Medication-Related Osteonecrosis: Why the Jawbone?

Medication-related osteonecrosis of the jaw (MRONJ) has emerged as a complication of anti-resorptive medications. Despite its low incidence rate, this problem has gained attention in recent years due to its devastating consequences and lack of preventive strategy. The fact that MRONJ incidence has been exclusive to the jawbones, despite the systemic effect of anti-resorptive medications, could be a starting point to unravel the multifactorial pathogenesis of this condition. This review aims to negotiate the question of why the jawbone is more susceptible to MRONJ than other skeletal sites. Approaching the problem from this perspective could provide new directions for the prevention of MRONJ and expand our understanding of the unique oral microenvironment.

O-GlcNAc glycosylation orchestrates fate decision and niche function of bone marrow stromal progenitors.

In mammals, interactions between the bone marrow (BM) stroma and hematopoietic progenitors contribute to bone-BM homeostasis. Perinatal bone growth and ossification provide a microenvironment for the transition to definitive hematopoiesis; however, mechanisms and interactions orchestrating the development of skeletal and hematopoietic systems remain largely unknown. Here, we establish intracellular O-linked ß-N-acetylglucosamine (O-GlcNAc) modification as a posttranslational switch that dictates the differentiation fate and niche function of early BM stromal cells (BMSCs). By modifying and activating RUNX2, O-GlcNAcylation promotes osteogenic differentiation of BMSCs and stromal IL-7 expression to support lymphopoiesis. In contrast, C/EBPß-dependent marrow adipogenesis and expression of myelopoietic stem cell factor (SCF) is inhibited by O-GlcNAcylation. Ablating O-GlcNAc transferase (OGT) in BMSCs leads to impaired bone formation, increased marrow adiposity, as well as defective B-cell lymphopoiesis and myeloid overproduction in mice. Thus, the balance of osteogenic and adipogenic differentiation of BMSCs is determined by reciprocal O-GlcNAc regulation of transcription factors, which simultaneously shapes the hematopoietic niche.

Matrix-Bound Zolzoledronate Enhances the Biofilm Colonization of Hydroxyapatite: Effects on Osteonecrosis.

(1) Background: The aim of this study was to test whether matrix-bound zoledronate (zol) molecules enhanced the oral biofilm colonization of a mineralized matrix, rendering the alveolar bone more susceptible to medication-related osteonecrosis of the jaw (MRONJ) following invasive dental procedures. (2) Methods: We tested the effect of matrix-bound zol on the growth and attachment of Porphyromonas gingivalis (Pg), Fusobacterium nucleatum (Fn) and Actinomyces israelii (Ai), and whether the nitrogen-containing component of zol contributed to such effect. The role of oral bacteria in the induction of osteonecrosis was then tested using an extra-oral bone defect model. (3) Results: The attachment of biofilm to hydroxyapatite discs increased when the discs were pre-treated with zol. Bacterial proliferation was not affected. Matrix-bound zol was more potent than non-nitrogen-containing etidronate in enhancing the colonization. Stimulation was dampened by pre-treating the bacteria with histidine. The delivery of oral biofilm to a tibial defect caused osteonecrosis in zol-treated rats. (4) Conclusions: We conclude that matrix-bound zol enhances the oral biofilm colonization of hydroxyapatite. This enhancement depended on the presence of the nitrogen-containing group. The oral biofilm rendered the extra-oral bone susceptible to medication-related osteonecrosis, suggesting that it has an important role in the induction of MRONJ.

Stimulation of angiotensin II receptor 2 preserves cognitive function and is associated with an enhanced cerebral vascular density after stroke.

Angiotensin signaling is known to be sexually dimorphic. Although it is a well-studied target for intervention in stroke and cognitive impairment, female studies are rare. With females suffering a disproportionately greater negative impact of stroke and dementia vs. males, effective interventions are of utmost urgency. The aim of the current study was to determine the impact of activation of the angiotensin II type 2 receptor (AT2R) with the agonist compound 21 (C21) on the development of post-stroke cognitive impairment, after experimental ischemic stroke. Ovariectomized (OVX) spontaneously hypertensive rats (SHRs) were subjected to 1 h of middle cerebral artery occlusion (MCAO). At 24 h, rats with a significant neurologic deficit were randomized to receive either saline or C21 (0.03 mg/kg/day) intraperitoneally (IP) for 5 days, then orally (0.12 mg/kg/day) for a total of 6 weeks. Cognitive function, brain structure by MRI and vascular architecture by microCT angiography were measured. C21 preserved cognitive function, specifically spatial memory, and improved vascular density in the ischemic hemisphere at 6 weeks, reflecting both arteriogenesis and angiogenesis. In conclusion, C21 prevented cognitive impairment after stroke, likely through a mechanism involving vascular protection and restoration.

