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.

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.

Effects of drug discontinuation after short-term daily alendronate administration on osteoblasts and osteocytes in mice.

In order to determine whether osteoclastic bone resorption is restarted after withdrawn of bisphosphonates, we conducted histological examinations on murine osteoclasts, osteoblasts and osteocytes after discontinuation of a daily regimen of alendronate (ALN) with a dosage of 1 mg/kg/day for 10 days. After drug discontinuation, metaphyseal trabecular number and bone volume remained unaltered for the first 4 days. Osteoclast number did not increase, while the number of apoptotic osteoclasts was elevated. On the other hand, tissue non-specific alkaline phosphatase-immunoreactive area was markedly reduced after ALN discontinuation. In addition, osteocytes showed an atrophic profile with empty lacunar areas during and after ALN treatment. Interestingly, as early as 36 h after a single ALN injection, osteocytes show signs of atrophy despite the presence of active osteoblasts. Structured illumination microscopy system showed shortening of osteocytic cytoplasmic processes after drug cessation, suggesting a possible morphological and functional disconnection between osteocytes and osteoblasts. Taken together, it appears that osteoclastic bone resorption is not resumed after ALN discontinuation; also, osteoblasts and osteocytes hardly seem to recover once they are inactivated and atrophied by ALN. In summary, it seems that one must pay more attention to the responses of osteoblasts and osteocytes, rather focusing on the resuming of osteoclastic bone resorption after the ALN discontinuation.

Inhibitory effect of bisphosphonate on osteoclast function contributes to improved skeletal pain in ovariectomized mice.

The aim of this study was to evaluate skeletal pain associated with osteoporosis and to examine the inhibitory effect of bisphosphonate (BP) on pain in an ovariectomized (OVX) mouse model. We evaluated skeletal pain in OVX mice through an examination of pain-like behavior as well as immunohistochemical findings. In addition, we assessed the effects of alendronate (ALN), a potent osteoclast inhibitor, on those parameters. The OVX mice showed a decrease in the pain threshold value, and an increase in the number of c-Fos immunoreactive neurons in laminae I-II of the dorsal horn of the spinal cord. Alendronate caused an increase in the pain threshold value and inhibited c-Fos expression. The serum level of tartrate-resistant acid phosphatase 5b, a marker of osteoclast activity, was significantly negatively correlated with the pain threshold value. Furthermore, we found that an antagonist of the transient receptor potential channel vanilloid subfamily member 1, which is an acid-sensing nociceptor, improved pain-like behavior in OVX mice. These results indicated that the inhibitory effect of BP on osteoclast function might contribute to an improvement in skeletal pain in osteoporosis patients.

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 histology after intermittent PTH treatment - animal models -].

Intermittent administration of parathyroid hormone, PTH, appears to promote preosteoblastic proliferation and osteoblastic bone formation, giving rise to anabolic effect in bone. We investigated the behavior of osteoblastic cells after intermittent PTH treatment and attempted to elucidate the role of osteoclasts on the mediation of PTH-driven bone anabolism. As a consequence, bone formation was increased in PTH-treated wild-type mice, whereas in the osteoclast-deficient c-fos - / - mice, there was no significant increase in bone formation, despite the highly-increased population of preosteoblasts. It seems likely that the absence of osteoclasts might hinder PTH-driven bone anabolism, and also that osteoclastic presence may be necessary for full osteoblastic differentiation and enhanced bone formation seen after intermittent PTH administration. We will also discuss the pivotal role of osteocytes in PTH-mediated anabolic effect.

[Updates on rickets and osteomalacia: biological function of osteocyte and FGF23/klotho system].

Osteocytes are known to synthesize FGF23 which would bind to FGFR1c/klotho complex in proximal renal tubules in kidney, thereby, reducing serum concentration of Pi and the activity of 1α-hydroxylase. Meanwhile, recent studies suggest the possibility that osteocytes might induce osteolysis of lacuna walls. Compact, cortical bone develops well-organized distribution of osteocyte-lacunar canalicular system (OLCS) , which appears to be efficient for osteocytic function. There seems some relation between the geometrical regularity of OLCS and osteocytic regulation of systemic and local mineral balance.

[Encouragement for developing research mind of dental students].

