Bone Flap Resorption After Cranioplasty: Risk Factors and Proposal of the Flap Integrity Score.

BACKGROUND: Bone flap resorption is a known complication of postdecompressive autologous cranioplasty. Although several potential etiopathogenetic factors have been investigated, their role is still under discussion. To further complicate things, resorption is not an all-or-nothing event, patients frequently presenting with different degrees of flap remodeling. Focus of this paper was to describe the elaboration of a score quantifying bone resorption according to a set of clinical and radiological criteria, hopefully allowing prompt identification of patients needing resurgery before the development of adverse events. METHODS: In a 10-year period, 281 autologous cranioplasties were performed at our institution following decompressive craniectomy. Pertinent clinical and radiological information was registered. A set of 3 clinical and 3 radiological parameters was established to score the degree of resorption, identified under the acronym FIS (Flap Integrity Score). Three groups of patients emerged, respectively showing no (208), partial (32), and advanced (41) resorption. RESULTS: An overall 14.6% incidence of advanced bone resorption was found in our series. Younger age, bone multifragmentation, higher postcranioplasty Glasgow Outcome Scale scores, <2 cm distance of medial craniectomy border from the midline, and cause leading to decompressive craniectomy were associated to a statistically significant higher risk of developing a relevant bone flap resorption. The first three variables were confirmed as risk factors in multivariate analysis. Flap Integrity Score well discriminated the 3 different groups. CONCLUSIONS: Autologous bone repositioning is still a valuable, low-cost, cosmetically and functionally satisfactory procedure. Nonetheless, although resorption affects a minor percentage of patients, its early identification and treatment can improve long-term results.

The potential role of mechanotransduction in the management of pediatric calvarial bone flap repair.

Pediatric patients suffering traumatic brain injuries may require a decompressive craniectomy to accommodate brain swelling by removing a portion of the skull. Once the brain swelling subsides, the preserved calvarial bone flap is ideally replaced as an autograft during a cranioplasty to restore protection of the brain, as it can reintegrate and grow with the patient during immature skeletal development. However, pediatric patients exhibit a high prevalence of calvarial bone flap resorption post-cranioplasty, causing functional and cosmetic morbidity. This review examines possible solutions for mitigating pediatric calvarial bone flap resorption by delineating methods of stimulating mechanosensitive cell populations with mechanical forces. Mechanotransduction plays a critical role in three main cell types involved with calvarial bone repair, including mesenchymal stem cells, osteoblasts, and dural cells, through mechanisms that could be exploited to promote osteogenesis. In particular, physiologically relevant mechanical forces, including substrate deformation, external forces, and ultrasound, can be used as tools to stimulate bone repair in both in vitro and in vivo systems. Ultimately, combating pediatric calvarial flap resorption may require a combinatorial approach using both cell therapy and bioengineering strategies.

Condylar resorption following mandibular advancement or bimaxillary osteotomies: A systematic review of systematic reviews.

Several systematic reviews have been published on the effects of mandibular surgery on condylar remodeling without reaching a consensus. The purpose of this systematic review of systematic reviews was to assess the impact of mandibular advancement or bimaxillary surgeries on condylar resorption. A literature search, using several electronic databases, was carried out by two reviewers independently. Article preselection was based on titles and abstracts, and final article selection based on full-text analysis of preselected studies. After final study selection, the quality of studies was assessed using the AMSTAR 2 tool. A decision algorithm was subsequently established to choose the best body of evidence. From an initial yield of 1'848 articles, 23 systematic reviews were identified for further analysis, with ten studies being included in the final selection. Despite the generally low quality of the reviews, certain associations could be made: young patients, female patients, and those with a high mandibular plane angle are more prone to condylar resorption following mandibular advancement osteotomies, especially if anterior rotation of the mandible is performed during surgery. Patients undergoing bimaxillary surgery also appear to have a higher risk of developing condylar resorption. In conclusion, these results confirm the multi-factorial nature of condylar resorption, stressing the need for well-controlled prospective studies with long-term follow-up to clearly identify potential risk factors associated with orthognathic surgery.

Role of nitric oxide in type 1 diabetes-induced osteoporosis.

