Interleukin-33 Deficiency Exacerbates Bone Loss Associated with Porphyromonas Gingivalis-Induced Experimental Periodontitis in Female Mice.

BACKGROUND/AIMS: Interleukin 33 (IL-33) plays a significant role in immunity but its role in bone physiology and periodontitis needs to be further investigated. The aim of this study was to decipher the contribution of IL-33 to bone homeostasis under physiological conditions, and to alveolar bone loss associated with experimental periodontitis (EP) in IL-33 knockout (KO) mice and their wildtype (WT) littermates. METHODS: The bone phenotype of IL-33 KO mice was studied in the maxilla, femur, and fifth lumbar vertebra by micro-computed tomography (micro-CT). EP was induced by a ligature soaked with the periopathogen Porphyromonas gingivalis (Pg) around a maxillary molar. Alveolar bone loss was quantified by micro-CT. The resorption parameters were assessed via toluidine blue staining on maxillary sections. In vitro osteoclastic differentiation assays using bone marrow cells were performed with or without lipopolysaccharide from Pg (LPS-Pg). RESULTS: First, we showed that under physiological conditions, IL-33 deficiency increased the trabecular bone volume/total volume ratio (BV/TV) of the maxillary bone in male and female mice, but not in the femur and fifth lumbar vertebra, suggesting an osteoprotective role for IL-33 in a site-dependent manner. The severity of EP induced by Pg-soaked ligature was increased in IL-33 KO mice but in female mice only, through an increase in the number of osteoclasts. Moreover, osteoclastic differentiation from bone marrow osteoclast progenitors in IL-33-deficient female mice is enhanced in the presence of LPS-Pg. CONCLUSION: Taken together, our data demonstrate that IL-33 plays a sex-dependent osteoprotective role both under physiological conditions and in EP with Pg.

Relevance of surgical management of patients affected by bisphosphonate-associated osteonecrosis of the jaws. A prospective clinical and radiological study.

OBJECTIVES: Actually, consensus management of osteonecrosis of the jaws (ONJ) related to nitrogen-containing bisphosphonates (NBPs) is mostly a conservative approach. It does not always control the symptoms and the progression of the disease. The aim of this study was to evaluate the clinical and radiological outcomes of three therapeutic management strategies of established ONJ. MATERIALS AND METHODS: Three treatment strategies, i.e., conservative approach, minimal invasive surgery, and extensive surgery were evaluated in 39 ONJ patients treated with NBPs for malignant diseases or osteoporosis. The patients were closely monitored, and the outcome (extension, improvement, or healing) of mucosa and bone was clinically and radiographically evaluated on a long-term period (27.05 ± 2.96 months). RESULTS: Primary pathology (osteoporosis or malignancies) and clinical severity of ONJ (mild, moderate, severe) were decisive factors. Osteoporotic patients showed more frequently complete mucosa or bone healing (p = 0.0128 and p = 0.00021, respectively) than malignant patients. Mucosa closure and bone improvement occurred more in mild ONJ patients than in severe ONJ (p = 0.0053 and p = 0.0319, respectively). Treatment strategy appeared to be a crucial factor for mucosa but not for bone healing. The rate of complete mucosa healing increased after an extensive surgical procedure (p = 0.0096). CONCLUSIONS: A surgical management of patients with ONJ positively influenced the clinical outcome by enhancing mucosa healing. CLINICAL RELEVANCE: These results deserve further investigations involving a larger cohort. However, they strongly suggest that the guidelines of management of patients with ONJ related to NBPs have to be reconsidered.

Effectiveness of treatment by coronoidectomy and active rehabilitation in Langenbeck or Jacob diseases. A retrospective study of 20 cases.

