Management of osteoradionecrosis of the jaws with pentoxifylline-tocopherol: a systematic review of the literature and meta-analysis.

Osteoradionecrosis (ORN) of the jaws remains among the most commonly encountered and challenging complications of radiotherapy to the head and neck. The purpose of this study was to provide a review of the medical management for ORN and evaluate the reported outcomes with the use of pentoxifylline and tocopherol (PENTO), by means of a systematic review and meta-analysis. The predictor variable was the use of PENTO in the treatment of ORN. The outcome variable was the proportion of full recovery or significant improvement not requiring further intervention. The likelihood function was used to combine the studies and estimate the proportion and standard deviation of each outcome by the maximum likelihood estimation. Seven studies met the inclusion criteria. A total 211 patients were treated. One hundred twenty-six patients recovered fully or improved significantly not requiring further intervention. Sixty patients remained the same, 10 were lost to follow-up, and the disease progressed in 15. The current literature supports the use of PENTO in the treatment of ORN of the jaws. Additional well-designed prospective studies are needed in order to further validate the regimen that can then be employed in the treatment of ORN.

Life threatening bleeding from an osteonecrosis of the jaw: Are bisphosphonates safe in irradiated head and neck cancer patients?

Osteonecrosis of the jaw is a significant complication secondary to radiation therapy or drug therapy, most commonly bisphosphonates. Safety data regarding the administration of bisphosphonates in bone metastatic head and neck cancer patients with history of jaw irradiation are almost non-existent. In this paper, we report the case of a Head and Neck (HNC) patient, with history of radiation therapy to the mandible region, treated with intravenous bisphosphonates for bone metastases that resulted in gross, life threatening mouth hemorrhage secondary to advanced, locally invasive ONJ.

Immunoexpression of calcitonin and glucocorticoid receptors in central giant cell lesions of the jaws.

BACKGROUND: This study analyzed the immunoexpression of calcitonin receptor (CTR) and glucocorticoid receptor (GR) in central giant cell lesions (CGCLs) and verified potential associations with patient's response to clinical treatment with intralesional injection of triamcinolone. MATERIALS AND METHODS: Fifty-four cases of CGCLs, including 22 non-aggressive, and 32 aggressive, were investigated by immunohistochemistry. RESULTS: Surgery was the therapeutic choice for 53.1% of the aggressive CGCLs, and 46.9% were submitted to the conservative treatment with intralesional triamcinolone injections. Among patients submitted to conservative treatment, 60% (n = 9) showed favorable response. CTR expression was observed in 68.51%, and GR in 94.44% of the total sample. There were no differences in the expression of CTR, neither GR in mononucleated stromal cells (MSCs) or multinucleated giant cells (MGCs), in relation to aggressiveness, treatment performed for and the response to conservative treatment. Both markers showed a positive correlation between their expression in MSCs and MGCs in the total sample (P < 0.0001). CTR expression on MSCs showed a positive correlation with MGCs in the aggressive and non-aggressive groups (P < 0.0001). CONCLUSIONS: Calcitonin receptor and GR expression were diffuse and similar in non-aggressive and aggressive cases, and it did not influence the response to clinical treatment with triamcinolone in the sample studied.

Follow-up of patients with systemic immunological diseases undergoing fatty-degenerative osteolysis of the jawbone surgery and treated with RANTES 27CH.

