Effect of Botulinum Toxin Type A on Mandibular Fracture Healing: An Experimental Study in Rabbits.

PURPOSE: The effect of botulinum toxin type A (BTX-A) on fracture healing of the long bones is controversial, and no controlled clinical or experimental study has investigated the effect of BTX-A on mandibular fractures. The purpose of this study was to investigate whether BTX-A injection into the masseter muscles affects bone healing by reducing the displacing forces in an unfavorable mandibular fracture model. MATERIALS AND METHODS: Forty-eight male New Zealand white rabbits were used. Ten units of BTX-A was injected into each masseter muscle in the animals in the BTX-A group, whereas saline solution was injected in the animals in the control group. A unilateral osteotomy and fixation with a microplate were performed. Bone healing was evaluated by radiodensitometric, biomechanical, histologic, and histomorphometric methods after 21 days. RESULTS: The mean bone mineral density in the fracture area was significantly higher in the BTX-A group (P = .038). The mean failure load and bending modulus values were significantly higher in the BTX-A group than in the control group (P = .032 and P = .005, respectively). The mean histologic bone healing scores, bone volume-total volume values, and trabecular diameter values were significantly higher in the BTX-A group than in the control group (P = .001, P = .001, and P = .026, respectively). CONCLUSIONS: BTX-A application into the masseter muscles improves bone healing of a unilateral mandibular fracture in rabbits.

Evaluation of the effect of teriparatide therapy on mandibular fracture healing in rats with medication-related osteonecrosis of the jaw.

OBJECTIVE: The aim of this study was to evaluate the effect of teriparatide therapy on mandibular fracture healing in rats with medication-related osteonecrosis of the jaw (MRONJ). MATERIALS AND METHODS: To induce MRONJ, a total of 120 rats received intravenous zoledronate 0.06 mg/kg once a week for 6 weeks and their right mandibular first molar was extracted. Eighty of 94 rats with MRONJ were randomly selected and underwent unilateral mandibular osteotomy to replicate a fracture. After surgery, the rats were randomly assigned to T (teriparatide-treated) and C (control) groups. Group T (n = 40) received subcutaneous injection of 2 µg/kg/day teriparatide and group C (n = 40) received the same volume of normal saline until sacrifice. Four and 8 weeks after surgery, 20 rats in each group were sacrificed. Fracture healing was scored using a histological grading system (1 to 10). RESULTS: In group C, at 4 weeks and 8 weeks post-fracture, fibrous and cartilaginous tissues and scant bone formation at the fracture site and lacunae without osteocyte in adjacent mandibular bone were seen. In group T, substantial amounts of new trabecular bone rimmed by osteoblasts and some areas of remodeled mature bone were seen. After 8 weeks, extensive replacement of trabecular bone with mature bone occurred. Except between C4 and C8 groups, the healing score was significantly different between all subgroups. CONCLUSION: Teriparatide therapy successfully improved mandibular fracture healing in rats with MRONJ. However, this study was limited by the use of an animal model whose anatomy, physiology, and drug metabolism might be different from humans. CLINICAL RELEVANCE: The present study showed that teriparatide therapy may be used adjunctive to surgery in the treatment of mandibular fractures in MRONJ patients.

Beneficial Therapeutic Effects of Sildenafil on Bone Healing in Animals Treated with Bisphosphonate.

OBJECTIVES: The purpose of the present study was to evaluate the effects of sildenafil on mandibular fracture healing in animals treated with zoledronic acid by using histologic, histomorphometric, immunohistochemical, and radiodensitometric methods. MATERIALS AND METHODS: A total of 36 Sprague-Dawley rats (3 months old) were used. All animals were treated intraperitoneally with 0.1 mg/kg zoledronate three times per week, for a total of 8 weeks. Postoperatively, the animals were divided into two groups: zoledronate group (Z), which had no treatment applied (n = 18), and zoledronate + sildenafil (ZS), which were treated daily with 10 mg/kg sildenafil (n = 18). Each group was divided into two subgroups and the animals were sacrificed at the end of week 1 (Z1 and ZS1, n = 9) and week 4 (Z4 and ZS4, n = 9) after the operation. Histologic, histomorphometric, immunohistochemical analysis, and radiodensitometry were performed on the test subjects. RESULTS: Sildenafil-treated groups showed a significant increase in fracture healing scores. This result was supported by the densitometric, histologic, histomorphometric, and immunohistochemical findings. CONCLUSIONS: Sildenafil may have positive effects on accelerating and improving fracture healing, and it may be used as a supporting factor in bone healing in patients treated with bisphosphonate (BP) to prevent negative effects of BP's.

