Search

The association of the high blood pressure D variant of the angiotensin-converting enzyme (ACE) gene with medication-related jaw osteonecrosis (MRONJ) is described in two Greek patients. The first patient, a 73-year-old man, took zolendronate, 4 mg/100 ml IV once per month for two years for prostate cancer and bone metastases. Three months after drug discontinuation, extraction of the first premolar was performed. After the intervention, he suffered from osteonecrosis of the mandible. He presented with hypertension and genetic testing revealed that he was homozygous for the high blood pressure D variant of the ACE gene. The second patient, a 65 years old woman, took denosumab, 120 mg subcutaneously once per month for 6 months for possible bone metastases from breast cancer. Three months after extraction of the first molar, she suffered from MRONJ. He also presented with hypertension and genetic testing revealed that she had the high blood pressure D variant of the ACE gene in a heterozygous state, which moderately predisposes to hypertension. To our knowledge, this is the first report indicating that genetic predisposition to hypertension may increase risk for MRONJ., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Avascular necrosis (AVN) of the talus bone is a progressive and debilitating consequence of trauma or exposure to a variety of risk factors. The Ficat classification describes current understanding of the natural history of AVN, including preclinical, preradiographic, precollapse, postcollapse, and arthritic stages. The size and location of the avascular region likely determines risk of progression; however, symptoms do not correlate with stage. Patients may be minimally symptomatic despite diffuse involvement for long periods. Joint-sparing strategies have shown promise but do not universally prevent progression of the disease. When bone structure fails, joint-sacrificing strategies may be required., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The Wnt/β-catenin signaling pathway is associated with the pathogenesis of steroid-induced osteonecrosis. Our investigation studied whether aberrant CpG island hypermethylation of the FZD1 gene was present in patients with osteonecrosis of the femoral head (ONFH), which results in Wnt/β-catenin signaling inactivation and subsequent cell dysfunction. Bone marrow was collected from the proximal femurs of patients with steroid-associated ONFH (n = 21) and patients with new femoral neck fractures (n = 22), and then mesenchymal stem cells (MSCs) were isolated. We investigated cell viability, the transcription and translation levels of Wnt/β-catenin signaling-related genes, the extent of methylation at CpG islands of the FZD1 promoter, and the osteogenic and adipogenic differentiation abilities of MSCs from the control group and from the ONFH group treated with or without 5'-Aza-dC. According to the results, MSCs from the ONFH group showed a reduced proliferation ability, low transcription and translation levels of FZD1, inhibition of the Wnt/β-catenin signaling pathway, weakened osteogenesis and enhanced adipogenesis ability. Aberrant CpG island hypermethylation of FZD1 was observed in the ONFH group. Treatment with 5'-Aza-dC resulted in de novo FZD1 expression, reactivation of the Wnt/β-catenin signaling pathway and promotion of osteogenesis. Taken together, our study not only provides novel insights into the regulation of the Wnt/β-catenin signaling pathway in this disease but also reveals potential for the use of demethylating agents for the treatment of GC-associated ONFH.

Objective: In acute lymphoblastic leukemia (ALL), various clinical risk factors and genetic predispositions contribute to the development of bone complications during and after chemotherapy. In this study, we aimed to investigate whether vitamin D receptor ( VDR ) Fok1 and collagen protein Col1A1 Sp1-binding site gene polymorphisms, which are important in bone mineral and matrix formation, have effects on the development of bone abnormalities in childhood ALL survivors., Materials and Methods: Fifty children with ALL who were treated with the ALL Berlin-Frankfurt-Muenster-95 protocol between 1998 and 2008 and were followed for at least 7 years were enrolled. The control group consisted of 96 healthy children. VDR Fok1 and Col1A1 Sp1-binding site gene polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymorphism. Bone mineral density (BMD) and markers of bone metabolism were all noted. All patients who presented with pain in the joints were examined for bone pathologies while on chemotherapy or during long-term follow-up., Results: Low BMD (16%), osteoporosis (12%), and osteonecrosis (8%) were present in a total of 18 patients (36%). The frequency of osteonecrosis and total bone abnormalities was significantly higher in children aged ≥10 years (p=0.001). The risk of low BMD and osteonecrosis was higher in those with vitamin D deficiency. Only the Col1A1 Sp1-binding site gene polymorphism showed a significant association in ALL patients with osteonecrosis., Conclusion: The development of therapy-induced bone mineral loss and osteonecrosis in children with ALL is frequent and the risk is especially higher in children aged ≥10 years and with vitamin D deficiency. The association between Col1A1 Sp1-binding site gene polymorphisms and osteonecrosis has to be assessed in a larger group of ALL survivors.

Objective: Juvenile ischemic osteonecrosis (JIO) of the femoral head is one of the most serious hip disorders causing a permanent deformity of the femoral head in childhood. We recently reported that interleukin 6 (IL6) is predominantly increased in the hip synovial fluid of patients with JIO and that articular chondrocytes are primary source of IL6. This study investigated whether an inhibition of IL6 receptor improves cartilage preservation and bone healing in JIO., Method: A small animal model (i.e., 6-week-old mouse) of JIO was treated with either saline or tocilizumab, an IL6 receptor blocker, for 6 weeks., Results: TUNEL-positive chondrocytes in the articular cartilage were reduced by the tocilizumab treatment, concomitant with the increase in cartilage matrix. The levels of a cartilage anabolic marker Sox9 was significantly increased in the articular cartilage of mice treated with tocilizumab. Micro-CT assessment showed tocilizumab treatment significantly increased trabecular epiphyseal bone volume (P = 0.001, n = 10), thickness (P = 0.007) and number (P = 0.014) and decreased bone separation (P = 0.002) and its deformity (P = 0.003). A bone formation marker, BMP2, and an angiogenic marker, vascular endothelial growth factor (VEGF), were both significantly increased by tocilizumab treatment under hypoxia using human chondrocytes while the bone resorption marker, RANKL/OPG ratio, was reduced., Conclusion: Tocilizumab treatment following ischemic osteonecrosis has cartilage anabolic effect and increases bone volume in JIO mouse model. The findings lead to a possible application of tocilizumab for preclinical study using a large animal model of JIO and a clinical trial to validate this treatment., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Introduction: The reporting of osteonecrosis of the jaw (ONJ) related to anticancer agents without known antiresorptive properties (non-antiresorptives), such as antiangiogenics, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, immune checkpoint inhibitors, and cytotoxic chemotherapy is increasing., Objective: To review characteristics of ONJ in cancer patients receiving non-antiresorptives., Methods: A systematic review of the literature between 2009 and 2017 was conducted by the Bone Study Group of MASCC/ISOO., Results: Of 6249 articles reviewed and from personal communication, 42 ONJ cases related to non-antiresorptives were identified. No gender predilection was noted. Median age was 60 years and ONJ stage 2 was most common, with predilection for posterior mandible. Exposed bone, pain, and infection were common at diagnosis. In comparison to bone targeting agents (BTAs), radiology, histology, and management were similar, with medication often discontinued. Delayed diagnosis (median 8 weeks) was noted. Important differences included earlier time to ONJ onset (median 20 weeks), absence of trigger event (40%), and greater likelihood of healing and shorter healing time (median 8 weeks) as compared to BTA-related ONJ. Gastrointestinal cancers predominated, followed by renal cell carcinomas compared to breast, followed by prostate cancers in BTA-related ONJ, reflecting different medications., Conclusions: Data about non-antiresorptive-related ONJ is sparse. This type of ONJ may have better prognosis compared to the BTA-related ONJ, suggested by greater likelihood of healing and shorter healing time. However, the delay in diagnosis highlights the need for more education. This is the first attempt to characterize ONJ associated with different non-antiresorptives, including BRAF and immune checkpoint inhibitors.

