Gingival fibroblasts and medication-related osteonecrosis of the jaw: Results by real-time and wound healing in vitro assays

ObjectiveThis study investigated the effects of bisphosphonates and denosumab on human gingival fibroblasts (HGFs) that could influence inflammation, wound healing, and angiogenesis in medication-related osteonecrosis of the jaw (MRONJ).MethodsA real-time in vitro assay was performed on HGFs with and without the addition of bacterial lipopolysaccharide and a mononuclear cell co-culture to observe the effects of zoledronate, ibandronate, alendronate, clodronate, denosumab, and combinations of zoledronate and denosumab at varied concentrations. A wound healing assay was performed, and gene and protein expression was analyzed for inflammatory, angiogenic, and osteoclastogenic cytokines and mediators including interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNFα), IL-8, vascular endothelial growth factor (VEGF), RANKL, and osteoprotegerin.ResultsHigher concentrations of antiresorptives resulted in impaired wound healing and HGF death, which also occurred without mechanical damage. These effects were increased with bacterial lipopolysaccharide and mononuclear cells. Increased levels of IL-1β, TNFα, IL-8, VEGF, osteoprotegerin, and decreased levels of IL-6 were observed.ConclusionsAntiresorptive exposure was associated with HGF death and delayed wound healing, which could be attributed to an elevated inflammatory response and immune dysfunction contributing to MRONJ development. There was no evidence of anti-angiogenic effects. Our experiments present the first results of denosumab with HGFs.     

Surgical treatment of stage 2 medication-related osteonecrosis of the jaw compared to osteomyelitis

Objective: To compare the characteristics and outcomes of patients who underwent surgical treatment for stage 2 medication-related osteonecrosis of the jaw (MRONJ) versus osteomyelitis.

Methods: This retrospective study compared the following variables in 73 patients with stage 2 MRONJ versus 89 patients with osteomyelitis: impaired wound healing after surgery, sex, age, the presence of actinomycosis, location of the jaw lesion, and involvement of the inferior alveolar nerve (IAN).

Results: There were significant differences between the groups in age, sex, rates of impaired wound healing, actinomycosis, and the location (anterior/posterior) of the lesion. Impaired wound healing after surgical treatment in the stage 2 MRONJ group was associated with patient age. All patients with impaired wound healing after the initial surgery recovered fully after reoperation.

Conclusions: These findings for surgical treatment of stage 2 MRONJ may help clinicians plan surgical treatment of MRONJ.     

Genetic predisposition for medication-related osteonecrosis of the jaws: a systematic review

The purpose of this study was to assess whether genetic variation is a predictor for the development of medication-related osteonecrosis of the jaws (MRONJ) in patients receiving bisphosphonate therapy for various conditions. A systematic review based on the PRISMA guidelines was performed. A search strategy was developed. Comprehensive searches of major databases were conducted for studies published January 2003 through July 2018. The PICOS strategy was used to develop the inclusion criteria. The analysis in each study was performed primarily using single nucleotide polymorphism (SNP) frequency mean values and odds ratios between cases and controls. A total of 3301 patients were enrolled in the 15 included studies (two genome-wide association studies, n = 1877; 10 candidate gene studies, n = 1195; three whole genome/whole exome studies, n = 229). Multiple myeloma was the most prevalent primary disease (54.8%). Zoledronate was prescribed in 68.8% of patients. No one SNP was definitively identified as a risk factor for the development of MRONJ. To date, studies have failed to show a single gene as a risk factor for MRONJ. Heterogeneity of case and control populations may be contributory. Next generation sequencing studies may help elucidate the role and interplay of genetic events in the development of MRONJ.     

