Surgical and conservative treatment outcomes of medication-related osteonecrosis of the jaw located at tori: a retrospective study.

PURPOSE: Tori and exostoses are considered risk factors for the development of medication-related osteonecrosis of the jaw (MRONJ). The aims of this study were to present the prevalence of MRONJ located at tori in the Copenhagen ONJ Cohort, evaluate the surgical treatment of MRONJ located at tori and explore trauma to tori as an additional risk factor in patients on antiresorptive medication. METHODS: Data from a consecutive series of 506 patients with MRONJ (Copenhagen ONJ Cohort) were reviewed for the presence of tori and MRONJ located at tori. Demographic and medical data were analyzed, and healing outcomes and pain after the prophylactic removal of tori, surgical treatment of MRONJ located at tori, and conservative treatment of MRONJ located at tori were evaluated and compared using Fisher's exact test. RESULTS: MRONJ located at tori was frequent and could be identified in 53% of the patients with tori, which accounts for a prevalence of 5.1% in the entire cohort. Of the 28 surgically treated patients, 27 (96.4%) healed uneventfully with no exposed bone after their first or second revision surgery. Fourteen (41.2%) patients with tori underwent therapeutic removal, eight (23.5%) underwent prophylactic removal, and six (17.6%) underwent both therapeutic and prophylactic removals. Two (33.3%) of the six conservatively treated patients healed spontaneously. Both treatment types resulted in a significant decrease in pain. CONCLUSION: Prophylactic and therapeutic surgical removal of tori are reliable treatments and should be considered if a patient's general health allows surgery. TRIAL REGISTRATION: The study was approved by the Regional Scientific Ethical Committee (H-6-2013-010) on November 20, 2013, and was retrospectively registered.

Group 3 ITI Consensus Report: Materials and antiresorptive drug-associated outcomes in implant dentistry.

OBJECTIVES: The aim of Working Group 3 was to address the influence of both material- and anti-resorptive drug- related factors on clinical and biological outcomes and complications in implant dentistry. Focused questions were addressed on (a) implant materials other than titanium (alloy)s, (b) transmucosal abutment materials and (c) medications affecting bone metabolism were addressed. MATERIALS AND METHODS: Three systematic reviews formed the basis for discussion in Group 3. Consensus statements and clinical recommendations were formulated by group consensus based on the findings of the systematic reviews. Patient perspectives and recommendations for future research were also conveyed. These were then presented and accepted following further discussion and modifications as required by the plenary. RESULTS: Zirconia is a valid alternative to titanium as material for implant and transmucosal components, allowing soft and hard tissue integration with clinical outcomes-identified by implant survival, marginal bone loss and peri-implant probing depths-up to 5-years comparable to titatnium. However, most of the evidence for zirconia implants is based on 1-piece implants limiting the indication range. Furthermore, based on expert opinion, zirconia transmucosal components might be preferred in the esthetic zone. In patients receiving low-dose bisphosphonate therapy, the rate of early implant failure is not increased, while the long-term effects remain poorly studied. Although it has not been sufficiently addressed, similar outcomes can be expected with low-dose denosumab. A drug holiday is not recommended when considering implant placement in patients treated with low-dose ARD. However, the specific therapeutic window, the cumulative dose and the administration time should be considered. Access to peri-implant supportive care is mandatory to prevent peri-implantitis-related medication-related osteonecrosis of the jaw (MRONJ) or implant-related sequestra (IRS). In patients receiving low-dose anti-resorptive drugs (ARD) therapy, the risk of complications related to implant placement is high, and implant procedures in this specific population should be strictly treated in a comprehensive multidisciplinary center. Finally, healthy dental implants should not be removed before low or high-dose ARD. CONCLUSIONS: Zirconia implants can be an alternative to titanium implants in selected indications. However, the current state of evidence remains limited, especially for 2-piece implant designs. Administration of low-dose ARD did not show any negative impact on early implant outcomes, but careful follow-up and supportive care is recommended in order to prevent peri-implant MRONJ and IRS. Implant placement in high-dose patients must be strictly considered in a comprehensive multidisciplinary center.

