysial side of the growth cartilage, the lesions were fully reversible.

Interference with growth was directly proportionate to the damage caused by compression to the epiphysial side of the growth plate and, in general, to the duration of compression.

The first signs of interference with the metaphysial side of the plate were the lack of vascular progression and concomitant retardation of calcification.

When severe degeneration was not present the growth cartilage recovered within four days.

The matrix was ready for calcification all the time, as shown by the extremely rapid calcification occurring soon after the compression had ceased and the vessels were able to reach their proper place.

It seems justified to believe that the first hypertrophic cell not to be calcified after removal of the clamp is the one around which the matrix has not yet changed sufficiently to have an affinity for the apatite crystals. As in moderate compression, the division of the proliferative cells continues and it seems it must be the age, or even more likely the distance from the transudate coming from the epiphysial side of the growth cartilage that conditions the maturity of the cell, which prepares the field for calcification and thus initiates the osteogenic process.

Views similar to this have been advanced by Ham (1957) and his school.

We report a postal survey of 59 families of children with osteogenesis imperfecta. From the 51 replies we collected data on developmental milestones and walking ability and related them to the Sillence and the Shapiro classifications of osteogenesis imperfecta. Twenty-four of the patients had been treated by intramedullary rodding.

Both classifications helped to predict eventual walking ability. We found that independent sitting by the age of ten months was a predictor for the use of walking as the main means of mobility with 76% attaining this. Of the patients who did not achieve sitting by ten months, walking became the main means of mobility in only 18%. The developmental pattern of mobility was similar in the rodded and non-rodded patients.

In a clinical, radiological and biochemical study of forty-two patients from Oxford with osteogenesis imperfecta, it was found that patients could be divided simply into mild, moderate and severe groups according to deformity of long bones. In the severe group (seventeen patients) a family history of affected members was uncommon and fractures began earlier and were more frequent than in the mild group (twenty-two patients); sixteen patients in the severe group had scoliosis and eleven had white sclerae; no patients in the mild group had white sclerae or scoliosis. Radiological examination of the femur showed only minor modelling defects in patients in the mild group, whereas in the severe group five distinct appearances of bone (thin, thick, cystic and buttressed bones, and those with hyperplastic callus) were seen. The polymeric (structural) collagen from skin was unstable to depolymerisation in patients in the severe group, but normal in amount, whereas the reverse was found in the mild group. This division according to long bone deformity may provide a basis for future research more useful than previous classifications.

1. The venographic findings in clinical primary osteoarthritis are described.

2. Experimental venous engorgement, of the knee joint and of healing fibular fractures, results in accelerated bone formation and disturbed cartilage formation.

3. Changes in pH, ppCO₂, and PPO₂ are indicated as the chemical means by which chondrogenesis and osteogenesis can be altered.

4. It is suggested that chronic venous stress in joints is a causal factor in primary osteoarthritis.

1. Two girls with non-familial osteogenesis imperfecta who subsequently developed osteosarcoma of the femur are described. One is of special interest in that there were multiple bone metastases.

2. It is suggested that the tumours arose spontaneously and were not related to the underlying bone disorder.

3. Because of the relative frequency of hyperplastic callus formation in osteogenesis imperfecta it is most important that adequate biopsy material of any suspicious lesion is examined because the early clinical picture may be indistinguishable from a tumour.

1. Fifty operations of fragmentation and rodding in the long bones of patients with osteogenesis imperfecta are reported.

2. The technique of the operation is described and a modification of Sofield's original method is suggested.

3. The results and complications of treatment are described.

1. The pattern of tritiated thymidine labelling in the cells of the epiphysial cartilage and metaphysis of the tibia in the rat is described for intervals of one hour to twenty-eight days after injection.

2. The region of dividing cells is defined and evidence given for a zone of reserve cells at the top of the cartilage columns.

3. The difficulties of quantitative grain count studies are discussed, and some approximate values are given for the generation time and mitotic cycle periods of the cartilage plate cells.

4. Some further evidence is given about the life cycles of the osteoblast and the osteoclast.

This paper describes a procedure of activating osteogenesis by the use of the "petal" technique. The osteogenetic effect of these "petals" has been established in experimentally produced fractures and pseudarthroses in rats by radiographical, biomechanical, mechanical and histological examinations.

The conventional concept of the osteogenetic activity of bone transplants is discussed.

The authors feel that this method will find its clinical application in the operative treatment of pseudarthroses and, in selected cases, of fractures that are known for their tendency to unite slowly.

We report the results of distraction osteogenesis (callotasis) for the reconstruction of extensive defects after the excision of skeletal tumours in the limbs. Bone transport was performed in ten patients (five osteosarcomas and five giant-cell tumours), shortening-distraction in three (two osteosarcomas and one Ewing’s sarcoma), and distraction osteogenesis combined with an intramedullary nail to reduce the time of external fixation in six (three osteosarcomas, two chondro-sarcomas, and one malignant fibrous histiocytoma).

