Sweet Battle of the Epimers─Continued Exploration of Monosaccharide-Derived Delivery Agents for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a cancer therapy in which boron delivery agents play a crucial role. In theory, delivery agents with high tumor targeting capabilities can lead to selective eradication of tumor cells without causing harmful side effects. We have been working on a GLUT1-targeting strategy to BNCT for a number of years and found multiple promising hit compounds which outperform the clinically employed boron delivery agents in vitro. Herein, we continue our work in the field by further diversification of the carbohydrate scaffold in order to map the optimal stereochemistry of the carbohydrate core. In the sweet battle of the epimers, carborane-bearing d-galactose, d-mannose, and d-allose are synthesized and subjected to in vitro profiling studies─with earlier work on d-glucose serving as the reference. We find that all of the monosaccharide delivery agents display a significantly improved boron delivery capacity over the delivery agents approved for clinical use in vitro, thus providing a sound foundation for advancing toward in vivo preclinical assessment studies.

New keys for old locks: carborane-containing drugs as platforms for mechanism-based therapies.

Icosahedral carboranes in medicine are still an emerging class of compounds with potential beneficial applications in drug design. These highly hydrophobic clusters are potential "new keys for old locks" which open up an exciting field of research for well-known, but challenging important therapeutic substrates, as demonstrated by the numerous examples discussed in this review.

Immunohistological expression of human ß-defensin-1 and human ß-defensin-2 in exacerbation of acute and secondary chronic osteomyelitis of the mandible.

BACKGROUND: The majority of patients diagnosed with osteomyelitis of the jaw have severe complaints. Unfortunately, the pathogenesis still remains unclear. Human ß-defensins expressed in epithelial and bone tissues as a part of the innate immunity may be involved in disease development. In this study, we hypothesize that expression levels of human ß-defensin-1 and -2 in the acute and secondary chronic osteomyelitis may be altered in comparison with healthy bone and with bisphosphonate-associated necrosis as well as irradiation from a previous study. METHODS: Bone samples were collected during surgical debridement in a total of eight patients suffering from acute or secondary chronic osteomyelitis of the jaw. Expression levels of hBD-1 and -2 were quantified and related to non-stained cells. Ratios were compared by one-way ANOVA and multiple tests by Holm-Bonferroni. RESULTS: Multiple testing revealed no significant differences for expression levels of human ß-defensin-1 between all groups, whereas labeling index of human ß-defensin-2 was significantly different between specimens of bisphosphonate-associated osteonecrosis of the jaws and all other groups. No significant difference occurred between samples of floride osteomyelitis and healthy bone for expression of hBD-1 and -2. CONCLUSIONS: Although the affected patients showed all clinical signs of acute inflammation, expression levels in acute and secondary chronic osteomyelitis in the jaws did not reveal statistically significant differences compared with healthy bone samples. The weak immunological host response in terms of a putative genetically predisposition should be further discussed as pathogenesis factor for osteomyelitis in the future.

Sinus floor augmentation with autogenous bone vs. a bovine-derived xenograft - a 5-year retrospective study.

OBJECTIVES: The long-term outcome after sinus augmentation with autogenous bone or a bovine xenograft (Bio-Oss(®)) was assessed in 47 patients. Inclusion criterion was a vertical dimension of the maxilla of <4 mm. After a functional loading period of 60 months, implant survival and reduction in the augmentation height were compared between the two groups evaluated. MATERIAL AND METHODS: Sinus augmentation was performed using mandibular bone grafts or Bio-Oss(®). In the autogenous bone group, 70 implants were placed in 23 patients, while in the Bio-Oss(®) group, 24 patients received 98 implants. Fisher's exact test and equivalence testing were used to compare implant survival rates. RESULTS: The overall survival rate of the implants was 95.8% 5 years after implant insertion. In the autogenous bone group, the implants had a survival rate of 97.1%, while in the Bio-Oss(®) group, 94.9% of the implants survived. The difference was not statistically significant (P > 0.05); both treatments are equivalent (confidence interval 90%) for the equivalence interval [-0.1; 0.1]. 43.5% of the cases showed no reduction in the augmentation height 5 years after implant insertion, when augmentation was performed with autogenous bone, while in the Bio-Oss(®) group, no resorption was found in 50% of the augmented areas. Up to 25% reduction in augmentation height was found in 47.8% in the autogenous and in 45.8% in the Bio-Oss(®) group. In 8.7% of all cases in the autogenous bone group and in 4.2 % in the Bio-Oss(®) group, up to 50% of the augmented height was resorbed. CONCLUSION: After a 5 years evaluation period, Bio-Oss(®) as material for the indication maxillary sinus augmentation shows to be equivalent to autogenous bone grafting.