Impact Statement: A composite hydrogel embedded with porous microspheres fabricated by phase separation methods was developed and showed excellent long-term anticancer drug delivery capability to cancer cells.

This study evaluated the effects of local application of autologous platelet-rich plasma (PRP) on the tooth extraction site of rats presenting the main risk factors for medication-related osteonecrosis of the jaw (MRONJ). For seven weeks, senile rats were submitted to systemic treatment with vehicle (VEH and VEH-PRP) or 100 μg/Kg of zoledronate (ZOL and ZOL-PRP) every three days. After three weeks, the first lower molar was extracted. VEH-PRP and ZOL-PRP received PRP at the tooth extraction site. Euthanasia was performed at 28 days postoperatively. Clinical, histopathological, histometric and immunohistochemical analyses were carried out in histological sections from the tooth extraction site. ZOL showed lower percentage of newly formed bone tissue (NFBT), higher percentage of non-vital bone tissue (NVBT), as well as higher immunolabeling for TNFα and IL-1β. In addition, ZOL presented lower immunolabeling for PCNA, VEGF, BMP2/4, OCN and TRAP. VEH and ZOL-PRP showed improvement in the tooth extraction site wound healing and comparable percentage of NFBT, VEGF, BMP2/4 and OCN. Local application of autologous PRP proved a viable preventive therapy, which is safe and effective to restore tissue repair capacity of the tooth extraction site and prevent the occurrence of MRONJ following tooth extraction.

Tarsal navicular osteonecrosis in adults is a rare condition with unclear etiology, and the optimal treatment has not been established. Here we report a case of tarsal navicular osteonecrosis with a complete course of treatment and comprehensive imaging studies starting at an early stage. A 37-year-old female diagnosed with tarsal navicular osteonecrosis was first treated with percutaneous decompression, but her symptoms persisted postoperatively. The tarsal navicular showed no further collapse, but follow-up magnetic resonance imaging (MRI) at 6 months postoperatively revealed persistent osteonecrotic changes. Debridement of the necrotic bone with preservation of the cortical shell and bone substitute packing for the defect (light bulb procedure) were performed. The symptoms resolved by 3 months postoperatively, and the patient could return to work. At a 6-year follow-up visit, the patient was free of symptoms, and MRI showed remodeling of the tarsal navicular without further collapse., (Copyright © 2018. Published by Elsevier Inc.)

Objective: To test whether patients with spontaneous osteonecrosis of the knee (SONK) are characterized by abnormal levels of thrombophilia-associated factors., Design: Twenty-five patients with SONK were recruited. Inclusion criteria were (1) age >40 years, (2) acute onset knee pain not precipitated by trauma, and (3) MRI findings consistent with SONK. Exclusion criteria were (1) history of cancer and chemotherapy and (2) factors associated with secondary osteonecrosis. Blood tests included 13 thrombophilia-associated factors that were either heritable mutations or acquired factors. Descriptive statistics included medians, ranges, means, and standard deviations. Mann-Whitney test was used to compare thrombophilia-associated factor levels between the sexes. Spearman's rank test was used to test correlations between smoking status and each thrombophilia-associated factor. Level of significance was set at 0.05., Results: Median patient age was 62 years (range, 44-77 years). There were 16 (64%) men. Thirteen (52%) patients had thrombophilia-associated factor abnormalities of which 9 were elevated fibrinogen but this was less than 1 standard deviation above norm threshold. Other findings were 3 patients with marginally decreased antithrombin below norm threshold, low protein S Ag in only 1 patient, and factor V Leiden mutation heterozygosity in 2 patients, which was not higher than normal population prevalence. Thrombophilia-associated factors neither differed between sexes ( P = nonsignificant) nor correlated with smoking status ( P = nonsignificant)., Conclusion: Thrombophilia-associated factor abnormalities in patients with SONK were minimal. Therefore, clinical workup and treatment strategy in this disease should focus on addressing alternative etiologies leading to abnormal subchondral bone metabolism with focal osteopenia.

In this report, we deliver a concise and up-to-date review of osteonecrosis, a pathologic, painful, and often disabling condition that is believed to result from the temporary or permanent disruption of blood supply to an affected area of bone. We will discuss the epidemiology (disease distribution), pathogenesis (mechanism of development), etiology (associated risk factors, causes, and disorders), clinical manifestations (reported symptoms and physical findings), diagnosis and classification, and treatment options for hip osteonecrosis.

Background: In a small proportion of cases, spontaneous osteonecrosis of the knee (SONK) involves the medial tibial plateau (MT). Here, we introduced the clinical characteristics of spontaneous osteonecrosis of the MT and unicompartmental knee arthroplasty (UKA) as the favorable treatment for this situation based on a retrospective case study., Methods: Patients with spontaneous osteonecrosis of the MT, confirmed by magnetic resonance imaging (MRI) at Guangdong Provincial Hospital of Chinese Medicine (China) from March 2015 to June 2016, were included as a case serial and analyzed retrospectively. All patients underwent Oxford Medial UKA. The characteristics of their lesions, corresponding treatment, and results of follow-up were presented. The lesion scores and grade were determined according to the criteria of Ficat and Arlet., Results: In total, 22 patients (5 men, 17 women; mean age, 64.1 years) with spontaneous osteonecrosis of the MT were analyzed. The lesion stages assessment showed that 3 (14%) were Stage II, 10 (45%) were Stage III, 7 (32%) were Stage IV, and 2 (9%) were Stage V. In the sagittal plane, 7 (32%) were in the anterior region (MTa) and 15 (68%) were central (MTc). The lesion volume averaged 2.24 ± 0.79 cm 3 (range: 1.57-3.08 cm 3 ). Seventeen patients (77%) had Level III posterior medial meniscus root tears (MMRTs). All the patients underwent UKA. Average follow-up was 30.0 ± 6.4 months with a range of 23.0-38.0 months. The visual analog scale score was 7.78 ± 0.67 before surgery while decreased to 2.22 ± 1.09 at the final follow-up (P < 0.001). The Hospital for Special Surgery scores of pre-/post-surgery were 65.67 ± 5.45 and 84.10 ± 4.20, respectively (P < 0.001)., Conclusions: SONK often occurs in the anterior and central tibial plateau due to abnormal stresses. Most of the patients had Level III posterior medial meniscus root tears. MRI is recommended for suspected cases to identify SONK at an early stage. The use of the Oxford Medial UKA for SONK of the MT is reliable both immediately and at follow-up., Competing Interests: There are no conflicts of interest

Ischemic injuries and local hypoxia can result in osteocytes dysfunction and play a key role in the pathogenesis of avascular osteonecrosis. Conventional imaging techniques including magnetic resonance imaging (MRI) and computed tomography (CT) can reveal structural and functional changes within bony anatomy; however, characterization of osteocyte behavioral dynamics in the setting of osteonecrosis at the single cell resolution is limited. Here, we demonstrate an optical approach to study real-time osteocyte functions in vivo. Using nicotinamide adenine dinucleotide (NADH) as a biomarker for metabolic dynamics in osteocytes, we showed that NADH level within osteocytes transiently increase significantly after local ischemia through non-invasive photo-induced thrombosis of afferent arterioles followed by a steady decline. Our study presents a non-invasive optical approach to study osteocyte behavior through the modulation of local environmental conditions. Thus it provides a powerful toolkit to study cellular processes involved in bone pathologies in vivo.