The School of Dental Medicine in Japan nurtures well-trained professionals who are at the cutting edge of the present knowledge in the fields of Dentistry and Dental Technology. As an important part of its mission, many Schools of Dental Medicine in Japan, including Hokkaido University, also encourages dental students to pursue basic research in the many aspects of Dentistry. It is of importance to cultivate research-minded students in Dental Medicine. Laboratory assignment conducted by the School of Dental Medicine, Hokkaido University, is one process of education curriculum to assign students in the fifth and sixth grade to laboratories of basic sciences. Every dental student should belong to one laboratory, which accepts the fixed number of the students. By means of the research activity of the laboratory assignments, some students obtain new insights on their research projects, and will often have an opportunity for presenting their findings in some academic meetings. Meanwhile, many academic meetings in Japan, including The Japanese Association of Anatomists, often feature special sessions where undergraduate students can present their findings under the guidance of their mentors. Such initiatives led by the Dental School and the academic meetings are geared towards raising interest in research and preparing young investigators for the future.

Structure and formation of the twisted plywood pattern of collagen fibrils in rat lamellar bone.

This study was designed to elucidate details of the structure and formation process of the alternate lamellar pattern known to exist in lamellar bone. For this purpose, we examined basic internal lamellae in femurs of young rats by transmission and scanning electron microscopy, the latter employing two different macerations with NaOH at concentrations of 10 and 24%. Observations after the maceration with 10% NaOH showed that the regular and periodic rotation of collagen fibrils caused an alternation between two types of lamellae: one consisting of transversely and nearly transversely cut fibrils, and the other consisting of longitudinally and nearly longitudinally cut fibrils. This finding confirms the consistency of the twisted plywood model. The maceration method with 24% NaOH removed bone components other than cells, thus allowing for three-dimensional observations of osteoblast morphology. Osteoblasts extended finger-like processes paralleling the inner bone surface, and grouped in such a way that, within a group, the processes arranged in a similar direction. Transmission electron microscopy showed that newly deposited fibrils were arranged alongside these processes. For the formation of the alternating pattern, our findings suggest that: (1) osteoblasts control the collagen fibril arrangement through their finger-like process position; (2) osteoblasts behave similarly within a group; (3) osteoblasts move their processes synchronously and periodically to promote alternating different fibril orientation; and (4) this dynamic sequential deposition of fibrils results in the alternate lamellar (or twisted plywood) pattern.

Immunolocalization of sclerostin synthesized by osteocytes in relation to bone remodeling in the interradicular septa of ovariectomized rats.

This study aimed at elucidating whether estrogen deficiency would affect the synthesis of an osteocyte-derived factor, sclerostin, in the mesial region of alveolar bone. Eight 9-week-old Wistar female rats were ovariectomized (OVX) and eight other rats were Sham-operated (Sham). After 4 weeks, the interradicular septa of mandibular first molar were embedded in paraffin and then histochemically examined. Sclerostin-positive osteocytes were located in the superficial layer of the mesial region of Sham bones, whereas the OVX mesial region showed less sclerostin-reactive osteocytes. There was no significant difference in the distribution of estrogen receptor α and terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick end-labeling -positive cells in the groups studied. The Sham mesial region featured many osteoclasts, and OVX specimens showed numerous osteoclasts in association with intense immunolabeling of the receptor activator of the nuclear factor kB ligand. Contrary to the observations in Sham specimens, a complex meshwork of cement lines was seen in the OVX mesial region, accompanied by an irregularly distributed osteocytic lacunar-canalicular system. In conclusion, estrogen deficiency appears to inhibit osteocyte-derived sclerostin synthesis in the mesial region of the interradicular septum, in a process that seems to be mediated by accelerated bone remodeling rather than by direct effects on osteocytes.

[Biological function of bone cells on the PTH-driven anabolic effect].