Osteonecrosis of the jaw in a Crohn's disease patient following a course of Bisphosphonate and Adalimumab therapy: a case report.

BACKGROUND: Bisphosphonates have a widespread indication for osteoporosis and are also applied in cancer patients with skeletal-related conditions. Bisphosphonate-associated osteonecrosis of the jaw (BRONJ) is a feared side effect which is hard to treat and often affects patient's quality of life in an extensive manner. Adalimumab (Humira®), a fully human recombinant antibody specific for tumor necrosis factor- α, is approved for treatment in patients with Inflammatory Bowel Disease like ulcerative colitis or Crohn's disease. CASE PRESENTATION: In March 2013, a 36-year-old female presented with right-sided perimandibular swelling, recurrent facial pain and exposed necrotic bone after previous extraction of tooth 47. She had the medical history of Crohn's disease for more than one decade with chronic active enterocolitis, fistula disease as well as previous oral manifestation and was currently treated with Adalimumab since September 2008. Due to steroid-induced osteoporosis, diagnosed in 2004, she received oral Bisphosphonates (Risedronate) from 2004 until 2007 followed by two infusions of Zoledronic acid in 2008 and 2009. CONCLUSION: This patient with a medical history of Crohn's disease and gastrointestinal remission under Adalimumab therapy presented with osteonecrosis of the jaw after suspended oral and intravenous Bisphosphonate therapy implicating that the biologic therapy with an anti-TNF-α antibody might promote the manifestation of osteonecrosis and compromise oral healing capacity.

The effect of load on heat production, thermal effects and expenditure of time during implant site preparation - an experimental ex vivo comparison between piezosurgery and conventional drilling.

OBJECTIVES: Piezoelectric surgery (PS) is meant to be a gentle osteotomy method. The aim of this study was to compare piezosurgical vs. conventional drilling methods for implant site preparation (ISP) - focusing on load-dependent thermal effect on hard tissue and the expenditure of ISP time. MATERIALS AND METHODS: Three hundred and sixty ISP were performed on ex vivo pig heads using piezosurgery, spiral burs (SB) and trephine burs (TB). The load applied was increased from 0 to 1000 g in 100-g intervals. Temperature within the bone was measured with a thermocouple, and duration was recorded with a stop watch. Thermal effects were histomorphometrically analysed. Twelve ISPs per technique were performed at the lateral wall of the maxillary sinus. RESULTS: PS yields the highest mean temperatures (48.6 ± 3.4°C) and thermal effects (200.7 ± 44.4 µm), both at 900-1000 g. Duration is reduced with a plus of load and significantly longer in either case for PS (P < 0.05). There is a correlation of the applied load with all other examined factors for PS and TB. Temperature and histological effects decrease for SB beyond 500 g. CONCLUSIONS: PS yields significantly higher temperatures and thermal tissue alterations on load levels higher than 500 g and is significantly slower for ISP compared to SB and TB. For ISP with PS, a maximum load of 400 g should be maintained.

The outcome after surgical therapy of bisphosphonate-associated osteonecrosis of the jaw--results of a clinical case series with an average follow-up of 20 months.