Therapeutic Effects of Sildenafil on Experimental Mandibular Fractures.

OBJECTIVES: No previous studies have examined the effect of sildenafil on fracture healing. This study was designed to investigate the effect of sildenafil on the fracture healing process. METHODS: Thirty-six female Sprague-Dawley rats (3-month-old) were used in this study. Animals were randomly divided into 2 groups based on treatment duration (1 week versus 4 weeks) and each group was then divided further into 2 subgroups, control (C) and study (S) groups. Group C (C1, C2) was treated daily with saline solution and group S (S1, S2) was treated daily with 10 mg/kg of sildenafil. Histologic, histomorphometric, radiological, and immunohistochemical analyses were performed at 1 week and 4 weeks after a fracture. RESULTS: The sildenafil group showed a significant increase in fracture healing scores (P = 0.00). The authors observed a transition from fibrous callus to cartilage tissue and immature bone tissue in group S1; and an increased transition of cartilage tissue to completely immature bone tissue in group S2, both of which were administered sildenafil. The strong expression of bone morphogenetic protein 2 and col-1 was observed in the fibrous matrix and osteoblasts within areas of new bone formation, especially in group S1. This group also showed an increase in bone density measurements at 1 week that was statistically significant (P = 0.03). CONCLUSIONS: Sildenafil accelerates fracture healing and can be used as a supporting factor in the improvement of fracture healing under various conditions.

[Use of adaptogens for antioxidant system correction in complex treatment of mandibular fractures].

Antioxidatic protection has been studied in 84 patients with mandibular fractures between the ages of 21 and 40; the patients were divided into two groups. Activation of lipid peroxidation in both groups was revealed. The increase of antioxidant's activity system in 37.18% in the main study group that along with traditional treatment received Epsorin was determined. No complications in the main group during the post-surgery period were recorded.

[Immunological aspects of delayed regeneration of mandibular fractures].

The level of complications in patients with the mandibular fractures does not have a tendency to the decline. A research purposes is a study of the basic laws of immunological reactions and possibility of optimizing processes osteogenesis by drugs-cytokines at patients with the mandibular fractures with delayed consolidation of bone tissue. 46 patients with the mandibular fractures were observed. The maintenance of cytokines IL - 1ß, TNF - α, IL - 4, SICAM-1 in the blood serum, IgA, IgM, IgG in a mouth liquid was probed. It is set that in pathogenesis of delayed consolidation a basic role is played by changes reactivity of organism, which realized in three directions: immunodeficit of humoral immunity, immunodepression of cellular factors of defence, disbalance in functioning of the cytokines system. It is necessary to count the levels of products SICAM-1 and cytokine IL-1ß in the blood serum by the diagnostic criteria of bone repair features at patients with the mandibular fractures: development of delayed consolidation of mandibular fragments is accompanied the increase of their parameters at the control group more than in 2 and in 15 times (668,2±10,3 pg/ml and 363,4 ±6,6 pg/ml relatively). Includding in the complex treatment of the mandibular fractures of immunomodulator Ronkoleukin showed clinico-immunological efficiency for the patients with impaired bone repair.

[Application of immunomodulators in the treatment of mandibular fractures in elderly patients with incomplete secondary adentia].

