Teriparatide therapy for severe, refractory osteoradionecrosis of the jaw.

Although osteoradionecrosis (ORN) is a serious complication of craniofacial radiotherapy, the current management methods remain suboptimal. Teriparatide (TPTD), a recombinant human parathyroid hormone (1-34), has shown beneficial effects on osseous regeneration in medication-related osteonecrosis of the jaw or periodontitis. However, TPTD therapy in irradiated bones has not been indicated yet because of the theoretical risk of osteosarcoma seen in rat models. Hence, we first report here two patients with tongue cancer with late-emerging ORN who were successfully treated with TPTD for 4-6 months with serum calcium and vitamin D supplementation. In contrast to the usual progress of ORN, the bone defect regenerated well and bone turnover markers including serum C-terminal telopeptide of type 1 collagen and osteocalcin were restored with TPTD therapy. Our experience might suggest that TPTD therapy with careful monitoring can provide an effective treatment option for patients with ORN in select refractory cases, with the benefits outweighing the potential risks.

New perspectives on the conservative management of osteoradionecrosis of the mandible: A literature review.

Over the last decades, several therapeutic options were considered in the treatment of the osteoradionecrosis (ORN) of the mandible, including supportive measures, ultrasound therapy, corticosteroids, hyperbaric oxygen, surgical resection with reconstruction, and, more recently, drugs capable of reversing the fibroatrophic process. Once established, the ORN does not spontaneously disappear and a standard treatment has not yet been defined. The clear clinical effectiveness of hyperbaric oxygen therapy (HBOT) varies according to the literature and there are some economic/logistic issues to be considered; the triplet tocopherol/pentoxifylline/clodronate demands greater evidence from randomized clinical trials and also resilience from the patient, given the long treatment duration and its possible side effects. Controversy around the ideal treatment of the initial stage ORN of the mandible persists. More rigorous randomized prospective trials are essential. The purpose of this article was to review the relevant literature on the physiopathology of ORN of the mandible and discuss the new perspectives of its conservative treatment. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016.

Use of pentoxifylline and tocopherol in the management of osteoradionecrosis.

Osteoradionecrosis (ORN) is a complication of radiotherapy, and is difficult to manage once established. However, its pathogenesis has been reinvestigated, and it is now thought to be potentially amenable to treatment with pentoxifylline and tocopherol (vitamin E). We made a retrospective analysis of 62 patients with established ORN who were treated in this way. When only pentoxifylline and vitamin E was used ORN resolved in 14/25 (56%) but paradoxically, when it was combined with antibiotics, only 6/22 resolved (27%). The next stage would ideally be to incorporate the treatment in a randomised clinical trial against both standard antibiotic treatment and hyperbaric oxygen.

Tissue repair in osteoradionecrosis using pentoxifylline and tocopherol--report of three cases.

PURPOSE: Osteoradionecrosis is a complication of head and neck radiotherapy, with a difficult resolution and no well-established treatment. The disease progression can cause important loss on patient's quality of life after cancer treatment. The options for treatment are limited and include clinical monitoring, prescription, or surgical procedures. As an alternative for bone necrosis treatment, a combination of drugs, pentoxifylline and tocopherol, can be used. Studies have shown that this combination significantly reduces chronic radiotherapy damage. The article reports successful treatment with this prescription protocol. METHODS: We report three cases of patients referred to the Service of Oral and Maxillofacial Surgery at Erasto Gaertner Hospital, in Curitiba, Brazil. They were submitted to radiotherapy for the treatment of malignant head and neck tumors and later developed osteoradionecrosis. They were treated with the combination pentoxifylline and tocopherol. RESULTS: All patients achieved complete remission in less than 1 year, with complete healing of bone exposure and without clinical symptoms. CONCLUSIONS: This results show that this combination of drugs is beneficial in cases of bone necrosis induced by radiation, avoiding more aggressive treatments and reducing morbidity.

Osteoradionecrosis of the Posterior Maxilla: A New Approach Combining Erbium: Yttrium Aluminium Garnet Laser and Bichat Bulla Flap.