OBJECTIVES: The present case series evaluates the success rate of osteotomy and primary wound closure in patients with bisphosphonate-associated osteonecrosis of the jaw (BRONJ). MATERIALS AND METHODS: Eighty patients suffering from BRONJ were included in the study. All patients received intravenous bisphosphonate therapy and underwent osteotomy and primary wound closure according to a standardised protocol. After discharge, the patients were reviewed on a regular basis over an average time period of 20 months. RESULTS: During follow-up in 11 patients, a recurrence of BRONJ occurred in the former operation field. Seventeen patients died due to their underlying disease. The success rate of osteotomy and primary wound closure in the treatment of BRONJ was calculated at 84.2 % 20 months after surgery. The results showed non-significant difference concerning the outcome of surgery in the different clinical stages of BRONJ. CONCLUSIONS: In accordance with previous studies, stage-independent osteotomy and primary wound closure combined with antibiotics shall be deemed a viable treatment option in patients suffering from BRONJ. CLINICAL RELEVANCE: With a high success rate, osteotomy in combination with primary wound closure seems to be a viable alternative to more conservative protocols in the treatment of BRONJ.

Carboranes as Potent Phenyl Mimetics: A Comparative Study on the Reversal of ABCG2-Mediated Drug Resistance by Carboranylquinazolines and Their Organic Isosteres.

Multidrug resistance is a major challenge in clinical cancer therapy. In particular, overexpression of certain ATP-binding cassette (ABC) transporter proteins, like the efflux transporter ABCG2, also known as breast cancer resistance protein (BCRP), has been associated with the development of resistance to applied chemotherapeutic agents in cancer therapies, and therefore targeted inhibition of BCRP-mediated transport might lead to reversal of this (multidrug) resistance (MDR). In a previous study, we have described the introduction of a boron-carbon cluster, namely closo-dicarbadodecaborane or carborane, as an inorganic pharmacophore into a polymethoxylated 2-phenylquinazolin-4-amine backbone. In this work, the scope was extended to the corresponding amide derivatives. As most of the amide derivatives suffered from poor solubility, only the amide derivative QCe and the two amine derivatives DMQCc and DMQCd were further investigated. Carboranes are often considered as sterically demanding phenyl mimetics or isosteres. Therefore, the organic phenyl and sterically demanding adamantyl analogues of the most promising carborane derivatives were also investigated. The studies showed that the previously described DMQCd, a penta-methoxylated N-carboranyl-2-phenylquinazolin-4-amine, was by far superior to its organic analogues in terms of cytotoxicity, inhibition of the human ABCG2 transporter, as well as the ability to reverse BCRP-mediated mitoxantrone resistance in MDCKII-hABCG2 and HT29 colon cancer cells. Our results indicate that DMQCd is a promising candidate for further in vitro as well as in vivo studies in combination therapy for ABCG2-overexpressing cancers.

Intraoral microvascular anastomosis for segmental mandibular reconstruction following removal of an ameloblastoma.

Cases of immediate bony microvascular reconstruction following segmental mandibulectomy in children are hard to find in the current literature. Moreover, microvascular segmental mandibular reconstruction that adopts an intraoral anastomosis technique has not been described so far. Therefore, the present clinical report aims at extending the armamentarium of bony microvascular reconstruction in pediatric cases of segmental mandibulectomy by highlighting an intraoral microvascular anastomosing technique.A 6-year-old boy, who suffered from an ameloblastoma of the mural type in the mandible, received a radical segmental mandibular resection because of the high recurrence rate of this tumor entity. Immediate reconstruction was carried out with a fibular double-barrel graft. Microvascular anastomoses were performed in an end-to-end fashion with the facial artery and vein as recipient vessels. The postoperative course was uneventful. There was no impairment of speech, deglutition, mastication, and facial nerve function. The facial appearance remained unobtrusive. On removal of the reconstruction plate 3 months after the reconstruction procedure, bleeding from the reconstructed mandibular segment indicated vascularization of the graft.It seems that segmental mandibulectomy and simultaneous microvascular bony reconstruction do not necessarily lead to impaired function as far as speech, deglutition, and mastication are concerned. Instead, the intraoral anastomosis technique allows waiving extraoral skin incisions and subsequent scarring, leaving the facial appearance unchanged and unobtrusive. Especially, the potential risk of stigmatization of the patient is avoided. Therefore, decision making in the choice of 1 or the other reconstruction option following segmental mandibulectomy should always consider the adoption of an intraoral anastomosing technique.

