Effect of intraoral administration of parathyroid hormone on osseous and soft tissue healing around implants in ovariectomized rat maxillae.

OBJECTIVES: Intermittent administration of parathyroid hormone (PTH) increases systemic bone mass. However, the effect of PTH on osseous and soft tissue healing around implants in osteoporosis patients remains unclear. This study aimed to investigate the effects of PTH on tissue healing around implants in ovariectomized rats and to compare systemic and intraoral administration routes. MATERIAL AND METHODS: Implants were placed at the healed sites of ovariectomized rats 3 weeks after maxillary first molar extraction. Rats were randomly divided into two groups that received either daily systemic subcutaneous or local intraoral PTH administration. Maxillae were dissected to examine bone architectures with micro-computed tomography images. Histomorphometric and immunohistochemical analyses were performed to evaluate osseous and soft tissue healing around the implants. RESULTS: Regardless of the administration route, PTH significantly increased bone area and the numbers of osteoblasts, osteoclasts, and osteocytes in the first and second inside and outside areas of implant threads, in addition to decreasing the number of sclerostin+ osteocytes. However, the intraoral PTH administration route was superior to the systemic route by significantly improving bone quality and promoting collagen production in the connective tissue around implants. CONCLUSIONS: Parathyroid hormone administration promoted both osseous and soft tissue healing around implants, irrespective of administration route. Interestingly, intraoral administration improved the evaluated parameters more than systemic administration. Thus, the intraoral route could become a useful treatment strategy for implant treatment in osteoporosis patients.

Medication-related osteonecrosis of the jaw: A literature review and update.

Since the initial description of medication-related osteonecrosis of the jaw (MRONJ) almost two decades ago, the potential pathophysiology and risk factors have been elaborated on in many investigations and guidelines. However, the definitive pathophysiology based on scientific evidence remains lacking. Consequently, the optimal clinical treatment and prevention strategies for MRONJ have not been established. Despite their different mechanisms of action, many drugs, including bisphosphonates, denosumab, angiogenesis inhibitors, and other medications, have been reported to be associated with MRONJ lesions in cancer and osteoporosis patients. Importantly, MRONJ occurs predominantly in the jawbones and other craniofacial regions, but not in the appendicular skeleton. In this up-to-date review, the currently available information and theories regarding MRONJ are presented from both clinical and basic science perspectives. The definition and epidemiology of MRONJ, triggering medication, and histopathology are comprehensively summarized. The immunopathology and the potential pathophysiology based on immune cells such as neutrophils, T and B cells, macrophages, dendritic cells, and natural killer cells are also discussed. In addition, antiangiogenesis, soft tissue toxicity, necrotic bone, osteocyte death, and single-nucleotide polymorphisms are examined. Moreover, other possible mechanisms of MRONJ development are considered based on the unique embryological characteristics, different cell behaviors between jawbones and appendicular skeleton, unique anatomical structures, and sustained bacterial exposure in the oral cavity as a basis for MRONJ site specificity. Based on the literature review, it was concluded that multiple factors may contribute to the development of MRONJ, although which one is the key player triggering MRONJ in the craniofacial region remains unknown.

Zoledronic Acid Deteriorates Soft and Hard Tissue Healing of Murine Tooth Extraction Sockets in a Dose-Dependent Manner.

