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Abstract Context Antiresorptive therapy has been associated with osteonecrosis of the jaw (ONJ), an infrequent but potentially serious adverse event. Objective To assess information on invasive oral procedures and events (OPEs)—dental implants, tooth extraction, natural tooth loss, scaling/root planing, and jaw surgery—during the 7-year Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) Extension study and to present details of positively adjudicated ONJ cases. Design Randomized, double-blind, placebo-controlled, 3-year trial (FREEDOM) followed by 7 years of open-label denosumab (FREEDOM Extension). At Extension Year 3, women were asked to record their history of invasive OPEs since the start of the Extension to Year 2.5 and oral events in the prior 6 months. The questionnaire was then administered every 6 months until the end of the Extension. Setting Multicenter, multinational clinical trial. Patients Postmenopausal women with osteoporosis. Interventions Subcutaneous denosumab 60 mg or placebo every 6 months for 3 years, then 7 years of open-label denosumab. Main Outcome Measures Self-reports of OPEs and adjudicated cases of ONJ. Results Of respondents, 45.1% reported at least one invasive OPE. The exposure-adjusted ONJ rate in FREEDOM Extension was 5.2 per 10,000 person-years. ONJ incidence was higher in those reporting an OPE (0.68%) than not (0.05%). Conclusions Although invasive OPEs were common in these denosumab-treated women and were associated with an increased ONJ incidence, the overall rate of ONJ was low, and all cases with complete follow-up resolved with treatment. Self-reported invasive OPEs were common in women treated with denosumab up to 10 years and were associated with increased ONJ incidence; however, the overall rate of ONJ was low.

PurposeBisphosphonates reduce bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We describe risk factors for BRONJ and compare BRONJ provoked by infection or trauma with spontaneous lesions, which carry a better prognosis.MethodsSWOG 0307 randomized women with stage I–III breast cancer to receive zoledronic acid (ZA), clodronate (CL), or ibandronate (IB) for 3 years, implemented BRONJ prevention guidelines, and collected information about dental health and development of BRONJ. All statistical tests were two-sided.ResultsOf 6018 women, 48 developed BRONJ. Infection was present in 21 (43.8%). Median time to BRONJ was 2.1 years for ZA, 2.0 years for IB, and 3.4 years for clodronate (p = 0.04). BRONJ was associated with bisphosphonate type (28/2231 (1.26%) for ZA, 8/2235 (0.36%) for CL, 12/1552 (0.77%) for IB), dental calculus (OR 2.03), gingivitis (OR 2.11), moderate/severe periodontal disease (OR 2.87), and periodontitis > 4 mm (OR 2.20) (p < 0.05). Of 57 lesions, BRONJ occurred spontaneously in 20 (35.1%) and was provoked by dental extraction in 20 (35.1%), periodontal disease in 14 (24.6%), denture trauma in 6 (10.5%), and dental surgery in 2 (3.5%). Spontaneous BRONJ occurred more frequently at the mylohyoid ridge. There were no differences in dental disease, infection, or bisphosphonate type between spontaneous and provoked BRONJ.ConclusionZA and worse dental health were associated with increased incidence of BRONJ, with a trend toward additive risk when combined. BRONJ incidence was lower than in similar studies, with prevention strategies likely linked to this.Clinical trial numberNCT00127205Registration dateJuly 2005

Fatty degenerative osteonecrosis of the jaw (FDOJ) is a chronic, aseptic inflammatory condition that is characterized by molecular disruptions in bone metabolism and necrotic bone marrow within the jawbone cavities. In contrast to the overt clinical signs typically observed in osteopathies, FDOJ frequently presents with a “silent inflammation” phenotype. The electronic databases PubMed, Scopus, and Embase were searched using appropriate search terms, and the methodology was performed according to PRISMA-ScR guidelines. The elevated expression of inflammatory mediators, particularly C-C motif Chemokine Ligand-5/Regulated on Activation, Normal T Cell Expressed and Secreted (CCL5/RANTES), fibroblast growth factor-2, and interleukin-1 receptor antagonist, distinguishes FDOJ at the molecular level and links it to systemic inflammatory and autoimmune diseases. These immunohistochemical markers play a pivotal role in the pathogenesis of chronic inflammation, immune response regulation, and abnormal bone remodeling. Advanced diagnostic tools, such as conebeam computed tomography and trans-alveolar ultrasonography, facilitate the detection of pathological changes that are not easily discernible with conventional radiography. Surgical intervention remains the primary treatment modality, often complemented by therapies that target these molecular pathways to modulate chronic inflammation. This article underscores the importance of integrating molecular diagnostics, advanced imaging, and clinical data for effective FDOJ detection and management.