2-Carboranylquinazoline: The Path to an ABCG2 Inhibitor.

The role of ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR) in anti-cancer therapy is often challenging, frequently leading to inefficiency of treatments. Cancer cells exploit efflux transporters, like the breast cancer resistance protein (BCRP, ABCG2), to secrete chemotherapeutic substances. In this study, an N-phenyl-2-carboranylquinazolin-4-amine (8) was designed as inorganic-organic hybrid BCRP inhibitor. In particular, the ABCG2-transporter inhibitor-prominent scaffold N-phenylquinazolin-4-amine was combined with a boron-carbon cluster (carborane) moiety. Introducing a carborane at 2-position of the quinazoline scaffold resulted in an increased inhibitory activity towards human ABCG2 (hABCG2) compared to its recently published regioisomer N-carboranyl-2-phenyl-quinazolin-4-amine. The carboranylquinazoline 8 further showed the ability to reverse hABCG2-mediated drug resistance in MDCKII-hABCG2 cells by lowering the IC50 value of the BCRP-substrate mitoxantrone, similar to the standard reference and strong inhibitor Ko143, without exhibiting intrinsic toxicity in the lower micromolar ranges. These results make compound 8 a promising scaffold for the design of further BCRP inhibitors.

Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin.

The ABCG2 transporter protein, as part of several known mechanisms involved in multidrug resistance, has the ability to transport a broad spectrum of substrates out of the cell and is, therefore, considered as a potential target to improve cancer therapies or as an approach to combat drug resistance in cancer. We have previously reported carborane-functionalized quinazoline derivatives as potent inhibitors of human ABCG2 which effectively reversed breast cancer resistance protein (BCRP)-mediated mitoxantrone resistance. In this work, we present the evaluation of our most promising carboranyl BCRP inhibitors regarding their toxicity towards ABCG2-expressing cancer cell lines (MCF-7, doxorubicin-resistant MCF-7 or MCF-7 Doxo, HT29, and SW480) and, consequently, with the co-administration of an inhibitor and therapeutic agent, their ability to increase the efficacy of therapeutics with the successful inhibition of ABCG2. The results obtained revealed synergistic effects of several inhibitors in combination with doxorubicin or cisplatin. Compounds DMQCa, DMQCc, and DMQCd showed a decrease in IC50 value in ABCB1- and ABCG2-expressing SW480 cells, suggesting a possible targeting of both transporters. In an HT29 cell line, with the highest expression of ABCG2 among the tested cell lines, using co-treatment of doxorubicin and DMQCd, the effective inhibitory concentration of the antineoplastic agent could be reduced by half. Interestingly, co-treatment of compound QCe with cisplatin, which is not an ABCG2 substrate, showed synergistic effects in MCF-7 Doxo and HT29 cells (IC50 values halved or reduced by 20%, respectively). However, a literature-known upregulation of cisplatin-effluxing ABC transporters and their effective inhibition by the carborane derivatives emerges as a possible reason.

The More the Better-Investigation of Polymethoxylated N-Carboranyl Quinazolines as Novel Hybrid Breast Cancer Resistance Protein Inhibitors.