The pathophysiology, histopathology, and immunopathology of bisphosphonate-related osteonecrosis of the jaw (BRONJ) Stage 0 remain unclear. The aim of this study was to investigate the effects of high-dose bisphosphonates on tooth extraction socket healing by creating a murine model of BRONJ Stage 0-like lesions using 8-week-old female C57BL/6J mice. Zoledronic acid (Zol) was administered subcutaneously twice a week for 7 weeks at doses of 0.1 mg/kg/week (moderate dose; Zol-M), 0.5 mg/kg/week (high dose; Zol-H1), and 1.0 mg/kg/week (higher dose; Zol-H2). Saline was used as a control (VC). Both maxillary first molars were extracted 3 weeks after drug treatment. Maxillae, long bones, and sera were collected 4 weeks post-extraction (n = 7 mice/group). Microcomputed tomography, histological, immunohistochemical, and ELISA analyses were performed. A ceiling effect for Zol was noted at the Zol-H1 dose. Osseous healing of extraction sites was significantly impaired with increased necrotic bone and the number of empty lacunae in a Zol dose-dependent manner. Zol significantly decreased epithelial thickness, due to a decrease in thickness of the stratum spinosum, in both Zol-H1 and Zol-H2. Both Zol-H1 and Zol-H2 significantly suppressed the distribution of F4/80+ macrophages in the connective tissue of tooth extraction sockets, although gross healing appeared to be normal. Intriguingly, both Zol-H1 and Zol-H2 significantly increased the numbers of TRAP+ mononuclear cells and detached osteoclasts in the connective tissue and bone marrow of extraction sites compared to VC and Zol-M, correlated with serum TRAcP5b levels. The created murine model of BRONJ Stage 0-like lesions becoming more severe in a dose-dependent manner may help to understand the pathophysiology and histopathology of BRONJ Stage 0 in humans.

Controlled mechanical early loads improve bone quality and quantity around implants: An in vivo experimental study.

OBJECTIVES: This study aimed to investigate the effects of early loads on bone quality and quantity around implants and to compare the effects of early loads on bone quality and quantity with the effects of conventional loads. MATERIALS AND METHODS: Grade IV-titanium implants with buttress threads were placed in rat maxillary bone 4 weeks after extraction of first molars. A controlled mechanical load (10 N, 3 Hz, 1800 cycles, 2 days/week) was started via the implants 1 and 3 weeks after implant placement for 2 weeks (early and conventional loads, respectively). Bone quality, defined as distribution of bone cells, types and orientation of collagen fibers, and production of semaphorin3A, its receptor neuropilin-1, and sclerostin, were quantitatively evaluated. RESULTS: Early loads substantially and positively affected bone quality by changing the preferential alignment of collagen fibers with increased production of type I and III collagens, semaphorin3A, and neuropilin-1, increased osteoblast numbers, decreased production of sclerostin, and decreased osteoclast numbers both inside and outside the implant threads, when compared with non-loaded conditions. Conventional loads changed bone quality around implants slightly. Interestingly, early loads had significantly stronger effects on bone quality and quantity based on the evaluation parameters than conventional loads. CONCLUSIONS: This is the first report to provide scientific evidence for load initiation time based on both bone quality and quantity around implants. These new findings show that implants with buttress threads transmitted early loads optimally to bone tissue by improving bone quality and quantity inside and outside the implant threads.

Altered immunolocalization of FGF23 in murine femora metastasized with human breast carcinoma MDA-MB-231 cells.

INTRODUCTION: After the onset of bone metastasis, tumor cells appear to modify surrounding microenvironments for their benefit, and particularly, the levels of circulating fibroblast growth factor (FGF) 23 in patients with tumors have been highlighted. MATERIALS AND METHODS: We have attempted to verify if human breast carcinoma MDA-MB-231 cells metastasized in the long bone of nu/nu mice would synthesize FGF23. Serum concentrations of calcium, phosphate (Pi) and FGF23 were measured in control nu/nu mice, bone-metastasized mice, and mice with mammary gland injected with MDA-MB-231 cells mimicking primary mammary tumors. RESULTS AND CONCLUSIONS: MDA-MB-231 cells revealed intense FGF23 reactivity in metastasized lesions, whereas MDA-MB-231 cells cultured in vitro or when injected into the mammary glands (without bone metastasis) showed weak FGF23 immunoreactivity. Although the bone-metastasized MDA-MB-231 cells abundantly synthesized FGF23, osteocytes adjacent to the FGF23-immunopositive tumors, unlike intact osteocytes, showed no FGF23. Despite significantly elevated serum FGF23 levels in bone-metastasized mice, there was no significant decrease in the serum Pi concentration when compared with the intact mice and mice with a mass of MDA-MB-231 cells in mammary glands. The metastasized femora showed increased expression and FGFR1 immunoreactivity in fibroblastic stromal cells, whereas femora of control mice showed no obvious FGFR1 immunoreactivity. Taken together, it seems likely that MDA-MB-231 cells synthesize FGF23 when metastasized to a bone, and thus affect FGFR1-positive stromal cells in the metastasized tumor nest in a paracrine manner.