BACKGROUND: The objective of this study was to evaluate the mouth opening (MO) in patients with Langenbeck or Jacob diseases after a multimodal treatment combining the coronoidectomy and a self or assisted postoperative rehabilitation. METHODS: This observational retrospective study included patients who had clinically impacted MO limitation. All patients underwent unilateral or bilateral coronoidectomy and then physical therapy for at least 3 months. MO measurements were compared between the preoperative time (M0), the immediate postoperative time (M1) and the last follow-up (M2). Other data regarding the surgical procedure and the postoperative rehabilitation were collected. RESULTS: Twenty patients were included. The MO was significantly improved from 19.15 ± 7.02 mm at M0 to 38.00 ± 7.62 mm at M1 (p = 0.0002). After a mean follow-up of 21.5 ± 40.5 months, the mean MO was 32.85 ± 5.69 mm (M2). All patients underwent coronoidectomy through an intraoral approach except for one patient who was given a combined extra-oral approach for a recurrent disease. Rehabilitation protocol included assisted physiotherapy and self-rehabilitation in 7 patients as well as just self-rehabilitation in 13 patients. No patient showed worsening or stagnation of MO. CONCLUSIONS: The multimodal treatment combining the surgical removal of the coronoid process and an active rehabilitation performed by the patient himself or assisted by a physiotherapist seems effective in Langenbeck or Jacob diseases.

New insights into inflammatory osteoclast precursors as therapeutic targets for rheumatoid arthritis and periodontitis.

Rheumatoid arthritis (RA) and periodontitis are chronic inflammatory diseases leading to increased bone resorption. Preventing this inflammatory bone resorption is a major health challenge. Both diseases share immunopathogenic similarities and a common inflammatory environment. The autoimmune response or periodontal infection stimulates certain immune actors, leading in both cases to chronic inflammation that perpetuates bone resorption. Moreover, RA and periodontitis have a strong epidemiological association that could be explained by periodontal microbial dysbiosis. This dysbiosis is believed to be involved in the initiation of RA via three mechanisms. (i) The dissemination of periodontal pathogens triggers systemic inflammation. (ii) Periodontal pathogens can induce the generation of citrullinated neoepitopes, leading to the generation of anti-citrullinated peptide autoantibodies. (iii) Intracellular danger-associated molecular patterns accelerate local and systemic inflammation. Therefore, periodontal dysbiosis could promote or sustain bone resorption in distant inflamed joints. Interestingly, in inflammatory conditions, the existence of osteoclasts distinct from "classical osteoclasts" has recently been reported. They have proinflammatory origins and functions. Several populations of osteoclast precursors have been described in RA, such as classical monocytes, a dendritic cell subtype, and arthritis-associated osteoclastogenic macrophages. The aim of this review is to synthesize knowledge on osteoclasts and their precursors in inflammatory conditions, especially in RA and periodontitis. Special attention will be given to recent data related to RA that could be of potential value in periodontitis due to the immunopathogenic similarities between the two diseases. Improving our understanding of these pathogenic mechanisms should lead to the identification of new therapeutic targets involved in the pathological inflammatory bone resorption associated with these diseases.

Alendronate or Zoledronic acid do not impair wound healing after tooth extraction in postmenopausal women with osteoporosis.

BACKGROUND: Bisphosphonates (BPs) are widely used for the prevention or treatment of osteoporosis. One of the most serious complications associated with BPs is medication-related osteonecrosis of the jaw (MRONJ) but its incidence in patients with osteoporosis is very low ranging from 0.001-0.15%. A major predisposing factor for MRONJ is tooth extraction (TE). Controversies persist about the influence of current BP therapy regarding socket healing after TE. The aims of this study were to investigate prospectively, (i) alveolar bone healing, i.e., filling of the bony socket by new bone and (ii) mucosal healing, i.e., closure of the overlying mucosa, after TE in women receiving current BP therapy for the prevention or the treatment of postmenopausal osteoporosis. METHODS: Women with osteoporosis under current treatment with BPs (BP+ group) or other anti-osteoporotic medications (BP- group) undergoing single TE were included in this study. No antibiotic prophylaxis was prescribed solely for the BP therapy, but antibiotic treatment may have been required for local infectious conditions. Chlorohexidine mouthwashes were systematically prescribed in all study patients for one week after TE. New bone height (NBH) and rate of socket filling (RSF) were recorded using intraoral standardized radiographs one month and 3 months after TE (T30 and T90 respectively). The closure of the overlying mucosa was assessed by measuring the wound extent with an electronic caliper at 1 week and at 1 month after TE (T7 and T30 respectively). RESULTS: At T30, NBH was not statistically different between the BP+ and BP- groups (p = .76). At T90, more than a two-fold in NBH increase was recorded for both groups with no statistically significant difference between them (p = .76). At T30 and T90, RSF was similar in both groups (p = .58 and p = .32 respectively). More than a two-fold RSF increase was founded between T30 and T90 in both groups. No demographic or BPs-related factors were correlated with the RSF at T90. At T7, the mucosa wound extent was reduced by more than two-fold with no statistically significant difference between both groups (p = .80). At this time, mucosa healing was achieved in 11.9% of the BP+ group and 10% of the BP- group (p = .99). At T30, mucosal healing was achieved in all patients but two, and at T90 it was achieved in all patients. CONCLUSION: This study provides new insights into bone and mucosal healing in patients with osteoporosis taking BPs after TE. In this population, TE can be managed successfully with an appropriate surgical protocol and without discontinuation of BP treatment.