Epidermal growth factor-like domain-containing protein 7 (EGFL7), a member of the epidermal growth factor (EGF)-like protein family, is a potent angiogenic factor expressed in many different cell types. EGFL7 plays a vital role in controlling vascular angiogenesis during embryogenesis, organogenesis, and maintaining skeletal homeostasis. It regulates cellular functions by mediating the main signaling pathways (Notch, integrin) and EGF receptor cascades. Accumulating evidence suggests that Egfl7 plays a crucial role in cancer biology by modulating tumor angiogenesis, metastasis, and invasion. Dysregulation of Egfl7 has been frequently found in several types of cancers, such as malignant glioma, colorectal carcinoma, oral and oesophageal cancers, gastric cancer, hepatocellular carcinoma, pancreatic cancer, breast cancer, lung cancer, osteosarcoma, and acute myeloid leukemia. In addition, altered expression of miR-126, a microRNA associated with Egfl7, was found to play an important role in oncogenesis. More recently, our study has shown that EGFL7 is expressed in both the osteoclast and osteoblast lineages and promotes endothelial cell activities via extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3), and integrin signaling cascades, indicative of its angiogenic regulation in the bone microenvironment. Thus, understanding the role of EGFL7 may provide novel insights into the development of improved diagnostics and therapeutic treatment for cancers and skeletal pathological disorders, such as ischemic osteonecrosis and bone fracture healing., (© 2018 Wiley Periodicals, Inc.)

Multifocal avascular osteonecrosis (AON) is a serious manifestation of systemic lupus erythematosus (SLE). Prothrombotic factors, especially antiphospholipid antibodies (aPL), have been associated with the development of AON; therefore, attenuating the procoagulant state while balancing the haemorrhagic risks might have a rationale when managing this condition. We report a case of a 37-year-old patient with SLE, treated with low doses of corticosteroids and immunosuppressive therapy, who was started on vitamin K antagonist following an episode of deep vein thrombosis while having persistent positivity for aPL. After 2 years, he presented with multifocal AON, involving both femurs and shoulders. The patient underwent a bilateral hip replacement, but despite appropriate anticoagulation therapy after 2 years, he developed another episode of AON at both distal epiphyses of the femurs and proximal epiphyses of the tibias. Multifocal AON should be suspected, especially in the presence of aPL positivity. Its aetiology is still unknown and is most likely multifactorial. Its management is challenging and requires combined approaches., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Treatment-related osteonecrosis (ON) is a serious complication of treatment of acute lymphoblastic leukemia (ALL)., Procedure: This study included 1,489 patients with ALL, aged 1-45 years, treated according to the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol, using alternate-week dexamethasone during delayed intensification, with prospective registration of symptomatic ON. We aimed at comparing risk factors, timing, and clinical characteristics of ON in children and young adults., Results: ON was diagnosed in 67 patients, yielding a 5-year cumulative incidence of 6.3%, but 28% in female adolescents. Median age at ALL diagnosis was 12.1 years and 14.9 years for females and males, respectively. At ON diagnosis, 59 patients had bone pain (91%) and 30 (46%) had multiple-joint involvement. The median interval between ALL and ON diagnosis was significantly shorter in children aged 1.0-9.9 years (0.7 years [range: 0.2-2.1]) compared with adolescents (1.8 years [range: 0.3-3.7, P < 0.001]) and adults (2.1 years [range: 0.4-5.3, P = 0.001]). Female sex was a risk factor in adolescent patients (hazard ratio [HR] = 2.1, 95% confidence interval [CI]: 1.1-4.2) but not in children aged 1.1-9.9 years (HR = 2.4, 95% CI: 0.9-6.2, P = 0.08) or adults aged 19-45 years (HR = 1.1, 95% CI: 0.3-4.0). Age above 10 years at ALL diagnosis (odds ratio [OR] = 3.7, P = 0.026) and multiple joints affected at ON diagnosis (OR = 3.4, P = 0.027) were risk factors for developing severe ON., Conclusion: We provide a detailed phenotype of patients with ALL with symptomatic ON, including description of risk factors and timing of ON across age groups. This awareness is essential in exploring measures to prevent development of ON., (© 2018 Wiley Periodicals, Inc.)

Drilling to the bones is required to re-fix them at their appropriate location using the implants. During drilling some thermal and mechanical losses may be faced by the bone and surrounding tissues which may lead to the serious issue in terms of osteonecrosis. Osteonecrosis is one of the reasons for impaired healing process for the fractured bone and causes further complications like low pullout strength of cortical screws and bone crush. In order to maintain the low temperature during bone drilling, this study focused the thermal damages observed by the bone and its surrounding during bone drilling and compared the results of conventional and vibrational drilling techniques. Parametric optimization under the influence of vibrations was also studied. Drilling has been done with the both drilling technique, and results were recorded in terms of temperature raise. Optimal solution for drilling the bone has been accessed using Taguchi optimization technique. The morphological comparison has been done for conventional and vibrational drilled holes using histopathology of drilled bones sections. From Taguchi optimization, it was observed that R1F1A1 is the parametric combination which gives minimum thermal injury to the bone in case of vibrational bone drilling. Analysis of variance cleared that the all parameters involved significantly affect the results (P ≤ 0.05). Rotational speed was found to be the most influential factor among the all with 80.53%. Histopathology studies of bone specimens help to understand how heat generation affects the bone morphology during drilling. The specimens drilled with vibrational drilling show less damage in terms of osteonecrosis near the drill site which shows the significance of vibrational drilling in case of orthopedic surgeries. The raise in temperature during drilling is collective result of different drilling parameters. Vibrational drilling was observed a helping tool to control the thermal damage in bone drilling.