Medication-related osteonecrosis of the jaw-like lesions in rodents: A comprehensive systematic review and meta-analysis.

OBJECTIVE: The aim of this comprehensive systematic review and meta-analysis was to investigate the pathology and pathogenesis of medication-related osteonecrosis of the jaw (MRONJ) in rodents. BACKGROUND: Medication-related osteonecrosis of the jaw occurs in patients taking antiresorptive drugs, such as bisphosphonates and denosumab, and anti-angiogenesis agents. However, there is limited information about the pathology of MRONJ at the clinical level. Moreover, no information about the exact mechanisms of MRONJ is clinically available. MATERIALS AND METHODS: The PubMed, SCOPUS and Medline databases were used to search for relevant articles up to April 2018 by two independent reviewers. A systematic review and meta-analysis were performed. RESULTS: Of the 1841 studies, 10 articles met the eligibility criteria. The most commonly observed pathology of MRONJ-like lesions was exposed bone without epithelial coverage, decreases in the number of osteocytes and increases in necrotic bone with more empty lacunae. No definitive pathogenesis of MRONJ-like lesions was found. Both zoledronic acid (ZA) monotherapy and ZA/chemotherapeutic and/or dexamethasone combination therapy were significant high-risk factors for developing MRONJ-like lesions (P < 0.00001 and P < 0.0001, respectively). CONCLUSION: Based on rodent studies, common pathological findings were extracted in bisphosphonate-related ONJ (BRONJ)-like lesions, whereas no definitive pathogenesis was identified. There is no information about the pathology and pathogenesis of denosumab-related ONJ. These findings clearly suggest that accumulation of scientific evidence based on animal studies is absolutely necessary to explore the pathology and pathogenesis of MRONJ in humans. ZA administration would be a significant risk factor for developing BRONJ-like lesions.

Effect of anti-angiogenesis induced by chemotherapeutic monotherapy, chemotherapeutic/bisphosphonate combination therapy and anti-VEGFA mAb therapy on tooth extraction socket healing in mice.

Osteonecrosis of the jaw (ONJ), which is a rare but severe adverse effect, mainly occurs in oncology patients receiving chemotherapeutic agents and bisphosphonates. However, the combined impact of chemotherapy and bisphosphonates on wound healing after tooth extraction remains unknown. The aim of this study was to determine the precise etiology of ONJ induced by chemotherapy and bisphosphonate combination therapy. Mice received zoledronate (ZA) monotherapy, cyclophosphamide (CY) monotherapy or CY/ZA combination therapy. The maxillary first molars were extracted 3 weeks after the initiation of drug treatment. Moreover, antivascular endothelial growth factor A (VEGFA) monoclonal antibody (mAb) was administered once every 2 days just after tooth extraction for 2 weeks. Soft and hard tissue wound healing was evaluated 2 and 4 weeks post-extraction using histomorphometry, microcomputed tomography and immunohistochemistry. ZA monotherapy did not induce impaired oral wound healing and ONJ-like lesions 2 and 4 weeks post-extraction, respectively. Tooth extraction socket healing worsened with severe anti-angiogenesis by CY monotherapy and CY/ZA combination therapy 2 weeks post-extraction. However, CY monotherapy rarely induced ONJ-like lesions with severe angiogenesis suppression, whereas CY/ZA combination therapy frequently induced ONJ-like lesions with severe angiogenesis inhibition 4 weeks post-extraction. Interestingly, anti-VEGFA mAb therapy delayed osseous wound healing with normal soft tissue wound healing of tooth extraction sockets, although this therapy significantly suppressed blood vessel formation. Our findings suggest that anti-angiogenesis alone is not the main cause of ONJ-like lesions induced by CY/ZA combination therapy. The combination of suppressed osteoclasts and anti-angiogenesis, in addition to other risk factors such as chemotherapy, may contribute to the development of ONJ.