Osteoradionecrosis (ORN) of the jaw is a complication of radiation therapy for head and neck cancers. We report a case of ORN of the posterior maxilla treated with Er: YAG laser and a pedicled buccal fat pad (bichat bulla adipose) flap. A 69-year-old man presented complaining of pain on left maxilla. He had received high-dose radiotherapy (90 Gy) for squamous cell carcinoma of the left soft palate 2 years earlier. Clinical and radiographic examinations revealed ORN of the left maxillary molar region and maxillary sinusitis. Daily home care consisted of 0.9% saline irrigation and 0.8% H2O2 gel application. Sequestrectomy and tooth extraction were followed by debridement with Er: YAG laser and repair with a pedicled buccal fat pad flap. Complete resolution of ORN and maxillary sinusitis was established one year postsurgically. The excellent clinical outcome suggests that Er: YAG laser debridement and pedicled buccal fat pad flap are a viable option to treat ORN of the posterior maxilla.

Pharmacologic modalities in the treatment of osteoradionecrosis of the jaw.

Managing osteoradionecrosis (ORN) of the facial bones is a challenge in maxillofacial head and neck surgery. Changes in understanding of ORN of the jaws has led to new studies using novel therapeutic modalities to manage this disorder. These treatment regimens may allow medical management to replace major reconstructive surgery for some patients who have already undergone chemoradiotherapy or combined modality therapy for head and neck cancer.

Changing trends and the role of medical management on the outcome of patients treated for osteoradionecrosis of the mandible: experience from a regional head and neck unit.

This study is a retrospective review of treatment outcomes of osteoradionecrosis (ORN) of the mandible with specific reference to the evolving role of medical management with pentoxifylline, tocopherol, and doxycycline. We reviewed the presentation and management of 71 patients treated for ORN of the mandible at the regional head and neck unit during a 15-year period to January 2011, and categorised them into three grades using the Notani classification: grade I (n=28), grade II (n=16), and grade III (n=27). Twelve patients with grade I ORN, 3 with grade II, and 10 with grade III, were prescribed medical treatment. Of these, three with grade I, and two with grade II ORN were cured, and progression of the disease had halted and there was satisfactory control of symptoms in eight with grade I and four with grade III disease. Patients who failed to respond to conservative treatment were further analysed for the need for free flap reconstruction. Medical management was introduced as a standard treatment in January 2006. Of the 39 patients diagnosed before this, 20 (51%) required resection and free flap reconstruction compared with only 8/32 (25%) after it had been introduced.

Resolution of pain and complete healing of mandibular osteoradionecrosis using pentoxifylline and tocopherol: a case report.

The radiation-induced fibroatrophic process (RIF) is a time-dependent adverse sequela to high-dose radiotherapy that can result in irreversible tissue death and bone exposure in the irradiated tissue. Osteoradionecrosis (ORN) is a late effect of RIF, described as bony exposure present for more than 3 months that can occur in 20% of patients irradiated for head and neck cancer. The intractable characteristics of ORN make both management and resolution of the disease process challenging, with 25% of cases recurring despite aggressive treatment with resection and reconstruction of the necrotic bone. In this article, we present a case of a 66-year-old man with unevoked ORN of the left posterior lingual mandibular cortex that was successfully treated and resolved with 6 months of pentoxifylline 400 mg twice a day and tocopherol 1000 IU every day.

Complete restoration of refractory mandibular osteoradionecrosis by prolonged treatment with a pentoxifylline-tocopherol-clodronate combination (PENTOCLO): a phase II trial.