Medication-related osteonecrosis occurs exclusively in the jaw bones. However, the exact pathogenesis of medication-related osteonecrosis of the jaw (MRONJ) and the unique predisposition of the jaw bones have not been elucidated, making its treatment a challenge. Recent evidence indicates that macrophages might play a pivotal role in MRONJ pathogenesis. The aim of the present study was to compare the macrophage populations between the craniofacial and extracranial skeleton and to investigate the changes induced by zoledronate (Zol) application and surgical interventions. An experiment was performed. 120 wistar rats were randomized to 4 groups (G1, G2, G3, G4). G1 served as an untreated control group. G2 and G4 received Zol injections for 8 weeks. Afterwards, the right lower molar of the animals from G3 and G4 was extracted and the right tibia osteotomized followed by osteosynthesis. Tissue samples were taken from the extraction socket and the tibia fracture at fixed time points. Immunohistochemistry was conducted to determine the labeling indexes of CD68 and CD163 macrophages. Comparing the mandible and the tibia, we observed a significantly higher number of macrophages and a heightened pro-inflammatory environment in the mandible compared to the tibia. Tooth extraction caused an increase of the overall number of macrophages and a shift toward a more pro-inflammatory microenvironment in the mandible. Zol application amplified this effect. Our results indicate fundamental immunological differences between the jaw bone and the tibia, which might be a reason for the unique predisposition for MRONJ in the jaw bones. The more pro-inflammatory environment after Zol application and tooth extraction might contribute to the pathogenesis of MRONJ. Targeting macrophages might represent an attractive strategy to prevent MRONJ and improve therapy. In addition, our results support the hypothesis of an anti-tumoral and anti-metastatic effect induced by BPs. However, further studies are needed to delineate the mechanisms and specify the contributions of the various macrophage phenotypes.

Fetal alcohol spectrum disorders (FASD) describe ethanol-induced developmental defects including craniofacial malformations. While ethanol-sensitive genetic mutations contribute to facial malformations, the impacted cellular mechanisms remain unknown. Signaling via bone morphogenetic protein (Bmp) is a key regulatory step of epithelial morphogenesis driving facial development, providing a possible ethanol-sensitive mechanism. We found that zebrafish carrying mutants for Bmp signaling components are ethanol-sensitive and affect anterior pharyngeal endoderm shape and gene expression, indicating that ethanol-induced malformations of the anterior pharyngeal endoderm cause facial malformations. By integrating FASD patient data, we provide the first evidence that variants of the human Bmp receptor gene BMPR1B associate with ethanol-related differences in jaw volume. Our results show that ethanol exposure disrupts proper morphogenesis of, and tissue interactions between, facial epithelia that mirror overall viscerocranial shape changes and are predictive for Bmp−ethanol associations in human jaw development. Our data provide a mechanistic paradigm linking ethanol to disrupted epithelial cell behaviors that underlie facial defects in FASD.