[Dental Implant Treatment in Patients Receiving Anti-resorptive Agents.]

Dental implant treatment is one of the most reliable therapeutic options for replacing missing teeth. In 2003, it was demonstrated that osteonecrosis of the jaw(ONJ)occurred in patients taking bisphosphonates(BRONJ). Recently, ONJ has also been demonstrated to occur in patients taking anti-receptor activator of nuclear factor-kappaB ligand antibody(denosumab:DRONJ). However, the precise mechanisms of ONJ remain unclear and definitive treatment strategies for ONJ have not been developed. There has been little information regarding the relationship between ONJ and dental implant treatment. However, a recent systematic review indicated that dental implant treatment is a triggering factor for BRONJ. The aim of this study was to provide the most current information on dental implant treatment in patients receiving anti-resorptive agents. A literature search has suggested that implant treatment becomes a risk factor for BRONJ around dental implants. Implantitis may also be a risk factor for BRONJ around dental implants. No available information regarding DRONJ around dental implants was noted. Hence, caution should be exercised when dental implant treatment is carried out in the patients taking anti-resorptive agents such as bisphosphonates and denosumab.

Mouse anti-RANKL antibody delays oral wound healing and increases TRAP-positive mononuclear cells in bone marrow.

OBJECTIVES: Denosumab, a human monoclonal antibody (mAb) that neutralizes receptor activator for nuclear factor κB ligand (RANKL), is associated with osteonecrosis of the jaw. However, the effect of denosumab on oral wounds is unclear. The aim was to determine the effect of anti-RANKL mAb on oral wounds and bone marrow. MATERIALS AND METHODS: The direct effect of the mAb on fibroblasts, macrophages, and osteoclasts were assessed in vitro. In vivo, mouse anti-RANKL mAb was administered to mice for 9 weeks prior to palatal bone denudation surgery. Mice were euthanized 3 weeks post-surgery, and wound healing was histomorphometrically analyzed. Long bones were assessed using micro-computed tomography, quantitative real-time polymerase chain reaction, and flow cytometry. RESULTS: The mAb had no effect on macrophages and fibroblasts but significantly suppressed osteoclast proliferation in vitro. The mAb treatment significantly increased bone mass by suppressing osteoclasts in vivo. The expression of pro-osteoclastic genes was promoted in the bone marrow of the mAb-administered animals. Consistently, the mAb significantly induced the development of tartrate-resistant acid phosphatase (TRAP)-positive mononuclear cells (MNCs) but not osteoclasts in bone marrow. The mAb treatment had no effect on gross healing of the palatal wounds. However, significant inflammation was retained in the connective tissue facing the once denuded bone surface. CONCLUSIONS: Repair of the damaged palate was delayed, and significant inflammation was sustained in the connective tissue by anti-RANKL mAb treatment. CLINICAL RELEVANCE: Denosumab impairs osteoclastic bone repair. Care should be exercised to minimize osseous trauma when invasive procedures are performed on patients taking denosumab.

Influence of Implant Neck Design on Bone Formation Under Mechanical Repetitive Loading: Histomorphometric and Microcomputed Tomographic Studies in Rabbit Tibiae.

PURPOSE: The aim of this study was to investigate effects of implant neck design on the original concept of osseointegration and bone formation when applying mechanical repetitive loading by bone-integrated implants. MATERIALS AND METHODS: Twenty-eight anodized Ti-6Al-4V alloy implants with +60° or -60° grooves in the implant neck were placed in the proximal tibial metaphysis of 14 rabbits. Fourteen implants received mechanical repetitive loading along the long axis of the implant for 8 weeks at 12 weeks after implant placement. The remaining 14 implants received no loading. Histomorphometric and microcomputed tomographic analyses were then performed. RESULTS: No effect of neck design was observed without mechanical loading, whereas osseointegration around the +60° grooves was upregulated with mechanical loading. Calculated load effects on bone structure around the implant neck with +60° grooves were larger when compared with the -60° grooves under mechanical loading. CONCLUSIONS: These findings indicate that the establishment of osseointegration and bone formation around the implant neck with +60° grooves is superior to those with -60° grooves under loaded conditions.