Objectives: To determine the effect of osteonecrosis (ON) on the clinical and functional outcome after open reduction and internal fixation of proximal humerus fractures., Design: Prospective cohort study., Setting: Academic medical center., Patients: Over a 12-year period, patients were screened and identified on presentation to the emergency department or in the clinical office for inclusion in an institutional review board-approved registry. One hundred sixty-five patients with 166 proximal humerus fractures met inclusion criteria. Eight patients developed radiographic evidence of ON (4.8%)., Intervention: Surgical repair of proximal humerus fractures., Main Outcome Measure: Patients were divided into 2 cohorts; 1 cohort being those diagnosed with ON and the other cohort being those who were not. All patients were prospectively followed and assessed for clinical and functional outcomes at the latest follow-up visit (mean = 22.9 months) using the Disabilities of Arm, Shoulder and Hand survey along with ranges of motion of the injured extremity., Results: Average postoperative forward elevation for patients with ON was worse than those without ON (P = 0.002). Additionally, there was a significant difference in Disabilities of Arm, Shoulder and Hand scores at the latest follow-up between the 2 groups (P = 0.026). There was no difference in external rotation or mean length of follow-up between the 2 groups (P > 0.05)., Conclusions: This study demonstrates the negative effects of ON after open reduction and internal fixation of proximal humerus fractures. Those who develop ON have poorer functional and clinical outcomes as compared with patients without ON. Consequently, the development of ON can be used as a predictor of poor outcomes., Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Predictive models permitting personalized prognostication for patients with cannulated screw fixation for the femoral neck fracture before operation are lacking. The objective of this study was to train, test, and cross-validate a Naive Bayes Classifier to predict the occurrence of postoperative osteonecrosis of cannulated screw fixation before the patient underwent the operation. The data for the classifier model were obtained from a ambispective cohort of 120 patients who had undergone closed reduction and cannulated screw fixation from January 2011 to June 2013. Three spatial displaced parameters of femoral neck: displacement of centre of femoral head, displacement of deepest of femoral head foveae and rotational displacement were measured from preoperative CT scans using a 3-dimensional software. The Naive Bayes Classifier was modelled with age, gender, side of fractures, mechanism of injury, preoperative traction, Pauwels angle and the three spatial parameters. After modelling, the ten-fold cross-validation method was used in this study to validate its performance. The ten-fold cross-validation method uses the whole dataset to be trained and tested by the given algorithm. Two of the three spatial parameters of femoral neck (displacement of center of femoral head and rotational displacement) were included successfully in the final Naive Bayes Classifier. The Classifier achieved good performance of the accuracy (74.4%), sensitivity (74.2%), specificity (75%), positive predictive value (92%), negative predictive value (42.9%) and AUC (0.746). We showed that the Naive Bayes Classifier have the potential utility to be used to predict the osteonecrosis of femoral head within 5 years after surgery. Although this study population was restricted to patients treated with cannulated screws fixation, Bayesian-derived models may be developed for application to patients with other surgical procedures at risk of osteonecrosis., (Copyright © 2018. Published by Elsevier Ltd.)

Bisphosphonates are among several drugs known in modern medicine to have a potentially deleterious effect on the mandible with chronic use. While purportedly causing a necrotic reaction in the bone, the complete mechanism is not fully elucidated yet as cases are quite rare in the general public. Despite the esoteric nature of this entity, patients suffering from bisphosphonate induced necrosis have a complicated and prolonged course often involving varying degrees of mandibular debridement with severe cases requiring reconstruction. In this report, we present the unique case of a patient with a progressive mandibular osteonecrosis requiring complete mandibulectomy and fibula flap reconstruction., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Several pathologic conditions may manifest as an osteochondral lesion of the knee that consists of a localized abnormality involving subchondral marrow, subchondral bone, and articular cartilage. Although understanding of these conditions has evolved substantially with the use of high-spatial-resolution MRI and histologic correlation, it is impeded by inconsistent terminology and ambiguous abbreviations. Common entities include acute traumatic osteochondral injuries, subchondral insufficiency fracture, so-called spontaneous osteonecrosis of the knee, avascular necrosis, osteochondritis dissecans, and localized osteochondral abnormalities in osteoarthritis. Patient demographics, the clinical presentation, and the role of trauma are critical for differential diagnosis. A localized osteochondral defect can be created acutely or can develop as an end result of several chronic conditions. MRI features that aid in diagnosis include the location and extent of bone marrow edema, the presence of a fracture line, a hypointense area immediately subjacent to the subchondral bone plate, and deformity of the subchondral bone plate. These findings are essential in diagnosis of acute traumatic injuries, subchondral insufficiency fracture, and its potentially irreversible form, spontaneous osteonecrosis of the knee. If the lesion consists of a subchondral region demarcated from the surrounding bone, the demarcation should be examined for completeness and the presence of a "double-line sign" that is seen in avascular necrosis or findings of instability, which are important for proper evaluation of osteochondritis dissecans. Subchondral bone plate collapse, demonstrated by the presence of a depression or a fluid-filled cleft, can be seen in advanced stages of both avascular necrosis and subchondral insufficiency fracture, indicating irreversibility. Once the diagnosis is established, it is important to report pertinent MRI findings that may guide treatment of each condition. © RSNA, 2018 An earlier incorrect version of this article appeared online. This article was corrected on August 23, 2018.

Rationale: Preiser disease or avascular necrosis (AVN) of the scaphoid causes intolerable wrist pain and malalignment of the carpal bones. In previously reported cases, patients have had a history of steroid use for systemic illness such as autoimmune hemolytic anemia, systemic lupus erythematosus, or renal transplantation, or have had other risk factors, such as smoking, alcoholism, or infection. In particular, systemic glucocorticoid therapy has been most commonly associated with the disease. Although there are reports of AVN of the scaphoid induced by systemic glucocorticoids, no prior report has associated AVN of the carpal bones with repeated local injections of glucocorticoids., Patient Concerns: We present a case in which it was strongly suspected that AVN of the scaphoid was induced by repeated local glucocorticoid injections. The patient had no history of excessive alcohol use, smoking, or trauma, except for local repeated steroid injections., Diagnoses: Initially, she had diagnosed with de Quervain's disease and was treated by repeated local glucocorticoid injections followed by surgery for de Quervain's disease. Five years after surgery for de Quervain's disease, the patient presented at our hospital with sudden onset of intolerable pain in her right wrist without a history of trauma. In spite of nonsurgical treatment with rest, immobilization, analgesia, and surgery, her wrist pain was not improved. After further repeated local steroid injections in her wrist, radiographs, and magnetic resonance imaging of her wrist showed the AVN of the scaphoid., Interventions: Surgery was performed and the fragmented proximal scaphoid and the entire lunate were resected., Outcomes: The diagnosis was confirmed according to the histopathological examination of the proximal scaphoid bone, which showed the characteristic of AVN of the scaphoid. At follow-up evaluation, radiographs of the right wrist showed no progression of osteoarthritis. The patient had no tenderness or residual pain at the wrist and had no desire to pursue additional surgery., Lessons: We have presented a case with AVN of the scaphoid, which was strongly suspected to be associated with the repeated local steroid injections. Further studies are required to more fully elucidate the association between AVN of the scaphoid and repeated local steroid injections.