Biochemical and X-ray micro-computed tomographic analyses of critical size bone defects grafted with autogenous bone and mercerized bacterial cellulose membranes salified with alendronate.

OBJECTIVES: This study aimed to evaluate the repair of critical-sized bone defects grafted with autogenous bone and mercerized bacterial cellulose membranes (BCm) salified with alendronate (ALN). METHODS: Forty-eight male Wistar rats underwent surgery to create a 5 mm-diameter bone defect in the calvarium. The removed bone was particularized, regrafted into the defect, and covered by a BCm according to the group: control group (CG), simply mercerized BCm; group 1 (G1), negatively charged BCm (BCm-CM-) salified with ALN; and group 2 (G2), positively charged BCm (BCm-DEAE+) salified with ALN. Serum samples were collected preoperatively and before euthanasia to analyze osteoprotegerin (OPG), parathyroid hormone (PTH), sclerostin (SOST), and fibroblast growth factor 23 (FGF23) levels. The animals were euthanized after 15 or 60 d. Calvaria were analyzed using quantitative microtomography (µCT). RESULTS: There was an increased level of PTH in the CG compared to the G2 group, at day 60 (p = 0.019). When analyzing the same group over time, G1 presented an increased FGF23 level on days 15 and 60 (p < 0.05). CG presented an increase in PTH (p = 0.037) at day 60. The µCT analysis detected increased trabecular separation on day 15 in G2 compared to G1 (p = 0.040). CONCLUSIONS: Salification of ionized BCm with ALN had no direct effect on bone repair; however, BCm-CM- increased the levels of FGF23 over time. BCm-DEAE+ decreased PTH levels compared to mercerized BCm. BCm-CM-salified with ALN-induced superior bone quality, with respect to trabecular separation, compared to BCm-DEAE+.

Effect of Age and Sodium Alendronate on Femoral Fracture Repair: Biochemical and Biomechanical Study in Rats.

BACKGROUND: Bisphosphonates are drugs widely used to reduce bone resorption, increase bone mineral density and control age-related bone loss. Although there are studies reporting differences in bone structure between young and old adults, it is still difficult to predict changes related to bone aging. The aim of this study was to evaluate the effect of age and sodium alendronate on bone repair of femoral fractures in rats. METHODS: Wistar rats (n = 40) were allocated into groups: O (control old-rats), Y (control young-rats), OA (alendronate old-rats) and YA (alendronate young-rats). All animals underwent linear fracture surgery followed by fixation. Groups OA and YA received 1 mg/kg alendronate three times a week until euthanasia. Biochemical analysis of calcium and alkaline phosphatase was done. After euthanasia, femurs were evaluated in relation to cross-section and flexural strength, with three-point bending test. Data were submitted to statistical analysis with significance level of 0.05. RESULTS: There was no difference in calcium and alkaline phosphatase levels (p > 0.05). Young animals presented lower cross-section than older animals (p < 0.05). Only fractured side, young animals presented major flexural strength than older animals (p < 0.05). There was no difference between the animals that used or not alendronate in relation to cross-section and flexural strength (p > 0.05). When compared fractured and non-fractured femurs, major cross-section on fractured side was observed (p < 0.05). Flexural strength presented higher values in femurs on non-fractured side (p < 0.05). There was correlation of weight and cross-section (R = +0.91) and weight with flexural strength of fractured and non-fractured side, respectively (R = -0.97 and -0.71). CONCLUSION: In short, there was no difference of calcium and alkaline phosphatase during the bone repair process. Age has influence in cross-section and flexural strength. Alendronate showed no association with these factors.

Odontogenesis-related candidate genes involved in variations of permanent teeth size.