Parathyroid hormone (PTH) -driven anabolism in bone appears to involve the osteoblastic activation and the increased population of preosteoblastic lineages. Given that the activities of osteoclasts and osteoblasts are intertwined during normal bone remodeling, it is plausible that the anabolic action of PTH is either directly or indirectly related to the osteoclast. We have recently reported that the absence of osteoclasts in c-fos( - / - ) mice might hinder PTH-driven bone anabolism, and that osteoclastic presence may be necessary for full osteoblastic differentiation and enhanced bone formation seen after intermittent PTH administration. Alternatively, it was suggested that PTH administration inhibits sclerostin synthesis by osteocytes, thereby allowing for active bone formation. Taken together, PTH affects bone cells in a dual pathway - mediating osteoblastic (preosteoblastic) activities or osteocytic synthesis of sclerostin -.

[Frontiers in vitamin D; basic research and clinical application. A review on histological findings in bones administered with eldecalcitol].

This review will show the histological findings in femora of ovariectomized (OVX) rats administered with or without eldecalcitol, a second-generation of vitamin D analog, which were published in our recent article. The OVX group showed markedly-reduced bone mineral density, and the decreased trabecular number and thickness, which was consistent to increased osteoclastic number and bone resorption parameters. After eldecalcitol administration, the number of osteoclasts was diminished, accompanied with elevated bone mineral density. Interestingly, eldecalcitol did promote a type of focal bone formation that is independent of bone resorption, a process known as bone mini-modeling. Taken together, our findings suggest that eldecalcitol mainly inhibits osteoclastic bone resorption, but, in part, stimulates focal bone formation in the OVX bone.

[Animal models for bone and joint disease. Bone disease of osteoprotegerin deficient mouse].

Osteoprotegerin (OPG) acts as a decoy receptor for the receptor activator of the nuclear factor κ B (RANK) ligand (RANKL) , preventing its association with RANK and inhibiting osteoclastogenesis. Therefore, mice homozygous for targeted disruption of the OPG gene reveal stimulated bone resorption and bone formation, resulting in enhanced bone remodeling. The OPG deficient (OPG( - / - )) mouse showed the diturbed distribution of collagen fibers and complex meshwork of cement lines, which implies weakened strength of OPG( - / - ) bone against mechanical stress. In addition, the abnormally promoted remodeling of the OPG( - / - ) bone caused the disorganized distribution of osteocyte lacunar canalicular system (OLCS) . Histochemical assessment revealed the markedly reduced synthesis of sclerostin in the OPG( - / - ) OLCS while the synthesis of dentin matrix protein-1 was not extremely affected by the OPG deficiency. Taken together, OPG deficient mouse appears to be a valid model for extremely-stimulated bone remodeling, and would provided important clues for better understanding for activities of bone cells in a pathological state in bone.

Gene expression analysis of fresh extraction wounds prior to onset of bisphosphonate-related osteonecrosis of the jaw-like lesions in mice: A preliminary animal study.

Purpose The aim of the present study was to investigate the effects of chemotherapeutic/bisphosphonate combination therapy with tooth extraction on gene expression patterns of fresh extraction wounds during initial stages prior to their diagnosis as bisphosphonate-related osteonecrosis of the jaw (BRONJ)-like lesions in mice.Methods Female C57BL/6J mice were used. To create a high-prevalence BRONJ mouse model, combination therapy with the chemotherapy drug cyclophosphamide (CY) and zoledronic acid (ZA) was performed (CY/ZA). Both maxillary first molars were extracted 3 weeks after drug therapy. Saline was used as the control (VC). Soft tissues near the fresh extraction wounds were dissected at 72 h postextraction to investigate the gene expression patterns. Maxillae and long bones at 2 and 4 weeks postextraction were also analyzed.Results CY/ZA significantly increased the relative expression levels of IL-6 and decreased those of IL-10 and IGF-1 when compared with those in VC. Moreover, CY/ZA significantly reduced the relative expression levels of CCR-7, cxcl12, cxcr4, and CD105 when compared with those in VC, whereas the level of F4/80 was significantly increased by CY/ZA. Furthermore, CY/ZA significantly decreased the relative expression levels of VEGFA, VEGFB, and VEGFC at 72 h postextraction compared with those in VC.Conclusions Considering that the present study lacked adequate in vitro models, CY/ZA markedly changed the gene expression patterns associated with wound healing from the initial stages prior to onset of BRONJ-like lesions, which may help us to understand the pathophysiology of BRONJ in humans.

Distinct immunopathology in the early stages between different antiresorptives-related osteonecrosis of the jaw-like lesions in mice.