The ineffectiveness and failing of chemotherapeutic treatments are often associated with multidrug resistance (MDR). MDR is primarily linked to the overexpression of ATP-binding cassette (ABC) transporter proteins in cancer cells. ABCG2 (ATP-binding cassette subfamily G member 2, also known as the breast cancer resistance protein (BCRP)) mediates MDR by an increased drug efflux from the cancer cells. Therefore, the inhibition of ABCG2 activity during chemotherapy ought to improve the efficacy of the administered anti-cancer agents by reversing MDR or by enhancing the agents' pharmacokinetic properties. Significant efforts have been made to develop novel, powerful, selective, and non-toxic inhibitors of BCRP. However, thus far the clinical relevance of BCRP-selective MDR-reversal has been unsuccessful, due to either adverse drug reactions or significant toxicities in vivo. We here report a facile access towards carboranyl quinazoline-based inhibitors of ABCG2. We determined the influence of different methoxy-substitution patterns on the 2-phenylquinazoline scaffold in combination with the beneficial properties of an incorporated inorganic carborane moiety. A series of eight compounds was synthesized and their inhibitory effect on the ABCG2-mediated Hoechst transport was evaluated. Molecular docking studies were performed to better understand the structure-protein interactions of the novel inhibitors, exhibiting putative binding modes within the inner binding site. Further, the most potent, non-toxic compounds were investigated for their potential to reverse ABCG2-mediated mitoxantrone (MXN) resistance. Of these five evaluated compounds, N-(closo-1,7-dicarbadodecaboran(12)-9-yl)-6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-quinazolin-4-amine (DMQCd) exhibited the strongest inhibitory effect towards ABCG2 in the lower nanomolar ranges. Additionally, DMQCd was able to reverse BCRP-mediated MDR, making it a promising candidate for further research on hybrid inorganic-organic compounds.

Synthesis and In Vitro Evaluation of a Set of 6-Deoxy-6-thio-carboranyl d-Glucoconjugates Shed Light on the Substrate Specificity of the GLUT1 Transporter.

Glucose- and sodium-dependent glucose transporters (GLUTs and SGLTs) play vital roles in human biology. Of the 14 GLUTs and 12 SGLTs, the GLUT1 transporter has gained the most widespread recognition because GLUT1 is overexpressed in several cancers and is a clinically valid therapeutic target. We have been pursuing a GLUT1-targeting approach in boron neutron capture therapy (BNCT). Here, we report on surprising findings encountered with a set of 6-deoxy-6-thio-carboranyl d-glucoconjugates. In more detail, we show that even subtle structural changes in the carborane cluster, and the linker, may significantly reduce the delivery capacity of GLUT1-based boron carriers. In addition to providing new insights on the substrate specificity of this important transporter, we reach a fresh perspective on the boundaries within which a GLUT1-targeting approach in BNCT can be further refined.

Increased human defensine levels hint at an inflammatory etiology of bisphosphonate-associated osteonecrosis of the jaw: an immunohistological study.

BACKGROUND: Human ß-defensins (hBD) are antimicrobial peptides that are an integral part of bone innate immunity. Recently, it could be shown that expression of hBD-1, -2 and -3 were upregulated in cases of osteomyelitis of the jaws. In order to gain insight into the possible impairment of hBD metabolism in bisphosphonate-associated osteonecrosis of the jaws (BONJ), the present exploratory study was designed so as to determine the qualitative and quantitative expression of afore mentioned hBDs in BONJ and infected osteoradionecrosis (ORN), both of which represent inflammatory bone diseases. METHODS: Bone samples were collected from patients with BONJ (n = 20) and ORN (n = 20). Non-infected healthy bone samples (n = 20) were included as controls. Immunohistological staining in an autostainer was carried out by the (Strept-ABC)-method against hBD-1,-2,-3. Specific positive vs. negative cell reaction of osteocytes (labeling index) near the border of bony resection was determined and counted for quantitative analysis. Number of vital osteocytes vs. empty osteocytes lacunae was compared between groups. RESULTS: hBD-1,-2 and -3 could be detected in BONJ as well as ORN and healthy bone samples. Immunoreactivity against hBD-2 and -3 was significantly higher in BONJ than in ORN and healthy jaw bone samples. Number of empty osteocyte lacunae was significantly higher in ORN compared with BONJ (P = 0.001). CONCLUSION: Under the condition of BONJ an increased expression of hBD-1,-2,-3 is detectable, similarly to the recently described upregulation of defensins in chronically infected jaw bones. It remains still unclear how these findings may relate to the pathoetiology of these diseases and whether this is contributing to the development of BONJ and ORN or simply an after effect of the disease.

Diabetes mellitus negatively affects peri-implant bone formation in the diabetic domestic pig.

