The role of microbial biofilms in osteonecrosis of the jaw associated with bisphosphonate therapy.

Microbial biofilms have been observed and described in bone specimens of patients with bisphosphonate (BP)-associated osteonecrosis of the jaw (BONJ) and investigators are more recently suggesting that this condition essentially represents an osteomyelitis of the jaw clinically, with greater susceptibility in some patients on BP therapy. This article explains the role of microbial biofilms in BONJ and also discusses associated factors in the disease pathogenesis, which include BP effects on bone remodeling, anti-angiogenesis, matrix necrosis, microcracks, soft tissue toxicity, and inflammation and wound healing. Recent findings suggest a key role for microbial biofilms in the pathogenesis of BONJ; this has important therapeutic implications because biofilm organisms represent a clinical target for prevention and treatment efforts aimed at reducing the significant morbidity and costs associated with this condition.

Septic arthritis in adults with sickle cell disease often is associated with osteomyelitis or osteonecrosis.

BACKGROUND: Septic arthritis is a known complication of sickle cell disease (SCD) in children, and the association with osteomyelitis and osteonecrosis has been described. However, it is unclear whether this association applies to adults. QUESTIONS/PURPOSES: We therefore asked whether septic arthritis is a frequent complication in adults with SCD and whether it also is associated with osteomyelitis or osteonecrosis. METHODS: We retrospectively reviewed the charts of 2000 consecutive adult patients diagnosed with SCD and recorded symptoms, select findings during physical examination, laboratory data, and select radiographic CT, and MRI observations. RESULTS: Fifty-nine of the 2000 patients (3%) had septic arthritis, 56 of the 59 patients had hemoglobin SS. Thirty-six of the 59 infections (61%) were in the hip. The most frequent findings were pain, swelling, fever greater than 38.2 degrees C (71% of cases), a leukocyte count exceeding 15,000/mm(3) (range, 7900-32,300/mm(3)), a Westergren sedimentation rate greater than 24 mm/hour, and C-reactive protein exceeding 20 mg/L. Cultures were positive in 96% of the joint aspirates. Staphylococcus and Gram-negative infection predominated; no patients had Salmonella joint infections. Preexisting factors of bacterial arthritis included osteonecrosis (29 patients) and osteomyelitis (37 cases) in childhood. Diabetes, rheumatoid arthritis, glucocorticoids, and immunoparesis related to medical treatment by hydroxyurea were associated comorbidities. CT and MRI confirmed the diagnosis of associated osteonecrosis or osteomyelitis and allowed joint aspiration and detection of soft tissue abscess. CONCLUSIONS: The incidence of septic arthritis in adults with SCD is low, but often is associated with osteomyelitis or osteonecrosis. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Resolution of oral bisphosphonate and steroid-related osteonecrosis of the jaw--a serial case analysis.

PURPOSE: To offer recommendations of risk factors, prevention, and treatment of oral bisphosphonate and steroid-related osteonecrosis of the jaw (BSRONJ) in Taiwan. MATERIALS AND METHODS: Twelve patients were clinicopathologically proved to have bisphosphonate-related osteonecrosis of the jaw (BRONJ). All of the patients were taking oral bisphosphonates and were concurrently administered long-term steroids. Of the 12 patients, 3 patients were assigned to the first stage of BRONJ; 5 patients were assigned to the second stage, and 4 patients were assigned to the third stage. The patients' symptoms, localization of necrosis, presence of a fistula, and association with possible triggering factors for onset of the lesion were recorded. RESULTS: The radiologic investigations revealed osteolytic areas and scintigraphy demonstrated increased bone metabolism. Microbiologic analysis showed pathogenic actinomycosis organisms in a majority of patients (91.6%). Antibiotic therapy, minor debridement surgery, and combined hyperbaric oxygen therapy were useful in obtaining short-term symptomatic relief. CONCLUSIONS: Comorbidities of steroid use along with bisphosphonates may cause osteonecrosis of the jaw to occur sooner, be more severe, and respond more slowly to a drug discontinuation. The clinical disease of BSRONJ is more severe and more unpredictable to treat than BRONJ. From the data gained from other published studies of BRONJ and our clinical experience with the series of cases of BSRONJ, we offer recommendations of risk factors, prevention, and treatment of BSRONJ in southern Taiwan.

Evaluation of the oral flora in 150 patients suffering from chronic craniofacial pain: a retrospective study.

