Overview and Emerging Trends in the Treatment of Osteoradionecrosis.

OPINION STATEMENT: Osteoradionecrosis (ORN) of the mandible is a rare but devastating complication which occurs following radiation therapy for head and neck malignancies. Left untreated, ORN often results in pathologic fracture of the mandible leading to pain, trismus, difficulty eating, and overall poor quality of life. Historically, early intervention relied on hyperbaric oxygen and local debridement. Patients whose disease progressed despite therapy required segmental resection of the mandible with osseous free flap reconstruction, a highly invasive operation. Patients that presented with a moderate disease without pathologic fracture were often doomed to fail non-operative management, ultimately leading to disease progression and fracture. The traditional dichotomous treatment paradigm left a void of options for patients with moderate disease. The ideal intervention for this category of patients would provide renewed vascularity to the diseased tissue bed allowing for the osteogenesis and reestablishment of strong, load-bearing bone. The innovative technique termed the vascularized fascia lata "rescue flap" has proven to be an effective treatment for moderate ORN and will likely transform dated treatment algorithms.

Etanercept prevents TNF-α mediated mandibular bone loss in FcγRIIb-/- lupus model.

Patients with systemic lupus erythematosus are at increased risk for alveolar bone loss due to periodontitis possibly as a result of a pathogenic immune response to oral bacteria and inflammation. The aim of the present study was to investigate whether an anti-TNF-α antagonist could prevent mandibular bone loss in the FcγRIIb-/- mouse model of lupus. Mice lacking FcγRIIb had decreased cancellous and cortical bone volume at 6 months of age. Etanercept increased cancellous but not cortical bone volume in WT and increased both cancellous bone volume and cortical thickness in FcγRIIb-deficient mice. FcγRIIb deficiency decreased mRNA levels for osteoblast marker genes, Osx, Col1a1 and Alp without any change in osteoclast marker genes. Etanercept increased Osx, Alp, and Ocn in both WT and FcγRIIb-/- mice. Osteoclast marker genes including TNF-α, Trap and RANKL/OPG ratio was decreased in WT. Serum markers of proinflammatory cytokines, TNF-α, IFNγ, IL-6, and IL-17A, were increased in FcγRIIb-/- mice and etanercept antagonized these effects in FcγRIIb-/- mice. Etanercept increased serum PTH levels in the FcγRIIb-/- mouse model of lupus. Our results suggest that deletion of FcγRIIb induces osteopenia by increasing the level of proinflammatory cytokines. Etanercept is effective in preventing mandibular bone loss in FcγRIIb-/- mice, suggesting that anti-TNF-α therapy may be able to ameliorate mandibular bone loss in SLE patients with periodontitis.

Does the administration of meloxicam before head and neck radiotherapy reduce the risk of mandibular osteoradionecrosis? An animal model study.

OBJECTIVE: To assess whether the administration of meloxicam before head and neck radiotherapy reduces the risk of mandibular osteoradionecrosis in rats. MATERIAL AND METHODS: Sixty male Wistar rats were randomly divided into 6 groups (n = 10) according to the meloxicam administration and radiation therapy: control (C), irradiated (I), single dose of meloxicam (M1), single dose of meloxicam and irradiated (M1I), triple dose of meloxicam (M3), triple dose of meloxicam and irradiated (M3I). Meloxicam was administrated (20 mg/kg per dose) 1 h before the radiation therapy (single dose of 20 Gy) and 24 h and 48 h after the radiation therapy for groups with two additional doses. Ten days after the radiation therapy, the three right mandibular molars were extracted from all rats, who were euthanatized after 21 or 35 days (n = 5 per group). The mandibles were assessed by macroscopic evaluation and micro-CT analysis. RESULTS: The right hemimandibles of the irradiated groups revealed macroscopic signs of osteoradionecrosis, and those of the non-irradiated groups revealed complete gingival healing. A significant delay in alveolar socket healing in all irradiated groups was observed in the micro-CT assessment regardless meloxicam treatment. CONCLUSION: The administration of meloxicam before head and neck radiotherapy does not reduce the risk of mandibular osteoradionecrosis when associated to dental extractions. CLINICAL RELEVANCE: Since meloxicam has been shown to be a potential radiation-protective agent, and osteoradionecrosis physiopathology is believed to be related to an inflammatory process, possible interactions are relevant to be investigated.

Effect of α2­macroglobulin in the early stage of jaw osteoradionecrosis.

