Arno Wutzl

TREATMENT RESULTS OF BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAWS

Osteonecrosis of the jaws occurs after the administration of bisphosphonates. An unequivocal treatment strategy is yet to be devised. We assess the treatment of patients with bisphosphonate‐related osteonecrosis of the jaws (BRONJ).

Inhibition of lamin A/C attenuates osteoblast differentiation and enhances RANKL-dependent osteoclastogenesis.

Age‐related osteoporosis is characterized by low bone mass, poor bone quality, and impaired osteoblastogenesis. Recently, the Hutchinson‐Gilford progeria syndrome (HGPS), a disease of accelerated aging and premature osteoporosis, has been linked to mutations in the gene encoding for the nuclear lamina protein lamin A/C. Here, we tested the hypothesis that inhibition of lamin A/C in osteoblastic lineage cells impairs osteoblastogenesis and accelerates osteoclastogenesis. Lamin A/C was knocked‐down with small interfering (si)RNA molecules in human bone marrow stromal cells (BMSCs) differentiating toward osteoblasts. Lamin A/C knockdown led to an inhibition of osteoblast proliferation by 26% and impaired osteoblast differentiation by 48% based on the formation of mineralized matrix. In mature osteoblasts, expression levels of runx2 and osteocalcin mRNA were decreased by lamin A/C knockdown by 44% and 78%, respectively. Furthermore, protein analysis showed that osteoblasts with diminished levels of lamin A/C also secreted less osteocalcin and expressed a lower alkaline phosphatase activity (−50%). Lamin A/C inhibition increased RANKL mRNA and protein levels, whereas osteoprotegerin (OPG) expression was decreased, resulting in an increased RANKL/OPG ratio and an enhanced ability to support osteoclastogenesis, as reflected by a 34% increase of TRACP+ multinucleated cells. Our data indicate that lamin A/C is essential for proper osteoblastogenesis. Moreover, lack of lamin A/C favors an osteoclastogenic milieu and contributes to enhanced osteoclastogenesis.

Factors influencing surgical treatment of bisphosphonate‐related osteonecrosis of the jaws

Bisphosphonates are known to be associated with osteonecrosis of the jaw. We assess factors underlying the success of surgical treatment in patients with bisphosphonate‐related osteonecrosis of the jaw (BRONJ).

Complication rates in the operative treatment of mandibular angle fractures: a 10-year retrospective.

PURPOSE Large-scale studies assessing complication rates and correlation of complications are still missing considering different fracture locations in the mandible. In the present retrospective study, complication rates of mandibular angle fractures treated by open reduction were assessed. MATERIALS AND METHODS Three hundred twenty-two patients (259 men, 63 women) with 335 surgically treated mandibular angle fractures were included in this study. RESULTS Fractures were caused by fights (46.6%), falls (19.2%), traffic accidents (14.6%), sports (11.9%), wisdom tooth removal (7.3%), and 0.9% other causes. Successful treatment occurred in 93.69% of fractures with 1 open reduction and in 6.31% with 2 open reductions. Of surgically treated patients, 71.47% (238) were completely free of complications. A detailed complication correlation matrix is given in the text. Ninety-five fractures treated with 1 miniplate, 170 with 2 miniplates, and 70 with other osteosynthesis concepts were compared regarding osteosynthesis failure and pseudarthrosis. CONCLUSION Similar osteosynthesis failure rates were shown for 1 miniplate and 2 miniplates.

Long-term success of surgery in bisphosphonate-related osteonecrosis of the jaws (BRONJs)

OBJECTIVES Bisphosphonates are associated with osteonecrosis of the jaw. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) may be treated conservatively or by surgery. PATIENTS AND METHODS 108 patients underwent surgery and 88 patients were followed for a mean period of 337 days. Age, gender, dental procedures, underlying disease, and the role of bisphosphonate treatment in the success of surgery were evaluated retrospectively. RESULTS Surgical treatment improved the stage distribution from 19% stage I, 56% stage II and 25% stage III to 59% intact mucosa, 19% stage I and 13% stage II and 8% stage III. The improvement in the stage of disease achieved by surgery was statistically significant. Further relevant parameters that favor a positive outcome of surgery were the event triggering the outbreak of BRONJ (p=0.05) and the underlying disease (p=0.05). BRONJ in the maxilla necessitated repeat surgery significantly earlier than did BRONJ in the mandible (p=0.03). CONCLUSION Effective surgery might improve the outcome of BRONJ, although prevention still is the most important aspect of this condition.