IL-36γ is a pivotal inflammatory player in periodontitis-associated bone loss.

Periodontitis is a prevalent chronic inflammatory disease due to the host response (IL-1ß, IL-6, TNF-α and IL-17A) to oral bacteria such as Porphyromonas gingivalis. The newer members of the IL-1 family, IL-36s (IL-36α/IL-36ß/IL-36γ/IL-36Ra/IL-38) are known to be involved in host defense against P. gingivalis in oral epithelial cells (OECs) and are considered as key inflammatory mediators in chronic diseases. The aim of this study was to investigate the potential role of IL-36s in periodontitis. We showed here that IL-36γ mRNA gingival expression is higher in periodontitis patients, whereas IL-36ß and IL-36Ra mRNA expression are lower compared to healthy controls. Interestingly, the elevated IL-36γ expression in patients is positively correlated with the RANKL/OPG ratio, an index of bone resorption. In vitro, IL-36γ expression was induced through TLR2 activation in primary OECs infected with P. gingivalis but not in gingival fibroblasts, the most widespread cell type in gingival connective tissue. In OECs, recombinant IL-36γ enhanced the expression of inflammatory cytokines (IL-1ß, IL-6, TNF-α and IL-36γ), of TLR2 and importantly, the RANKL/OPG ratio. These findings suggest that IL-36γ could be a pivotal inflammatory player in periodontitis by perpetuating gingival inflammation and its associated alveolar bone resorption and could be a relevant therapeutic target.

A nationwide survey of French dentists' knowledge and implementation of current guidelines for antibiotic prophylaxis of infective endocarditis in patients with predisposing cardiac conditions.

OBJECTIVES: To prevent infective endocarditis in patients with predisposing cardiac conditions, antibiotic prophylaxis is recommended worldwide, except in the United Kingdom. To determine the relevance of this strategy, investigating how the current guidelines are applied is crucial. The first aim of this study was to assess dentists' implementation of the current guidelines. The secondary aims were to identify relevant areas to improve the training of dentists and to determine temporal trends in practitioners' attitudes by comparison with 2 previous surveys conducted in 1991 and 2001. STUDY DESIGN: An electronic national survey was sent to the 12,000 member practitioners of the French Union for Oral Health. RESULTS: Even though 58.9% of the respondents stated that their knowledge of current guidelines was good, a scoring system showed that only 34.5% had overall knowledge of these guidelines. CONCLUSIONS: This study revealed relevant areas to improve the training of dentists, such as knowledge of some cardiac conditions, the potential side effects of the antibiotics used, and the pathogenesis of infective endocarditis. Consequently, dentists' knowledge should be improved before any conclusions can be drawn on the relevance of this antibiotic prophylaxis strategy and its influence on infective endocarditis incidence.

Dental procedures, antibiotic prophylaxis, and endocarditis among people with prosthetic heart valves: nationwide population based cohort and a case crossover study.