Type 1 diabetes (T1D)-induced osteoporosis is characterized by decreased bone mineral density, bone quality, rate of bone healing, bone formation, and increased bone resorption. Patients with T1D have a 2-7-fold higher risk of osteoporotic fracture. The mechanisms leading to increased risk of osteoporotic fracture in T1D include insulin deficiency, hyperglycemia, insulin resistance, lower insulin-like growth factor-1, hyperglycemia-induced oxidative stress, and inflammation. In addition, a higher probability of falling, kidney dysfunction, weakened vision, and neuropathy indirectly increase the risk of osteoporotic fracture in T1D patients. Decreased nitric oxide (NO) bioavailability contributes to the pathophysiology of T1D-induced osteoporotic fracture. This review discusses the role of NO in osteoblast-mediated bone formation and osteoclast-mediated bone resorption in T1D. In addition, the mechanisms involved in reduced NO bioavailability and activity in type 1 diabetic bones as well as NO-based therapy for T1D-induced osteoporosis are summarized. Available data indicates that lower NO bioavailability in diabetic bones is due to disruption of phosphatidylinositol 3­kinase/protein kinase B/endothelial NO synthases and NO/cyclic guanosine monophosphate/protein kinase G signaling pathways. Thus, NO bioavailability may be boosted directly or indirectly by NO donors. As NO donors with NO-like effects in the bone, inorganic nitrate and nitrite can potentially be used as novel therapeutic agents for T1D-induced osteoporosis. Inorganic nitrites and nitrates can decrease the risk for osteoporotic fracture probably directly by decreasing osteoclast activity, decreasing fat accumulation in the marrow cavity, increasing osteoblast activity, and increasing bone perfusion or indirectly, by improving hyperglycemia, insulin resistance, and reducing body weight.

Incidence of condylar resorption after bimaxillary, Lefort I, and mandibular surgery: an overview.

The aim of the present overview was to evaluate the outcomes of systematic reviews to determine the incidence of condylar resorption in patients submitted to orthognathic surgery and analyze whether the risk of developing this condition is related to a specific type of surgery. Searches were conducted in the PubMed/MEDLINE, Embase, and Cochrane electronic databases for systematic reviews with quantitative data on condylar resorption due to any type of orthognathic surgery for dentoskeletal deformities published up to May 25, 2019. The AMSTAR 2 and Glenny tools were applied for the quality appraisal. Five systematic reviews were included for analysis. Only one article was considered to have high quality. Among a total of 5128 patients, 12.32% developed condylar resorption. From those patients, 70.1% had double jaw surgery, 23.4% had mandibular surgery alone, and in 6.5% a Lefort I technique was used. Based on these findings, bimaxillary surgery could be considered a risk factor for condylar resorption. However, these results should be interpreted with caution, since other factors, such as pre-operative skeletal deformities, type of movement, and type of fixation, can contribute to the development of this condition. Further studies should consider reporting main cephalometric data, temporomandibular diagnosis, hormonal levels, and tomographic measures before and after the surgery at least every 6 months during the firsts two years to identify accurately risk factors for condylar resorption.

Cranioplasty with Autologous Bone Flaps Cryopreserved with Dimethylsulphoxide: Does Tissue Processing Matter.

OBJECTIVE: The aim of this article was to study the outcome of patients who underwent cranioplasty with cryopreserved autologous bone after decompressive craniectomy. METHODS: Data from 74 patients were retrospectively analyzed. They were divided into groups according to the storage time and the age at cranioplasty. To assess the predictive potential for complication, factors were related to successive stages (preoperative, craniectomy, tissue processing, cranioplasty, and postoperative). Cooling and warming rates applied on bone flap were calculated. The ability to inhibit microbial growth was determined exposing bone fragments to a panel of microorganisms. The concentration of antibiotics eluted from the bone was also determined. A bone explant culture method was used to detect living cells in the thawed cranial bone. RESULTS: Hydrocephalus was significantly more frequent in pediatric patients (26.7%) than in adults (5.1%). The overall rate of bone flap resorption was 21.6% (43.7% of which required reoperation). Surgical site infection after cranioplasty was detected in 6.8% of patients. There was no correlation between infection as a postoperative complication and previous microbiological-positive culture during processing. The cause of craniectomy did not influence the risk of bone flap contamination. Vancomycin was the only antibiotic detected in the supernatant where the bone was incubated. Outgrowth from bone explants was observed in 36.8% of thawed skulls. An early start of bone flap processing at the tissue bank had a positive effect on cell viability. CONCLUSIONS: The outcome after autologous cranioplasty is a multifactorial process, which is modulated by patient-related, surgery-related, and bone-related factors.