This study was conducted to determine if microbial infection was a significant factor in patients with undiagnosed craniofacial pain. Of the 150 patients from whom intra-bony cultures were obtained, 23 different groups of isolates were obtained. There were 49 (32.67%) patients whose cultures exhibited growth of microbes other than routine oral flora, mixed skin flora or routine respiratory flora. The most common was of the Streptococcus species (11 or 22.91%) of the 49. Sixty-seven (67) (44.67%) of the total cultures demonstrated the growth of mixed skin flora, nineteen (12.67%) demonstrated the growth of routine respiratory flora and sixteen (10.67%) demonstrated the growth of routine oral flora. No bacterial isolates were found in 16 (10.67%) cultures. The most common histological diagnoses of those who exhibited pathogenic microbial growth were, in order: 1. focal osteoporotic marrow defect; 2. ischemic osteonecrosis; and 3. chronic nonsuppurative osteomyelitis.

The role of external fixation in the management of infected avascular necrosis after traumatic talus fractures.

PURPOSE: Avascular necrosis (AVN) after fractures of the talus is a distinct and challenging clinical entity that is associated with poor outcomes. Although several articles are published on the management of posttraumatic AVN of the talus, very little is known about the management of infected AVN after talus fractures. Therefore, three cases of infected AVN were treated successfully by extensive debridement, external fixation and arthrodesis. METHODS: Three cases of infected AVN of the talus were encountered after a mean of 3 months (range 2-6 months) after initial reconstructive surgery. Suspected infection was confirmed by positron emission tomography scan (PET-CT). Management involved extensive debridement, PMMA cement if necessary and final fusion using medial external fixator, accompanied by culture guided antibiotics. Functional outcome was assessed using the Foot Function Index (FFI) and the American Orthopaedic Foot and Ankle Society hindfoot score (AOFAS). Quality of life (QOL) was measured by the EuroQol-5D (EQ-5D). RESULTS: After a mean follow up of 24 months (range 13-29), FFI index scores ranged from poor to good (23, 50, 56) with similar AOFAS scores indicating poor to fair functional outcome (38, 41, 71). The EQ-5D score was 0.78. Overall patient satisfaction was high with a mean VAS of 8.3 (range 8-9). CONCLUSION: Infected talar AVN is a rare condition associated with severe long-term morbidity in term of joint function. The authors recommend extensive debridement and arthrodesis by means of external fixation, followed by post-operative culture-guided antibiotics for the treatment of infected avascular necrosis of traumatic talar fractures. Shared decision-making and expectation management are of crucial importance and may lead to high patient satisfaction despite low functional outcomes. LEVEL OF EVIDENCE: IV, Retrospective case series.

Bisphosphonate-related osteonecrosis of the jaw: the role of actinomyces.

The etiology of bisphosphonate-related osteonecrosis of the jaw is unknown but was initially postulated to be mediated by bisphosphonate accumulation within the jaws, resulting in avascular necrosis. Bisphosphonates may not be the primary cause. Actinomyces are an underrecognized agent in pathogenesis, and timely actinomycosis-specific treatment may improve outcome.

Osteonecrosis of the jaw: an update and review of recommendations.

Bisphosphonates have had a very positive impact as therapeutic agents for cancer and osteoporosis, but have also been associated with osteonecrosis of the jaw (ONJ) which has emerged as an idiosyncratic oral complication. Bisphosphonate-associated ONJ has generated wide attention despite its considerably rare occurrence. Many speculations exist as to why bisphosphonates may increase the incidence of ONJ. The American Society for Bone and Mineral Research established a task force on bisphosphonate-associated ONJ and recently released a summary report of their findings. A case definition delineated a confirmed case of ONJ as 'an area of exposed bone in the maxillofacial region that did not heal within 8 weeks after identification by a health care provider, in a patient who was receiving or had been exposed to a bisphosphonate and had not had radiation therapy to the craniofacial region'. Treatment recommendations have been developed by the American Dental Association, the American Association of Oral and Maxillofacial Surgeons and the American Society for Bone and Mineral Research. Considering the scientific evidence, little is known about the true incidence and pathophysiology, and many questions persist. New epidemiologic studies are surfacing and attempts to ameliorate the condition may shed light on the likely complex etiology. The bones of the oral cavity provide a unique environment relative to blood flow, oral microbiota, bone structure and function. Although little is known of the mechanisms and course of ONJ, even less is known about the spectrum of issues of altered healing that could fall short of defined ONJ.