Objectives Osteonecrosis of the jaws (MRONJ) is a frequent side effect of antiresorptive (AR) drugs used in oncology. MRONJ may have endodontic consequences, as reported in this clinical case. Material and Methods A 64‐year‐old woman being treated with antiresorptive (AR) drugs targeting bone metastasis of a primitive breast cancer consulted at the dental service of Pitié‐Salpêtrière Hospital. She first experienced symptomatic apical periodontitis followed by symptomatic irreversible pulpitis, which were initially explained as resulting from occlusal trauma. Despite endodontic treatment, exacerbation of the symptomatology was noted. MRONJ was suspected, and the affected tooth was extracted. Results The presence of necrotic bone during the surgery confirmed the diagnosis. Surgical treatment led to complete healing and total disappearance of clinical and radiological signs at 4 months. Conclusions MRONJ can induce alterations in adjacent tooth vascularization and secondary pulpal disease. Early diagnosis is difficult because early‐stage MRONJ occurs without clear radiographic signs. Summary MRONJ is a side effect of antiresorptive (AR) drugs used in oncology. MRONJ may have endodontic consequences, as reported in this clinical case. Endodontists should be aware of the side effects of AR drugs and their possible consequences on dental pulp to avoid delayed diagnosis and invasive interventions.

•This study compared laser auriculotherapy with the occlusal splint, a standard treatment for temporomandibular disorders.•It is the first study to compare laser auriculotherapy with occlusal splints in the treatment of temporomandibular disorders in a prospective clinical study.•The results showed that the two treatments were similar in terms of the number of symptom aspects that they improved, but that they differed in exactly which symptoms were involved.•This paper will be of interest because it addresses a viable, non-invasive treatment alternative for chronic orofacial pain caused by temporomandibular disorders. This study evaluated the effects of low-power laser auriculotherapy (LA) on the physical and emotional symptoms of patients with temporomandibular disorders (TMDs), in comparison with occlusal splints (OS). Randomized, blinded, prospective, non-inferiority clinical trial. The patients received OS (control group) or LA (experimental group). Following the Consolidated Standards of Reporting Trials (CONSORT) guidelines, patients with TMD were evaluated by using axes I and II of the Research Diagnostic Criteria for RDC-TMD. Both intra- and intergroup quantitative variables were analyzed with ANOVA (p < 0.05), while qualitative variables were analyzed with the Kruskal–Wallis (intergroup evaluations; p < 0.05) or Mann–Whitney tests (intragroup analyses; p < 0.05). OS improved five physical symptoms of TMD (pain in the right temporal muscle, right and left masseter muscles, left joint, and left intraoral region), while LA improved six (jaw functioning; pain in left masseter muscle, right and left joints, and right and left intraoral regions). Similarly, OS improved seven emotional symptoms (degree of depression, degree of non-specific physical symptoms, excluding pain, degree of non-specific physical symptoms including pain, average pain value in the past 6 months, presence of depression, intensity and characteristics of pain, non-specific physical symptoms including pain), while LA improved five (degree of non-specific physical symptoms including pain, presence of depression, intensity and characteristics of pain, non-specific physical symptoms including pain, non-specific physical symptoms excluding pain). LA improved the physical and emotional symptoms of TMD, with results similar to OS. For the physical and emotional symptoms associated with TMD, LA showed similar outcomes as OS.

This study aimed to evaluate the bone regeneration capacity of a customized alloplastic material and xenograft with recombinant human bone morphogenetic protein-2 (rhBMP-2). We prepared hydroxyapatite (HA)/tricalcium phosphate (TCP) pure ceramic bone blocks made using a 3D printing system and added rhBMP-2 to both materials. In eight beagle dogs, a total of 32 defects were created on the lower jaws. The defective sites of the negative control group were left untreated (N group; 8 defects), and those in the positive control group were filled with particle-type Bio-Oss (P group; 12 defects). The defect sites in the experimental group were filled with 3D-printed synthetic bone blocks (3D group; 12 defects). Radiographic and histological evaluations were performed after healing periods of 6 and 12 weeks and showed no significant difference in new bone formation and total bone between the P and 3D groups. The 3D-printed custom HA/TCP graft with rhBMP-2 showed bone regeneration effects similar to that of particulate Bio-Oss with rhBMP-2. Through further study and development, the application of 3D-printed customized alloplastic grafts will be extended to various fields of bone regeneration.