Serine/threonine phosphatases in osteoclastogenesis and bone resorption.

Maintenance of optimal bone mass is controlled through the concerted functions of several cell types, including bone resorbing osteoclasts. Osteoclasts function to remove calcified tissue during developmental bone modeling, and degrade bone at sites of damage during bone remodeling. Changes to bone homeostasis can arise with alterations in osteoclastogenesis and/or catabolic activity that are not offset by anabolic activity; thus, factors that regulate osteoclastogenesis and bone resorption are of interest to further our understanding of basic bone biology, and as potential targets for therapeutic intervention. Several key cytokines, including RANKL and M-CSF, as well as co-stimulatory factors elicit kinase signaling cascades that promote osteoclastogenesis. These kinase cascades are offset by the action of protein phosphatases, including members of the serine/threonine phosphatase family. Here we review the functions of serine/threonine phosphatases and their control of osteoclast differentiation and function, while highlighting deficiencies in our understanding of this understudied class of proteins within the field.

Anatomical tibial component is related to more medial tibial stress shielding after total knee arthroplasty in Korean patients.

PURPOSE: This study aimed to investigate stress shielding of anatomical tibial components (ATCs) in comparison to conventional symmetric tibial components (STCs) in Korean patients which may be related to medial tibial bone loss. METHOD: 78 knees in 59 patients with ATCs (Persona™) and 74 knees in 58 patients with STCs (NexGen LPS-Flex™) were retrospectively reviewed. Radiographic parameters and clinical outcomes in both groups were compared. Logistic regression analysis was performed to identify risk factors for medial tibial bone loss. RESULTS: Medial tibial bone loss was significantly greater in the ATC group (1.6 ± 1.3 mm) than in the STC group (0.4 ± 0.8 mm) (p < 0.001). The ATC group showed a shorter distance between the distal metal tip and anteromedial cortex and higher invading into the sclerotic bone lesion (ISBL) than the STC group (p = 0.034 and p = 0.044, respectively). Multiple logistic regression analysis suggested ATC, a shorter distance to the anteromedial cortex, and the presence of ISBL as risk factors for medial tibial bone loss. The odds ratios of medial tibial bone loss according to type of prosthesis, distance to anteromedial cortex, and presence of ISBL were 6.25 (range 2.86-13.63, p < 0.001), 0.69 (range 0.51-0.93, p = 0.015), and 3.79 (range 1.56-9.21, p = 0.003), respectively. Notwithstanding, there was no difference in clinical outcomes between the two groups. CONCLUSION: In Korean patients, ATCs potentially causes greater medial tibial bone loss due to stress shielding than STCs. The design, however, does not yet appear to affect clinical outcomes at mid-term follow-up. LEVEL OF EVIDENCE: Retrospective cohort study, level III.

Incidence of condylar resorption after bimaxillary, Lefort I, and mandibular surgery: an overview

Abstract The aim of the present overview was to evaluate the outcomes of systematic reviews to determine the incidence of condylar resorption in patients submitted to orthognathic surgery and analyze whether the risk of developing this condition is related to a specific type of surgery. Searches were conducted in the PubMed/MEDLINE, Embase, and Cochrane electronic databases for systematic reviews with quantitative data on condylar resorption due to any type of orthognathic surgery for dentoskeletal deformities published up to May 25, 2019. The AMSTAR 2 and Glenny tools were applied for the quality appraisal. Five systematic reviews were included for analysis. Only one article was considered to have high quality. Among a total of 5128 patients, 12.32% developed condylar resorption. From those patients, 70.1% had double jaw surgery, 23.4% had mandibular surgery alone, and in 6.5% a Lefort I technique was used. Based on these findings, bimaxillary surgery could be considered a risk factor for condylar resorption. However, these results should be interpreted with caution, since other factors, such as pre-operative skeletal deformities, type of movement, and type of fixation, can contribute to the development of this condition. Further studies should consider reporting main cephalometric data, temporomandibular diagnosis, hormonal levels, and tomographic measures before and after the surgery at least every 6 months during the firsts two years to identify accurately risk factors for condylar resorption.