OBJECTIVE: The aim of the study was to evaluate the association between genetic polymorphisms in RUNX2, BMP4, BMP2, TGFß1, EGF, and SMAD6 and variations in permanent tooth size (TS). MATERIALS AND METHODS: This cross-sectional study evaluated 110 individuals' dental casts to determine the maximum tooth crown size of all fully erupted permanent teeth (third molars were excluded) in the mesiodistal (MD) and buccolingual (BL) dimensions. Genomic DNA was obtained from the epithelial cells of the oral mucosa to evaluate the genetic polymorphisms in RUNX2 (rs59983488 and rs1200425), BMP4 (rs17563), BMP2 (rs235768 and rs1005464), TGFß1 (rs1800470), EGF (rs4444903), and SMAD6 (rs2119261 and rs3934908) through real-time PCR. The data were submitted to statistical analysis with a significance level of 0.05. RESULTS: The genetic polymorphisms rs59983488, rs1200425, rs17563, rs235768, rs1005464, rs1800470, and rs4444903 were associated with MD and BL TS of the upper and lower arches (p < 0.05). The polymorphism rs2119261 was associated with variation in TS only in the upper arch (p < 0.05). The rs3934908 was not associated with any TS measurement (p > 0.05). CONCLUSIONS: In summary, this study reports novel associations between variation in permanent TS and genetic polymorphisms in RUNX2, BMP4, BMP2, TGFß1, EGF, and SMAD6 indicating a possible role of these genes in dental morphology. CLINICAL RELEVANCE: Polymorphisms in odontogenesis-related genes may be involved in dental morphology enabling a prediction of permanent TS variability. The knowledge regarding genes involved in TS might impact the personalized dental treatment, considering that patients' genetic profile would soon be introduced into clinical practice to improve patient management.

Dendritic cell derived exosomes loaded with immunoregulatory cargo reprogram local immune responses and inhibit degenerative bone disease in vivo.

Chronic bone degenerative diseases represent a major threat to the health and well-being of the population, particularly those with advanced age. This study isolated exosomes (EXO), natural nano-particles, from dendritic cells, the "directors" of the immune response, to examine the immunobiology of DC EXO in mice, and their ability to reprogram immune cells responsible for experimental alveolar bone loss in vivo. Distinct DC EXO subtypes including immune-regulatory (regDC EXO), loaded with TGFB1 and IL10 after purification, along with immune stimulatory (stimDC EXO) and immune "null" immature (iDCs EXO) unmodified after purification, were delivered via I.V. route or locally into the soft tissues overlying the alveolar bone. Locally administrated regDC EXO showed high affinity for inflamed sites, and were taken up by both DCs and T cells in situ. RegDC EXO-encapsulated immunoregulatory cargo (TGFB1 and IL10) was protected from proteolytic degradation. Moreover, maturation of recipient DCs and induction of Th17 effectors was suppressed by regDC EXO, while T-regulatory cell recruitment was promoted, resulting in inhibition of bone resorptive cytokines and reduction in osteoclastic bone loss. This work is the first demonstration of DC exosome-based therapy for a degenerative alveolar bone disease and provides the basis for a novel treatment strategy.

Age-related increase of kynurenine enhances miR29b-1-5p to decrease both CXCL12 signaling and the epigenetic enzyme Hdac3 in bone marrow stromal cells.

Mechanisms leading to age-related reductions in bone formation and subsequent osteoporosis are still incompletely understood. We recently demonstrated that kynurenine (KYN), a tryptophan metabolite, accumulates in serum of aged mice and induces bone loss. Here, we report on novel mechanisms underlying KYN's detrimental effect on bone aging. We show that KYN is increased with aging in murine bone marrow mesenchymal stem cells (BMSCs). KYN reduces bone formation via modulating levels of CXCL12 and its receptors as well as histone deacetylase 3 (Hdac3). BMSCs responded to KYN by significantly decreasing mRNA expression levels of CXCL12 and its cognate receptors, CXCR4 and ACKR3, as well as downregulating osteogenic gene RUNX2 expression, resulting in a significant inhibition in BMSCs osteogenic differentiation. KYN's effects on these targets occur by increasing regulatory miRNAs that target osteogenesis, specifically miR29b-1-5p. Thus, KYN significantly upregulated the anti-osteogenic miRNA miR29b-1-5p in BMSCs, mimicking the up-regulation of miR-29b-1-5p in human and murine BMSCs with age. Direct inhibition of miR29b-1-5p by antagomirs rescued CXCL12 protein levels downregulated by KYN, while a miR29b-1-5p mimic further decreased CXCL12 levels. KYN also significantly downregulated mRNA levels of Hdac3, a target of miR-29b-1-5p, as well as its cofactor NCoR1. KYN is a ligand for the aryl hydrocarbon receptor (AhR). We hypothesized that AhR mediates KYN's effects in BMSCs. Indeed, AhR inhibitors (CH-223191 and 3',4'-dimethoxyflavone [DMF]) partially rescued secreted CXCL12 protein levels in BMSCs treated with KYN. Importantly, we found that treatment with CXCL12, or transfection with an miR29b-1-5p antagomir, downregulated the AhR mRNA level, while transfection with miR29b-1-5p mimic significantly upregulated its level. Further, CXCL12 treatment downregulated IDO, an enzyme responsible for generating KYN. Our findings reveal novel molecular pathways involved in KYN's age-associated effects in the bone microenvironment that may be useful translational targets for treating osteoporosis.