There is limited information about denosumab-related osteonecrosis of the jaw (DRONJ), unlike bisphosphonate-related ONJ (BRONJ). The mode of action is clearly different between denosumab and bisphosphonates. DRONJ occurs mainly following tooth extraction in cancer patients treated with the combination of denosumab and other drugs including chemotherapy. However, DRONJ animal models similar to these clinical situations have not been developed. The aims of this study were to 1) create a new model of high-prevalence chemotherapy/anti-RANKL antibody-related ONJ-like lesions to mimic patients receiving a denosumab/chemotherapy combination; and 2) compare the histopathological and immunopathological findings in the early stages of BRONJ-like and anti-RANKL antibody-related ONJ-like lesions. Cyclophosphamide (CY) and anti-mouse RANKL monoclonal antibody (mAb) or zoledronate combination therapy (CY/mAb and CY/ZA, respectively) was performed to create ONJ-like lesions in female C57BL/6J mice. Both maxillary first molars were extracted at 3 weeks after drug administration. The animals were euthanized at either 2 or 4 weeks after tooth extraction. Increased necrotic bone and empty lacunae with decreased living bone and osteocyte numbers were common histopathological findings in CY/mAb- and CY/ZA-induced impaired wound healing at 4 weeks after tooth extraction, and they were diagnosed as ONJ-like lesions based on validation of BRONJ and DRONJ in humans. In areas of impaired healing at 2 weeks post-extraction, decreases in angiogenesis and F4/80+LYVE-1- macrophages were noted as common immunopathological findings, although anti-angiogenesis was worse with CY/mAb than with CY/ZA. Interestingly, CY/mAb did not reduce F4/80+LYVE-1+ cells and normal lymphangiogenesis remained, whereas CY/ZA profoundly suppressed the larger size of F4/80+LYVE-1+ cells, similar to vessels with a concomitant decrease in lymphangiogenesis. Therefore, the distribution of the larger size of F4/80+LYVE-1+ cells differed in the early stages between different antiresorptive-induced ONJ-like lesions in conjunction with lymphangiogenesis, although the histopathological findings were similar. These findings suggest that the pathogenesis of BRONJ and DRONJ may differ due to the distributions of F4/80+LYVE-1+ tube-like-structured cells.

Effects of surface sub-micrometer topography following oxalic acid treatment on bone quantity and quality around dental implants in rabbit tibiae.

BACKGROUND: To explore the effects of topographical modification of titanium substrates at submicron level by oxalic acid treatment on bone quality and quantity around dental implants in rabbit tibiae. METHODS: A total of 60 blasted CP-grade IV titanium dental implants were used. Twenty-eight control implant surfaces were treated with a mixture of HCl/H2SO4, whereas 28 other test implant surfaces were treated with oxalic acid following HCl/H2SO4 treatment. Two randomly selected sets of control or test implants were placed in randomly selected proximal tibiae of 14 female Japanese white rabbits. Euthanasia was performed 4 and 8 weeks post-implant placement. Bone to implant contact (BIC), bone area fraction (BAF), ratios of mature and immature bone to total bone, and the amount and types of collagen fibers were evaluated quantitatively. Two control and two test implants were used to analyze surface characteristics. RESULTS: Treatment by oxalic acid significantly decreased Sa and increased Ra of test implant surfaces. BIC in test implants was increased without alteration of BAF and collagen contents at 4 and 8 weeks after implant placement when compared with control implants. The ratios of immature and mature bone to total bone differed significantly between groups at 4 weeks post-implantation. Treatment by oxalic acid increased type I collagen and decreased type III collagen in bone matrices around test implants when compared with control implants at 8 weeks after implant placement. The effects of topographical changes of implant surfaces induced by oxalic acid on BAF, mature bone, collagen contents, and type I collagen were significantly promoted with decreased immature bone formation and type III collagen in the later 4 weeks post-implantation. CONCLUSIONS: Treatment of implant surfaces with oxalic acid rapidly increases osseointegration from the early stages after implantation. Moreover, submicron topographical changes of dental implants induced by oxalic acid improve bone quality based on bone maturation and increased production of type I collagen surrounding dental implants in the late stage after implant placement.