Bisphosphonates and osteonecrosis of the jaw: moving from the bedside to the bench.

Osteonecrosis of the jaw (ONJ) has received significant attention as a potential side effect of bisphosphonate treatment. The limited understanding of the underlying pathophysiology of the condition emphasizes the need to transition ONJ research from the bedside to the bench, supplementing ongoing clinical research with animal/basic science studies. The goal of this review is to briefly highlight the most commonly proposed mechanisms for ONJ and then summarize our laboratory's recent efforts to begin transitioning ONJ research to an animal model. Remodeling suppression, disrupted angiogenesis and infection have all been proposed to connect bisphosphonates to ONJ, although most supportive data for each of these are either indirect or nonexistent. Our laboratory has begun studying the dog as a potential model of ONJ. We have shown regions of necrotic bone matrix within the mandible of dogs treated with oral or intravenous bisphosphonate. We hypothesize these regions are the result of remodeling suppression, and if combined with additional factors such as dental intervention or infection, would result in manifestation of exposed oral lesions, the clinical definition of ONJ. Although these findings suggest the dog may be a viable animal model to study ONJ, many questions remain unanswered. No matter what animal model is found to mimic the clinical presentation of ONJ, once established it will allow significant progress toward understanding the specific role of bisphosphonates in the pathophysiology of ONJ and if/how the entity of ONJ can best be treated and prevented.

Osteomyelitis of the jaw: resistance to clindamycin in patients with prior antibiotics exposure.

The purpose of this paper was to review our clinical experience in patients with osteomyelitis (OM) of the jaw, focusing on aspects of antimicrobial resistance. A retrospective review of the medical records of adult patients with jaw OM was carried out. Among 46 cases of jaw OM, the cause was odontogenic in 32 (seven had recent dental implants and four bisphosphonate osteonecrosis), postoperative/post-traumatic in eight, and secondary to osteoradionecrosis in six. Clinical features were chronic in 91.3%. The infection was polymicrobial in 24/41 (65.9%). Viridans streptococci were the most commonly isolated agents. Among 26 viridans streptococci tested, 81% were susceptible to penicillin and 96% to fluorquinolones, but only 11.5% to clindamycin. Overall, 35/38 (92.1%) had at least one clindamycin-resistant isolate. Appropriate antibiotics were administered for a mean of 5.8 +/- 3.2 months. Beta-lactams were used in 19 cases and fluorquinolones in 14. Among 39 cases with long-term follow-up, only two relapsed. Currently, jaw OM is commonly related to osteoradionecrosis, dental implants, and bisphosphonates. In patients with prior antibiotics exposure, a high percentage of infections were caused by clindamycin-resistant microorganisms, thus, beta-lactams should be the antibiotic of choice. In penicillin-allergic cases, the new fluorquinolones, probably in combination with rifampin and/or clindamycin, could be a promising alternative.

Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy.

PURPOSE: Biofilm theory has emerged to explain the etiology of the chronic infections that have come to constitute between 65% to 80% of the microbial diseases treated by physicians in the developed world. The purpose of this article is to report for the first time the observation of multispecies microbial biofilms on affected bone in patients with osteonecrosis of the jaws (ONJ) secondary to bisphosphonate therapy. PATIENTS AND METHODS: A program has been established at the University of Southern California to monitor and evaluate patients with ONJ as a multidisciplinary collaboration between the School of Dentistry, Center for Biofilms, Center for Craniofacial Molecular Biology and the Keck School of Medicine. From this cohort, 4 patients with active ONJ who were scheduled for necessary treatment in the form of sequestrectomy gave informed consent for this study. Bone samples were evaluated using conventional histopathologic techniques and scanning electron microscopy, a technique applicable to biofilm characterization. RESULTS: Bone specimens from affected sites in all patients showed large areas occluded with biofilms comprising mainly bacteria, and occasionally yeast, embedded in extracellular polymeric substance. The number of bacterial morphotypes in the biofilms ranged from 2 to 15, and they included species from the genus Fusobacterium, bacillus, actinomyces, staphylococcus, streptococcus, Selenomonas, and 3 different types of treponemes. The yeast identified was consistent with Candida species. Co-aggregation was observed between different species within the biofilms. CONCLUSION: These findings have important clinical and therapeutic implications and may suggest a role for microbial biofilms in the disease process of ONJ.

Chronic myelogenous leukemia presenting with osteonecrosis of the jaw as a rare but debilitating toxicity of dasatinib: a case report and literature review.