Objective To assess the relation between invasive dental procedures and infective endocarditis associated with oral streptococci among people with prosthetic heart valves.Design Nationwide population based cohort and a case crossover study.Setting French national health insurance administrative data linked with the national hospital discharge database.Participants All adults aged more than 18 years, living in France, with medical procedure codes for positioning or replacement of prosthetic heart valves between July 2008 and July 2014.Main outcome measures Oral streptococcal infective endocarditis was identified using primary discharge diagnosis codes. In the cohort study, Poisson regression models were performed to estimate the rate of oral streptococcal infective endocarditis during the three month period after invasive dental procedures compared with non-exposure periods. In the case crossover study, conditional logistic regression models calculated the odds ratio and 95% confidence intervals comparing exposure to invasive dental procedures during the three month period preceding oral streptococcal infective endocarditis (case period) with three earlier control periods.Results The cohort included 138 876 adults with prosthetic heart valves (285 034 person years); 69 303 (49.9%) underwent at least one dental procedure. Among the 396 615 dental procedures performed, 103 463 (26.0%) were invasive and therefore presented an indication for antibiotic prophylaxis, which was performed in 52 280 (50.1%). With a median follow-up of 1.7 years, 267 people developed infective endocarditis associated with oral streptococci (incidence rate 93.7 per 100 000 person years, 95% confidence interval 82.4 to 104.9). Compared with non-exposure periods, no statistically significant increased rate of oral streptococcal infective endocarditis was observed during the three months after an invasive dental procedure (relative rate 1.25, 95% confidence interval 0.82 to 1.82; P=0.26) and after an invasive dental procedure without antibiotic prophylaxis (1.57, 0.90 to 2.53; P=0.08). In the case crossover analysis, exposure to invasive dental procedures was more frequent during case periods than during matched control periods (5.1% v 3.2%; odds ratio 1.66, 95% confidence interval 1.05 to 2.63; P=0.03).Conclusion Invasive dental procedures may contribute to the development of infective endocarditis in adults with prosthetic heart valves.

Position paper for the evaluation and management of oral status in patients with valvular disease: Groupe de Travail Valvulopathies de la Société Française de Cardiologie, Société Française de Chirurgie Orale, Société Française de Parodontologie et d'Implantologie Orale, Société Française d'Endodontie et Société de Pathologie Infectieuse de Langue Française.

Oral health is of particular importance in patients with heart valve diseases because of the risk of infective endocarditis. Recommendations for antibiotic prophylaxis before dental procedures have been restricted, but the modalities of oral evaluation and dental care are not detailed in guidelines. Therefore, a multidisciplinary working group reviewed the literature to propose detailed approaches for the evaluation and management of buccodental status in patients with valvular disease. Simple questions asked by a non-dental specialist may draw attention to buccodental diseases. Besides clinical examination, recent imaging techniques are highly sensitive for the detection of inflammatory bone destruction directly related to oral or dental infection foci. The management of buccodental disease before cardiac valvular surgery should be adapted to the timing of the intervention. Simple therapeutic principles can be applied even before urgent intervention. Restorative dentistry and endodontic and periodontal therapy can be performed before elective valvular intervention and during the follow-up of patients at high risk of endocarditis. The detection and treatment of buccodental foci of infection should follow specific rules in patients who present with acute endocarditis. Implant placement is no longer contraindicated in patients at intermediate risk of endocarditis, and can also be performed in selected high-risk patients. The decision for implant placement should follow an analysis of general and local factors increasing the risk of implant failure. The surgical and prosthetic procedures should be performed in optimal safety conditions. It is therefore now possible to safely decrease the number of contraindicated dental procedures in patients at risk of endocarditis.

Dendritic-cell-derived osteoclasts: a new game changer in bone-resorption-associated diseases.

Bone-resorbing cells, osteoclasts (OCs), and antigen-presenting cells, dendritic cells (DCs), share several features. They are derived from a common hematopoietic precursor, exhibit phagocytic activities and their functions are dependent upon receptor activator of nuclear factor κB ligand (RANKL). Upon inflammatory conditions, DCs can transdifferentiate toward functional OCs in the presence of RANKL. It has then been assumed that the increase in proinflammatory cytokines could provide a supportive environment for this transdifferentiation. In this review, we emphasize the molecular mechanisms underlying the potential for DCs to give rise to resorbing OCs in the context of bone-destruction-associated diseases upon inflammatory conditions. Whether these mechanisms reveal new strategies for the discovery of therapeutic targets and drugs is discussed extensively.