Implant-assisted removable partial dentures: Part I. a scoping review of clinical applications.

PURPOSE: This scoping review aimed to systematically map research regarding implant-assisted removable partial dentures (IARPDs), and identify existing gaps in knowledge. STUDY SELECTION: Two reviewers independently conducted a search of the MEDLINE-PubMed and Scopus databases according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) extension for Scoping Review and included articles published in English up to August 31, 2022, including human studies, reviews, and in vitro studies. Expert opinions, animal studies, and clinical studies involving complete overdentures were excluded, and ten aspects for establishing the treatment strategy for IARPDs were examined. RESULTS: One hundred and twelve articles were chosen. There were two treatment modalities: IARPDs retained by implant- and tooth-supported surveyed single crowns (SCs) or fixed partial dentures (FPDs). In IARPDs retained by tooth-supported surveyed SCs or FPDs, the survival rate of dental implants for IARPDs was relatively higher with a wide range of marginal bone loss and many complications, but with improved functional performance, oral health-related quality of life, and patient satisfaction. There were limited data on survival or success rates and designs of IARPDs, attachment selections, length and diameter, inclination, placement sites, and loading protocols of implants, regardless of prosthetic types. There was limited information on maxillary IARPDs except for survival rates of implants. CONCLUSIONS: Although IARPDs could become a useful treatment strategy, there is limited scientific consensus with gaps in knowledge about their use. Additional well-designed clinical and in vitro studies are necessary to scientifically establish IARPDs as definitive prostheses in implant dentistry.

Implant-assisted removable partial dentures: Part II. a systematic review of the effects of implant position on the biomechanical behavior.

PURPOSE: This systematic review aimed to evaluate the effects of implant placement sites on the biomechanical behavior of implant-assisted removable partial dentures (IARPDs) using finite element analysis (FEA). STUDY SELECTION: Two reviewers independently conducted manual searches of the PubMed, Scopus, and ProQuest databases for articles investigating implant location in IARPDs using FEA, according to the 2020 Systematic Reviews and Meta-analyses statement. Studies published in English up to August 1, 2022, were included in the analysis based on the critical question. RESULTS: Seven articles meeting the inclusion criteria were systematically reviewed. Six studies investigated mandibular Kennedy Class I and one study investigated mandibular Kennedy Class II. Implant placement reduced the displacement and stress distribution of the IARPD components, including dental implants and abutment teeth, regardless of the Kennedy Class type and dental implant placement site. Most of the included studies showed that, based on the biomechanical behavior, the molar region, rather than the premolar region, is the preferred implant placement site. None of the selected studies investigated the maxillary Kennedy Class I and II. CONCLUSIONS: Based on the FEA regarding mandibular IARPDs, we concluded that implant placement in both the premolar and molar regions improves the biomechanical behaviors of IARPD components, regardless of the Kennedy Class. Implant placement in the molar region results in more suitable biomechanical behaviors compared with implant placement in the premolar region in Kennedy Class I. No conclusion was reached for Kennedy Class II due to the lack of relevant studies.

Bone Augmentation With Alloplastic Graft Material in a Patient Under Bisphosphonate Therapy: A Case Report and Literature Review.

Cases of relatively safe dental implant treatment in patients with low-volume bisphosphonate (BP) have been gradually reported. Although bone augmentation is commonly used when the bone volume is insufficient for implant placement, the studies and case reports regarding the safety of bone augmentation in patients treated with BP remain insufficient. Herein, we report a case wherein bone augmentation was performed after BP treatment with bone healing realized according to imaging, and we review the literature regarding BP and bone augmentation. A 67-year-old Japanese woman requested implant treatment for a hopeless lower right second molar. She had been taking minodronic acid hydrate (50 mg/4 wk) for 18 months to treat steroid-induced osteoporosis. After obtaining informed consent, tooth extraction and bone augmentation within the extraction socket were performed. The tooth was extracted atraumatically to preserve the surrounding alveolar bone, and the extraction socket was intensely curetted. Subsequently, the socket was filled with carbonate apatite granules and covered with a biodegradable membrane, and the wound was sutured without tension. Although protracted wound healing without any symptoms of infection was observed, the wound healed completely. No clinical symptoms were observed, the color of the mucosa at the site was healthy, and imaging findings at 6 months postoperation indicated that osteogenesis had progressed uneventfully.