Effect and timing of parathyroid hormone analog administration for preventing medication-related osteonecrosis of the jaws in a murine model

The aim of this study was to investigate the effect and timing of recombinant human parathyroid hormone analog (PTH) administration for preventing medication-related osteonecrosis of the jaws (MRONJ) using a murine model. After standardized MRONJ induction using zoledronic acid and dexamethasone injections, 48 female Sprague-Dawley rats were divided into four groups according to the timing of PTH administration before or after dental extraction. Rats were euthanized 3 weeks after dental extraction, followed by clinical and histologic analyses. No clinical improvements were observed in the preoperative and postoperative PTH groups, compared to controls (p = 0.638 and 0.496, respectively). However, on histological analysis, the number of empty lacunae reduced significantly, and the number of blood vessels increased in the preoperative PTH group (p = 0.004 and 0.002, respectively). The postoperative PTH group did not show significant differences for empty lacunae and blood vessels compared to controls (p = 0.075 and 0.194, respectively). The reduction in the empty lacunae and the increase in the blood vessels in the preoperative PTH group were significant compared to other groups, suggesting more viable bone tissue in this group.In perspective, preoperative PTH use may represent a better prophylactic regimen for preventing the occurrence of MRONJ after traumatic dental or surgical procedures, especially in patients with a history of long-term bisphosphonate administration or at high risk of developing MRONJ. However, the findings should be proven in further studies on other animals followed by clinical trials.     

Comparison of the histopathological characteristics of osteomyelitis,medication-related osteonecrosis of the jaw,and osteoradionecrosis

The purpose of this study was to compare the histopathological parameters of chronic/suppurative osteomyelitis, medication-related osteonecrosis of the jaw (MRONJ), and osteoradionecrosis (ORN), and to examine the hypothesis that distinct histological features can be related to a specific disease, allowing for diagnosis based on microscopic evaluation alone. One hundred and ten samples were reviewed by two examiners in a blinded fashion, and a semi-quantitative histomorphometric analysis was performed. The parameters evaluated included the presence or absence of necrotic bone, inflammation, reactive bone formation, bacteria, and osteoclasts. No statistically significant differences were found between groups for any parameter. Necrotic bone was common to all three diagnoses. Inflammation and reactive bone formation were present in all three diagnoses. The presence of bacteria was a prominent feature in all cases. Osteoclasts were scarce in MRONJ and osteomyelitis, and non-existent in ORN. The results of this study failed to identify distinctive microscopic characteristics in any of the three entities that could be used to differentiate between them. Therefore, it is impossible to reach a specific final diagnosis based on microscopic findings alone. The role of microscopic analysis is to serve as an aid to diagnosis that must be complemented by the patient’s history and imaging.     

药物相关性颌骨坏死的发病机制及其防治

药物相关性颌骨坏死(MRONJ)近年来发病率不断增高,目前认为其机制可能为骨重建抑制学说、血管生成抑制学说、口腔微生物感染学说、免疫抑制学说、细胞毒性、颌骨微裂纹形成及单核苷酸多态性等,但基于单机制进行防治效果均不理想.药物治疗前规范的口腔检查及相关疾病预处理,药物治疗期间定期口腔随访对MRONJ的预防具有重要意义.在...     

Medication-related osteonecrosis of the jaws and quality of life: review and structured analysis

Medication-related osteonecrosis of the jaws (MRONJ) is a rare complication of bisphosphonates, or antiresorptive or antiangiogenic medication. Treatment is difficult as the bone has a poor capacity for healing, and further progression after surgery can occur. Quality of life (QoL) in patients with MRONJ has not been well documented. The aim of this study therefore was to identify and analyse data on QoL in this group of patients. Eight studies that were identified through a systematic search of the literature were qualitatively analysed. Overall, data on QoL are lacking and are complicated by concurrent disease such as cancer. Patients generally have a poor QoL because of MRONJ, and multiple oral-specific complaints including pain and problems with speech. Development of a questionnaire specific to patients with MRONJ would help improve the specificity of the data collected. Prospective questionnaires before and after intervention, including information on stage and comorbidities, would guide future treatment strategies.     

Effective ancillary role and long-term course of daily or weekly teriparatide treatment on refractory medication-related osteonecrosis of the jaw: a clinical case series

Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse side effect of antiresorptive agents. However, withdrawal of such agents in patients with osteoporosis may increase the risk of fracture. The treatment of MRONJ is challenging, and standard treatment guidelines have yet to be established. In this study, the aim was to find out whether adjuvant daily or weekly teriparatide (TPTD) injections were beneficial for exposed bony MRONJ lesions compared with standard conservative management. We also studied the complications and the patients’ response to TPTD therapy. We enrolled 27 patients (January 2012 - December 2016) with chronic and refractory MRONJ. There were four men and 23 women (85% female). Nine patients who did not select TPTD therapy for several reasons formed the non-TPTD group; the remaining 18 were randomly assigned to the daily (n=9) or weekly (n=9) groups. All patients in both groups continued standard conservative therapy in addition to their daily or weekly subcutaneous injection of TPTD (20 μg or 56.5 μg, respectively). We evaluated the complications of TPTD and its benefits. Three patients in the daily group did not complete the study, resulting in six patients in the daily group, nine in the weekly group, and nine in the non-TPTD group in the final analysis. The exposed bone was completely covered with normal mucosa in all patients in the TPTD groups, and the healing period was shorter than that in the non-TPTD group. No patient had complications of atypical fractures of the femoral head. Daily and weekly TPTD treatment resulted in a shortened treatment period compared with standard conservative therapy, with no increase in the rate of complications or worsening of osteoporosis.     

双膦酸盐性颌骨坏死：病例报告及文献复习

双膦酸盐类药物临床用于治疗骨质疏松症、变形性骨炎和其他代谢性骨病、多发性骨髓瘤以及与肿瘤转移相关的骨骼疾病。该类药物通过抑制破骨细胞介导的骨吸收而产生临床治疗作用。然而,双膦酸盐类药物,尤其是静脉用双膦酸盐类药物有致颌骨骨坏死的危险。目前,国内尚未有该类药物致下颌骨坏死的报道。作者报告1例口服双膦酸盐类药物阿仑膦酸钠（Alendronate,商品名福善美,Fosamax）致下颌骨骨坏死病例,并结合文献对双膦酸盐性颌骨坏死的发病机制、临床表现及其预防和治疗进行讨论。     

双膦酸盐相关性颌骨坏死1例报告及文献复习

双膦酸盐类药物被广泛用于治疗骨质疏松、恶性肿瘤骨转移等相关的骨骼疾病,引起颌骨骨坏死是其严重的并发症。这种并发症或自然发生,或发生于简单牙槽外科手术后。本文报告1例静脉使用双膦酸盐类药物唑来膦酸(zoledronic acid)致上颌骨骨坏死病例,并结合文献,对双膦酸盐相关性颌骨坏死的发病机制、临床表现、预防和治疗进行讨论。     

Conservative surgical treatment of medication related osteonecrosis of the jaw (MRONJ) lesions in patients affected by osteoporosis exposed to oral bisphosphonates: 24 months follow-up

The purpose of the study was to evaluate the efficacy of conservative surgical treatment of medication related osteonecrosis of the jaw (MRONJ) in patients affected by osteoporosis and exposed to oral bisphosphonates (BPs).Subjects diagnosed with MRONJ and osteoporosis under oral BPs that had undergone conservative surgery and had at least 24 months follow-up were included. All patients received medical-antibiotic therapy and then underwent conservative surgical treatment consisting of sequestrectomy, soft tissue debridement and bone curettage with limited or no extension.A total of 53 patients, mean age of 71.9 ± 10.2 years (range 41–87), were enrolled. Two years after conservative surgical therapy 45 patients (91.8%) showed complete healing. The presence of rheumatoid arthritis (p = 0.003) and a more severe initial MRONJ stage (p = 0.023) were associated with a negative surgical outcome while the presence of bone sequestrum was strongly associated with a positive outcome (p = 0.036).Conservative surgical treatment of MRONJ lesions in patients affected by osteoporosis and receiving only oral BPs may represent a valid therapeutic approach determining a high number of complete healing cases. Conservative surgery should be encouraged at early MRONJ stages and after medical therapy failure.     

Fluorescence-guided bone resection: A histological analysis in medication-related osteonecrosis of the jaw