Unexpected Bone Resorption in Mentum Induced by the Soft-Tissue Filler Hyaluronic Acid: A Preliminary Retrospective Cohort Study of Asian Patients.

BACKGROUND: As one of the most commonly used soft-tissue fillers, hyaluronic acid is generally considered safe and efficacious. However, evident bone resorption in mentum was observed. In this study, the authors analyzed the impact of hyaluronic acid on bone resorption in mentum and the influencing factors. METHODS: The authors retrospectively compared the computed tomographic scans of patients with or without mentum augmentation using hyaluronic acid. The body mass index- and sex-matched control group was selected randomly. Semimandibular bone resorption index was calculated as the ratio of bone thickness in the incisive fossa to that in the mandibular symphysis. Injection volume, injection interval, the number of injections, product, complication were also recorded. RESULTS: From January of 2014 to June of 2019, 80 patients (160 cases) and 80 controls were recruited. The bone resorption index in the hyaluronic acid injection cohort was significantly lower than in the controls (75.25 ± 10.02 versus 82.86 ± 6.38; p = 0.000). Patients injected with greater than or equal to 1 ml per time were more susceptible to bone erosion compared with patients injected with less (68.89 ± 10.84 versus 76.49 ± 9.42; p = 0.000). There was no significant difference between one- versus multiple-injection groups and short-injection-interval versus long-injection-interval (≥6 months) groups. Furthermore, no reduced aesthetics were realized. CONCLUSIONS: Hyaluronic acid injection could induce bone resorption in the mentum; nevertheless, the aesthetics were not impaired. The severity of the bone loss was positively correlated with the injection volume per time; therefore, large-volume injection of hyaluronic acid should be performed with caution. The patients should be fully informed about this complication preoperatively. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Does Fusion Affect Anterior Bone Loss in Adjacent Cervical Disc Arthroplasty in Contiguous Two-Level Hybrid Surgery?

OBJECTIVE: To investigate whether anterior bone loss (ABL) in cervical discarthroplasty (CDA) in 2-level hybrid surgery (HS) is affected by adjacent fusion in vivo compared with 1-level CDA alone. METHODS: A total of 180 patients undergoing either a 1-level CDA or contiguous 2-level HS were retrospectively reviewed. The clinical and radiographic outcomes were collected preoperatively and at routine postoperative intervals of 1 week, 3, 6, and 12 months, and at the last follow-up. The initial and postoperative radiographs were compared to determine the incidence and degree of ABL. RESULTS: ABL was identified in 68.7% of CDA cases (37.9% mild, 34.8% moderate, and 27.3% severe) and 44.0% of HS cases (54.1% mild, 27.0% moderate, and 18.9% severe). Sex, age, bone mineral density, operation time, blood loss, postoperative alignment, and range of movement at the arthroplasty segment were not related to the incidence of ABL. According to the logistic regression analysis results, ABL showed a significant correlation with the surgery type and body mass index. However, there was no significant difference in the incidence and degree of ABL with or without an adjacent fusion level. Compared with preoperative values, clinical outcome scores significantly improved after surgery in both the HS and CDA groups. No definite clinical effect associated with ABL was found. CONCLUSIONS: ABL was common in both CDA and HS. Although HS had a lower incidence rate and degree than did CDA, the fusion location in HS did not affect the ABL of adjacent CDA.

Risk factors for bone flap resorption after autologous bone cranioplasty: Protocol for a systematic review and meta-analysis.