Effect of zoledronate on the responses of osteocytes to acute parathyroid hormone.

The bone anabolic effect of parathyroid hormone (PTH) therapy is blunted when used in patients who were previously on bisphosphonate treatment. Osteocytes may play a role in the bisphosphonate silencing effect on PTH therapy since bisphosphonates have been shown to reach the lacunocanalicular system. In vivo osteocyte studies pose a significant challenge. For the current study, we developed a simple method to isolate RNA from cortical bone enriched with osteocytes. Our purpose was to investigate how zoledronate (ZA) treatment modulates the responses of osteocytes and the bone marrow (BM) to acute PTH treatment. Mice received ZA treatment for 3 months and a single PTH injection prior to death. Bone was histomorphometrically evaluated. Gene expression was assessed at the RNA level in osteocytes and BM. Endothelial progenitor cells (EPCs) and γδT cells were analyzed in the BM and blood using flow cytometry. We found that ZA treatment altered bone responses to PTH. Expression of Sfrp4, a Wnt antagonist, was significantly increased in ZA-affected osteocytes. BM EPCs were increased in response to acute PTH but not when treatment was combined with ZA. ZA treatment augmented EPCs in the BM but not in blood, which suggests that ZA treatment may have differential effects between the BM and blood. These findings indicate that osteocytes and BM EPCs in mice on ZA treatment respond differently to acute PTH from those not receiving ZA. This may partially explain the mechanisms of previous reports that ZA therapy attenuates the anabolic effect of PTH in bone.

Parathyroid hormone related to bone regeneration in grafted and nongrafted tooth extraction sockets in rats.

OBJECTIVE: The quality and quantity of bone formed in tooth extraction sockets impact implant therapy. Therefore, the establishment of a new approach to enhance bone formation and to minimize bone resorption is important for the success of implant therapy. In this study, we investigated whether intermittent parathyroid hormone (PTH) therapy enhanced bone formation in grafted sockets. METHODS: Tooth extractions of the maxillary first molars were performed in rats, and the sockets were grafted with xenograft. Intermittent PTH was administered either for 7 days before extractions, for 14 days after extractions, or both. The effect of PTH therapy on bone formation in the grafted sockets was assessed using microcomputed tomography at 14 days after extractions. RESULTS: PTH therapy for 7 days before extractions was not effective to augment bone fill, whereas PTH therapy for 14 days after operation significantly augmented bone formation in the grafted sockets. CONCLUSIONS: Intermittent PTH therapy starting right after tooth extractions significantly enhanced bone fill in the grafted sockets, suggesting that PTH therapy can be a strong asset for the success of the ridge preservation procedure.

Medication-related Osteonecrosis of the Jaw Induced by Regenerative Therapy in Implant Dentistry: A Scoping Review.