PurposeSurgical treatment of medication-related osteonecrosis of the jaw (MRONJ) consists of necrotic bone removal followed by dense mucosal closure. Fluorescence-guided surgery has become a promising tool to intraoperatively distinguish between healthy and necrotic bone. Until now, there has been a lack of histopathological studies correlating the intraoperative fluorescence situation to histopathological analyses of the respective bone areas in order to further validate this method.Materials and methodsHistopathological sections from intraoperatively detected fluorescence- and non?fluorescence-labeled bone were analyzed detecting osteocyte and collagen content, RANK(L) and TRAP expression as well as proportion of immature bone regeneration. Samples were compared with viable-looking bone areas according to the intraoperative clinical situation.ResultsStaining revealed a significant decrease of osteocytes and collagen type-I fibers in necrotic, non-fluorescing areas compared to fluorescing bone (R/RGB [%]: 0.56 ± 0.38 (fluorescence positive) vs. 3.18 ± 2.22 (fluorescence negative), p = 0.041). Furthermore, the number of osteocytes was higher in fluorescing, clinically viable bone samples (cell/mm²: 151.26 ± 95.77 (fluorescence positive) vs. 0.56 ± 0.38 (fluorescence negative), p = 0.028). Additionally, the amount of immature bone was substantially increased in luminescent jaw bone (proportion of red [%]: 6.78 ± 7.00 (fluorescence positive) vs. 2.24 ± 1.36 (fluorescence negative), p = 0.442). RANK(L) and TRAP expression did not differ between the investigated areas, resembling a generalized decrease in osteocyte?osteoclast function all over the jaw (RANK(L) ?positive cells per mm²: 8.97 ± 7.85 (fluorescence positive) vs. 7.76 ± 6.41 (fluorescence negative), p = 0.793; TRAP-positive cells per mm²: 0.36 ± 0.38 (fluorescence positive) vs. 0.33 ± 0.41 (fluorescence negative), p = 0.887).ConclusionIntraoperative fluorescence-guided surgery might be more precise in identifying and resecting the necrotic bone compared to previous indicators like bone bleeding, which could be useful to further improve surgical therapy in MRONJ patients.     

血管化腓骨瓣修复二膦酸盐颌骨骨坏死导致的下颌骨缺损：病例报告及文献复习

二膦酸盐（Bisphosphonates, BPs）作为一种强效骨吸收作用抑制剂已经用于临床30多年,广泛用于控制与骨更新改变相关的疾病。近年来发现,临床长期应用二膦酸盐类药物可导致颌骨骨坏死。对于二膦酸盐颌骨骨坏死的治疗,学术界观点不一,包括保守治疗、手术刮治、颌骨切除（重建或不重建）。本文介绍1例采用血管化腓骨瓣修复二膦酸盐颌骨骨坏死造成的下颌骨缺损,效果满意。     

Medication-related osteonecrosis of the mandible: an unusual presentation and treatment

A 71-year-old woman was referred to the clinic with extensive medication-related osteonecrosis of the jaw (MRONJ) involving the mandible. She had received 7 years of zoledronate therapy. On cone beam computed tomography, the MRONJ presented as a large sequestrum spanning from the left to the right condylar process, surrounded by thick sub-periosteal bone. The sequestrum was excised via an intraoral approach, leaving the newly formed sub-periosteal bone as a neo-mandible. The patient recovered well from the operation and was discharged 5 days after surgery. She healed completely without complications. This case report presents an alternative surgical treatment that may be considered if there is clinically stable sub-periosteal bone surrounding extensive MRONJ.     

The treatment of bisphosphonate-associated osteonecrosis of the jaws with bone resection and autologous platelet-derived growth factors

BACKGROUND: Bisphosphonates administered intravenously are used to treat patients with cancer who have hypercalcemia associated with malignant disease, multiple myeloma or metastatic tumors (breast, lung, prostate) in the bones. Bisphosphonates are bone resorption inhibitors and have been associated with osteonecrosis of the jaws. In this article, the authors provide an alternative treatment modality for refractory bisphosphonate-associated osteonecrosis (BON). CASE DESCRIPTION: The authors treated 12 patients with refractory BON and a history of long-term bisphosphonate therapy. Each patient had mucosal ulceration with exposed necrotic bone. The treatment combined bone resection with platelet-derived growth factors (PDGFs). The surgical intervention they used was a marginal resection limited to the alveolar bone. Ten of the patients recovered with complete mucosal and bone healing. CONCLUSION: BON has been shown to be refractory to antibiotics, minor local débridement and 0.12 percent chlorhexidine oral rinse. Treatment of refractory BON with a combination of marginal resection and PDGF has shown favorable results, including complete wound healing in most patients. This modality has been shown to be effective in treating BON and may be a useful alternative to existing treatment strategies.     