The mean length of the defects after excision of the lesion was 8.4 cm. The mean external fixation index was 39.5 days/cm for the group treated by bone transport, 34.1 days/cm for the shortening-distraction group, and 24.0 days/cm for the group treated by distraction and an intramedullary nail. Functional evaluation gave excellent results in 12 patients, good in five and fair in two. There were ten complications in 19 patients, all of which were successfully treated.

We also classified reconstruction using distraction osteogenesis into five types based on the location of the defects after resection of the tumour: type 1, diaphyseal; type 2, metaphyseal; type 3, epiphyseal; type 4, subarticular reconstruction; and type 5, arthrodesis.

Our results suggest that reconstruction using distraction osteogenesis provides bone which will develop sufficient biomechanical strength and durability. It is beneficial in patients with an expectation of long-term survival and in growing children.

A case of hyperplastic callus formation is reported in a girl of eleven; several bones were affected. There were no associated fractures. She is believed to be suffering from a mild non-familial type of osteogenesis imperfecta without blue sclerotics and presents multiple bony excrescences unassociated with injury. The relevant literature is reviewed. The effect of a trial of treatment with A.C.T.H. and with deep x-ray is reported.

Results are given of a study of four cases of osteogenesis imperfecta using biophysical methods comprising microradiography, microscopy using polarised light, and x-ray diffraction. Rebuilding of bone tissue was infrequent in the material studied and has been shown to occur in an abnormal manner. The mineralisation of the bone is more uniform than is found in normal bone. The collagen has an abnormal organisation and is sparse. The ultrastructure of bone salts and their orientation are as in normal bone.

Most patients with dominantly inherited osteogenesis imperfecta have blue sclerae and relatively mild symptoms. However, in a small group of families the patients have normal sclerae and this disorder has been classified as Type 4 osteogenesis imperfecta. This paper reports the clinical and radiographical features of 48 patients from 16 families with Type 4 osteogenesis imperfecta and compares the findings with those of the classical disorder with blue sclerae (Type 1 osteogenesis imperfecta). The two types are similar in usually causing a mild disease but with a wide range of severity, and in both types the rate of fracture declines in adolescence. There are, however, some significant differences apart from the colour of the sclerae. In Type 4 the first fracture more commonly occurs at birth, dentinogenesis imperfecta is more frequent than in Type 1 and bruising and nose-bleeds are less common. As in Type 1, the radiographic appearances of the bones may be normal. It is important that Type 4 osteogenesis imperfecta should be recognised because of the need for competent genetic counselling, because the management may be different from that appropriate for Type 1 and because it may be mistaken for idiopathic juvenile osteoporosis or child abuse.

1. Six cases of development of heterotopic bone around joints in association with paralysis from intracranial lesions are presented. It is suggested that such bone may occur more commonly than is realised.

2. The features of these cases are very similar to those seen in association with paraplegia.

3. Extensive new bone is usually associated with fixed contractures.

4. Operation is hazardous in paraplegia but should not necessarily be so in other paralytic conditions.

5. In the presence of returning motor function excision of the bone, allowing correction of the deformity together with some movement, is a worthwhile procedure. In the hip, osteotomy alone usually requires plaster fixation with the attendant risks of venous thrombosis. Previous excision of the bone allows internal fixation of the osteotomy with early mobilisation.

1. In the experiments undertaken autogenous vesical mucosal transplants were made in guinea-pigs. The transplanted mucosa proliferates and forms a nodule. Central necrosis of the nodule and the secretion of the proliferating epithelium combine to form a cyst filled with a viscous fluid.

2. Before the cyst is well defined some of this fluid diffuses into the sub-epithelial connective tissue, producing areas of tissue oedema which later are transformed into translucent hyaloid islands. With further condensation of the collagen fibres, these areas are converted into primitive bone. The hyaloid islands act as a bone precursor. Bone always formed in the wall of the cyst within thirty days except in cases of sepsis or death of the transplant, when there was no osteogenesis. Homografts of vesical mucosa were found unreliable in their capacity to induce bone.

3. The results of the histochemical investigation and radiographic diffraction of the hyaloid areas suggest that the proliferating mucosa is the source of the inducing agent.

4. Bone can be induced only in sites where a primitive vascular connective tissue is growing and where there exists an adequate blood supply.

5. The rapid rate of osteogenesis can be seen in the radiographs of induced bone in radial defects. The electron-microscopic study of the induced bone at three weeks confirmed that osteoid had been formed so quickly that calcification had not yet taken place.