The aim of the work was to study the experience of using complex pharmacotherapy in the treatment of mandibular fractures in elderly patients with incomplete secondary periodontitis, which were divided into two groups. In the first group, patients (n = 46; average age 69.0 ± 3.6) were treated using the authors' original device combined with application of antimicrobial MetrogilDenta gel onto gums two times a day during ten days. Patients in the second group (n = 52; average age 61.0 ± 3.1) were treated with the same device combined with (i) application of MetrogilDenta antimicrobial gel onto gums two times a day during ten days, (ii) application of 1.5 ml of Cycloferon 5% liniment by cotton pellet for 20 min during the same 10 days (30 minutes after the antimicrobial gel), and (iii) intramuscular injections of 6 mg of synthetic immunomodulator Polyoxidonium once a day for 3 days, then once every two days (for a total of 17 days). It is established that the use of the combination of interferon inducers of immunomodulator group--Cycloferon in the form of liniment and synthetic immunomodulator Polyoksidonium together with MetrogilDenta antimicrobial gel--led to the most pronounced regression of inflammatory and destructive processes in periodontal tissues (in 7.1%, d = 0.05), optimized the state of local immunity of the oral cavity, and normalized microflora in periodontal pockets in elderly patients with incomplete secondary adentia.

The effects of zoledronic acid on mandibular fracture healing in an osteoporotic model: a stereological study.

The aim of this study was to evaluate the effect of zoledronic acid (ZA) in the ovariectomized rat on mandibular fracture. Corpus osteotomies were performed on the mandible of ovariectomized rats. Miniplates were placed on these rats, which were randomly divided into 4 groups. After 7 days, groups 3 and 4 were injected with 0.1 mg/kg ZA. Groups 1 and 2 were control groups, so they were injected 0.1 mg/kg saline solution. Animals in groups 1 and 3 were killed at 4 weeks, whereas groups 2 and 4 were killed 8 weeks after operation. The new bone volume of the fracture gap was examined stereologically. Although the difference was not statistically significant compared with the other groups (groups 1 and 3), more bone formation was found in ZA-treated groups (groups 2 and 4) (P < 0.05).

The Promoting Effect of a Local Pulsatile Parathyroid Hormone Delivery on Healing of the Mandibular Fracture in Rats.

Parathyroid hormone (PTH) can promote bone formation and mineralization in mandibular fractures, and is systemically administered through daily injections. In this study, the local delivery of PTH using carboxymethyl chitosan/polyvinyl alcohol and alginate was investigated. Bovine serum albumin was used as a drug substitute, and the delivery system was verified to release drugs in a pulsed rhythm. After the delivery system was subcutaneously implanted in Sprague-Dawley (SD) rats, no rejection reaction was detected, indicating that it has good biocompatibility and biodegradability in vivo. Then, an SD rat model of mandibular fracture was established, and 24 rats were randomly divided into two groups. The control group was reduced and fixed with screws and a microplate, and the experimental group received pulsatile PTH release system (14 µg PTH) + screws and microplate fixation. The animals were euthanized on postoperative weeks 1-4. Observation of gross specimens, digital radiography, and hematoxylin and eosin showed that the local PTH pulsatile release system promoted osteogenesis and accelerated fracture healing. In summary, PTH can be loaded by biomaterials to locally target the fracture and stimulate bone formation. Moreover, the pulsatile PTH release system provides a potential therapeutic protocol for mandibular fracture. Impact statement Our study prepares a drug release system that could impulsively release parathyroid hormone. The system could enhance bone regeneration in rats with mandibular fracture. These data provide a foundation for future studies aimed to understand and optimize the use of bioactive molecule pulsatile delivery for bone regeneration and tissue engineering applications.

A Case Report of Oral Bisphosphonate Treatment for Osteoporosis Leading to Atypical Femoral Fracture and Pathologic Mandibular Fracture.