Bone morphogenetic proteins 2, 5, and 6 in combination stimulate osteoblasts but not osteoclasts in vitro.

Bone regeneration is required for fracture healing. Various procedures have been used to promote osteogenesis with bone morphogenetic proteins (BMPs). We assessed the effects of BMP‐2, BMP‐5, and BMP‐6 in isolated and combined use on the generation of osteoblasts and osteoclasts by comparing the osteoclastic potency of each on osteoclasts of primary murine bone marrow cells. Subsequently, cells were stained for tartrate‐resistant acid phosphatase, and real time PCR analysis of receptor activator of NKκB ligand and osteoprotegerin was conducted. The same combination of BMPs was used to assess their potential to enhance osteoblasts, employing a mineralization assay and real‐time PCR analysis of collagen type‐1, runx2, and osterix. While BMP‐2 alone and the combination of BMP‐2 and BMP‐5 significantly enhanced osteoclastogenesis, BMP‐2, BMP‐5, and BMP‐6 in combination did not have additional effects. However, the combined use of BMP‐2, BMP‐5, and BMP‐6 had an additive effect on matrix mineralization and osterix expression in osteoblasts. Our study shows that the combination of BMP‐2, BMP‐5, and BMP‐6 stimulates osteoblasts but not osteoclastogenesis. Thus, the synergistic use of various BMPs might improve effective bone regeneration in the clinical setting.

Biodegradable polymer membrane used as septal splint

The treatment of a crooked nose is one of the most challenging rhinoplastic procedures. Correction of the abnormally curved or fractured septum has been reported using mostly scoring techniques, septoplasty and submucous resection techniques; cartilaginous spreader grafts can also be sutured to the distorted septum. Extracorporal septal straightening and repositioning/refixation is another useful but difficult technique. A common problem of septal cartilaginous grafting techniques is to harvest enough straight cartilage to correct the deformity. (Other donor sites such as rib cartilage are used, but harvesting additional cartilage is a time-consuming procedure and carries the risk of donor site morbidity.) Recent studies have been published using alloplastic internal splinting of the deformed septum. The use of poly p-dioxanone foils and porous polyethylene has been suggested before. In this study, a novel grafting material, a PolyMax membrane that has potential advantages over both materials, is presented. This is a porous biodegradable polymer made out of 70:30 poly(L-lactide-co-D,L-lactide) that remains stable for at least 7 months. Poly p-dioxanone loses its stability after only 2 months, whereas porous polyethylene is a permeable material that is controversial due to possible complications in cases of membrane exposure and infection. In this preliminary report the PolyMax membrane was used successfully in 3 patients.

Complication rates of operatively treated mandibular fractures--the mandibular neck.

BACKGROUND Surgical treatment of mandibular neck fractures is frequently associated with postoperative complications. This study aims at an in-depth analysis of complication rates of surgically treated mandibular neck fractures. METHODS All treated patients (264 male, 103 female patients, with 429 mandibular neck fractures) of the Vienna University Clinic of Maxillofacial Surgery in the period of 1995 to 2005 with at least 1 mandibular neck fracture were included. RESULTS Of surgically treated fractures, 94.8% healed successfully after 1 open reduction, 4.4% had 2, and 0.8% had 3 open reductions. Osteosynthesis failure was 11.3% for 1 miniplate, 6.7% for 2 miniplates, and 8.5% for 1 lag screw. Of the surgically treated, 53 (21.3%) had 1 complication, 12 (4.8%) had 2, and 4 (1.6%) had 3 complications. Comparing isolated and mandibular neck fractures combined with other mandibular fractures the risk of suffering osteosynthesis failure is 3.59 in case of isolated (P = .004). CONCLUSIONS Predominant causes of revision surgery are osteosynthesis failure, pseudarthrosis, and malposition.