6. The relationship between the bone induced by transplanting vesical epithelium and the formation of urinary calculi is discussed and their common origin postulated.

We describe a patient in whom an initially intact sciatic nerve became rapidly encased in heterotopic bone formed in the abductor compartment after reconstruction of the posterior wall of the acetabulum following fracture. Prompt excision and neural release followed by irradiation and administration of indometacin resulted in a full neurological recovery and no recurrence 27 months later.

In patients with traumatic brain injury and fractures of long bones, it is often clinically observed that the rate of bone healing and extent of callus formation are increased. However, the evidence has been unconvincing and an association between such an injury and enhanced fracture healing remains unclear. We performed a retrospective cohort study of 74 young adult patients with a mean age of 24.2 years (16 to 40) who sustained a femoral shaft fracture (AO/OTA type 32A or 32B) with or without a brain injury. All the fractures were treated with closed intramedullary nailing. The main outcome measures included the time required for bridging callus formation (BCF) and the mean callus thickness (MCT) at the final follow-up. Comparative analyses were made between the 20 patients with a brain injury and the 54 without brain injury. Subgroup comparisons were performed among the patients with a brain injury in terms of the severity of head injury, the types of intracranial haemorrhage and gender. Patients with a brain injury had an earlier appearance of BCF (p < 0.001) and a greater final MCT value (p < 0.001) than those without. There were no significant differences with respect to the time required for BCF and final MCT values in terms of the severity of head injury (p = 0.521 and p = 0.153, respectively), the types of intracranial haemorrhage (p = 0.308 and p = 0.189, respectively) and gender (p = 0.383 and p = 0.662, respectively).

These results confirm that an injury to the brain may be associated with accelerated fracture healing and enhanced callus formation. However, the severity of the injury to the brain, the type of intracranial haemorrhage and gender were not statistically significant factors in predicting the rate of bone healing and extent of final callus formation.

Objectives

The need for bone tissue supplementation exists in a wide range of clinical conditions involving surgical reconstruction in limbs, the spine and skull. The bone supplementation materials currently used include autografts, allografts and inorganic matrix components; but these pose potentially serious side-effects. In particular the availability of the autografts is usually limited and their harvesting causes surgical morbidity. Therefore for the purpose of supplementation of autologous bone graft, we have developed a method for autologous extracorporeal bone generation.

The role of three genetically distinct collagen types in the formation of endochondral bone and in calcification and resorption of cartilage has been assessed. Using antibodies specific to types I, II and III collagen we have demonstrated in the embryonic chick tibia that endochondral bone formation began with deposition of type III collagen in lacunae of hypertropic chondrocytes by invading bone-marrow-derived cells. This was followed by the deposition of type I collagen, which is the collagenous constituent of endochondral osteoid. At later stages of development endochondral osteoid was found in the epiphysial growth plate in apparently intact lacunae of hypertrophic chondrocytes; this indicated that the latter might contribute to the synthesis of osteoid type I collagen. Immuno-histological staining for collagen types, and von Kossa staining for calcium phosphate on parallel sections, demonstrated that type I and type II collagen matrices were substrates for calcification. Endochondral bone (with type I collagen) was found on scaffolding of both uncalcified and calcified cartilage (with type II collagen), indicating that calcification of endochondral osteoid and of the underlying cartilage occurred independentyl. Spicules of endochondral cancellous bone of a four-week-old chick contained a core of calcified type II collagen.

1. It has been shown that in experimental rickets the well known changes in the epiphysial cartilage which so seriously affect growth are accompanied by severe interference with the progress of the metaphysial vessels into the growth cartilage.

2. Further evidence has been found that, by the repeated increase in their number, the cartilage cells occupying the more distal part of the proliferative segment become more and more affected by their remoteness from the epiphysial vessels, which supply the transudates to these cells. At a given distance these cells are affected and change, becoming hypertrophic, with increasingly large vacuolae, and are rich in glycogen and alkaline phosphatase.

3. The hypertrophic cells alter the nature of the intercellular substance they deposit and this becomes calcifiable. Provided that the metaphysial vessels are situated at an appropriate distance–about three cell capsules away–and that the blood has its necessary components, calcification occurs.

4. Calcification produces the advancing, rigid multitubular structure within which the progressing metaphysial vessels are protected.

5. The interruption of calcification by the withdrawal of fat-soluble vitamins breaks down the whole mechanism of growth and stops the vessels growing into their proper position. The administration of the required vitamins re-establishes the normal sequence of events and allows the vessels to play their decisive role in osteogenesis.

6. Any mechanism which causes the interruption of the vascular progression, whether from metaphysial ischaemia (Trueta and Amato 1960), from severe pressure (Trueta and Trias 1961) or from lack of calcification by withdrawing the fat-soluble vitamins, equally interrupts growth.