Management of dental extraction in patients undergoing anticoagulant oral direct treatment: a pilot study.

OBJECTIVE: The main goal of this study was to compare the incidence of postoperative bleeding events after dental extractions between patients treated with direct oral anticoagulants (DOACs) and those treated with vitamin K antagonists (VKAs) without withdrawal of oral anticoagulant therapy (OAT). Our second objective was to evaluate the risk factors affecting postoperative hemorrhage after tooth extraction in patients taking DOACs. STUDY DESIGN: This prospective observational study included 51 patients who were being treated with oral anticoagulants and required dental extractions. They were divided into two groups: 31 patients receiving a DOAC and 20 control patients taking VKA with an international normalized ratio between 2.0 and 3.0. In both groups, extractions were performed under continued OAT, and the same local hemostatic measures were applied. All procedures were performed in an outpatient facility. A bleeding event was defined as persistent oozing or marked hemorrhage over 20 minutes after tooth extraction despite local hemostasis procedures or all bleeding episode occurring during the first postoperative week. RESULTS: Five patients taking DOACs had seven bleeding episodes, and four patients receiving VKAs had five bleeding episodes during the postoperative follow-up period. The difference in the number of bleeding events between the two groups was not statistically significant (adjusted odds ratio = 0.77; 95% confidence interval 0.19-3.19; P = .723). Eleven (91.67%) bleeding events were mild and controlled by mechanical compression with gauzes, and one (8.33 %) was managed with a revision of the wound, application of fibrin glue, and resuturing. No bleeding required hospitalization or blood transfusion. All bleeding episodes occurred during the first 3 postoperative days. CONCLUSIONS: According to our preliminary outcome data, dental extractions can be performed safely in an outpatient facility in patients treated with DOAC by applying local hemostatic measures, without interrupting or modifying OAT.

Interleukin-33 and RANK-L Interplay in the Alveolar Bone Loss Associated to Periodontitis.

INTRODUCTION: Chronic Periodontitis (CP) is an inflammatory disease of bacterial origin that results in alveolar bone destruction. Porphyromonas gingivalis (Pg), one of the main periopathogens, initiates an inflammatory cascade by host immune cells thereby increasing recruitment and activity of osteoclasts, the bone resorbing cells, through enhanced production of the crucial osteoclastogenic factor, RANK-L. Antibodies directed against some cytokines (IL-1ß, IL-6 and TNF-α) failed to exhibit convincing therapeutic effect in CP. It has been suggested that IL-33, could be of interest in CP. OBJECTIVE: the present study aims to analyze whether and how IL-33 and RANK-L and/or their interplay are involved in the bone destruction associated to CP. MATERIAL AND METHODS: mRNAs and protein expressions of IL-33 and RANK-L were analyzed in healthy and CP human gingival samples by immunohistochemistry (IHC) and RT-qPCR. Murine experimental periodontitis (EP) was induced using Pg infected ligature and Pg free ligature around the first maxillary molar. Alveolar bone loss was recorded by µCT. Mouse gingival explants were stimulated for 24 hours with IL-33 and RANK-L mRNA expression investigated by RT-qPCR. Human oral epithelial cells were infected by Pg for 6, 12; 24 hours and IL-33 and RANK-L mRNA expressions were analyzed by RT-qPCR. RESULTS: IL-33 is overexpressed in gingival epithelial cells in human affected by CP as in the murine EP. In human as in murine gingival cells, RANK-L was independently induced by Pg and IL-33. We also showed that the Pg-dependent RANK-L expression in gingival epithelial cells occured earlier than that of IL-33. CONCLUSION: Our results evidence that IL-33 overexpression in gingival epithelial cells is associated with CP and may trigger RANK-L expression in addition to a direct effect of Pg. Finally, IL-33 may act as an extracellular alarmin (danger signal) showing proinflammatory properties in CP perpetuating bone resorption induced by Pg infection.