BACKGROUND: One of the most common complications following autologous cranioplasty is bone flap resorption (BFR). Severe BFR can lead to revision surgery with implantation of synthetic bone flap and also necessarily lead to higher hospital expenses. This study aims to perform a meta-analysis to summarize available evidence regarding risk factors of BFR requiring a second surgery in patients with autologous cranioplasty. METHODS: Cohort, case-control, and cross-sectional studies that report the incidence and risk factors of BFR among patients with autologous cranioplasty, published in English, will be considered for selection. Three databases from inception to May 2020 will be searched. The process of data selection, quality assessment, and data extraction will be assessed by 2 authors independently. The study quality will be assessed by Newcastle-Ottawa Scale (NOS) and Agency for Healthcare Research and Quality checklist.The statistical analysis of this meta-analysis will be calculated by Review manager version 5.3. RESULTS: The results of this systematic review and meta-analysis will be disseminated through academic conferences and expected to publish in a peer-reviewed journal CONCLUSION:: This study will offer high-quality evidence about risk factors for BFR after autologous cranioplasty. REGISTRATION NUMBER: INPLASY202050063.

Biochemical bone turnover markers in hormonal disorders in adults: a narrative review.

BACKGROUND: Hormonal disorders are often associated with abnormal levels of bone turnover markers (BTMs). N-terminal propeptide of type I procollagen (PINP) and serum C-terminal cross-linking telopeptide of type I collagen (CTX-I) are the reference markers of bone formation and bone resorption, respectively. METHODS: A comprehensive literature search within the MEDLINE and Web of Science databases was performed. RESULTS: Acromegaly is associated with higher BTM levels, which decrease during the remission after treatment. Adult-onset growth hormone deficiency is often associated with decreased BTM levels. Growth hormone replacement therapy stimulates bone turnover and increases BTM levels. Hypothyroidism is characterized by general slowing of bone metabolism which is reflected by lower BTM levels. The replacement thyroid hormone therapy increases the bone turnover rate and BTM levels increase. Patients with thyroid cancer receive a suppressive dose of thyroid hormones and may have slightly elevated BTM levels. Patients with overt hyperthyroidism had higher BTM levels and anti-thyroid therapy induces a rapid decrease in the BTM levels. Patients with overt primary hyperparathyroidism have higher BTM levels, whereas those with asymptomatic and normocalcemic hyperparathyroidism usually have normal BTM levels. Hypoparathyroidism is characterized by slightly decreased BTM levels. Cushing's syndrome is characterized consistently by markedly decreased osteocalcin concentration, whereas data on other BTMs are discordant. CONCLUSIONS: BTMs help us to better understand mechanisms of the impact of hormonal disorders and their treatment on bone metabolism. However, it is unknown whether BTMs may be used to monitor the effect of their treatments on bone in the clinical practice.

Aseptic bone-flap resorption after cranioplasty - incidence and risk factors.

OBJECTIVE: One of the common complications occurring after cranioplasty (CP) is aseptic bone-flap resorption (ABFR). Reoperation necessary because of the development of ABFR can lead to unfavorable complications during subsequent surgery using a synthetic skull implant, and also necessarily leads to higher costs. The aim of this study is to identify prognostic factors that may help to predict the development of ABFR. METHODS: In this study, 303 CP surgeries performed between 2002 and 2017 were examined retrospectively to identify factors predicting the occurrence of ABFR. A number of these factors (e.g., time lapse between decompressive craniectomy (DC) and CP, bone-flap size, specific laboratory signs, and the reason for the original DC) were analyzed as possibly influencing the risk of developing ABFR. RESULTS: ABFR of an autologous bone flap that subsequently required a CP with synthetic skull implants occurred in 10 of 303 patients (3.0%). CP timing and patients' Karnofsky Performance Scores (KPS) (p = 0.008; p = 0.012) were identified as significant factors with an impact on the development of ABRF. Age did not reveal a significant value, but statistical analysis shows a clear trend. The younger the age, the more likely it was that an ABFR would develop. CONCLUSION: The risk of ABFR lessens the longer the period of time elapsed between DC and CP. Age does not reveal a significant value, but statistical analysis shows that there is a clear trend.

Specific Effects of Anorexia Nervosa and Obesity on Bone Mineral Density and Bone Turnover in Young Women.