Advanced osteoradionecrosis (ORN) is one of the most serious complications in patients with head and neck cancer, resulting in poor prognosis. Numerous studies have therefore focused on the pathogenesis and interventions of ORN early stage. The present study aimed to investigate whether α2­macroglobulin (α2M) could prevent early­stage jaw osteoradionecrosis caused by radiotherapy (RT). Following local injection of α2M, a single dose of 30 Gy was delivered to rats for pathological exploration. For 28 days, the irradiated mandible and soft tissues were examined for potential changes. Furthermore, primary human bone marrow mesenchymal stem cells pretreated with α2M followed by 8 Gy irradiation (IR) were also used. Tartrate­resistant acid phosphatase assay, terminal uridine deoxynucleotidyl nick end labeling assay and immunohistochemical staining were performed on irradiated mandibular bone, tongue or buccal mucosa tissues from rats. Cell proliferation was assessed by evaluating the cell morphology by microscopy and by using the cell counting kit­8. Fluorescence staining, flow cytometry and western blotting were conducted to detect the reactive oxygen species level, cell apoptosis and protein expression of superoxide dismutase 2 (SOD2), heme oxygenase­1 (HO­1) and phosphorylated Akt following irradiation. The results demonstrated that α2M attenuated physical inflammation, osteoclasts number and fat vacuole accumulation in mandibular bone marrow and bone marrow cell apoptosis following IR in vivo. Furthermore, α2M pretreatment suppressed the expression of 8­hydroxy­2'­deoxyguanosine in mandibular bone and tongue paraffin embedded sections, which is a marker of oxidative damage, and increased SOD2 expression in mucosa and tongue paraffin embedded sections. The present study demonstrated the efficient regulation of antioxidative enzymes, including SOD2 and heme oxygenase­1, and reduction in oxidative damage by α2M. In addition, in vitro results confirmed that α2M may protect cells from apoptosis and suppress reactive oxygen species accumulation. Overall, the present study demonstrated that α2M treatment may exert some radioprotective effects in early­stage ORN via antioxidant mechanisms, and may therefore be considered as a potential alternative molecule in clinical prophylactic treatments.

Ameliorative effect of black grape juice on systemic alterations and mandibular osteoradionecrosis induced by whole brain irradiation in rats.

PURPOSE: Whole brain irradiation (WBI) causes a variety of secondary side-effects including anorexia and bone necrosis. We evaluated the radiomodifying effect of black grape juice (BGJ) on WBI alterations in rats measuring food and water intake, body weight, hemogram, and morphological and histological mandibular parameters. MATERIALS AND METHODS: Forty male rats (200-250 g) were exposed to eight sessions of cranial X-ray irradiation. The total dose absorbed was 32 Gy delivered over 2 weeks. Four groups were defined: (i) NG: non-irradiated, glucose and fructose solution-supplemented (GFS); (ii) NJ: non-irradiated, BGJ-supplemented; (iii) RG: irradiated, GFS-supplemented; and (iv) RJ: irradiated, BGJ-supplemented. Rats received daily BGJ or GFS dosing by gavage starting 4 days before, continuing during, and ending 4 days after WBI. RESULTS: RJ rats ingested more food and water and showed less body weight loss than RG rats during the irradiation period. Forty days after WBI, irradiated animals started losing weight again compared with controls as a consequence of masticatory hypofunction by mandibular osteoradionecrosis (ORN). Osteoclastic activity and inflammation were apparent in RG rat mandibles. BGJ was able to attenuate the severity of ORN as well as to improve white and red blood cell counts. CONCLUSIONS: Fractionated whole brain irradiation induces mandibular changes that interfere with normal feeding. BGJ can be used to mitigate systemic side-effects of brain irradiation and ORN.

Preventing Complications from High-Dose Rate Brachytherapy when Treating Mobile Tongue Cancer via the Application of a Modular Lead-Lined Spacer.

PURPOSE: To point out the advantages and drawbacks of high-dose rate brachytherapy in the treatment of mobile tongue cancer and indicate the clinical importance of modular lead-lined spacers when applying this technique to patients. METHODS: First, all basic steps to construct the modular spacer are shown. Second, we simulate and evaluate the dose rate reduction for a wide range of spacer configurations. RESULTS: With increasing distance to the source absorbed doses dropped considerably. Significantly more shielding was obtained when lead was added to the spacer and this effect was most pronounced on shorter (i.e. more clinically relevant) distances to the source. CONCLUSIONS: The modular spacer represents an important addition to the planning and treatment stages of mobile tongue cancer using HDR-ISBT.

Can calcitonin nasal spray reduce the risk of recurrence of central giant cell granuloma of the jaws? A double-blind clinical trial.