Zoledronate effects on systemic and jaw osteopenias in ovariectomized periostin-deficient mice.

Osteoporosis and periodontal disease (PD) are frequently associated in the elderly, both concurring to the loss of jaw alveolar bone and finally of teeth. Bisphosphonates improve alveolar bone loss but have also been associated with osteonecrosis of the jaw (ONJ), particularly using oncological doses of zoledronate. The effects and therapeutic margin of zoledronate on jaw bone therefore remain uncertain. We reappraised the efficacy and safety of Zoledronate (Zol) in ovariectomized (OVX) periostin (Postn)-deficient mice, a unique genetic model of systemic and jaw osteopenia. Compared to vehicle, Zol 1M (100 µg/kg/month) and Zol 1W (100 µg/kg/week) for 3 months both significantly improved femur BMD, trabecular bone volume on tissue volume (BV/TV) and cortical bone volume in both OVX Postn(+/+) and Postn(-/-) (all p<0.01). Zol 1M and Zol 1W also improved jaw alveolar and basal BV/TV, although the highest dose (Zol 1W) was less efficient, particularly in Postn(-/-). Zol decreased osteoclast number and bone formation indices, i.e. MAR, MPm/BPm and BFR, independently in Postn(-/-) and Postn(+/+), both in the long bones and in deep jaw alveolar bone, without differences between Zol doses. Zol 1M and Zol 1W did not reactivate inflammation nor increase fibrous tissue in the bone marrow of the jaw, whereas the distance between the root and the enamel of the incisor (DRI) remained high in Postn(-/-) vs Postn(+/+) confirming latent inflammation and lack of crestal alveolar bone. Zol 1W and Zol 1M decreased osteocyte numbers in Postn(-/-) and Postn(+/+) mandible, and Zol 1W increased the number of empty lacunae in Postn(-/-), however no areas of necrotic bone were observed. These results demonstrate that zoledronate improves jaw osteopenia and suggest that in Postn(-/-) mice, zoledronate is not sufficient to induce bone necrosis.

Structure and remodelling of the human parietal bone: an age and gender histomorphometric study.

OBJECTIVE: Despite its clinical usefulness, the internal structure and remodelling of parietal bone remained poorly documented. The aim of this study was to gain reliable information on parietal bone remodelling in living humans. MATERIALS AND METHODS: This study provided a site-specific analysis of static indices of turnover in relation to gender and age by using leftovers of parietal bone sampled in 100 patients (78 females; 22 males, aged 16-79 years). RESULTS: The bone architecture, cortical thickness, trabecular volume and cortical volume (C.Th, BV/TV, BV/CV) did not vary with gender. The number of osteoclasts (N.Oc/BPm) and the resorption surface (Oc.S/BS) were higher in females (p<0.05) when osteoclast resorbing activity did not vary with gender. Bone formation, osteoid surface (OS/BS) and surface covered by alkaline phosphatase-positive osteogenic cells (ALPS/BS) were higher in females (p<0.05 and p<0.01 respectively). All these parameters remained stable with aging. The osteocytic parameters, number of osteocytes (Ot.N/B.Ar) and number of osteocyte lacunae (T.L.N/B.Ar) were higher in females (p<0.05) and decreased with age in both genders (p<0.01). CONCLUSION: This study highlights the low and stable remodelling in the parietal bone. It appears to be higher in women. This stability probably reflects the low mechanical strains applied to the skull, particularly to the parietal bone.

Physiopathology and management of osteonecrosis of the jaws related to bisphosphonate therapy for malignant bone lesions. A French expert panel analysis.