BACKGROUND Bisphosphonates inhibit bone resorption in patients with postmenopausal osteoporosis and reduce osteoporotic fracture incidence. Medication-related osteonecrosis of the jaws (MRONJ) and atypical femoral fractures (AFF) are both rare but serious adverse effects of anti-resorptive drugs (ARD) such as bisphosphonates. The most advanced form of MRONJ is termed stage 3 and can lead to severe local sequelae like pathologic mandibular fractures (PMF). This study reports a case of MRONJ-related PMF and AFF with osteomyelitis secondary to bisphosphonate treatment for osteoporosis. CASE REPORT A 63-year-old white woman was diagnosed with PMF related to MRONJ stage 3 during treatment of an AFF with osteomyelitis. She had been treated for postmenopausal osteoporosis with 70 mg of alendronate weekly for 2 years. The PMF was treated by stable internal fixation combined with debridement and sequestrectomy, but further debridement was required and 2 mandibular implants were then removed. Postoperative recovery was uneventful and the mandibular infection was controlled after the second surgery. Three weeks later, she was discharged from the hospital, instructed to discontinue the use of alendronate, and referred for 30 sessions of hyperbaric oxygen therapy. At the 3-year follow-up, the PMF was completely healed without signs of mandibular infection or bone exposure. CONCLUSIONS This report raises awareness of both MRONJ and AFF as possible adverse effects of short-term bisphosphonate therapy for postmenopausal osteoporosis, and highlights the importance of dental and orthopedic follow-ups. It is crucial to emphasize the need for early diagnosis and treatment to prevent MRONJ progression to PMF.

Antibiotic use in mandibular fracture surgery - An international survey and a review of the literature.

OBJECTIVE: To clarify antibiotic use by oral and maxillofacial surgeons in mandibular fracture patients and evaluate practices based on scientific evidence. MATERIAL AND METHODS: We assessed antibiotic use in simple symphysis and angle mandibular fractures among oral and maxillofacial surgeons in the Nordic countries through an e-survey. In addition, we performed a literature review of antibiotic administration in mandibular fracture surgery. RESULTS: A total of 41 oral and maxillofacial surgeons who treat mandibular fractures responded to the questionnaire. Timing and duration of antibiotic use varied. The duration of postoperative antibiotic treatment ranged from 1 to 7 days (mean 5.6 days). Respondents' practices were not in concordance with scientific evidence. According to previous studies, restricting antibiotic exposure to a maximum of 24 hours postoperatively was not related to a higher risk of surgical site infections. No articles described a benefit of prolonged postoperative antibiotic therapy. CONCLUSIONS: Antibiotic use in connection with mandibular fracture treatment varied in the Nordic countries and antibiotic practices are not in concordance with the current literature. Restricting antibiotic exposure to a maximum of 24 hours postoperatively should be considered. Clear guidelines for antibiotic prophylaxis as part of the surgical management of mandibular fractures are required.

The efficacy of teriparatide (Cinnopar®) on bone repair in mandibular fractures: A single blinded randomized clinical trial.

This study focused on the effects of teriparatide (CinnoPar) on healing and postoperative complications in mandibular bone fractures. In this single-blind randomized controlled trial, 30 patients with a mandibular fracture hospitalized for open reduction internal fixation were randomly assigned to the intervention (I) (n = 15) and control (C) (n = 15) groups. Both groups received daily acetaminophen and cephalexin for 1 week. For 1 month, Group I received daily subcutaneous teriparatide injections. The Radiographic Union Scale of the Mandible (RUSM) was used to assess mandibular bone fusion subjectively, and the Hounsfield unit (HU) was used to objectively assess radiodensity in a computed tomography (CT) scan. In both groups, the visual analog scale (VAS) score was used to assess postoperative complications such as pain, swelling, wound opening, pus secretion, and bitter taste. There was no significant difference in bone repair between the two groups in this study (P > 0.05). Teriparatide also had no effect on the postoperative complication rate in the control group (P > 0.05). Within the limitations of the study it seems that in mandibular fractures, teriparatide did not affect bone fusion or postoperative complications, so its use is not recommended for better bone fusion and fewer postoperative complications of mandibular fracture during the first month.

[Rational (injection) of calcitonin for stimulation of the mandibular reparative regeneration].

This investigation permit to detect, that first resorption stage of the mandible reparative regeneration terminats after fracture 5 days later. Calcitonine injection during 5 days after fracture i.e. in paratiroid hormone dependent stage distorts normal reparative process. Rats with traumatic osteomielitis become 1.5 times more and rats with normal regeneration become 3 times less. Injection calcitonine in KT-dependent stage, i.e. in 6-11 days after fracture increases quantity of rats with normal regeneration in 7 times and decreases quantity animals with traumatic osteomielitis on 50%. There's recommendation to inject KT from 6 days after trauma.