OBJECTIVE: The threefold aim was to (1) compare areal bone mineral density (aBMD), bone turnover markers, and periostin levels in young women with either anorexia nervosa (AN) or obesity (OB) and controls (CON); (2) model the profiles according to age; and (3) determine the parameters associated with aBMD. SUBJECTS AND METHODS: One hundred and fifty-two young women with ages ranging from 16.0 to 27.0 years were subdivided into 3 groups (AN, OB, CON). The CON group was age-matched by ±6 months. aBMD, bone turnover markers, and periostin levels were evaluated. RESULTS: aBMD modeling showed that hip aBMD was higher in OB than in the other 2 groups from 19 years, and AN presented lower values than CON from 21 years. aBMD at the lumbar spine was higher in older OB and CON women, starting from 20 to 22 years, but in AN the difference with the other 2 groups increased with age. Periostin levels were lower in OB than in AN or CON, but no variation with age was observed. Compared with controls, OB and AN presented similarly lower markers of bone formation, although markers of bone resorption were lower in OB and higher in AN. A modeling approach showed that markers of bone formation and resorption were lower in older than in younger CON, whereas the values of these bone markers remained relatively constant in AN and OB. In all groups, lean body mass (LBM) was the parameter most positively correlated with aBMD. CONCLUSION: This study demonstrated that weight extremes (AN or OB) influence aBMD, bone remodeling and periostin profiles. Moreover, factors related to aBMD were specific to each condition, but LBM was the parameter most consistently associated with aBMD.

Association between polycyclic aromatic hydrocarbons exposure and bone turnover in adults.

BACKGROUND: Cigarette smoking is a risk factor of osteoporosis and bone fracture. Tobacco smoke contains several polycyclic aromatic hydrocarbons. Thus, we hypothesized that environmental polycyclic aromatic hydrocarbon exposure is associated with bone loss and fracture risk. The present study examined the association between polycyclic aromatic hydrocarbon exposure and bone turnover in the general adult population. METHODS: A total of 1408 eligible participants from the National Health and Nutrition Examination Survey (NHANES 2001-2006) were included in this cross-sectional analysis. The levels of urinary N-telopeptide and serum bone-specific alkaline phosphatase, which are biomarkers of bone resorption and formation, respectively, were assessed. Meanwhile, polycyclic aromatic hydrocarbon exposure was evaluated using the concentrations of urinary polycyclic aromatic hydrocarbon metabolites. The association between polycyclic aromatic hydrocarbon exposures and N-telopeptide, and bone-specific alkaline phosphatase levels was assessed using a multivariate linear regression model. RESULTS: All polycyclic aromatic hydrocarbon metabolites except 3-phenanthrene were significantly associated with increased N-telopeptide levels (P < 0.05) after adjustment of relevant covariables. However, no significant relationship was observed between polycyclic aromatic hydrocarbon metabolites and bone-specific alkaline phosphatase levels. This relationship remained significant after the participants were assessed according to sex (P < 0.05). Additionally, all polycyclic aromatic hydrocarbon metabolites showed a positive association with N-telopeptide levels in participants aged <60 years (P < 0.05). CONCLUSION: Polycyclic aromatic hydrocarbon exposure is associated with increased bone resorption among the general adult population in the United States. Further studies must assess the potential mechanisms associated with the adverse effects of polycyclic aromatic hydrocarbon exposure on bone loss.

A Comparison between Pediatric and Adult Patients after Cranioplasty: Aseptic Bone Resorption Causes Earlier Revision in Children.