Mechanisms involved in the inhibition of osteoclast generation by the benzothiophene SERM LY117018

ZusammenfassungSelektive Östrogen Rezeptor Modulatoren wirken auf verschiedene Gewebe durch Östrogen Rezeptoren und bewirken fördernde oder hemmende Effekte bei der Entstehung von Osteoporose. Ziel dieser Studie ist die Wirkung des Östrogen Rezeptor Modulators LY 117018, einem Raloxifen Analog, auf die Osteoklastogenese zu untersuchen. In primären Knochenmarkszellkulturen von Mäusen wurden Osteoklasten, definiert als TRAP-positive mehrkernige Zellen, mit 10–8 M 1,25-dihydroxy Vitamin D3 induziert. 10–12 M bis 10–9 M LY117018 reduzierte die Anzahl der Osteoklasten. Höhere Konzentrationen hatten keinen Effekt auf die Generation der Osteoklasten. LY117018 steigerte die Alkaline Phosphatase Aktivität von Maus Kalvarien Osteoblasten in einer Konzentration von 10–14 M bis 10–7 M, aber hatten keinen Einfluss auf die Proliferation und Transkription von RANKL und Osteoprotegerin. Mäusemilzzellen wurden mit LY117018 inkubiert um die Produktion von Knochenresorbierenden Zytokinen zu messen. Die Daten von vier Flow Zytometrie Analysen zeigten eine signifikant reduzierte Frequenz der Tumor Nekrose Faktor-α positiven CD8+ Zellen nach Behandlung mit LY117018. Die Untersuchung zeigt, dass LY117018 signifikant die Generation der Osteoklasten hemmt und gleichzeitig die osteogene Differenzierung von Osteoblasten in vitro stimuliert. Die Verminderung der Tumor Nekrose Faktor-α Produktion durch LY117018 könnte zu seinem anti-osteoklastären Effekt beitragen.SummarySelective estrogen receptor modulators are compounds that act via estrogen receptors in different tissues to mediate either estrogenic or estrogen antagonistic effects in osteoporosis patients. The aim of this study was to assess the effect of the selective estrogen receptor modulator LY117018, a raloxifene analogue, on osteoclastogenesis in vitro. In primary murine bone marrow cultures osteoclasts, defined as TRAP-positive multinucleated cells, were induced by 10–8 M 1,25-dihydroxyvitamin D3. LY117018 at concentrations between 10–12 M and 10–9 M significantly reduced the number of osteoclasts. At higher concentrations no effect of LY117018 on osteoclast generation was observed. LY117018 enhanced alkaline phosphatase activity of mouse calvaria osteoblasts at a concentration of 10–14 to 10–7 M, but had no influence on the proliferation and transcription of RANKL and osteoprotegerin. In order to study the effect of the compound on the production of cytokines that can stimulate bone resorption, spleen cells were incubated with LY117018. Data from four-color flow cytometric analysis indicate a significantly decreased frequency of tumor necrosis factor-α positive CD8+ cells after treatment with LY117018. These findings suggest that LY117018 can significantly inhibit the generation of osteoclasts and stimulate osteogenic differentiation in vitro. Suppression of tumor necrosis factor-α production by LY117018 may contribute to its anti-osteoclastogenic effect.

Facial esthetics and the assignment of personality traits before and after orthognathic surgery rated on video clips

Typically, before and after surgical correction faces are assessed on still images by surgeons, orthodontists, the patients, and family members. We hypothesized that judgment of faces in motion and by naïve raters may closer reflect the impact on patients’ real life, and the treatment impact on e.g. career chances. Therefore we assessed faces from dysgnathic patients (Class II, III and Laterognathia) on video clips. Class I faces served as anchor and controls. Each patient’s face was assessed twice before and after treatment in changing sequence, by 155 naïve raters with similar age to the patients. The raters provided independent estimates on aesthetic trait pairs like ugly /beautiful, and personality trait pairs like dominant /flexible. Furthermore the perception of attractiveness, intelligence, health, the persons’ erotic aura, faithfulness, and five additional items were rated. We estimated the significance of the perceived treatment related differences and the respective effect size by general linear models for repeated measures. The obtained results were comparable to our previous rating on still images. There was an overall trend, that faces in video clips are rated along common stereotypes to a lesser extent than photographs. We observed significant class differences and treatment related changes of most aesthetic traits (e.g. beauty, attractiveness), these were comparable to intelligence, erotic aura and to some extend healthy appearance. While some personality traits (e.g. faithfulness) did not differ between the classes and between baseline and after treatment, we found that the intervention significantly and effectively altered the perception of the personality trait self-confidence. The effect size was highest in Class III patients, smallest in Class II patients, and in between for patients with Laterognathia. All dysgnathic patients benefitted from orthognathic surgery. We conclude that motion can mitigate marked stereotypes but does not entirely offset the mostly negative perception of dysgnathic faces.