Osteonecrosis of the jaw is a significant complication secondary to radiation therapy or drug therapy, most commonly bisphosphonates. Safety data regarding the administration of bisphosphonates in bone metastatic head and neck cancer patients with history of jaw irradiation are almost non-existent. In this paper, we report the case of a Head and Neck (HNC) patient, with history of radiation therapy to the mandible region, treated with intravenous bisphosphonates for bone metastases that resulted in gross, life threatening mouth hemorrhage secondary to advanced, locally invasive ONJ.

Background: The aim of this retrospective study was to compare the morphological features of neurovascular canals and foramina of patients with medication-related osteonecrosis of the jaws (MRONJ) and healthy individuals by using cone beam computed tomography (CBCT)., Material and Methods: The CBCT images of 58 patients under bisphosphonate therapy diagnosed with MRONJ and age gender- matched controls were retrospectively evaluated. The diameter of mandibular and nasopalatine canal and mandibular, mental and lingual foramina were measured on several sections of CBCT. The value of mental index (MI) and panoramic mandibular index (PMI) were also assessed., Results: The mean value of diametric measurements for all neurovascular canals and foramina in MRONJ patients were narrower than controls. Left mandibular foramen was the most affected area (p<0.001). There were significantly difference in all measurements of mental foramen, lingual foramen and mandibular incisive canal between two groups (p<0.05). PMI of MRONJ subjects were also significantly differences in both sides (p<0.05)., Conclusion: In MRONJ patient, neurovascular canals and foramina are affected due to the alterations in bone remodeling. Therefore, the diametric measurement of neurovascular canals and assessment of MI and PMI on CBCT, is a potentially useful method for detection of early changes associated with bisphosphonate therapy and for predict areas where new necrosis may occur.

A 17-year-old male adolescent was diagnosed with diffuse large B cell lymphoma arising from the right humeral head. The lymphoma was found to be isolated to the bone, with a very small extraosseous component. After completion of a standard chemotherapy regimen, the Positron Emission Tomography-Computed Tomography (PET-CT) became PET negative but the CT and MRI appeared mostly unchanged in appearance, suggesting refractory disease. Repeat biopsy confirmed that no lymphoma remained, and he was in complete remission. Three months after completion of therapy, MRI continued to be abnormal. This case illustrates the unique challenges posed by the imaging characteristics of bone lymphoma, both during and after therapy. Biopsy is definitive but causes additional morbidity and may not be necessary. Imaging is done routinely to assess response to therapy, as with this patient, but in lymphomas of the bone imaging can be misleading and can lead to unnecessary procedures or follow-up imaging., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Total body irradiation (TBI) is commonly used in conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT) to treat benign and malignant disease. Though life-saving, these therapies place patients at risk for important side effects, including musculoskeletal complications such as short stature, osteonecrosis, slipped capital femoral epiphysis, and the development of benign and malignant bone tumors. With an increasing number of HSCT survivors, there is a growing need for awareness of the musculoskeletal complications of HSCT and TBI., (© 2017 Wiley Periodicals, Inc.)

Purpose: Stereotactic body radiation therapy (SBRT) is a highly effective and potentially ablative treatment for complex spinal metastases. Recent data have suggested radiobiologic effects of SBRT that expand beyond the traditional concept of DNA damage. Antitumor immunity, vascular damage leading to tumor necrosis, and increased rates of tumor apoptosis have been implied; however, in-human evidence remains scarce. The present study reports unique pathologic confirmation of SBRT-induced biological effects within spinal metastases treated with preoperative SBRT., Methods and Materials: Ten patients with spinal metastases secondary to various solid tumors were treated with preoperative single-fraction SBRT (18 Gy) to the magnetic resonance imaging-defined macroscopic metastasis, followed by spinal stabilization within 24 hours. Perioperative samples of spinal metastases were obtained, and 6 patients also had a pre-SBRT biopsy specimen available for a matched comparison. The samples were stained for tumor necrosis on routine hematoxylin-eosin-stained slices and, subsequently, immunohistochemical staining for T cells (CD3+, CD4+, CD8+), natural killer cells (CD56+), endothelium (CD31+), and apoptotic activity (caspase-3)., Results: Perioperative biopsy specimens were obtained ∼6 hours (range 4.5-7.5) or 21 hours (range 18.5-22.5) after SBRT. Necrosis was observed in 83% of the 21-hour post-SBRT samples (5 of 6) compared with 0% of pre-SBRT biopsies (0 of 6) and 6-hour post-SBRT biopsies (0 of 4). Tumor cell apoptosis had increased greatly in the 21-hour post-SBRT samples compared with before and 6 hours after SBRT. The CD31+ vessel counts decreased after SBRT, as did mitotic activity. Both of the renal cell metastases displayed major decreases in vessel density. Desmoplastic reaction was visible in 67% (4 of 6) of the pre-SBRT samples compared with 100% (10 of 10) the post-SBRT samples. The T-cell and natural killer cell counts were relatively unaffected., Conclusions: High-dose single-fraction SBRT induced tumor necrosis, desmoplasia, and tumor apoptosis and decreased tumor vessel density within 24 hours, even in renal cell metastases. The role of immune cells seems limited in this early phase. These first-in-human results imply direct vascular and DNA damage mechanisms important in the clinical efficacy specific to spinal SBRT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We report here a case of multiple vertebral osteonecroses with intrasomatic gaseous dissection (Kümmell's disease) occurring 1 year after the end of a 10-year course of denosumab treatment for osteoporosis without fractures. Histomorphometry and bone remodeling markers revealed major bone resorption and the persistence of an inhibition of bone formation. The presence of multiple empty lacunae in the bone provided evidence for high levels of osteocyte apoptosis. Osteocytes direct bone resorption (via the RANK/RANK-L/osteoprotegerin system) and formation (Wnt system, with SOST and DKK1) pathways. The vertebral osteonecrosis in our case may, therefore, have resulted from osteocyte apoptosis, decompensated by the sudden reactivation of bone remodeling after the cessation of denosumab treatment.

Introduction: Iloprost is a commercially available prostaglandin I 2 (PGI 2 ) analogue that is shown to have antithrombotic, vasodilatative and antiproliferative effects. A number of clinical studies have shown that Iloprost can be effective in the management of bone marrow oedema and the treatment of avascular necrosis. The aim of this manuscript is to present our current understanding on the effect of Iloprost on the treatment of these conditions., Areas Covered: The authors offer a comprehensive review of the existing literature on the experimental and clinical studies analysing the effect of Iloprost on bone, bone marrow oedema and avascular necrosis., Expert Opinion: The available data from the clinical studies suggest that Iloprost has limited effect in advanced stages of avascular necrosis. However, literature suggests that Iloprost administration can be a viable option in the management of bone marrow oedema and early stages of osteonecrosis. Despite these promising results its effect on bone homeostasis needs further elucidation. Moreover, further data on its safety, dosage and efficiency through randomized multicenter studies are desirable in order to reach final conclusions.