Recurrence is a major problem following the treatment of aggressive central giant cell granuloma (CGCG). The aim of this study was to compare the frequency of recurrence between patients who received calcitonin nasal spray after curettage of CGCGs and those who did not. A double-blind clinical trial was designed. Patients were allocated to one of two groups: those in the calcitonin group underwent curettage and received calcitonin salmon nasal spray 200IU/day once a day for 3 months after surgery; those in the control group underwent curettage of CGCGs and received a placebo once a day for 3 months after surgery. All patients were followed for 5 years after surgery. Twenty-four patients were treated in the two groups. There was no difference in age, sex, tumour size, or tumour location between the two groups (P>0.05). Eight of the 24 patients (33.3%) had recurrences during the follow-up period: one in the calcitonin group (9.1%) and seven in the control group (53.8%). Analysis of the data demonstrated a significant difference between the two study groups (P=0.033). It appears that calcitonin nasal spray may reduce the frequency of recurrence in aggressive CGCGs in the mandible and maxilla.

Comparison of Australian and New Zealand referral rates for hyperbaric oxygen in oro-facial osteoradionecrosis: evidence-based, funding constraint or clinician whim?

AIM: To compare Australian and New Zealand (NZ) rates of referral to hyperbaric units for patients with, or at risk of developing mandibular or maxillary osteoradionecrosis (ORN) due to a history of radiotherapy for oro-pharyngeal cancer. METHOD: Relevant patient treatment data from all hyperbaric units in Australia and NZ were collated and analysed. RESULTS: The rate of referral to hyperbaric units in Australia for treatment or prophylaxis of patients with, or at risk of oro-facial ORN, was 1.7 times the rate of referral in NZ. Within Australia, there was a greater than three-fold interstate variation. CONCLUSION: There is a significant referral rate difference both within Australia and between Australia and NZ for hyperbaric oxygen therapy for oro-facial ORN. Possible reasons for this difference include access to funding, logistical difficulties, clinician preference for an alternative treatment and clinician attitudes to hyperbaric oxygen.

Implant-supported mandibular overdentures can minimize mandibular bone resorption in edentulous patients: results of a long-term radiologic evaluation.

PURPOSE: It has been suggested that functional loading and light irritative stimuli could lead to changes in bone architecture, shape, and volume, and that by placing implants in the edentulous mandible and subsequently loading them, functional conditions could be created to limit bone resorption or even stimulate bone apposition (the latter was reported only for fixed implant-supported prosthetic reconstructions) in the distal area of the mandibular osseous crest. The aim of this study was to radiographically assess the bone height changes in the posterior area of the mandible after implant placement and loading with an overdenture on two or four implants over a mean follow-up period of 10.5 years. MATERIALS AND METHODS: Panoramic radiographs were taken of 82 totally edentulous patients before implant placement and at repeated follow-up intervals spread over a mean observation time of 10.5 years. All patients received an implant-supported overdenture as prosthetic treatment. The mandibular bone height in the distal part of the mandible was measured on each of the available radiographs and the initial, intermediate, and final values were compared. RESULTS: A mean mandibular bone height reduction of 0.5 mm was measured. CONCLUSION: No clinically relevant difference was found between the posterior mandible height before implant placement and at follow-up after functional loading with an implant-supported mandibular overdenture.

A digital evaluation of alveolar ridge preservation at implants placed immediately into extraction sockets: an experimental study in the dog.

OBJECTIVE: To compare with pristine sites bone resorption and soft tissue adaptation at implants placed immediately into extraction sockets (IPIES) in conjunction with deproteinized bovine bone mineral (DBBM) particles and a collagen membrane. MATERIAL AND METHODS: The mesial root of the third premolar in the left side of the mandible was endodontically treated (Test). Flaps were elevated, the tooth hemi-sectioned, and the distal root removed to allow the immediate installation of an implant into the extraction socket in a lingual position. DBBM particles were placed into the defect and on the outer contour of the buccal bony ridge, concomitantly with the placement of a collagen membrane. A non-submerged healing was allowed. The premolar on the right side of the mandible was left in situ (control). Ground sections from the center of the implant as well as from the center of the distal root of the third premolar of the opposite side of the mandible were obtained. The histological image from the implant site was superimposed to that of the contralateral pristine distal alveolus, and dimensional variation evaluated for the hard tissue and the alveolar ridge. RESULTS: After 3 months of healing, both histological and photographic evaluation revealed a reduction of hard and soft tissue dimensions. CONCLUSION: The contour augmentation performed with DBBM particles and a collagen membrane at the buccal aspects of implants placed IPIES was not able to maintain the tissue volume.

Hyperbaric oxygen therapy as a prevention modality for radiation damage in the mandibles of mice.