BACKGROUND AND STUDY AIMS/OBJECTIVE: Cranioplasty, a common neurosurgical intervention following decompressive craniectomy (DC), is associated with high complication rates. Bone flap resorption in particular leads to a considerable number of patients requiring further surgery. The aim of this study was to investigate the frequency and time of occurrence of complications following cranioplastic procedures in children and adults. MATERIAL AND METHODS: Data of children and adults who underwent cranioplasty between July 2010 and March 2018 were analyzed retrospectively. Clinical data, complications, and risk factors regarding aseptic bone resorption (ABR) were evaluated including patient age, occurrence of shunt-dependent hydrocephalus, and number of fragments in autologous bone flaps. RESULTS: Severe traumatic brain injury (TBI) was the leading cause for DC among children (66.7%), associated with a significantly higher number of fragments (p = 0.002). In the adult population, the most common cause was malignant infarction (55.9%) followed by TBI (24.6%). Pediatric patients in our institution received autologous bone flaps less frequently than adult patients (61.1% and 83.1%, respectively). Young age and a higher number of fragments in autologous bone flaps were associated with the occurrence of ABR. Children and adolescents showed significantly higher rates of aseptic bone necrosis (p = 0.007) and revision cranioplasty (p = 0.036). Kaplan-Meier estimates were used to further analyze bone flap resorption in children and adults, showing that revision surgery due to ABR was performed earlier in children (p = 0.001, log-rank test). CONCLUSION: Pediatric patients demand specific care when cranioplasty is performed following DC. We identified age as an independent risk factor. The higher number of fragments appears to be a correlation due to the higher number of TBIs in children. Our data indicate that young age is the most important risk factor for the development of ABR as a frequent and early complication with a shorter revision-free time interval in children. Consequently, the uncritical use of cryopreserved autologous bone flaps should be questioned in this population.

Double-Stranded RNA Is a Novel Molecular Target in Osteomyelitis Pathogenesis: A Translational Avian Model for Human Bacterial Chondronecrosis with Osteomyelitis.

Osteomyelitis remains a serious inflammatory bone disease that affects millions of individuals worldwide and for which there is no effective treatment. Despite scientific evidence that Staphylococcus bacteria are the most common causative species for human bacterial chondronecrosis with osteomyelitis (BCO), much remains to be understood about the underlying virulence mechanisms. Herein, we show increased levels of double-stranded RNA (dsRNA) in infected bone in a Staphylococcus-induced chicken BCO model and in human osteomyelitis samples. Administration of synthetic [poly(I:C)] or genetic (Alu) dsRNA induces human osteoblast cell death. Similarly, infection with Staphylococcus isolated from chicken BCO induces dsRNA accumulation and cell death in human osteoblast cell cultures. Both dsRNA administration and Staphylococcus infection activate NACHT, LRR and PYD domains-containing protein (NLRP)3 inflammasome and increase IL18 and IL1B gene expression in human osteoblasts. Pharmacologic inhibition with Ac-YVAD-cmk of caspase 1, a critical component of the NLRP3 inflammasome, prevents DICER1 dysregulation- and dsRNA-induced osteoblast cell death. NLRP3 inflammasome and its components are also activated in bone from BCO chickens and humans with osteomyelitis, compared with their healthy counterparts. These findings provide a rationale for the use of chicken BCO as a human-relevant spontaneous animal model for osteomyelitis and identify dsRNA as a new treatment target for this debilitating bone pathogenesis.

Bone invasion-targeted chemotherapy with a novel anionic platinum complex (3Pt) for oral squamous cell carcinoma.

Cisplatin (CDDP) is an important drug for chemotherapy in patients with head and neck squamous cell carcinoma. Nephrotoxicity and lack of an effect on bone invasion are limitations of CDDP. To increase its antitumor effect on bone invasion and reduce toxicity problems, anionic Pt complex (3Pt) has been developed. The present study aimed to characterize the basis of the cytotoxicity of the novel platinum complex 3Pt in comparison with that of CDDP for oral squamous cell carcinoma. The ionic platinum complex was prepared to increase solubility and avoid platinum nephrotoxicity. Furthermore, 3Pt was designed to target bone hydroxyapatite and has germinal bisphosphonate moieties for drug delivery. In vitro antitumor activity was assayed in two oral squamous cell carcinoma cell lines. To investigate the antitumor and nephrotoxic effects of 3Pt, nude mice with OSC-19 were given 3Pt and CDDP. The in vitro growth-inhibitory effect of 3Pt was significantly less than that of CDDP. However, both 3Pt and CDDP showed equivalent antitumor effects in vivo. Mice injected with CDDP developed renal cell apoptosis; however, those injected with 3Pt were almost free of renal cell injury. In addition to similar in vivo antitumor effects, 3Pt decreased the volume of bone resorption compared to that with CDDP in a bone invasion model using OSC-19. In conclusion, considering the potential advantages in terms of noticeable antitumor activity on bone invasion and reduced nephrotoxicity, 3Pt represents a significant improvement in the development of bone-targeting platinum drugs.