Outcome of healing after dental implant placement in patients with cancer on high-dose antiresorptive medications: a prospective feasibility study.

PURPOSE: Implant placement in patients with cancer receiving high-dose antiresorptive medication (HDAR) is considered contraindicated. This prospective, feasibility study tested the hypothesis that dental implants can be placed in such patients by applying a staged implant placement protocol with submerged healing. METHODS: Three groups of patients on HDAR were included as follows: group 1: patients who underwent tooth extraction, without the development of medication-related osteonecrosis of the jaws (MRONJ); group 2: patients with surgically treated MRONJ who had demonstrated clinical healing for at least 3 months; group 3: patients with established MRONJ who was planned for surgical resection and simultaneous implant placement. RESULTS: A total of 49 implants were placed in 27 patients (group 1: 12, group 2: 7 and group 3: 8). HDAR included bisphosphonates and denosumab. The mean HDAR time was 25 months (SD: ± 18.4, range 3-68 months). An abutment operation was performed 4 months following the implant placement (SD: ± 1.9, range 3-14 months). All patients healed uneventfully. CONCLUSIONS: This study demonstrated that it is feasible to insert dental implants and perform an abutment surgery in patients with cancer on HDAR, without the development of MRONJ. CLINICALTRIALS: gov Identifier: NCT04741906.

Surgical treatment of 61 consecutive patients with maxillary stage 3 medication-related osteonecrosis of the jaws using a pedicled buccal fat pad.

PURPOSE: Buccal fat pad (BFP) is used for the closure of large oroantral defects caused by surgical removal of the necrotic bone in patients with medication-related osteonecrosis of the jaw (MRONJ). This study aimed to evaluate the use of BFP for the closure of maxillary sinus defects in stage 3 MRONJ patients. METHODS: This study recruited 61patients with large oroantral defects caused by MRONJ, including 49 patients with cancer and 12 patients with osteoporosis. Lesions were evaluated clinically and radiographically. RESULTS: Among the 61 patients, 51 (83.6%) healed uneventfully, and 5 patients (8.2%) had local dehiscence and exposed bone; these 56 patients (91.8%) all healed after first or second operation. The Eastern Cooperative Oncology Group Performance Status was associated with being non-cured and might be an indicator for the healing process. All patients experienced a significant increase in body weight postoperatively. CONCLUSIONS: This study suggest that block resection with removal of the necrotic bone combined with radical sinusotomy and closure of the defect with BFP is a reliable method to cure MRONJ lesions with a high success rate, and successful operation and prosthetic rehabilitation may improve body weight and the quality of life. The study was approved by the appropriate ethical approval for the Copenhagen ONJ Cohort (protocol no. H-6-2013-010) November 20, 2013.

Medication-related osteonecrosis of the jaw and successful implant treatment in a patient on high-dose antiresorptive medication: A case report.

OBJECTIVES: Oral rehabilitation can be a challenge in patients on high-dose antiresorptive medication (HDAR), especially if the alveolar anatomy has changed due to previous medication-related osteonecrosis of the jaw (MRONJ) resection. In healthy patients, dental implant treatment has found wide acceptance in prosthetic rehabilitation as it increases the patient's oral health-related quality of life. However, it is considered contraindicated in patients on HDAR due to the risk of MRONJ, although a recent feasibility study indicates that implant treatment may indeed be an option in these patients. The aim of the present case report is to illustrate the risk of MRONJ in a patient with cancer on HDAR and to discuss the reasons behind the outcomes of the implant treatment. MATERIALS AND METHODS: A patient with prostate cancer with bone metastases on high-dose denosumab therapy with previous MRONJ had four implants inserted bilaterally in the maxilla (14, 13, 23, 24). Two identical implant-supported screw-retained cantilever bridges were fabricated. The patient was followed for more than 1 year. RESULTS AND CONCLUSION: Peri-implantitis, and/or MRONJ, was diagnosed around two of the implants (23, 24), probably induced by crestal bone trauma from a healing abutment and/or a misfitting prosthetic reconstruction. A peri-implantitis operation was performed, but without the desired response, and the two implants (23, 24) were later removed in an MRONJ resection. The implants on the other side of the maxilla (14, 13) remained without complications. Dental implant treatment is feasible in patients on HDAR, but comorbidities (e.g., diabetes mellitus) and polypharmacy (e.g., chemotherapy and steroids) may add to the risk of implant failure. Minimal trauma surgery and prosthodontics are crucial to increase the chance of successful healing in an HDAR patient.