The Role of Marine Organic Extract in Bone Regeneration: A Pilot Study.

Novel biomaterials capable of accelerating the healing process of skeletal tissues are urgently needed in dentistry. The present in vivo study assessed the osteoconductive and osteoinductive properties of experimental biphasic bioceramics (HA-TCP) modified or not by a nacre extract (marine organic extract, MOE) in a sheep model. Fabrication of MOE involved mixing ground nacre (0.05 g, particle sizes < 0.1 mm) with glacial ethanoic acid (5 mL, pH 7) for 72 hours using external magnetic stirring (25°C). Nonreactive carriers (sterile polythene tubes; 3/animal, radius: 2.5 mm, length: 10.0 mm) pertaining to the control (empty) or experimental groups (HA-TCP or MOE-modified HA-TCP) were implanted intramuscularly into the abdominal segment of the torso in sheep (n = 8, age: 2 years, weight: 45 kg). Euthanization of animals was performed at 3 and 6 months after surgery. Tissues harvested were subjected to macroscopic and radiographic assessments. Specimens were then stained for histological analysis. Both control and experimental animals were capable of inducing the neoformation of fibrous connective tissue at both time points where superior amounts of tissue formation and mineralization were detected for experimental groups (unaltered (at 3 and 6 mos) and MOE-modified HA-TCP (at 3 mos)). Histological results, however, revealed that mature bone formation was only observed for specimens fabricated with MOE-modified HA-TCP in a time-dependent manner. The present study has successfully demonstrated the in vivo utility of experimental biphasic bioceramics modified by MOE in an ectopic grafting sheep model. Promising osteoconductive and osteoinductive properties must be further developed and confirmed by subsequent research.

Picolinic acid, a tryptophan oxidation product, does not impact bone mineral density but increases marrow adiposity.

Tryptophan is an essential amino acid catabolized initially to kynurenine (kyn), an immunomodulatory metabolite that we have previously shown to promote bone loss. Kyn levels increase with aging and have also been associated with neurodegenerative disorders. Picolinic acid (PA) is another tryptophan metabolite downstream of kyn. However, in contrast to kyn, PA is reported to be neuroprotective and further, to promote osteogenesis in vitro. Thus, we hypothesized that PA might be osteoprotective in vivo. In an IACUC-approved protocol, we fed PA to aged (23-month-old) C57BL/6 mice for eight weeks. In an effort to determine potential interactions of PA with dietary protein we also fed PA in a low-protein diet (8%). The mice were divided into four groups: Control (18% dietary protein), +PA (700 ppm); Low-protein (8%), +PA (700 ppm). The PA feedings had no impact on mouse weight, body composition or bone density. At sacrifice bone and stem cells were collected for analysis, including µCT and RT-qPCR. Addition of PA to the diet had no impact on trabecular bone parameters. However, marrow adiposity was significantly increased in PA-fed mice, and in bone marrow stromal cells isolated from these mice increases in the expression of the lipid storage genes, Plin1 and Cidec, were observed. Thus, as a downstream metabolite of kyn, PA no longer showed kyn's detrimental effects on bone but instead appears to impact energy balance.

Role of dendritic cell-mediated immune response in oral homeostasis: A new mechanism of osteonecrosis of the jaw.