BACKGROUND: Radiation therapy (RT) as part head and neck cancer treatment often leads to irradiation of surrounding normal tissue, such as mandibular bone. A reduced reparative capacity of the bone can lead to osteoradionecrosis (ORN). Hyperbaric oxygen therapy (HBOT) is used to treat ORN, based on its potential to raise the oxygen tension in tissues. However, prevention of radiation-induced damage is of great interest. Our purpose was to investigate whether HBOT could prevent radiation-induced damage to murine mandibles. METHODS: Twenty-eight mice were irradiated in the head and neck region with a single dose (15 Gy) and half of them were subsequently subjected to HBOT. Another 14 mice did not receive any treatment and served as controls. Ten and 24 weeks after RT, mandibles were harvested and analysed histologically and by microcomputed tomography (micro-CT). RESULTS: Micro-CT analysis showed a reduction in relative bone volume by RT, which was partly recovered by HBOT. Trabecular thickness and separation were also positively influenced by HBOT. Morphologically, HBOT suppressed the osteoclast number, indicating decreased resorption, and decreased the amount of lacunae devoid of osteocytes, indicating increased bone viability. CONCLUSIONS: HBOT was able to partly reduce radiation-induced effects on microarchitectural parameters, resorption, and bone viability in mouse mandibles. HBOT could therefore potentially play a role in the prevention of radiation-induced damage to human mandibular bone.

Antiplatelet drugs reduce the immunoinflammatory response in a rat model of periodontal disease.

BACKGROUND AND OBJECTIVE: After activation, platelets express mediators that modulate inflammation. We hypothesized that drug-induced platelet inactivation may interfere in the inflammatory process in experimental periodontal disease by suppressing the release of biological mediators to the injury site. MATERIAL AND METHODS: To evaluate the effects of antiplatelet drugs on experimental periodontal disease, 60 rats were randomly assigned to six groups (n = 10) and ligatures were placed around lower first molars in three groups. The other three groups were not subjected to the induction of periodontal disease and were used as negative controls. During the experimental period, animals were given aspirin (30 mg/kg) or clopidogrel (75 mg/kg) intragastrically once daily for 3 d. On day 3, they were killed and gingival tissue were used to evaluate myeloperoxidase activity and the expression of the chemokine CXCL4. Hemi-mandibles were used for microscopic evaluation. RESULTS: Clopidogrel significantly reduced the inflammatory infiltrate and increased the amount of collagen fibers. Histometric analysis showed that clopidogrel impaired alveolar bone loss. Expression of CXCL4 was significantly increased (p < 0.001) in rats subjected to periodontal disease. Systemic administration of aspirin and clopidogrel induced a significant decrease ( p < 0.05) in the expression of CXCL4. Treatment with antiplatelet drugs resulted in a significant reduction of myeloperoxidase activity when compared to saline-treated animals with periodontal disease. CONCLUSION: Clopidogrel but not aspirin showed the ability of preventing bone loss in experimental periodontitis.

The ability of H1 or H2 receptor antagonists or their combination in counteracting the glucocorticoid-induced alveolar bone loss in rats.

BACKGROUND: The aim of the present study was to compare between three possible osteoporotic treatments in prevention of glucocorticoid-induced alveolar bone loss. METHODS: Fifty adult female Wistar rats with an average weight 150-200 g were randomized into five groups: group I (control) was intraperitoneally injected with saline. The other experimental groups (II & III, IV & V) were intraperitoneally injected with 200 µg/100 g body weight dexamethasone. The experimental groups III, IV and V received intraperitoneal injection of 10 mg/kg/day pheniramine maleate (H1 receptor antagonist), ranitidine hydrochloride (H2 receptor antagonist) and concomitant doses of both H1 & H2 receptor antagonists respectively. After 30 days, the rats have been sacrificed. The mandibles were examined histologically, histochemically and histomorphometrically. The bone mineral density was measured using dual-energy X-ray absorptiometry (DEXA). RESULTS: Histopathologically the glucocorticoid group showed wide medullary cavities with wide osteocytic lacunae. These marrow cavities were reduced in the prophylactic groups (III, IV) but increased in group V. Bone histomorphometric analysis revealed improvement in static bone parameters in groups III and IV and deterioration in group V in comparison to group II. The DEXA revealed significant reduction in the bone mineral density in all experimental groups compared to the control group. CONCLUSIONS: In a rat model, the administration of H1 or H2 receptor antagonists separately could minimize the alveolar bone loss caused by the administration of glucocorticoids while concomitant administration of both H1 and H2 receptor antagonists deteriorated the bone condition.

Professional attitudes in regard to hyperbaric oxygen therapy for dental extractions in irradiated patients: a comparison of two specialties.