Bisphosphonates (BP) are the current standard of care for preventing malignant skeletal related-events. Recent reports have documented the relationship between osteonecrosis of the jaws (ONJ) and the use of BPs. Based on the opinion of experts, the purpose of our analysis was to summarize current knowledge, to propose therapeutic options, and to define areas of research. Identified risk factors were long-lasting exposure to BPs, intravenous nitrogen-containing BPs, and poor dental status. Three major hypotheses could explain the genesis of ONJ: excess of bone turnover inhibition, antiangiogenic effect, and local infection. Before the onset of therapy, the dental status must be controlled, and followed during treatment. Dental procedures could worsen the risk of ONJ, and indications must be well evaluated. When an ONJ occurs, the management should be adapted according to its extent. Thereby, a customization of BP therapy should be applied taking into account the aggressiveness of the underlying disease.

Bisphosphonate-associated osteonecrosis of the jaw: a key role of inflammation?

Osteonecrosis of the jaw (ONJ) can be associated with nitrogen-containing bisphosphonates (NBPs) therapy. Various mechanisms of NBP-associated ONJ have been proposed and there is currently no consensus of the underlying pathogenesis. The detailed medical and dental histories of 30 ONJ patients treated with NBPs for malignant diseases (24) or osteoporosis (6) were analyzed. The necrotic bone was resected and analyzed histologically after demineralization. In 10 patients the perinecrotic bone was also resected and processed without demineralization. Alveolar bone samples from 5 healthy patients were used as controls. In 14 ONJ patients, serial technetium-99m-methylene diphosphonate scintigraphic scans were also available and confronted to the other data. Strong radionuclide uptake was detected in some patients several months before clinical diagnosis of ONJ. The medullary spaces of the necrotic bone were filled with bacterial aggregates. In the perinecrotic bone, the bacteria-free bone marrow characteristically showed an inflammatory reaction. The number of medullary inflammatory cells taken as an index of inflammation allowed us to discriminate two inflammation grades in the ONJ samples. Low-grade inflammation, characterized by marrow fibrosis and low inflammatory cells infiltration, increased numbers of TRAP(+) mono- and multineacleated cells was seen in patients with bone exposure<2 cm(2). High-grade inflammation, associated with larger lesions, showed amounts of tartrate-resistant acid phosphatase(+)/calcitonin receptor(-) mono- and multinucleated cells, osteocyte apoptosis, hypervascularization and high inflammatory cell infiltration. The clinical extent of ONJ was statistically linked to the numbers of inflammatory cell. Taken together these data suggest that bone necrosis precedes clinical onset and is an inflammation-associated process. We hypothesize that from an initial focus, bone damage spreads centrifugally, both deeper into the jaw and towards the mucosa before the oral bone exposure and the clinical diagnosis of ONJ.

Parietal bone as graft material for maxillary sinus floor elevation: structure and remodeling of the donor and of recipient sites.

Particulate parietal bone is used for maxillary sinus floor elevation procedure prior to dental implant placement. However, data on internal structure of the parietal bone and on graft remodeling and incorporation in the host bone are limited. We determined the structure and remodeling activities of 24 parietal bone specimens sampled at time of sinus grafting (T1 samples), and the amount and turnover of bone formed at the recipient site at time of implant placement (T2 samples, obtained 10 months after T1 samples, on average). In T1 samples, the outer cortex was 1.16+/-0.45 mm thick, had a typical haversian structure, and showed a low level of remodeling. In the cancellous portion of the samples, trabecular bone volume represented 52.8+/-10.3%. Bone remodeling was more active in the cancellous portion than in the cortical portion, but few osteoblasts and osteoclasts were seen. T2 samples consisted solely of trabecular bone, which occupied 49.4+/-18.4% of total sample volume. The boundary between new bone and the recipient bed was not discernible. Remnants of the graft particles were embedded within new bone, and showed signs of intense resorption. Bone remodeling was highly active, as shown by the presence of numerous osteoclasts resorbing new bone, together with thick osteoid seams and large osteoblasts. A loose cotton-like mineralized material was frequently observed in the marrow spaces; this acellular and non-collagenous material was strongly stained by toluidine blue, suggesting a glycoprotein nature. This study offers insights into cortical and trabecular bone structure and shows the low-level remodeling activity of parietal bone. About 10 months after grafting, the grafted chips were incorporated in new bone and almost completely resorbed. This high turnover may be beneficial for implant placement.