It has been shown in experimental animals that the living cells in a bone autograft can make an important contribution to osteogenesis. However, some common clinical techniques, such as the topical use of antibiotic powders on grafts or on the graft bed, are likely to damage or kill the cells. In this experimental study in rats, bone isografts dusted with chloramphenicol or methicillin powder or with Polybactrin spray before subcutaneous implantation produced little or no new bone over a period of two weeks whereas untreated, control grafts showed abundant osteogenesis, as did grafts pretreated with solutions of antibiotics. The effect of short-term storage of the grafts for 3 to 24 hours in air, saline or culture medium before implantation was also examined. Grafts stored in culture medium generally did as well as, or better than, fresh control grafts whereas immersion in saline inhibited osteogenesis. The importance of these results for clinical bone grafting is discussed.

The October 2023 Spine Roundup. 360. looks at: Cutting through surgical smoke: the science of cleaner air in spinal operations; Unlocking success: key factors in thoracic spine decompression and fusion for ossification of the posterior longitudinal ligament; Deep learning algorithm for identifying cervical cord compression due to degenerative canal stenosis on radiography; Surgeon experience influences robotics learning curve for minimally invasive lumbar fusion; Decision-making algorithm for the surgical treatment of degenerative lumbar spondylolisthesis of L4/L5; Response to preoperative steroid injections predicts surgical outcomes in patients undergoing fusion for isthmic spondylolisthesis

Aims. Existing literature indicates that inferiorly inclined glenoid baseplates following reverse total shoulder arthroplasty (RSA) produce better outcomes compared to superiorly inclined baseplates. We aim to compare clinical outcomes for RSAs with superiorly and neutrally/inferiorly inclined lateralized glenospheres. Methods. We retrospectively reviewed 154 consecutive patients undergoing RSA between July 2015 and July 2017 by one single-fellowship trained surgeon (AJ). Two raters (KAM and MVS) independently measured glenoid inclination in preoperative and minimum two year follow-up radiographs (anteroposterior/Grashey) using the RSA angle. Inclination was then compared to patient-reported outcomes, range of motion (ROM), and independently assessed degree of scapular notching and staging of heterotopic ossification at two year follow-up. Results. Median postoperative inclination for each group was found to be -3.6° (interquartile range (IQR) -2.1 to -6.9) and 6.0° (3.2° to 10.1°) for the neutrally/inferiorly and superiorly inclined cohorts, respectively. Preoperative inclination was highly associated with postoperative inclination (p = 0.004). When comparing superiorly and neutrally/inferiorly inclined glenospheres, there were no differences in heterotopic ossification (p = 0.606), scapular notching (p = 0.367), American Shoulder and Elbow Surgeons score (p = 0.419), Single Assessment Numeric Evaluation (p = 0.417), Visual Analogue Scale (VAS) pain score (p = 0.290), forward elevation (p = 0.161), external rotation (p = 0.537), or internal rotation (p = 0.656). Conclusion. Compared to neutral and inferior inclination, up to 6° ± 3° of superior glenoid baseplate inclination on a lateralized RSA design produces no differences in postoperative ROM or patient-reported outcomes, and produces similar levels of scapular notching and heterotopic ossification. Additionally, the degree of preoperative inclination represents an important factor in surgical decision-making as it is strongly associated with postoperative inclination. It is important to note that the findings of this study are only reflective of lateralized RSA prostheses. Cite this article: Bone Joint J 2021;103-B(2):360–365

The August 2023 Trauma Roundup. 360. looks at: A comparison of functional cast and volar-flexion ulnar deviation for dorsally displaced distal radius fractures; Give your stable ankle fractures some AIR!; Early stabilization of rib fractures – an effective thing to do?; Locked plating versus nailing for proximal tibia fractures: A multicentre randomized controlled trial; Time to flap coverage in open tibia fractures; Does tranexamic acid affect the incidence of heterotropic ossification around the elbow?; High BMI – good or bad in surgical fixation of hip fractures?

The February 2024 Shoulder & Elbow Roundup. 360. looks at: Does indomethacin prevent heterotopic ossification following elbow fracture fixation?; Arthroscopic capsular shift in atraumatic shoulder joint instability; Ultrasound-guided lavage with corticosteroid injection versus sham; Combined surgical and exercise-based interventions following primary traumatic anterior shoulder dislocation: a systematic review and meta-analysis; Are vascularized fibula autografts a long-lasting reconstruction after intercalary resection of the humerus for primary bone tumours?; Anatomical versus reverse total shoulder arthroplasty with limited forward elevation; Tension band or plate fixation for simple displaced olecranon fractures?; Is long-term follow-up and monitoring in shoulder and elbow arthroplasty needed?