Osteonecrosis of the femoral head (ONFH) is a common but intractable disease. In this study, we investigated the mechanisms regulating alterations in mesenchymal stem cell (MSC) differentiation in ONFH. Five patients who were diagnosed with ONFH were enrolled in this study. Bone MSCs (BMSCs) were isolated from the osteonecrotic zone in the femoral head (FH-pMSCs) and from the normal zone in the pelvis (hMSCs) of the same patient. Morphology, cell proliferation and expression of mediators of the Wnt signalling pathway were evaluated. There were significant differences in cell proliferation and expression of surface markers between the two populations of cells. FH-pMSCs exhibited significantly lower osteogenic differentiation compared with hMSCs (P < 0.0001). Dissection of the Wnt pathway showed that FH-pMSCs had significantly higher GSK3β expression compared with hMSCs (P < 0.001). Addition of LiCl, a GSK3β inhibitor, significantly increased osteogenic differentiation in FH-pMSCs, suggesting a relationship between the microenvironment and regulation of stem cell behaviour in ONFH. FH-pMSCs also exhibited significant downregulation of other mediators of the Wnt signalling pathway, including runx2 and β-catenin. Our data suggested that mediators of the Wnt signalling pathway, such as GSK3β could be important therapeutic targets for early-stage ONFH.

Transient osteoporosis of the hip(TOH) is classified as a type of bone marrow edema syndrome. TOH is lack of previous study and there is still controversy about his pathogenesis. In recent years, with the development of multi-discipline, such as imaging, pathology, molecular biology, the study has found that the pathological mechanism is complex, while its mechanism is still not clear, which need further research. This paper summarizes the research progress on the pathogenesis of TOH from neurogenic, osteonecrosis, abnormal vascular function, subchondral fracture, heredity and regional acceleration and son on., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© 2018 by the China Journal of Orthopaedics and Traumatology Press.)

We explored the mechanism of early stage osteonecrotic femoral head collapse by analyzing and comparing different regions in human osteonecrotic femoral head samples. Eight osteonecrotic femoral heads (ARCO II-III) were obtained from patients undergoing total hip arthroplasty. Bone structure was observed and evaluated by micro-computed tomography (CT) scans and pathology. Osteoblast and osteoclast activities were detected by tartrate-resistant acid phosphatase, alkaline phosphatase, and immunofluorescent staining. Some trabeculae had microfractures in the subchondral bone and necrotic region, which had lower bone mineral density, as well as trabecular thickness and number, but greater osteoclast activity. A sclerotic band had already appeared in certain samples which had greater trabecular thickness and number, bone mineral density, and osteoblast activity. The appearance of the femoral head did not change significantly in the early stage of osteonecrosis of the femoral head. However, osteoblast and osteoclast activities had already changed in different regions of the osteonecrotic femoral head, which may lead to eventual collapse of the femoral head. Therefore, osteonecrosis of the femoral head must be treated during the early stage. In addition, osteoblast activity should be promoted and osteoclast activity inhibited as early as possible to prevent collapse of an osteonecrotic femoral head., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Background: Osteonecrosis of the jaw is a very delicate side effect of Denosumab. The aim of this retrospective study was to assess the occurrence rate of Denosumab-related osteonecrosis of the jaw (DRONJ) at the Cancer Institute of Lorraine (ICL) and to highlight necrosis risk factors., Methods: To that purpose, we analyzed the medical records of 249 consecutive patients treated with Denosumab at the ICL during the past 5 years. Patients who received orofacial radiotherapy or a previous treatment with a bisphosphonate were excluded. The P-value was set at .005., Results: A total of 141 patients treated at the ICL between January 2010 and December 2015 were included. All patients were treated with XGEVA ® . Of the 141 patients included in the study, 10 developed DRONJ. The incidence of DRONJ increases with the duration of follow-up as follows: 3% at 1 year, 7% at 2 years, and 8% from 30 months on. No risk factor for necrosis could be identified except the realization of prior dental extraction (P = .025)., Conclusion: Our results raise important questions about the dental management of these patients, in particular, concerning the healing period between dental extractions and the initiation of Denosumab., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The purpose of the role of antioxidant enzymes and mitochondria in the developmental mechanism of steroid-associated osteonecrosis in the femur. In the present study Japanese white rabbits (mean weight 3.5kg) were injected into the gluteus with methylprednisolone (MP) 20mg/kg, and killed after 3 days (MP3 group), 5 days (MP5 group), and 14 days (MP14 group) (n=3 each). As a Control group (C group) Japanese white rabbits not administered MP were used. In experiment 1, the expression of the antioxidant enzymes Superoxide dismutade (SOD) and catalase was compared in liver, kidney, heart, humerus, and femur in C group, and the presence/absence of mitochondria transcription factor A (TFAM) expression was determined by Western blotting (WB) and used to evaluate the number of mitochondria and their function. In experiment 2, the presence/absence of necrosis was determined by immunohistochemistry, while changes in the expression of SOD, catalase, and TFAM in the femur after steroid administration were determined by Western blotting (WB). In experiment 1, intense expression of all of SOD, catalase, and TFAM was found in the liver, kidney, and heart as compared to the humerus and femur. In experiment 2, the expression of all of SOD, catalase, and TFAM in MP3 and MP5 groups was decreased on WB as compared with C group, while in MP14 group a tendency to improvement was seen. Accordingly, steroid-associated mitochondrial injury and redox failure are concluded to be important elements implicated in the pathogenesis of osteonecrosis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Long‑term administration of glucocorticoid hormones is considered one of predominant pathological factors inducing osteonecrosis of the femoral head (ONFH) development and progression, in which reduction of blood supply leads to a progressive bone loss and impairment of bone structure in the majority of cases. In a non‑hematopoietic system, erythropoietin (EPO) can stimulate angiogenesis and bone regeneration. However, the specific mechanism underlying the role of EPO in ONFH remains to be elucidated. Therefore, the purpose of this study was to determine the effect of EPO on the prevention of bone loss in ONFH. Male C57BL/6J mice 3 months old were divided into two groups: EPO group and control groups. ONFH was established by the administration prednisolone (PDS, 100 mg/kg) with co‑treatment of lipopolysaccharide (LPS, 1 mg/kg). ONFH mice received recombinant mouse EPO (500 U/kg/day) or saline intramuscularly. The mice were sacrificed at 2, 4, 6 and 8 weeks following the initiation of treatment. Alterations in the general architecture and histomorphology of the right femoral head were determined by hematoxylin and eosin staining and micro computed tomography (micro‑CT). The expression of runt‑related transcription factor 2 (Runx2), osteocalcin, vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule (CD31) in the femoral head was tested by immunohistochemistry. Terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling (TUNEL) assay was performed to detect apoptosis in femoral heads. Micro‑CT data revealed that EPO significantly improved bone volume/total volume and bone mineral density following 6 and 8 weeks of treatment. Histological analysis further demonstrated that EPO treatment improved the arrangement of trabeculae, thinning of trabeculae and other fractures in femoral heads, especially following 6 and 8 weeks of treatment. Immunohistochemical analysis suggested that EPO treatment up‑regulated the expressions of Runx2, osteocalcin, VEGF and CD31 at 4 and 8 weeks. The TUNEL apoptosis assay suggested that EPO intervention reduced apoptosis in avascular ONFH. Therefore, EPO prevents bone loss in ONFH in mice through enhancing Runx2‑mediated osteogenesis, VEGF‑mediated angiogenesis and inhibition of cell apoptosis.