PURPOSE: Osteoradionecrosis (ORN) is a nonhealing wound of the bone that is difficult to manage. Combined treatment with pentoxifylline and vitamin E reduces radiation-induced fibrosis and ORN with a good prognosis. We previously showed that the combination of pentoxifylline and vitamin E with clodronate (PENTOCLO) is useful in healing sternocostal and some mandibular ORN. Is PENTOCLO effective in ORN of poor prognosis? METHODS: 54 eligible patients previously irradiated for head and neck cancer (among 72 treated) a mean 5 years previously received exteriorized refractory mandibular ORN for 1.4 ± 1.8 years, mainly after local surgery and hyperbaric oxygen had been ineffective. The mean length of exposed bone (D) was 17 ± 8 mm as primary endpoint, and the mean Subjective, Objective, Management, and Analytic evaluation of injury (SOMA) score was 16 ± 4. Between August 2000 and August 2008, all patients were given daily oral PENTOCLO: 800 mg pentoxifylline, 1,000 IU vitamin E, and 1,600 mg clodronate 5 days per week alternating with 20 mg prednisone and 1,000 mg ciprofloxacin 2 days per week. The duration of treatment was related to consolidated healing. RESULTS: Prolonged treatment (16 ± 9 months) was safe and well tolerated. All patients improved, with an exponential progressive--(f[t] = a.exp(-b.t)--and significant (p < 0.0001) reduction of exposed bone (D), respectively (months): D(2) -42%, D(4) -62%, D(6) -77%, D(12) -92%, and D(18) -96%, combined with iterative spontaneous sequestrectomies in 36 patients. All patients experienced complete recovery in a median of 9 months. Clinical improvement was measured in terms of discontinuation of analgesics, new fracture, closed skin fistulae, and delayed radiologic improvement: SOMA(6) -64%, SOMA(12) -89%, and SOMA(30) -96%. CONCLUSION: Long-term PENTOCLO treatment is effective, safe, and curative for refractory ORN and induces mucosal and bone healing with significant symptom improvement. These findings will need to be confirmed in a randomized trial.

Osteoradionecrosis of the jaws: current understanding of its pathophysiology and treatment.

During the past 80 years a number of theories about the pathogenesis of osteoradionecrosis (ORN) have been proposed, with consequent implications for its treatment. Until recently tissue hypoxia and its consequences were accepted as the primary cause, and this led to the use of hyperbaric oxygen (HBO) for both treatment and prevention of complications of radiotherapy in the head and neck. The benefit of HBO has not been validated. A new theory for the pathogenesis of ORN has proposed that damage to bone is caused by radiation-induced fibrosis. Cells in bone are damaged as a result of acute inflammation, free radicals, and the chronic activation of fibroblasts by a series of growth factors. New treatments have therefore been devised that include pentoxifylline, a vasodilator that also inhibits fibrosis, and tocopherol (vitamin E) to reduce damage caused by free radicals. Impressive results in terms of reversing the process of ONR have been reported using these agents. It has been suggested that this theory and these agents could be the basis of future treatment and prevention of ORN.

Complete healing of severe osteoradionecrosis with treatment combining pentoxifylline, tocopherol and clodronate.

Osteoradionecrosis (ORN) is a late terminal sequela of irradiation that does not resolve spontaneously. In a preliminary study, a combination of pentoxifylline (PTX), tocopherol (Vit-E) and clodonate has been shown to be of clinical benefit with more than 50% regression of progressive ORN observed at 6 months in 12 patients. A 68-year-old woman presenting with severe exteriorized osteoradionecrosis had received radiotherapy for breast cancer 29 years previously. She had palpable breast fibrosis, including the sternum (15 cm x 11 cm) and a painful fistulous track in the upper part of the bone (orifice diameter 10 mm) surrounded by local inflammatory signs, and chronic osteitis with sequestra extrusion. MRI showed deep radiation-induced fibrosis below this area without cancer recurrence, and complete bone destruction over an area of 7 cm x 4 cm. Oral PTX (800 mg day(-1)), Vit.E (1000 IU day(-1)) and clodronate (1600 mg day(-1)) were administered daily for 3 years and were well tolerated. The patient exhibited regular clinical improvement until complete closure of the fistula and total regression of the clinical fibrosis. MRI confirmed the good response and showed heterogeneous restoration of the sternum, which was filled with new tissue. This is the first time that antifibrotic treatment with combined PTX-Vit.E plus clodronate has been shown to have a significant effect on necrosis, by completely reversing severe progressive ORN and the associated radiation-induced fibrosis.

Radiation-induced impairment of bone healing can be overcome by recombinant human bone morphogenetic protein-2.