OBJECTIVES: There is limited scientific evidence regarding the medication-related osteonecrosis of the jaw (MRONJ) induced by regenerative therapy (RT) associated with dental implant treatment. Thus, the current scoping review systematically maps the MRONJ research induced by RTs in implant dentistry and recognizes the existing gaps in knowledge. DATA: Original studies and reviews investigating the impact of RT on the development of MRONJ were included. SOURCES: Two reviewers independently searched the MEDLINE-PubMed and Scopus databases according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) extension for Scoping Review and included articles published in English up to March 31, 2023. STUDY SELECTION: Eighteen articles that fulfilled the inclusion and exclusion criteria were included in this study. Ten mapping parameters for investigating the association of RTs with MRONJ development were examined and evaluated within the selected articles. RESULTS: There was severely limited information regarding the procedures of RTs including; the grafting materials, surgical protocols, and success and failure rates. The RT associated with MRONJ cases was sinus floor augmentation in patients taking bisphosphonate and denosumab. Moreover, there were limited data on the implant treatment associated with RTs such as time of insertion, implant length and diameter, and loading protocol. CONCLUSION: The current scoping review revealed that some specific RTs associated with other factors hold a potential risk of MRONJ occurrence. However, the scientific evidence is limited with many gaps. Further investigations are needed to establish an evidence-based clinical guideline for treating high-risk patients. CLINICAL SIGNIFICANCE: Clinicians should cautiously assess the risk of MRONJ development during implant treatment planning for patients undertaking antiresorptive medications. The adverse outcome of RT procedures should not be underestimated and a complete explanation of the possible risks should be given to the patients.

Zoledronate/Anti-VEGF Neutralizing Antibody Combination Administration Increases Osteal Macrophages in a Murine Model of MRONJ Stage 0-like Lesions.

The pathophysiology, pathogenesis, histopathology, and immunopathology of medication-related osteonecrosis of the jaw (MRONJ) Stage 0 remain unclear, although 50% of MRONJ Stage 0 cases could progress to higher stages. The aim of this study was to investigate the effects of zoledronate (Zol) and anti-vascular endothelial cell growth factor A (VEGFA) neutralizing antibody (Vab) administration on polarization shifting of macrophage subsets in tooth extraction sockets by creating a murine model of MRONJ Stage 0-like lesions. Eight-week-old, female C57BL/6J mice were randomly divided into 4 groups: Zol, Vab, Zol/Vab combination, and vehicle control (VC). Subcutaneous Zol and intraperitoneal Vab administration were performed for 5 weeks with extraction of both maxillary first molars 3 weeks after drug administration. Euthanasia was conducted 2 weeks after tooth extraction. Maxillae, tibiae, femora, tongues, and sera were collected. Structural, histological, immunohistochemical, and biochemical analyses were comprehensively performed. Tooth extraction sites appeared to be completely healed in all groups. However, osseous healing and soft tissue healing of tooth extraction sites were quite different. The Zol/Vab combination significantly induced abnormal epithelial healing, and delayed connective tissue healing due to decreased rete ridge length and thickness of the stratum granulosum and due to decreased collagen production, respectively. Moreover, Zol/Vab significantly increased necrotic bone area with increased numbers of empty lacunae compared with Vab and VC. Most interestingly, Zol/Vab significantly increased the number of CD169+ osteal macrophages (osteomacs) in the bone marrow and decreased F4/80+ macrophages, with a slightly increased ratio of F4/80+CD38+ M1 macrophages compared to VC. These findings are the first to provide new evidence of the involvement of osteal macrophages in the immunopathology of MRONJ Stage 0-like lesions.

Depletion of macrophages deteriorates bisphosphonate-related osteonecrosis of the jaw-like lesions in mice.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a potentially intractable disease with no definitive pathophysiology and no treatment and prevention strategies. This study aimed to investigate whether time-selective depletion of macrophages worsens BRONJ-like lesions in mice. A murine model of high-prevalence BRONJ-like lesions in combination with zoledronate/chemotherapeutic drug administration and tooth extraction was created according to the methods of our previous studies. Daily intra-oral submucosal administration of clodronate-loaded liposomes, which temporarily depletes systemic macrophages, was performed immediately after tooth extraction. Spleens, femora, tibiae, and maxillae were dissected 2 weeks after extraction to evaluate BRONJ-like lesions and systemic conditions by micro-computed tomography analysis, histomorphometric and immunofluorescent analyses, and serum chemistry with ELISA. Depletion of macrophages significantly decreased the numbers of local and systemic macrophages and osteoclasts on the bone surface, which markedly worsened osseous healing, with increased necrotic bone and empty lacunae in the existing alveolar bone and newly formed bone in the extraction sockets, and soft tissue healing, with decreased collagen production and increased infiltration of polymorphonuclear cells. Interestingly, the depletion of macrophages significantly shifted macrophage polarization to M1 macrophages through an increase in F4/80+CD38+ M1 macrophages and a decrease in F4/80+CD163+ M2 macrophages, with decreases in the total number of F4/80+ macrophages. These data demonstrated that severe inhibition of osteoclasts in bone tissue and polarization shifting of macrophages in soft tissue are essential factors associated with BRONJ.