Background and Aims: Hyperbaric oxygen (HBO) therapy is increasingly used in medical practice as a means of enhancing the formation of collagen matrix and angiogenesis, thus promoting healing in wounds and necrotic tissue. However, there are concerns that oxygen can also associate with increased production of oxygen free radicals and oxidative stress. F 2 -Isoprostanes (F 2 -IsoPs) formed by non-enzymatic oxidation of arachidonic acid (AA) are reliable measures for assessing oxidative stress in vivo. In addition, under conditions of high oxygen tension isofurans (IsoFs) are preferentially formed from AA and are considered to better reflect oxidative stress in the setting of high oxygen tension. This study aimed to measure plasma IsoFs and F 2 -IsoP in patients receiving HBO therapy to treat osteonecrosis secondary to radiation therapy. Our hypothesis was that IsoFs would continue to rise with increasing oxygen pressures in contrast to F 2 -IsoPs whose synthesis would be reduced., Methods: Twelve patients receiving hyperbaric therapy to treat osteonecrosis secondary to radiation therapy were studied during hyperbaric treatment. Blood samples were collected prior to, during and after cessation of HBO therapy that lasted for 119min. Seven serial blood samples were collected for measurement of plasma F 2 -IsoPs and IsoFs, blood gases and haemoglobin., Results: Oxygen saturation and venous oxygen partial pressure (PvO 2 ) rose significantly during hyperbaric therapy. However, there were no significant changes in plasma IsoFs or F 2 -IsoPs during the hyperbaric therapy session., Conclusion: In this study of patients with osteonecrosis, HBO therapy at a maximum pressure of 2.4atm with up to 100% oxygen did not worsen oxidative stress assessed using plasma F 2 - IsoFs and IsoPs., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Non-traumatic osteonecrosis of the femoral head (NONFH) is a common clinical osteoarthropathy. The present study aimed to investigate the association between transforming growth factor β1 (TGF‑β1) and NONFH. Femoral head specimens were collected from patients with NONFH. Patients with traumatic osteonecrosis served as the control. Hematoxylin and eosin (H&E) staining was used to visualize the bone tissue architecture. Immunohistochemistry and densitometry were performed to quantify TGF‑β1 expression in tissues. Flow cytometry was used to detect cluster of differentiation (CD)3+, CD4+ and CD8+ cells, and the ratio of CD4+ to CD8+ T cells in the peripheral blood. H&E staining revealed osteonecrosis, disintegration of osteocytes with karyopyknosis and karyorrhexis, loss of osteocyte lacunae, aberrantly arranged circumferential lamellae, as well as dissolution of the lamellae and subtle osteogenesis in the experimental group, as opposed to the control group. Immunohistochemistry revealed that the expression of TGF‑β1 was significantly reduced in the experimental group (P<0.01). Further, the NONFH group had a decrease in the CD3+ and CD4+ cell populations (P<0.05 and P<0.01, respectively), an increase in the CD8+ cell population (P<0.05), as well as a reduction in the ratio of CD4+ to CD8+ cells (P<0.01). The present study indicated that TGF‑β1 expression was reduced in NONFH. This was associated with impaired repairing capacity of the femoral head and dysregulated subsets of T‑lymphocytes and possible immune functions.

The mechanism of steroid-associated femoral head necrosis remains unclear. The present study investigated the role of microRNA-23a-3p (miR-23a-3p) in the incidence of osteonecrosis in a rat model. An miR-23a-3p mimic, an inhibitor and a negative control were transfected into bone mesenchymal stem cells using a lentiviral vector, and then injected into the steroid-induced femoral head necrosis model. Osteonecrosis incidence was assessed by micro computed tomography and histopathology. Low-density lipoprotein receptor-related protein 5 (LRP-5) expression was assessed by immunohistochemistry. The results demonstrated the incidence of osteonecrosis decreased in the miR-23a-3p inhibitor group compared with the miR-23a-3p mimic group (18.2% vs. 75%; P<0.05). The ratio of bone volume/total volume and trabecular thickness were significantly increased in the miR-23a-3p inhibitor group compared with the miR-23a mimic group. The expression level of LRP-5 was higher in the miR-23a-3p inhibitor group. The present study indicated that miR may provide a novel and alternative approach for understanding the mechanism underlying steroid-associated necrosis of the femoral head.

Background: Avascular necrosis of bone (AVN) leads to sclerosis and collapse of bone and joints. The standard of care, vascularized bone grafts, is limited by donor site morbidity and restricted availability. The aim of this study was to generate and test engineered, axially vascularized SVF cells-based bone substitutes in a rat model of AVN., Methods: SVF cells were isolated from lipoaspirates and cultured onto porous hydroxyapatite scaffolds within a perfusion-based bioreactor system for 5days. The resulting constructs were inserted into devitalized bone cylinders mimicking AVN-affected bone. A ligated vascular bundle was inserted upon subcutaneous implantation of constructs in nude rats. After 1 and 8weeks in vivo, bone formation and vascularization were analyzed., Results: Newly-formed bone was found in 80% of SVF-seeded scaffolds after 8weeks but not in unseeded controls. Human ALU+cells in the bone structures evidenced a direct contribution of SVF cells to bone formation. A higher density of regenerative, M2 macrophages was observed in SVF-seeded constructs. In both experimental groups, devitalized bone was revitalized by vascularized tissue after 8 weeks., Conclusion: SVF cells-based osteogenic constructs revitalized fully necrotic bone in a challenging AVN rat model of clinically-relevant size. SVF cells contributed to accelerated initial vascularization, to bone formation and to recruitment of pro-regenerative endogenous cells., Statement of Significance: Avascular necrosis (AVN) of bone often requires surgical treatment with autologous bone grafts, which is surgically demanding and restricted by significant donor site morbidity and limited availability. This paper describes a de novo engineered axially-vascularized bone graft substitute and tests the potential to revitalize dead bone and provide efficient new bone formation in a rat model. The engineering of an osteogenic/vasculogenic construct of clinically-relevant size with stromal vascular fraction of human adipose, combined to an arteriovenous bundle is described. This construct revitalized and generated new bone tissue. This successful approach proposes a novel paradigm in the treatment of AVN, in which an engineered, vascularized osteogenic graft would be used as a germ to revitalize large volumes of necrotic bone., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Osteonecrosis (ON) is usually considered treatment related in patients with acute lymphoblastic leukemia (ALL). We report two patients with presentation of ON at the time of ALL diagnosis. Both were females and diagnosed with ALL at age 8 and 14 years. In the latter, some symptoms and radiologically verified ON in both knees were still present after the end of ALL therapy. No pediatric patients have previously been reported with ON presenting before initiation of ALL therapy., (© 2017 Wiley Periodicals, Inc.)