Radiotherapy of head and neck tumors very often results in impaired healing of craniomaxillofacial bones in the vicinity. Management of radionecrosis of bones after radiotherapy is an important clinical challenge. Bone morphogenetic proteins (BMPs) induce new bone differentiation. The aim of this study is to investigate the potential of BMPs in ameliorating radiation-induced impaired bone repair. Two 3-mm diameter defects were created in the calvaria of rats. The defects were treated with different doses of recombinant human (rh) BMP-2 using collagen type I as a carrier. Irradiation with a single dose of 1,200 rad was performed 2 or 7 days preoperatively. Unirradiated animals served as controls. New bone formation was assessed by quantitation of radiographs of the calvaria and histology on day 21 after surgery. Untreated, unirradiated defects showed a spontaneous osseous regeneration of 90 +/- 7% of the defect area within 21 days. Irradiation of the site (1,200 rad 2 days preoperatively) resulted in a profound decrease in the bone fill of the untreated defect (5 +/- 2%). Recombinant human BMP-2 in soluble collagen type I carrier delivered to the defect resulted in a significant increase of new bone formation (34 +/- 14%, P < 0.01 for 25 micrograms rhBMP-2; 77 +/- 19% for 35 micrograms rhBMP-2, P < 0.01). Type I collagen carrier alone resulted in only 7 +/- 2% healing. In conclusion, radiation-induced impairment of calvarial repair can be overcome by rhBMP-2. Thus, the concept of BMP-2-induced regeneration has potential applications in reconstructive craniomaxillofacial surgery after irradiation.

Effect of insulin-like growth factor type I on critical size calvarial bone defects in irradiated rats.

Irradiated wounds are characterized by a slow healing process. Insulin-like growth factor-1 (IGF-1), a somatomedin C, has been shown in previous studies to stimulate collagen synthesis and bony repair. The purpose of this investigation is to evaluate the potential beneficial effects of recombinant IGF-1 in the healing of critical size calvarial defects in previously irradiated adult male Sprague-Dawley rats.

Hyperbaric oxygen treatment of osteoradionecrosis of the mandible. Experience in 29 patients.

In recent years hyperbaric oxygen has gained an important role in the treatment of osteoradionecrosis of the mandible. In the treatment of 29 patients with osteoradionecrosis of the mandible, a combination of surgical debridement, antibiotics, and hyperbaric oxygen was used in 27 cases. In 20 of the 29 patients the osteoradionecrosis was considered to be resolved after treatment. In 31% of the patients, the continuity of the mandible was lost. It was concluded that combined treatment of surgical debridement, antibiotics, and hyperbaric oxygen gives acceptable results and may, when used in an early phase of the disease, limit the number of patients who lose continuity of the mandible.

Osteomyelitis of the mandible.

The presenting characteristics and clinical courses of 60 patients with mandibular bone infections are described. Fifteen of the patients had posttraumatic osteomyelitis, 13 had odontogenic osteomyelitis, and 28 had osteoradionecrosis. Most infections (93%) were polymicrobial, and anaerobes played an important role. Types of surgical procedures and use of adjunctive hyperbaric oxygen are described. There were minimal differences in presentation or response to treatment between these four different groups. A clinical staging system for mandibular bone infections is proposed and results of treatment are retrospectively analyzed by stage. The results support the concept that initial treatment planning can be safely and successfully based on the stage of the disease.

The management of osteoradionecrosis of the jaws.

Therapeutic measures used in the management of osteoradionecrosis (ORN) of the jaws are reviewed with reference to clinical case material. The development of rational treatment regimes designed to deal with the underlying pathological problem are discussed.

Hyperoxic myopia.

We have reported the development of 1.6 diopters of myopia in a group of patients exposed to reptitive oxygen breathing at two atmospheres absolute pressure. No significant change in corneal curvature accompanied this refractive change. During the three months following termination of the hyperoxic exposure, the myopia gradually disappeared. It is speculated that hyperoxygenation alters the metabolism of the adult lens producing an increase in its dioptric power.