Regulated-on-activation, normal T cell expressed and secreted (also called RANTES, CCL5 or R/C) is a chemotactic cytokine that plays a key role in recruiting immune cells to inflammatory sites. R/C is involved in the pathogenesis of many systemic immune-mediated diseases (SIDs) and is upregulated in fatty-degenerative osteolysis jawbone (FDOJ) cavitations. Surgical cleaning of degenerative areas reduces the source of chronic R/C but might not be sufficient to re-establish the altered immunological patterns. The aim of the present study was to collect clinical data from patients suffering from sids who underwent dental surgery of FDOJ areas (n=46), by measuring R/C serum levels at the first visit (V0) prior to surgery, and at the second visit (V1). The majority of patients (n=41) were treated one month with ultra-low dose RANTES (27CH), a medicine used in micro-immunotherapy, while five patients were not. Mean and standard deviation of R/C serum levels at V0 in treated and untreated patients were respectively 48.5±25.8ng/ml and 42.48±22.22ng/ ml. Untreated patients had a tendency towards higher R/C levels at V1 (68.36±30.7ng/ml; p=0.062), while an opposite tendency was observed in treated patients (40.9±20.3ng/ml; p=0.129). Investigators observed that a cut-off set at 40ng/ml at V0 seemed to be predictive of the efficacy of the dental surgery/treatment (p=0.0013, n=26) and that gender could influence R/C levels and patient's responsiveness. The Authors, being aware that this is a preliminary follow-up, wanted to lay the basis for forthcoming studies, in which a larger cohort of patients and well-defined inclusion/exclusion criteria will be established.

Effect of different doses and durations of teriparatide therapy on resolution of medication-related osteonecrosis of the jaw: A randomized, controlled preclinical study in rats.

OBJECTIVE: To evaluate the effects of different doses and durations of teriparatide therapy on MRONJ resolution in rats. SUBJECTS AND METHODS: A total of 120 rats that had been affected with MRONJ (after six weekly zoledronate injections and tooth extraction) were randomly divided into eight subgroups: 2, 10, and 20 µg/kg/day teriparatide were administered to L4, M4, and H4 for 4 weeks, and to L8, M8, and H8 for 8 weeks, respectively. C4 and C8 received saline for 4 and 8 weeks, respectively. One week after the final injection, rats were sacrificed and assessed clinically (bone exposure/fistula) and histologically (number of osteocytes in extraction socket and empty lacunae in alveolar bone). RESULTS: MRONJ was clinically improved in 72.2%, 61.5%, and 40% of stage I, II, and III experimental rats, respectively. In the control rats, the results were 20.8% for stage I and no improvement for stages II and III. Aside from L4 and L8, the experimental subgroups had a significantly higher rate of clinical and histological improvement compared with their corresponding controls. There was a significantly higher number of osteocytes and lower number of empty lacunae in M4 and H4 compared with C4, in H4 compared with L4, in M8 and H8 compared with C8, and in H8 compared with L8. CONCLUSION: Teriparatide therapy improved clinical and histological features of MRONJ in a dose-dependent manner, but clinically relevant doses of teriparatide might not be sufficient for MRONJ resolution in rats. Extending the duration of teriparatide therapy from 4 to 8 weeks did not affect treatment outcomes.

Denosumab as a Treatment Alternative for Central Giant Cell Granuloma: A Long-Term Retrospective Cohort Study.

PURPOSE: Giant cell granuloma (GCG) of the jaw is a rare disease with high morbidity. Various treatment options have been discussed in the past. Since 2010, a pharmaceutical therapy with denosumab seems to have been successful for giant cell tumors of the femur. The authors hypothesized the equally successful use of denosumab for GCGs of the jaws. MATERIALS AND METHODS: In the present retrospective cohort study, 5 patients with large GCGs of the jaws were treated with denosumab with a follow-up of 25 to 49 months. Frequent clinical follow-ups and a radiologic follow-up were performed and systematically analyzed. RESULTS: All patients showed a curative treatment response and complete metabolic resolution of the GCGs under treatment with denosumab. CONCLUSION: A brief review of the relevant literature and a detailed evaluation of current cases led to the conclusion that denosumab therapy should be considered a therapeutic option for large central GCGs of the jaws. The results of this study suggest denosumab is a successful treatment option. A treatment length no shorter than 12 months is recommended and monitoring of treatment response can be well managed by positron-emission tomographic computed tomography or magnetic resonance imaging.

Pentoxifylline - a review of its use in osteoradionecrosis.