Comparison of the effects of Twin Block and activator treatment on the soft tissue profile

The aim of this study was to evaluate and compare the effects of activator and Twin Block (TB) appliances on the soft tissue profile. The study included 50 skeletal Class II patients (25 girls and 25 boys, mean age: 11.9 +/- 0.16 years) who were randomly allocated to one of two functional appliance treatment groups. The control group included 25 untreated skeletal Class II patients (13 boys and 12 girls, mean age: 10.11 +/- 0.91 years). Data were obtained from standardized lateral cephalograms taken at the beginning (T0) and end (T1) of appliance wear. The mean treatment time was 9 months for the activator group and 8 months for the TB group. The observation period of the control group was 8 months. Soft tissue profile changes were evaluated by means of 12 linear and five angular measurements. The groups were compared at T0 and T1 using analysis of variance, and treatment/observation differences (T1-T0) were evaluated with the Kruskal-Wallis test. Treatment changes in both appliance groups differed significantly (P < or = 0.001) from those in the control group, except for Ss-y, Ls-y, Li-E, and A-y measurements in the TB group and Ls-y, Li-E, nasolabial angle, and A-y measurements in the activator group. When the effects of the two appliances were compared, significant differences were observed only for SS-y (P < or = 0.05), Ss-E (P < or = 0.05), Si-E (P < or = 0.05), and nasolabial angle (P < or = 0.01). The effects of the activator and TB appliances on the soft tissue profile were similar; both significantly changed the soft tissue profile.     

Bisphosphonate-related osteonecrosis of the jaws: a report of three cases demonstrating variability in outcomes and morbidity

BACKGROUND: Bisphosphonates are used widely to manage skeletal disorders resulting from malignancies that destroy bone and from some metabolic bone diseases. A strong association between bisphosphonate treatment and the appearance of painful exposed nonvital bone in the mandible and maxilla after oral surgery has been reported in the last decade. Extensive reviews have appeared in the dental literature regarding bisphosphonate-related osteonecrosis of the jaws (BRONJ), including protocols for diagnosis, management and diagnostic imaging for early detection; feature definition; and determination of extent of the disease. CASE DESCRIPTION: The authors provide three case reports to show the contrast in treatment outcomes and morbidity in patients with BRONJ. The cases involved diagnostic imaging modalities commonly used in the practice of dentistry: panoramic radiography and cone-beam volumetric computed tomography. CLINICAL IMPLICATIONS: These case reports demonstrate the usefulness of dental diagnostic imaging in the detection and management of BRONJ, corroborate the increasing number of reports regarding high levels of morbidity associated with various BRONJ treatments, and underscore the danger of performing invasive dental procedures for patients receiving bisphosphonate therapy.     

Comparison of two different techniques used for the maintenance of peri-implant soft tissue health: a pilot randomized clinical trial

Objectives: The aim of this pilot study was to compare the effectiveness of two different methods of debridement on maintaining and improving peri-implant soft tissue health over a period of 12 months.

Materials and methods: Twenty adult patients (25 implants) were enrolled in a randomized, single-blinded, parallel group clinical trial. All implants included showed no signs of pathologic bone loss. Patients were scheduled to be reviewed every 3 months over a 12 months period. Nine patients (15 implants) were randomly allocated to a test group and treated with a low abrasive air polishing powder (Air-Flow^® Perio, EMS) (AFP) and another nine (10 implants) to a control group and treated with titanium curettes (TC). Peri-implant crevicular fluid samples were analyzed to quantitatively measure the concentration of six interleukins (IL-6, IL-8, IL-1β, TNF, IL-10 and IL-12). A multilevel analysis was used to test the comparison between the two treatments. The same analysis was used to study the relationship between clinical parameters and cytokines while controlling for confounding factors.

Results: There was no significant difference in bleeding on probing (BOP) between the two treatment methods (p?=?.35). Both debridement techniques resulted in a similar reduction of BOP (40.04% and 39.93%). IL-6 was the only cytokine of the six investigated that demonstrated a correlation with a clinical parameter (BOP) (p?=?.05).

Conclusions: Both treatment methods were proven to be effective in reducing peri-implant inflammation and preventing further disease progression. Some cytokines may act as markers for peri-implant disease as the present study showed a significant relationship between IL-6 and BOP.