AIM: Diabetes mellitus is classified as a relative contraindication for implant treatment, and higher failure rates have been seen in diabetic patients. The aim of the present study was to investigate the effect of diabetes on peri-implant bone formation in an animal model of human bone repair. MATERIALS AND METHODS: Diabetes was induced by an intra-venous application of streptozotocin (90 mg/kg) in 15 domestic pigs. Implants were placed after significant histopathological changes in the hard and soft tissues were verified. The bone-implant contact (BIC), peri-implant bone mineral density (BMD), and expression of collagen type-I and osteocalcin proteins were qualitatively evaluated 4 and 12 weeks after implantation. Fifteen animals served as healthy controls. RESULTS: Diabetes caused pathological changes in the soft and hard tissues. The BIC and BMD were significantly reduced in the diabetic group after 4 and 12 weeks. Collagen type-I was increased in the diabetic group at both time points, whereas osteocalcin was reduced in the diabetic group. CONCLUSIONS: Poorly controlled diabetes negatively affects peri-implant bone formation and bone mineralization. These findings have to be taken into consideration for diabetic patients with an indication for implant therapy.

Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: a prospective clinical study with 12 months follow-up.

GOALS OF WORK: This is a prospective clinical study aimed at assessing the success rate of osteotomy and primary wound closure in patients with bisphosphonate-associated osteonecrosis of the jaw (BONJ). MATERIALS AND METHODS: Fifty patients who had received bisphosphonates intravenously and subsequently suffered from BONJ were included in the study. All patients underwent osteotomy of the affected jaw bone region and primary wound closure under general anaesthesia. They were followed up bimonthly for a period of 12 months. RESULTS: Macroscopically altered bone could be completely removed in all cases. In two patients with plasmocytoma, major bleeding occurred postoperatively that required monitoring in an intensive care unit. In two cases, recurrence of BONJ was diagnosed during the first 2 months. In three patients, recurrence appeared between the fourth and the sixth month. In these cases, an additional osteotomy had to be performed. Six patients died during the follow-up period. In the remaining 39 patients, no signs of recurrence could be detected during the follow-up of 12 months. The success rate of the surviving patients was 89% after 1 year. CONCLUSION: Due to the high success rate of osteotomy and primary wound closure, it should be checked for every patient suffering from BONJ if osteotomy is a viable treatment option.

Establishment of a streptozotocin-induced diabetic domestic pig model and a systematic evaluation of pathological changes in the hard and soft tissue over a 12-month period.

OBJECTIVE: The number of diabetic patients in need of medical treatment is growing steadily. Therefore, a diabetic animal model with high degree of similarities with humans, which is suitable for the systematic evaluation of biomaterials and medical devices, is needed. MATERIALS AND METHODS: Twenty domestic pigs were used for the study. Fifteen received Streptozotocin (STZ) to induce diabetes mellitus. Internal parameters were measured and bone as well as soft tissues biopsies were taken after 0, 6 and 12 months and evaluated qualitatively and quantitatively by means of scanning electronic microscopy, light microscopy and microradiography. RESULTS: The results of the clinical internal parameters, determined by the American Diabetes Association for the definition of diabetes mellitus could be fulfilled. Pathological changes of the skin vasculatures were already visible after 6 months with a significant wall thickening in the diabetic group. The bone mineralization was lower in the diabetic group after 6 months and with a significant difference after 12 months. CONCLUSION: From the present results, it can be concluded that a STZ dosage of 90 mg/kg body weight in the domestic pig is suitable for the induction of an apparent diabetes, leading to histolopathological changes in the hard and soft tissues already after 6 months. The high degree of similarities with humans makes it an interesting diabetic animal model for biomaterial research in a compromised animal model.

Panoramic radiograph, computed tomography or magnetic resonance imaging. Which imaging technique should be preferred in bisphosphonate-associated osteonecrosis of the jaw? A prospective clinical study.