Apical surgery in cancer patients receiving high-dose antiresorptive medication-a retrospective clinical study with a mean follow-up of 13 months.

PURPOSE: The aim of the study is to evaluate the results of apical surgery (AS) in patients receiving high-dose antiresorptive medication (HDAR). METHODS: Retrospective descriptive quality control study conducted in an Oral and Maxillofacial Department at a University Hospital. Fourteen patients on HDAR met the inclusion criteria. Only descriptive statistics were applied. RESULTS: Fourteen patients had operation on seventeen teeth. Mean HDAR treatment period before apical surgery: 25 months (SD, ± 24.27; range, 1-78 months). Drug holiday during surgery and initial healing: mean, 8 months (SD, ± 5.96; range, 0.4-22 months). Sixteen out of seventeen teeth healed clinically and showed complete or ongoing radiographic healing. All patients except one became free of symptoms. Mean follow-up: 13 months (SD, ± 9.05; range, 2-31 months). Radiographic healing according to Molven and Rud: 7, complete; 6, uncertain; 1, unsatisfactory. Three patients died during follow-up and were considered drop-outs. CONCLUSIONS: The present case series suggest that apical surgery is a valid treatment option for apical periodontitis in patients on HDAR, where orthograde endodontic retreatment is not possible. None of the patients developed medication-related osteonecrosis of the jaw. Further studies in larger study groups and with longer follow-up periods are needed. The regional scientific ethical committee provided a document exemption, registration date 20 November 2013, and the local data protection agency approved handling of the recorded data (No. 2012-41-0045), registration date 11 January 2012.

Pressure pain thresholds assessed over temporalis, masseter, and frontalis muscles in healthy individuals, patients with tension-type headache, and those with migraine--a systematic review.

A systematic review was conducted to identify and summarize the available scientific literature addressing pressure pain threshold (PPT) values over the temporalis, masseter, and frontalis muscles in healthy humans, patients with tension-type headache (TTH), and those with migraine both in males and females. Six relevant medical databases for the literature search were included: PubMed, Web of Science, Cochrane, CINAHL, BioMed Central, and Embase. The search strategy was performed applying 15 keywords (eg, pressure pain threshold, temporalis muscle, tension type headache, pressure algometer) and their combinations. A total of 156 articles were identified, and 40 relevant articles were included. The main outcomes of the systematic review were extracted, and it was demonstrated that the PPT values in general were lower in patients compared with healthy subjects, and this was especially noted for temporalis in both females (migraine: 231.2 ± 38.3 kPa < TTH: 248.4 ± 39.3 kPa < healthy: 282.1 ± 70.8 kPa) and males (migraine: 225.5 ± 61.2 kPa < TTH: 264.2 ± 32.5 kPa < healthy: 314.8 ± 63.3 kPa). The masseter muscle seemed to be more sensitive than the other 2 muscles, in both females (healthy: masseter 194.1 ± 62.7 kPa < frontalis 277.5 ± 51.1 kPa < temporalis 282.1 ± 70.8 kPa) and males (healthy: masseter 248.2 ± 48.4 kPa < temporalis 314.8 ± 63.3 < frontalis 388 kPa). Females had lower PPT values than those of males in temporalis, masseter, and frontalis muscles. This work is the first to systematically review the scientific literature addressing PPT values over craniofacial muscles of healthy subjects, patients with TTH, and those with migraine to provide the PPT value ranges. Based on these findings, a set of guidelines was established to assist future studies including PPT assessments over craniofacial muscles.