This report describes a case of osteonecrosis of the jaw developing after a routine dental extraction in a patient being treated with dasatinib, a tyrosine kinase inhibitor, for chronic myelogenous leukemia. As the role of tyrosine kinase inhibitors in cancer treatment expands, patterns of debilitating complications involving the osseous structures of the oral cavity have begun to emerge, and many long-term side effects of this promising therapy remain unknown. To limit the occurrence of known complications, health care providers and patients must be aware of the potential for serious complications of dasatinib, and appropriate protocols should be in place before administration of this medication.

Actinomycosis of the jaws--histopathological study of 45 patients shows significant involvement in bisphosphonate-associated osteonecrosis and infected osteoradionecrosis.

Actinomycosis of the jaws is a rare disease, which has been recently described in patients with infected osteoradionecrosis (IORN) and bisphosphonate-associated osteonecrosis (BON). We investigated our archive material for Actinomycosis of the jaws with special regard to underlying disease. Out of a total number of 45 patients with Actinomycosis, 43 (93.5%) suffered from BON (58.7%) or IORN (35.6%), while there were only 3 patients (6.7%) without anti-tumor treatment. In all cases, we found direct association of Actinomyces colonies with bone; in the surrounding medullary space, mixed inflammatory infiltrates with variable amounts of osteoclasts were a typical finding. Pseudoepitheliomatous hyperplasia occurred in 60.9% of patients. Cell-rich vessel obliteration was seen in less than 25.9% of BON patients, while hyalinized vessel obliteration was obtained in 37.5% of IORN patients. Additionally performed polymerase chain reaction (PCR) on paraffin-embedded and ethylene diamine tetracetic acid (EDTA)-decalcified tissue specimens confirmed the presence of Actinomyces israelii in seven of seven cases analyzed. We conclude that Actinomycosis of the jaws is a particular complication in patients with BON and/or IORN. Patients with Actinomycosis of the jaws during or after these forms of anti-cancer therapy are suggested to represent a distinct patient cohort with a relevant impairment of their general condition.

Clinical experiences with bisphopsphonate induced osteochemonecrosis of the jaws.

QUESTION: Bisphosphonates are frequently used drugs in the adjuvant therapy of bone metastases and tumour-induced hypercalcaemia, but also for osteoporosis or Pagets disease. Several publications within the last three years considered osteonecrosis of the jaws to be connected with bisphosphonate therapy. Until today possible treatment strategies contain antibiotics, hyperbaric therapy and operative treatment. The tendency of healing however seems to be extremely poor. All clinicians should be aware of this new kind of side effect of bisphosphonate therapy. METHODS: 14 patients with this new kind of osteonecrosis were admitted to the department of Cranio-Maxillofacial Surgery of the University Hospital of Zurich. 8 men and 6 women all received bisphosphonates for cancer therapy. A complete analysis of patients' data was performed. RESULTS: Of 14 patients in 7 the underlying disease disease was multiple myeloma. In one patient it was prostate cancer and in all female patients it was breast cancer. All of them had prior dental treatment and showed inflammatory signs and bacterial colonisation with localisation in the upper or lower jaw or in both. CONCLUSION: The infectious part of the bisphosphonate-induced osteonecrosis (ONJ) is considered to be more important than thought before. We presume that antimicrobial treatment is of utmost importance in the treatment of this kind of osteonecrosis. Patients with current or previous bisphosphonate therapy should be treated multidisciplinary to assure ideal prevention and treatment.

The association of medication-related osteonecrosis of the jaw with Actinomyces spp. infection.

Medication-related osteonecrosis of the jaw (MRONJ) represents a complication of bisphosphonate treatment that responds poorly to standard treatment. In a retrospective cohort study we investigated a possible role of Actinomyces spp. in the pathogenesis of MRONJ. Deep biopsies of necrotic bone were collected during surgical treatment of MRONJ and evaluated by histology and microbiology for the presence of Actinomyces spp. Microbiological, demographic and clinicpathological data were analyzed for risk of Actinomyces-associated MRONJ. Between 2005 and 2014, 111 patients suffering from histologically-confirmed MRONJ were identified. Actinomyces spp. were detected in 99 cases (89%) by histology and in six further patients by microbiological culture. A diverse microbial flora was found in all specimens without association with Actinomyces spp. Demographic and clinicopathological characteristics did not separate significantly Actinomyces-positive from Actinomyces-negative cases. Our observations confirm previous reports of a high prevalence of Actinomyces spp. in MRONJ in the single largest cohort available up to now. The high prevalence of Actinomyces spp. and the lack of clinicopathological risk factors underline the prominent role of Actinomyces spp. in MRONJ and may change the current understanding of MRONJ. Established prolonged antimicrobial treatment regimens against Actinomyces spp. infection could therefore be a mainstay of future MRONJ management.