Surgical Infection Society Guidelines for Antibiotic Use in Patients with Traumatic Facial Fractures.

Background: Facial fractures are common in traumatic injury. Antibiotic administration practices for traumatic facial fractures differ widely. Methods: The Surgical Infection Society's (SIS's) Therapeutics and Guidelines Committee convened to develop guidelines for antibiotic administration in the management of traumatic facial fractures. PubMed, Embase, and the Cochrane database were searched for pertinent studies. Pre-operative antibiotics were defined as those administered more than 1 hour before surgery. Peri-operative antibiotics were those administered within 1 hour of the start of surgery depending on the type of antibiotic and as late as ≤24 hours after surgery. Post-operative antibiotics were defined as those administered >24 hours after surgery. Prophylactic antibiotics were those administered for >24 hours without a documented infection. Evaluation of the published evidence was performed with the GRADE system. Using a process of iterative consensus, all committee members voted to accept or reject each recommendation. Results: We recommend that in adult patients with non-operative upper face, midface, or mandibular fractures, prophylactic antibiotics not be prescribed and that in adult patients with operative, non-mandibular fractures, pre-operative antibiotics likewise not be prescribed. We recommend that in adult patients with operative, mandibular fractures, pre-operative antibiotics not be prescribed; and in adult patients with operative, non-mandibular facial fractures, post-operative (>24 hours) antibiotics again not be prescribed. We recommend that in adult patients with operative, mandibular facial fractures, post-operative antibiotics (> 24 hours) not be prescribed. Conclusions: This guideline summarizes the current SIS recommendations regarding antibiotic management of patients with traumatic facial fractures.

Evaluation of the efficacy of salmon calcitonin nasal spray on bone healing following open reduction and internal fixation of mandibular fractures - A randomized controlled trial.

The objective of this study was to assess the efficacy of calcitonin spray on bone healing following open reduction internal fixation (ORIF) of mandibular fractures. Fourteen patients were subdivided into a study group and a control group. A standardized surgical protocol for ORIF was followed. Postoperatively, salmon calcitonin nasal spray was administered to only the study group. The outcome parameters assessed were serum osteocalcin, pain, and radiographic bone healing. Serum osteocalcin was assessed pre- and postoperatively. Postoperative pain was documented using a visual analogue scale (VAS) on the 7th, 14th, 23rd, and 30th days. An orthopantomogram was used to score fracture healing at four time intervals, as follows: 1 - absence of callus; 2 - presence of minimal callus; 3 - considerable callus; and 4 - complete fusion of fracture. Pain scores were lower for the study group, with no pain from the fifth day, while the control group produced a mean score for day 5 of 2.43 ± 0.98 (p = 0.001). Mean postoperative serum osteocalcin levels were higher for the study group (67.82 ± 8.89) compared with the control group (57.69 ± 6.22; p = 0.029). Bone healing at 12 weeks postoperatively was level 4 for 28.6% of patients in the study group and level 3 for 71.4%. In comparison, 85.7% in the control group demonstrated level 3 healing, while 14.3% remained at level 2 (p = 0.462). Within the limitations of the study, it can be concluded that intranasal salmon calcitonin spray reduces postoperative pain and facilitates fracture healing, although its economic efficiency is still to be proven.

Parathyroid hormone promotes cartilage healing after free reduction of mandibular condylar fractures by upregulating Sox9.