Dendritic cells are an important link between innate and adaptive immune response. The role of dendritic cells in bone homeostasis, however, is not understood. Osteoporosis medications that inhibit osteoclasts have been associated with osteonecrosis, a condition limited to the jawbone, thus called medication-related osteonecrosis of the jaw. We propose that disruption of the local immune response renders the oral microenvironment conducive to osteonecrosis. We tested whether zoledronate (Zol) treatment impaired dendritic cell (DC) functions and increased bacterial load in alveolar bone in vivo and whether DC inhibition alone predisposed the animals to osteonecrosis. We also analyzed the role of Zol in impairment of differentiation and function of migratory and tissue-resident DCs, promoting disruption of T-cell activation in vitro. Results demonstrated a Zol induced impairment in DC functions and an increased bacterial load in the oral cavity. DC-deficient mice were predisposed to osteonecrosis following dental extraction. Zol treatment of DCs in vitro caused an impairment in immune functions including differentiation, maturation, migration, antigen presentation, and T-cell activation. We conclude that the mechanism of Zol-induced osteonecrosis of the jaw involves disruption of DC immune functions required to clear bacterial infection and activate T cell effector response.

Monomethylfumarate protects against ovariectomy-related changes in body composition.

Osteoporosis, low bone mass that increases fracture susceptibility, affects approximately 75 million individuals in the United States, Europe and Japan, with the number of osteoporotic fractures expected to increase by more than 3-fold over the next 50 years. Bone mass declines with age, although the mechanisms for this decrease are unclear. Aging enhances production of reactive oxygen species, which can affect bone formation and breakdown. The multiple sclerosis drug Tecfidera contains dimethylfumarate, which is rapidly metabolized to monomethylfumarate (MMF); MMF is thought to function through nuclear factor erythroid-derived-2-like-2 (Nrf2), a transcription factor activated by oxidative stress which induces the expression of endogenous anti-oxidant systems. We hypothesized that MMF-elicited increases in anti-oxidants would inhibit osteopenia induced by ovariectomy, as a model of aging-related osteoporosis and high oxidative stress. We demonstrated that MMF activated Nrf2 and induced anti-oxidant Nrf2 target gene expression in bone marrow-derived mesenchymal stem cells. Sham-operated or ovariectomized adult female mice were fed chow with or without MMF and various parameters monitored. Ovariectomy produced the expected effects, decreasing bone mineral density and increasing body weight, fat mass, bone marrow adiposity and serum receptor activator of nuclear factor-kappa-B ligand (RANKL) levels. MMF decreased fat but not lean mass. MMF improved trabecular bone microarchitecture after adjustment for body weight, although the unadjusted data showed few differences; MMF also tended to increase adjusted cortical bone and to reduce bone marrow adiposity and serum RANKL levels. Because these results suggest the possibility that MMF might be beneficial for bone, further investigation seems warranted.

Serum C-terminal cross-linking telopeptide level as a predictive biomarker of osteonecrosis after dentoalveolar surgery in patients receiving bisphosphonate therapy: Systematic review and meta-analysis.

BACKGROUND: The authors' aim in this systematic review was to evaluate the validity of using preoperative serum C-terminal cross-linking telopeptide (CTX) levels as a predictive factor of increased risk of developing medication-related osteonecrosis of the jaw (MRONJ) in patients receiving bisphosphonate (BP) therapy who underwent invasive dental procedures. TYPES OF STUDIES REVIEWED: The authors searched PubMed, MEDLINE, and Web of Science and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. The authors conducted a meta-analysis on the risk ratio. The authors used the methodological index for nonrandomized studies and Quality Appraisal of Reliability Studies checklist to assess quality. RESULTS: The authors included 18 clinical trials involving 2,301 patients. Most patients received alendronate or risedronate for an average of 62.14 months. The average serum CTX level in patients who received BP before surgery was 198.25 picograms per milliliter. Meta-analysis results showed that the cutoff in CTX level (150 pg/mL) was not predictive of MRONJ risk. The sensitivity of CTX values lower than 150 pg/mL was 34.26%, and the specificity was 77.08%. CONCLUSIONS AND PRACTICAL IMPLICATIONS: The use of CTX levels to diagnose MRONJ risk after dental procedures in patients receiving BP is not justified. The cutoff of 150 pg/mL in serum CTX levels is not predictive of MRONJ. Further studies are needed to develop other reliable biomarkers.