Identification and characterization of second-generation invader locked nucleic acids (LNAs) for mixed-sequence recognition of double-stranded DNA.

The development of synthetic agents that recognize double-stranded DNA (dsDNA) is a long-standing goal that is inspired by the promise for tools that detect, regulate, and modify genes. Progress has been made with triplex-forming oligonucleotides, peptide nucleic acids, and polyamides, but substantial efforts are currently devoted to the development of alternative strategies that overcome the limitations observed with the classic approaches. In 2005, we introduced Invader locked nucleic acids (LNAs), i.e., double-stranded probes that are activated for mixed-sequence recognition of dsDNA through modification with "+1 interstrand zippers" of 2'-N-(pyren-1-yl)methyl-2'-amino-α-l-LNA monomers. Despite promising preliminary results, progress has been slow because of the synthetic complexity of the building blocks. Here we describe a study that led to the identification of two simpler classes of Invader monomers. We compare the thermal denaturation characteristics of double-stranded probes featuring different interstrand zippers of pyrene-functionalized monomers based on 2'-amino-α-l-LNA, 2'-N-methyl-2'-amino-DNA, and RNA scaffolds. Insights from fluorescence spectroscopy, molecular modeling, and NMR spectroscopy are used to elucidate the structural factors that govern probe activation. We demonstrate that probes with +1 zippers of 2'-O-(pyren-1-yl)methyl-RNA or 2'-N-methyl-2'-N-(pyren-1-yl)methyl-2'-amino-DNA monomers recognize DNA hairpins with similar efficiency as original Invader LNAs. Access to synthetically simple monomers will accelerate the use of Invader-mediated dsDNA recognition for applications in molecular biology and nucleic acid diagnostics.

High-affinity DNA targeting using readily accessible mimics of N2'-functionalized 2'-amino-α-L-LNA.

N2'-Pyrene-functionalized 2'-amino-α-L-LNAs (locked nucleic acids) display extraordinary affinity toward complementary DNA targets due to favorable preorganization of the pyrene moieties for hybridization-induced intercalation. Unfortunately, the synthesis of these monomers is challenging (~20 steps, <3% overall yield), which has precluded full characterization of DNA-targeting applications based on these materials. Access to more readily accessible functional mimics would be highly desirable. Here we describe short synthetic routes to a series of O2'-intercalator-functionalized uridine and N2'-intercalator-functionalized 2'-N-methyl-2'-aminouridine monomers and demonstrate, via thermal denaturation, UV-vis absorption and fluorescence spectroscopy experiments, that several of them mimic the DNA-hybridization properties of N2'-pyrene-functionalized 2'-amino-α-L-LNAs. For example, oligodeoxyribonucleotides (ONs) modified with 2'-O-(coronen-1-yl)methyluridine monomer Z, 2'-O-(pyren-1-yl)methyluridine monomer Y, or 2'-N-(pyren-1-ylmethyl)-2'-N-methylaminouridine monomer Q display prominent increases in thermal affinity toward complementary DNA relative to reference strands (average ΔT(m)/mod up to +12 °C), pronounced DNA-selectivity, and higher target specificity than 2'-amino-α-L-LNA benchmark probes. In contrast, ONs modified with 2'-O-(2-napthyl)uridine monomer W, 2'-O-(pyren-1-yl)uridine monomer X or 2'-N-(pyren-1-ylcarbonyl)-2'-N-methylaminouridine monomer S display very low affinity toward DNA targets. This demonstrates that even conservative alterations in linker chemistry, linker length, and surface area of the appended intercalators have marked impact on DNA-hybridization characteristics. Straightforward access to high-affinity building blocks such as Q, Y, and Z is likely to accelerate their use in DNA-targeting applications within nucleic acid based diagnostics, therapeutics, and material science.