OBJECTIVES: Mandibular osteoradionecrosis (ORN) is a serious complication of radiation therapy. The current use of hyperbaric oxygen therapy (HBO2) to prevent ORN when dental extractions are performed has been called into question. We sought to determine the current acceptability and confidence in this treatment by practitioners from two different specialties. METHODS: We surveyed both hyperbaric medicine physicians and radiation oncologists regarding their views on the use of HBO2 for the prevention of ORN. Separate web-based anonymous surveys were sent via email invitation. These two groups were compared, including statistical analysis using the chi-square test when appropriate. RESULTS: 175 radiation oncologists and 118 hyperbaric medicine physicians participated. Among those not recommending HBO2, lack of evidence was cited by 52% of radiation oncologists and 38% of hyperbaric medicine physicians (chi2 = 5.0, p = 0.03, 95%, CI 1.9% to 25.6%). A majority of radiation oncologists (79%) and hyperbaric medicine physicians (85%) believe it is important that a new randomized controlled trial (RCT) is conducted (chi2 = 1.3, p = NS). CONCLUSIONS: While HBO2 has been used for decades, recent tissue-sparing radiation techniques and advanced surgical techniques are now calling into question the continued use of HBO2 for ORN prevention. Our results demonstrate that there is overwhelming support among responding practitioners for a new RCT.

Polymethoxy flavonoids, nobiletin and tangeretin, prevent lipopolysaccharide-induced inflammatory bone loss in an experimental model for periodontitis.

Nobiletin, a polymethoxy flavonoid (PMF), inhibits systemic bone resorption and maintains bone mass in estrogen-deficient ovariectomized mice. This study examined the anti-inflammatory effects of PMFs, nobiletin, and tangeretin on lipopolysaccharide (LPS)-induced bone resorption. Nobiletin and tangeretin suppressed LPS-induced osteoclast formation and bone resorption and suppressed the receptor activator of NFκB ligand-induced osteoclastogenesis in RAW264.7 macrophages. Nobiletin clearly restored the alveolar bone mass in a mouse experimental model for periodontitis by inhibiting LPS-induced bone resorption. PMFs may therefore provide a new therapeutic approach for periodontal bone loss.

Effectiveness of intensity-modulated and image-guided radiotherapy to spare the mandible from excessive radiation.

We would like to assess the effectiveness of intensity-modulated radiotherapy (IMRT) or image-guided radiotherapy (IGRT) to decrease the risk of osteoradionecrosis in locally advanced head and neck cancer. We conducted a retrospective study of 83 patients with head and neck cancer undergoing concurrent definitive chemoradiation, post-operative radiotherapy or chemoradiation, or radiotherapy alone with IMRT or IGRT. Mean mandibular dose was, respectively, 43.6Gy and 43.8Gy for the IMRT and IGRT technique. At a median follow-up of 28 months (5-55 months), only one patient developed osteoradionecrosis requiring hyperbaric oxygen. Sharp dose falloff associated with IMRT and IGRT decreased excessive radiation of the mandible and may reduce the risks of osteoradionecrosis.

Platelet rich plasma for the prevention of osteoradionecrosis. A double blinded randomized cross over controlled trial.

Osteoradionecrosis of the jaws is a complication of radiotherapy and controversy remains about the management of teeth in the field of radiotherapy. Platelet rich plasma has been advocated in multiple surgical sites, both bone and soft tissue, to promote healing and reduce complications. A randomized double blinded controlled trial was performed on patients receiving bilateral radiotherapy that affected the mandible who required pre treatment dental extractions. One side received platelet rich plasma and the other acted as a control. Twenty-two patients were recruited over 12 months and over a 5-year period following treatment three developed osteoradionecrosis (14%). Platelet rich plasma failed to show any benefit in the prevention of osteoradionecrosis. Nor was there any benefit in pain scores or mucosal healing on sides that were treated with platelet rich plasma. Platelet rich plasma fails to show a benefit in the prevention of osteoradionecrosis. The rate of osteoradionecrosis is high compared to other published series and the prophylactic removal of molar teeth should be questioned as a preventative measure.

Osteoradionecrosis.

Osteoradionecrosis (ORN) is a severe complication of radiation therapy for head and neck cancer. The current theory in its pathophysiology is thought to be radiation-induced fibroatrophy of the bone. Location of primary tumor, stage of cancer, dose of radiation, oral hygiene, and smoking and alcohol use are risk factors in the development of ORN. Prevention is focused on thorough dental care before, during, and after radiation therapy. Treatment ranges from conservative management with oral rinses and local debridement to radical resection with microvascular free tissue transfer and reconstruction.