The Wnt pathway is a new target in bone therapeutic space. WNT proteins are potent stem cell activators and pro-osteogenic agents. Here, we gained insights into the molecular and cellular mechanisms responsible for liposome-reconstituted recombinant human WNT3A protein (L-WNT3A) efficacy to treat osteonecrotic defects. Skeletal injuries were coupled with cryoablation to create non-healing osteonecrotic defects in the diaphysis of the murine long bones. To replicate clinical therapy, osteonecrotic defects were treated with autologous bone graft, which were simulated by using bone graft material from syngeneic ACTB-eGFP-expressing mice. Control osteonecrotic defects received autografts alone; test sites received autografts treated ex vivo with L-WNT3A. In vivo µCT monitored healing over time and immunohistochemistry were used to track the fate of donor cells and assess their capacity to repair osteonecrotic defects according to age and WNT activation status. Collectively, analyses demonstrated that cells from the autograft directly contributed to repair of an osteonecrotic lesion, but this contribution diminished as the age of the donor increased. Pre-treating autografts from aged animals with L-WNT3A restored osteogenic capacity to autografts back to levels observed in autografts from young animals. A WNT therapeutic approach may therefore have utility in the treatment of osteonecrosis, especially in aged patients.

A number of nonneoplastic conditions can mimic tumors of bone. Some of the more common mimics of primary bone tumors include infectious, inflammatory, periosteal, and degenerative joint disease-associated lesions that produce tumorlike bone surface-based or intraosseous lesions. This article considers a spectrum of reactive and nonreactive processes including stress fracture, subchondral cysts, osteonecrosis, heterotopic ossification, osteomyelitis, sarcoidosis, and amyloidoma that can present in such a way that they are mistaken for a tumor arising primary in bone., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Bone margin analysis in cases of osteomyelitis, osteoradionecrosis, and medication-related osteonecrosis of the jaw is a controversial topic. There is little evidence to guide treatment and the interpretation of bone margin results. This article examines the significance of margin status and any possible effect on progression of the disease process. A review of various treatment adjuncts used for intraoperative margin analysis during removal of affected tissue is provided. Literature on the role of imaging is also discussed with regards to treatment planning for surgical resection. The histology of the three separate entities including the approach to surgical and pathologic evaluation of margins is also discussed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Osteonecrosis is a debilitating toxicity associated with acute lymphoblastic leukemia (ALL) treatment. A recent report associated interindividual differences in hip anatomy with the development of idiopathic osteonecrosis in adults. To evaluate the impact of hip anatomy on the development of therapy-related osteonecrosis, we retrospectively evaluated the femoral neck-shaft angle, femoral neck offset, and lateral center-edge angle using x-rays of 18 osteonecrosis cases and 46 control children treated for newly diagnosed ALL on a single protocol. Despite adequate statistical power, we found no association between hip anatomy and osteonecrosis. Investigation of other factors contributing to ALL-associated osteonecrosis is warranted., (© 2016 Wiley Periodicals, Inc.)

Objective: To assess the value of coronal short-tau inversion recovery whole-body MRI (STIR-WBMRI) for screening osteonecrosis in patients with polymyositis (PM)/dermatomyositis (DM)., Methods: The imaging and medical records of 129 patients with PM/DM who met the Bohan and Peter diagnostic criteria were retrospectively analyzed. STIR-WBMRI was performed in all patients. 18 patients had follow-up STIR-WBMRI. 12 patients underwent regional knee and/or hip MRI while 25 patients underwent radiography of the lower extremities., Results: STIR-WBMRI detected osteonecrosis in 15 (11.6%) patients. 38 joints were affected (mean, 2.5 per patient; range, 1-5 joints). Of the 38 joints affected by osteonecrosis, 33 had no clinical symptoms. Among the 12 patients who underwent regional MRI, STIR-WBMRI detected all 10 osteonecrotic sites seen on the regional MRI. The location, shape and size of the osteonecrotic lesions revealed on regional MRI were in accordance with those displayed on STIR-WBMRI. Of the 15 patients with osteonecrosis, 6 performed routine radiography of the affected joints and revealed no osteonecrotic lesions. Follow-up WBMRI detected new osteonecrosis in two patients whose first WBMRI revealed that there was no osteonecrosis in any skeleton., Conclusion: In addition to displaying muscle inflammation, STIR-WBMRI can efficiently detect early multifocal osteonecrosis in the whole bodies of patients with PM/DM. Advances in knowledge: In patients with PM/DM, WBMRI which takes 12-15 min can display muscular involvement and detect early multisite osteonecrosis in the whole body at the same time. Osteonecrotic lesions revealed by WBMRI are in accordance with those displayed on regional WBMRI.

This study elucidates the question of whether chronic inflammation in the jawbone contributes to the development of Chronic Fatigue Syndrome (CFS). Fatty degenerative osteonecrosis in jawbone (FDOJ) may contribute to CFS by induction of inflammatory mediators. We examined seven cytokines by multiplex analysis in jawbone samples from two groups of patients. In order to clarify neurological interrelations, specimens from 21 CFS patients were analyzed from areas of previous surgery in the retromolar wisdom tooth area. Each of the retromolar jawbone samples showed clinically fatty degenerated and osteonecrotic medullary changes. As control, healthy jawbone specimens from 19 healthy patients were analyzed. All fatty necrotic and osteolytic jawbone (FDOJ) samples showed high expression of RANTES and fibroblast growth factor (FGF)-2. FDOJ cohorts showed a 30-fold mean overexpression of RANTES and a 20-fold overexpressed level of FGF-2 when compared to healthy controls. As RANTES is discussed in the literature as a possible contributor to inflammatory diseases, we hypothesize that FDOJ in areas of improper and incomplete wound healing in the jawbone may hyperactivate signaling pathways. Constituting a hidden source of “silent inflammation” FDOJ may represent a hitherto unknown cause for the development of CFS.

Through a process called perilacunar remodeling, bone-embedded osteocytes dynamically resorb and replace the surrounding perilacunar bone matrix to maintain mineral homeostasis. The vital canalicular networks required for osteocyte nourishment and communication, as well as the exquisitely organized bone extracellular matrix, also depend upon perilacunar remodeling. Nonetheless, many questions remain about the regulation of perilacunar remodeling and its role in skeletal disease. Here, we find that suppression of osteocyte-driven perilacunar remodeling, a fundamental cellular mechanism, plays a critical role in the glucocorticoid-induced osteonecrosis. In glucocorticoid-treated mice, we find that glucocorticoids coordinately suppress expression of several proteases required for perilacunar remodeling while causing degeneration of the osteocyte lacunocanalicular network, collagen disorganization, and matrix hypermineralization; all of which are apparent in human osteonecrotic lesions. Thus, osteocyte-mediated perilacunar remodeling maintains bone homeostasis, is dysregulated in skeletal disease, and may represent an attractive therapeutic target for the treatment of osteonecrosis.

The use of prednisolone is one major risk factor for osteonecrosis in patients with systemic lupus erythematosus. Bone scintigraphy can be a diagnostic tool for early diagnosis. We present a case who had collar osteophytes at the bilateral femoral heads, which mimicked osteonecrosis in the planar bone scintigram. An SPECT/CT scan avoided this pitfall and increased the diagnostic accuracy for osteonecrosis.