Meta-Analysis and Evidence Base for the Efficacy of Autologous Bone Marrow Mesenchymal Stem Cells in Knee Cartilage Repair: Methodological Guidelines and Quality Assessment.

The aim of this study is to review all the published clinical trials on autologous bone marrow mesenchymal stem cells (BM-MSCs) in the repair of cartilage lesions of the knee. We performed a comprehensive search in three electronic databases: PubMed, Medline via Ovid, and Web of Science. A systematic review was conducted according to the guidelines of PRISMA protocol and the Cochrane Handbook for Systematic Reviews of Interventions. The modified Coleman methodology score was used to assess the quality of the included studies. Meta-analysis was conducted to estimate the effect size for Pain and function change after receiving BM-MSCs. Thirty-three studies-including 724 patients of mean age 44.2 years-were eligible. 50.7% of the included patients received cultured BM-MSCs for knee cartilage repair. There was improvement in the MINORS quality score over time with a positive correlation with the publication year. Meta-analysis indicated better improvement and statistical significance in the Visual Analog Scale for Pain, IKDC Function, Tegner Activity Scale, and Lysholm Knee Score after administration of noncultured BM-MSCs when compared to evaluation before the treatment. Meanwhile, there was a clear methodological defect in most studies with an average modified Coleman methodology score (MCMS) of 55. BM-MSCs revealed a clinically relevant improvement in pain, function, and histological regeneration.

Value of pre-operative CTX serum levels in the prediction of medication-related osteonecrosis of the jaw (MRONJ): a retrospective clinical study.

OBJECTIVES: The low incidence yet severe presentation of medication-related osteonecrosis of the jaw (MRONJ) makes it necessary to develop reliable predictive and preventive strategies. This study explored the value of pre-operative carboxy-terminal collagen crosslinks (CTX) serum level in the prediction of osteonecrosis-related complications in patients on bisphosphonate therapy. PATIENTS AND METHODS: We examined patient records over 4 years (a total of 137 patients). Biometric data were extracted, in addition to type of treatment, CTX levels, drug holiday, procedure, complications, and co-morbidities. Non-parametric Wilcoxon two-sample tests were used to test the effect of initial CTX level in IV or PO and whether it was predictive of complications. Two independent proportion tests were used for testing the two different complication incident rates before or after the drug holiday. RESULTS: A total of 93 patients were included in the study, of whom 88.17% were female. A total of 11 patients were receiving IV bisphosphonates at the time of initial presentation, 82 oral bisphosphonates. Out of 64 patients who underwent invasive dental procedure (IDP) before a drug holiday, eight were on IV bisphosphonates. Three patients in this group experienced osteonecrosis-related complications (37.5%). Out of the remaining 56 patients on oral bisphosphonates, four (7.14%) developed complications, significantly lower than the IV bisphosphonate group (p = 0.0364). On the other hand, of the 34 patients placed on a drug holiday prior to IDP, only one subject developed complications related to osteonecrosis. Five subjects who had operations both before and after drug holiday did not experience any complications. No statistical difference was detected in complication rates based on initial CTX level (above versus below 150 pg/ml), gender, comorbidities, or total duration of bisphosphonate treatment (p = 0.2675). The sensitivity and specificity of CTX cutoff of 150 pg/ml in predicting osteonecrosis were 37.5% and 57.7, respectively. CONCLUSIONS: Serum levels of CTX by itself are not reliable as a predictive or preventive measure for such complications. Our data also suggested that a drug holiday of 5 months was not helpful in preventing osteonecrosis-related complications in patients on intravenous bisphosphonates. Further studies are urgently needed to develop adequate predictive and preventive strategies of MRONJ.

The use of vascularized fibula flap in mandibular reconstruction; A comprehensive systematic review and meta-analysis of the observational studies.