It was the aim of the present study to find out which radiological imaging techniques allow assessing the extent of bisphosphonate-associated osteonecrosis of the jaw (BONJ) in an adequate way. Twenty-four patients suffering from BONJ were included in the study. Before surgery, each patient was examined with panoramic radiograph, contrast-enhanced magnetic resonance imaging (MRI) and non-enhanced computed tomography. The detectability of BONJ was assessed for the three imaging techniques. The extent of the jaw region affected by BONJ was determined in MRI and CT scans and compared to the intra-operative situation. The detectability of BONJ lesions was 54% for panoramic radiographs, 92% for MRI scans and 96% for computed tomography (CT) scans. The intra-operatively assessed extent of BONJ correlated significantly with the measurements on CT scans (p = 0.0004) but did not correlate significantly with the measurements in MRI scans (p = 0.241). The intra-operatively measured extent of BONJ differed significantly from the CT measurements (p = 0.00003) but not from the MRI data (p = 0.137). Although MRI as well as CT have a high detectability for BONJ lesions that exceeds that of panoramic radiographs by far, both techniques show problems with the exact assessment of the extent of BONJ lesions in the individual patients. Therefore, the relevance of MRI and CT for the preoperative assessment of the extent of BONJ lesions is limited. Future research should focus on the identification of imaging techniques that allow assessing the extent of BONJ lesions with a higher accuracy.

Saliva diagnostics in patients suffering from bisphosphonate-associated osteonecrosis of the jaw: Results of an observational study.

OBJECTIVE: One of the severe side effects of bisphosphonate (BP) therapy is bisphosphonate-associated osteonecrosis of the jaw (BONJ). However, there is no information available about its pathogenesis. Hence, the aim of this observational study was to contribute to discerning this pathogenesis by comparing salivary quantity and quality in patients with BONJ and undergoing BP treatment. MATERIALS AND METHODS: This study included 60 patients divided into three groups. The first group consisted of 20 patients with established BONJ, the second group had 20 patients undergoing BP treatment, and the third group comprised 20 healthy individuals. These groups were analysed for the flow rate of stimulated saliva, buffer capacity, and salivary pH level. RESULTS: Reduced salivation was observed in a significantly high number of patients with established BONJ (n = 8) and those undergoing BP treatment (n = 9) in comparison with the healthy control group (n = 4; p = 0.039). Though the distribution of the mean value of stimulated saliva flow rates in patients undergoing BP treatment was lower than in the control group, the difference was not significant. Moreover, there were no significant differences in the salivary pH level and buffer capacity in patients undergoing BP treatment as compared with the healthy control group. CONCLUSIONS: It is possible that the quantity of human saliva is affected by BP treatment. This reduction in saliva production could have a negative effect on mucosal health and is perhaps a cofactor in the pathogenesis of BONJ.

Which region of the median palate is a suitable location of temporary orthodontic anchorage devices? A histomorphometric study on human cadavers aged 15-20 years.

INTRODUCTION: Endosseus implants can provide a reliable anchorage during orthodontic treatment. The midpalatal structures around the sutura palatina mediana (SPM) are of special interest due to increasing placement of orthodontic implants in this area. Knowledge about the osseous conditions at this site is necessary to predict the expected degree of implant osseointegration. METHODS: The upper jaws of 10 human cadavers, aged 15-20 years, were decalcified, and cross-sectional specimens were obtained from four anterior-to-posterior palatal regions for histomorphometric analysis. The analyses focused on the amount of bone and the width of the SPM to determine the anatomical requirements for reliable insertion of palatal implants. RESULTS: Bone density [bone-volume (BV)/ tissue-volume (TV)] in all measured areas was 40-60%. The maximum density was measured at the level of the first premolars (54.9+/-5.9%) and the least values (44.2+/-9.6%) were measured at the level of the interconnecting line of the canines. The mean width of the SPM varies from 1.2 to 0.3 mm in different sections of the palate. In the median sagittal plane, the mean values of bone height to nasal cavity reached >5 mm as far as the level distal of the second premolars. Bone height 2 mm paramedian to the SPM decreased consistently from anterior (4.3+/-0.9 mm) to posterior (2.5+/-0.8 mm). CONCLUSIONS: Our results indicate that the amount and quality of bone along the anterior palatal midline in 15-to-20-year olds is sufficient for orthodontic implantation. Even implantation posterior to the recommended first premolar level, at which orthodontic implants are most often placed, may be suitable. There are some limitations, however, due to small number of samples and variations of anatomical structures.