After high fractures of the mandibular condyle, the insufficient blood supply to the condyle often leads to poor bone and cartilage repair ability and poor clinical outcome. Parathyroid hormone (PTH) can promote the bone formation and mineralization of mandibular fracture, but its effects on cartilage healing after the free reduction and internal fixation of high fractures of the mandibular condyle are unknown. In this study, a rabbit model of free reduction and internal fixation of high fractures of the mandibular condyle was established, and the effects and mechanisms of PTH on condylar cartilage healing were explored. Forty-eight specific-pathogen-free (SPF) grade rabbits were randomly divided into two groups. In the experimental group, PTH was injected subcutaneously at 20 µg/kg (PTH (1-34)) every other day, and in the control group, PTH was replaced with 1 ml saline. The healing cartilages were assessed at postoperative days 7, 14, 21, and 28. Observation of gross specimens, hematoxylin eosin staining and Safranin O/fast green staining found that every-other-day subcutaneous injection of PTH at 20 µg/kg promoted healing of condylar cartilage and subchondral osteogenesis in the fracture site. Immunohistochemistry and polymerase chain reaction showed that PTH significantly upregulated the chondrogenic genes Sox9 and Col2a1 in the cartilage fracture site within 7-21 postoperative days in the experimental group than those in the control group, while it downregulated the cartilage inflammation gene matrix metalloproteinase-13 and chondrocyte terminal differentiation gene ColX. In summary, exogenous PTH can stimulate the formation of cartilage matrix by triggering Sox9 expression at the early stage of cartilage healing, and it provides a potential therapeutic protocol for high fractures of the mandibular condyle.

Antimicrobial regimens used in the treatment of mandibular fractures in UK maxillofacial units: changes over 12 years.

In the case of most mandibular fractures, the prescription of antimicrobials for more than 24 hours postoperatively confers no clinical benefit. To establish the prescribing patterns for mandibular fractures in UK OMFS units, and to compare them with those used 12 years ago, we did a telephone and email survey of OMFS units in the UK. Antimicrobials were prescribed for more than 24 hours postoperatively by 76 units (65%) (considerably fewer than the 82 (87%) in 2005). The most commonly prescribed first-line antimicrobial was co-amoxiclav (75%). Although there has been some improvement since 2005, most units still prescribe antimicrobials for periods longer than 24 hours. National collaboration may improve their appropriate prescription.

[Use of biologically active preparations in prevention of complication in patients with open traumatic mandible fractures].

Original scheme of clinico-diagnostic treatment of patients with open mandible fractures described, based on sufficient clinical material - 100 traumatic patients passing the course of stationary and clinic observation. Contemporary methods of the objective evaluation of the structural-functional restoration of the damaged bone tissues were used for diagnostic purposes. The positive results of the study and treatment were obtained. Practical conclusions were made.

Facing the facts on prophylactic antibiotics for facial fractures: 1 day or less.

BACKGROUND: To evaluate the role of initial prophylactic antibiotics on facial fractures, outcomes were compared between a short course (≤24 hours) of antibiotics to those who received an extended course (>24 hours). METHODS: Adults admitted (2010-2015) to a Level I trauma center intensive care unit with at least one facial bone fracture and major injuries isolated to the head and neck were included. Our primary analysis compared infectious complications of the head or neck (H/N infection) between patients given short or extended courses of antibiotic prophylaxis. Multivariate logistic regression and analysis of propensity score matched pairs were performed. RESULTS: A total of 403 patients were included, 85.6% had blunt injuries and 72.7% had their facial fracture managed nonoperatively. The H/N infection rate was 11.2%. Two hundred eighty patients received a short course of antibiotics and 123 patients received an extended course. Median Injury Severity Score was 14 in both groups (p = 0.78). Patients receiving an extended course of antibiotics had higher rates of H/N infection (20.3% vs. 7.1%, p < 0.001). Factors associated with development of H/N infection included younger age, penetrating injury, open fracture, upper face or mandible fracture, fractures in multiple facial thirds, vascular injury, hypertension, and extended antibiotic course. Multivariate logistic regression identified younger age (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.96-1.00; p = 0.02), multiple facial third fractures (OR, 4.9; 95% CI, 2.4-10.2; p < 0.001), and penetrating mechanism (OR, 3.1; 95% CI, 1.5-6.4; p = 0.003) as independent predictors of H/N infection, but not antibiotic duration. Propensity score-matched analysis found no differences in H/N infection between short and extended antibiotic courses (11.4% vs. 12.5%; p = 1.0). Subgroup analyses demonstrated no differences in H/N infection between short or extended antibiotic courses by injury pattern, mechanism, or treatment (operative or nonoperative). CONCLUSION: These results lead us to believe that we should limit antibiotics to 24 hours or less upon admission for facial fractures. LEVEL OF EVIDENCE: Therapeutic/care management, level IV.