BACKGROUND: Vascularized fibular flaps are considered the gold standard for the reconstruction of segmental defects in the mandible. This review compares the complication and success rates of these techniques between primary and secondary reconstruction, as well as between lateral and antero-lateral defects. TYPE OF STUDIES REVIEWED: A systematic review and meta-analysis were conducted according to PRISMA protocol and the Cochrane Handbook for Systematic Reviews of Interventions. The authors performed an independent comprehensive search using PubMed, Ovid MEDLINE, Web of Science, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and COS Conference Papers Index according to established inclusion and exclusion criteria. The methodological index for nonrandomized studies (MINORS) was used to assess the quality of the included studies. Meta-analysis was conducted to compare the type of reconstruction and location of the defect. RESULTS: Seventy-eight studies, involving 2461 patients, were eligible. 83.7% of the included patient received primary reconstruction with vascularized fibular flap. The overall flap success rate was 93%. There was improvement in MINORS quality score over time with positive correlation with the publication year (r = 0.5549, P < 0.0001, CI 0.3693 to 0.6979). Meta-analysis indicated no significant association in flap success between primary and secondary reconstruction, or lateral and antero-lateral defects. CONCLUSION: Based on the available studies, this review found no evidence of difference in success or complication rates between primary and secondary reconstruction or between lateral and anterolateral defects. High-quality clinical studies are required to analyze the outcome of these techniques, especially regarding the impact of chemotherapy, radiation therapy, implant-supported dental prostheses, and preoperative planning, on the outcome of reconstruction.

Bone Marrow Derived Extracellular Vesicles Activate Osteoclast Differentiation in Traumatic Brain Injury Induced Bone Loss.

Traumatic brain injury (TBI) is a major source of worldwide morbidity and mortality. Patients suffering from TBI exhibit a higher susceptibility to bone loss and an increased rate of bone fractures; however, the underlying mechanisms remain poorly defined. Herein, we observed significantly lower bone quality and elevated levels of inflammation in bone and bone marrow niche after controlled cortical impact-induced TBI in in vivo CD-1 mice. Further, we identified dysregulated NF-κB signaling, an established mediator of osteoclast differentiation and bone loss, within the bone marrow niche of TBI mice. Ex vivo studies revealed increased osteoclast differentiation in bone marrow-derived cells from TBI mice, as compared to sham injured mice. We also found bone marrow derived extracellular vesicles (EVs) from TBI mice enhanced the colony forming ability and osteoclast differentiation efficacy and activated NF-κB signaling genes in bone marrow-derived cells. Additionally, we showed that miRNA-1224 up-regulated in bone marrow-derived EVs cargo of TBI. Taken together, we provide evidence that TBI-induced inflammatory stress on bone and the bone marrow niche may activate NF-κB leading to accelerated bone loss. Targeted inhibition of these signaling pathways may reverse TBI-induced bone loss and reduce fracture rates.

Inhibition of Osteocyte Membrane Repair Activity via Dietary Vitamin E Deprivation Impairs Osteocyte Survival.

Osteocytes experience plasma membrane disruptions (PMD) that initiate mechanotransduction both in vitro and in vivo in response to mechanical loading, suggesting that osteocytes use PMD to sense and adapt to mechanical stimuli. PMD repair is crucial for cell survival; antioxidants (e.g., alpha-tocopherol, also known as Vitamin E) promote repair while reactive oxygen species (ROS), which can accumulate during exercise, inhibit repair. The goal of this study was to determine whether depleting Vitamin E in the diet would impact osteocyte survival and bone adaptation with loading. Male CD-1 mice (3 weeks old) were fed either a regular diet (RD) or Vitamin E-deficient diet (VEDD) for up to 11 weeks. Mice from each dietary group either served as sedentary controls with normal cage activity, or were subjected to treadmill exercise (one bout of exercise or daily exercise for 5 weeks). VEDD-fed mice showed more PMD-affected osteocytes (+ 50%) after a single exercise bout suggesting impaired PMD repair following Vitamin E deprivation. After 5 weeks of daily exercise, VEDD mice failed to show an exercise-induced increase in osteocyte PMD formation, and showed signs of increased osteocytic oxidative stress and impaired osteocyte survival. Surprisingly, exercise-induced increases in cortical bone formation rate were only significant for VEDD-fed mice. This result may be consistent with previous studies in skeletal muscle, where myocyte PMD repair failure (e.g., with muscular dystrophy) initially triggers hypertrophy but later leads to widespread degeneration. In vitro, mechanically wounded MLO-Y4 cells displayed increased post-wounding necrosis (+ 40-fold) in the presence of H2O2, which could be prevented by Vitamin E pre-treatment. Taken together, our data support the idea that antioxidant-influenced osteocyte membrane repair is a vital aspect of bone mechanosensation in the osteocytic control of PMD-driven bone adaptation.