Background This study aims to investigate the clinical characteristics, imaging features, treatment, and prognostic factors of jaw Langerhans cell histiocytosis (JLCH), providing valuable insights for its clinical diagnosis and management. Method This study retrospectively analyzed the clinical and follow-up data of JLCH patients treated between January 2010 and January 2024. Data collected included gender, age, symptoms, imaging findings, treatment strategies, and outcomes. Univariate and multivariate Cox regression analyses were performed using SAS software to identify factors affecting treatment outcomes, with P  ≤ 0.05 considered statistically significant. Results A total of 68 patients (50 males, 18 females; median age 13.5 years) were included. Forty percent of patients were under 10 years old, and 71% had mandibular involvement. Disease classification included 49 cases of single-system unifocal (SS-s) disease, 10 cases of single-system multifocal (SS-m) disease, and 9 cases of multi-system (MS) disease. Common symptoms included jaw or tooth pain (28 cases), facial swelling (22), gingival ulceration (10), and loose teeth (9). Imaging revealed periodontal disease-like (7), cyst-like (17), and osteomyelitis-like (44) lesions. Univariate and multivariate Cox regression analyses identified that female patients had a lower risk of progression (P = 0.014, HR 0.071), while SS-m (P = 0.019, HR 4.992) and MS patients (P = 0.030, HR 4.182) exhibited higher progression risks compared to SS-s patients. Cyst-like (P = 0.001, HR 0.054) and osteomyelitis-like lesions (P < 0.001, HR 0.023) were associated with lower progression risks compared to alveolar lesions. Conclusion JLCH can affect individuals of all ages, though it is more common in children. Factors such as gender, lesion multiplicity, and lesion type (alveolar) are significant in predicting disease progression. Complete surgical resection combined with radiotherapy offers the highest likelihood of cure for SS-type JLCH.

Bisphosphonates (BSPs) are used for the treatment of multiple myeloma, metastatic breast and lung cancer, Paget's disease, osteoporosis, hypercalcemia due to malignancy, and many other skeletal diseases. BSPs reduce osteoclastic functions, which result in bone resorption. Bisphosphonates-related osteonecrosis of jaws (BRONJ) is a newly developed term that is used to describe the significant complication in patients receiving bisphosphonates. BSPs are known to exhibit an anti-angiogenetic effect that initiates tissue necrosis of the hard tissue. There is currently no consensus on the correct approach to this issue. The aim of this retrospective study is to compare the effects of laser surgery with biostimulation to conventional surgery in the treatment of BSP-induced avascular bone necrosis on 20 patients who have been treated in our clinic. BRONJ was evaluated in patients with lung, prostate, and breast cancer under intravenous BSP treatment. Twenty patients in this study developed mandibular or maxillary avascular necrosis after a minor tooth extraction surgery or spontaneously. Bone turnover rates were evaluated by serum terminal C-telopeptide levels (CTX) using the electrochemiluminescence immunoassay technique and patients were treated with laser or conventional surgical treatments and medical therapy. Ten patients were treated with laser surgery and biostimulation. An Er:YAG laser (Fotona Fidelis Plus II® Combine laser equipment, Slovenia) very long pulse (VLP) mode (200 mJ, 20 Hz) using a fiber tip 1.3 mm in diameter and 12 mm in length was used to remove the necrotic and granulation tissues from the area of avascular necrosis. Biostimulation was applied postoperatively using an Nd:YAG laser. Low-level laser therapy (LLLT) was applied to the tissues for 1 min from 4 cm distance using an Nd:YAG laser (Fotona-Slovenia) with a R24 950-µm fiber handpiece long-pulse (LP) mode, 0.25-W, 10 Hz power/cm 2 from the mentioned distance the spot size was 0.4 cm 2 , and power output was 2.5 J. Energy density from the mentioned distance was calculated to be 6.25 J/cm 2 . The other ten patients were treated with conventional surgery. Treatment outcomes were noted as either complete healing or incomplete healing. There were no statistically significant differences between laser surgery and conventional surgery ( p  > 0.05). CTX values also did not affect the prognosis of the patients. Treatment outcomes were significantly better in patients with stage II osteonecrosis than in patients with stage I osteonecrosis. Our findings suggest that dental evaluation of the patients prior to medication is an important factor in the prevention of BRONJ. Laser surgery is a beneficial alternative in the treatment of patients with this situation. Further randomized studies with larger patient numbers may also improve our understanding of treatment protocols for this situation.