Meningococcemia in Adults: A Review of the Literature.

We mainly refer to the acute setting of meningococcemia. Meningococcemia is an infection caused by Neisseria meningitidis, which has 13 clinically significant serogroups that are distinguishable by the structure of their capsular polysaccharides. N. meningitidis, also called meningococcus, is a Gram-negative, aerobic, diplococcus bacterium. The various consequences of severe meningococcal sepsis include hypotension, disseminated intravascular coagulation (DIC), multiple organ failure, and osteonecrosis due to DIC. The gold standard for the identification of meningococcal infection is the bacteriologic isolation of N. meningitidis from body fluids such as blood, cerebrospinal fluid (CSF), synovial fluid, and pleural fluid. Blood, CSF, and skin biopsy cultures are used for diagnosis. Meningococcal infection is a medical emergency that requires antibiotic therapy and intensive supportive care. Management of the systemic circulation, respiration, and intracranial pressure is vital for improving the prognosis, which has dramatically improved since the wide availability of antibiotics. This review of the literature provides an overview of current concepts on meningococcemia due to N. meningitidis infection.

Extensive maxillary sequestration resulting from mucormycosis.

Mucormycosis is an invasive and potentially lethal infection caused primarily by fungi of the order mucorales. An ulcer or extraction in the mouth can be the port of fungal invasion, particularly when the patient is immunocompromised. Early recognition and aggressive treatment have reduced the mortality and morbidity. We present a case of oral mucormycosis with extensive maxillary osteonecrosis that is of interest because the patient ignored the initial warning signs and was rescued from the fulminating stage by thorough debridement and medical treatment.

SURGICAL TREATMENT FOR INFECTED LONG BONE DEFECTS AFTER LIMB-THREATENING TRAUMA: APPLICATION OF LOCKED PLATE AND AUTOGENOUS CANCELLOUS BONE GRAFT.

BACKGROUND: Treatment strategies for bone defects include free bone grafting, distraction osteogenesis, and vascularized bone grafting. Because bone defect morphology is often irregular, selecting treatment strategies may be difficult. With the Masquelet technique, a fracture site is bridged and fixed with a locking plate after treating deep infection with antibiotic-containing cement, and a free cancellous bone-graft is concomitantly placed into the defects. This procedure avoids excessive bone resection. METHODS: We studied 6 patients who underwent surgical treatment for deep infection occurring after extremity trauma (2004 through 2009). Ages at surgery ranged from 29 to 59 years (largest age group: 30 s). Mean follow-up was 50.7 months (minimum/maximum: 36/72 months). One patient had complete amputation of the upper extremity, 3 open forearm fractures, 1 closed supracondylar femur fracture, and 1 open tibia fracture. In all patients, bone defects were filled with antibiotic-containing cement beads after infected site debridement. If bacterial culture of infected sites during curettage was positive, surgery was repeated to refill bone defects with antibiotic-containing cement beads. After confirmation of negative bacterial culture, osteosynthesis was performed, in which bone defects were bridged and fixed with locking plates. Concomitantly, crushed cancellous bone grafts harvested from the autogenous ilium was placed in the bone defects. RESULTS: Time from bone grafting and plate fixation to bone union was at least 3 and at most 6 months, 4 months on average. Infection relapsed in one patient with methicillin-resistant Staphylococcus aureus, necessitating vascularized fibular grafting which achieved bone union. No patients showed implant loosening or breakage or infection relapse after the last surgery during follow-up. CONCLUSION: The advantage of cancellous bone grafting include applicability to relatively large bone defects, simple surgical procedure, bone graft adjustability to bone defect morphology, rapid bone graft revascularization resulting in high resistance to infection, and excellent osteogenesis.

Varicella complicated by group A streptococcal sepsis and osteonecrosis.

A 5-year-old boy presented with primary varicella zoster virus infection, group A streptococcal sepsis, toxic shock, and multisite osteonecrosis. An association between osteonecrosis and group A streptococcal sepsis has not been previously reported. Clinical recognition with supportive radiologic and pathologic findings are presented. Therapeutic guidelines are suggested.