Clinical considerations for medication-related osteonecrosis of the jaw: a comprehensive literature review.

BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ), which was first reported as bisphosphonate-related osteonecrosis of the jaw (BRONJ) in bisphosphonate users, is a rare but severe soft and hard tissue disease induced by several types of medications. There has been a deluge of information about MRONJ, such as epidemiology, risk factors, clinical recommendations for dental treatment to prevent it, and treatment strategies in medication-prescribed users. The aim of this study was to comprehensively review recent articles and provide the current scientific information about MRONJ, especially clinical considerations or recommendations for dental treatment to prevent its occurrence. MATERIALS AND METHODS: The current literature review was mainly based on 14 systematic reviews with or without meta-analysis, 4 position papers, 1 consensus statement, 1 clinical guideline, and 2 clinical reviews regarding MRONJ after a PubMed database and manual searches according to inclusion and exclusion criteria. Moreover, 53 articles were selected by manual search in regard to all references from selected articles and other articles identified on the PubMed search, irrespective of publication date, and inclusion and exclusion criteria. RESULTS: The incidence and prevalence of MRONJ are relatively low, although they are clearly higher in cancer patients receiving high-dose antiresorptive agents or angiogenesis inhibitors rather than osteoporosis patients receiving oral bisphosphonates or denosumab. There are many types of local, systemic, and other risk factors for the development of MRONJ. Clinical recommendations are provided for each clinical situation of patients to prevent MRONJ. There are also treatment strategies for MRONJ in each stage. CONCLUSIONS: General dentists should perform appropriate dental treatment to prevent MRONJ in the patients prior to or when receiving medications that could induce MRONJ. Moreover, there are treatment strategies for MRONJ in each stage that oral surgeons could follow. Adequate and updated clinical information regarding MRONJ based on scientific data is required whenever possible.

Alendronate/dexamethasone combination therapy worsens soft and hard tissue wound healing around implants in rat maxillae.

Dental implant treatment in patients prescribed medications is associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ) around the implants. However, there is no scientific information on how bisphosphonate and/or steroid therapies affect wound healing around implants after implant placement. The aim of this study was to histopathologically and immunopathologically investigate the effects of bisphosphonate and/or steroid therapy on the early stages of soft and hard tissue wound healing around implants in rat maxillae. Eight-week-old female Wistar rats were used. Alendronate (ALN) monotherapy, dexamethasone (DEX) monotherapy, and ALN/DEX combination therapy were started 4 weeks after tooth extraction of right maxillary first molars. Saline was used as a control (n = 14/group). Implant placement was carried out after grossly and manually confirming no open wounds at 16 weeks post-extraction. Euthanasia was performed at 18 weeks post-extraction. Microcomputed tomography, histological stains and immunostaining to detect blood vessels and macrophages were performed to quantitatively analyze wound healing around implants. ALN/DEX combination therapy significantly increased necrotic bone with more empty lacunae and polymorphonuclear cell infiltration with open wounds when compared with all other therapy groups. Necrotic bone was broadly distributed from the crestal bone to the lower area near the apex of the implants in the ALN/DEX group. Interestingly, both ALN/DEX combination therapy and DEX monotherapy significantly increased the number of CD68+NG2- macrophages, whereas only ALN/DEX combination therapy, not DEX monotherapy, significantly shifted the M1/M2 ratio to M1 by significant increases in M1 macrophages and unchanged M2 macrophages in the connective tissue around implants. Within the limitations of this study, these findings may contribute to understanding the early stages of the histopathology and immunopathology of BRONJ-like lesions around dental implants. Continuous accumulation of M1 macrophages without alteration of M2 macrophages may be associated with developing BRONJ around implants.