Pentoxifylline has been used to treat complications related to fibrosis for over 20 years. Formerly used to treat those after radiotherapy such as osteoradionecrosis (ORN), it is now being tried for medication-related osteonecrosis of the jaw (MRONJ), which can occur after prolonged use of bisphosphonates. We review theories on the formation of fibrosis in patients with ORN, discuss the pharmacology of pentoxifylline and vitamin E, and report published outcomes. To our knowledge no prospective randomised controlled trial has investigated the benefits of these agents in cases of ORN, but reported outcomes in many published case series are encouraging.

Denosumab: Prevention and management of hypocalcemia, osteonecrosis of the jaw and atypical fractures.

Denosumab, a bone-modifying agent, reduces the risk of skeletal-related events in patients with bone metastases from solid tumors and is generally well tolerated. However, hypocalcemia, osteonecrosis of the jaw (ONJ) and atypical fracture are potential and important toxicities of denosumab therapy that require attention. In pivotal phase III trials in patients with bone metastases from solid tumors, the incidence of hypocalcemia was 9.6% in denosumab-treated patients, with most events being asymptomatic, grade 2 and resolving by week 4. Established hypocalcaemia requires additional short-term calcium and vitamin D supplementation and, if severe, administration of intravenous calcium. ONJ was reported in 1.8% of patients receiving denosumab over 3 years in these trials. Involvement of an experienced oro-maxillary surgeon is important if ONJ is suspected. Atypical fractures were rare in a large study of denosumab using the dose and scheduling approved for the treatment of osteoporosis. To prevent toxicities, patients should maintain calcium and vitamin D supplementation, good oral hygiene and regular dental reviews throughout treatment. This article presents case studies from our clinical practice and discusses the pathophysiology of these toxicities along with guidance on prevention, diagnosis and management.

Use of Vancomycin-Impregnated Calcium Sulfate in the Treatment of Osteomyelitis of the Jaw.

PURPOSE: The aim of this study was to describe the effect of vancomycin-impregnated calcium sulfate in the treatment of osteomyelitis of the jaw. MATERIALS AND METHODS: Twelve patients who were diagnosed with osteomyelitis of the jaw underwent treatment with vancomycin-impregnated calcium sulfate since July 2014 at the Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University (Shenyang, China). All patients underwent debridement of nonviable bone and implantation of vancomycin-impregnated calcium sulfate. The wounds were covered with an acellular dermal matrix and sutured. RESULTS: Ten patients had satisfactory wound healing. However, 2 cases of maxillary central osteomyelitis had delayed wound healing. The wounds healed after the surgical site was resutured under local anesthesia. At 3 months, the panoramic radiograph showed that most implants had been reabsorbed and replaced by new bone formation. All patients in this study had no recurrence of infection at 6 to 18 months (mean, 10.8 months) of follow-up. CONCLUSIONS: The use of vancomycin-impregnated calcium sulfate in the surgical debridement site for chronic osteomyelitis of the jaw has shown encouraging results. In addition, calcium sulfate can promote the formation of new bone to a certain extent.

Massive Craniofacial Gorham Disease Treated Successfully by Cisplatin and 5-Fluorouracil With Ten Years of Follow-Up: A Case Report and Literature Review.

Gorham disease (GD) is a rare osteolytic condition of unknown etiology that causes spontaneous, progressive bone resorption. The maxillofacial area is one of the regions most frequently involved in this disease. GD is characterized by its aggressiveness and rarity; therefore, the treatment modalities remain controversial, and no specific treatment method has been proved effective. The present report describes a case of GD with massive craniofacial bone involvement that was treated effectively using a combination of 5-fluorouracil and cisplatin, with 10 years of follow-up.

Ultrastructural Analyses of Alveolar Bone in a Patient With Osteomyelitis Secondary to Osteopetrosis: A Review of the Literature.

Osteopetrosis is a generic term for generalized sclerotic conditions caused by rare genetic disorders. Decreased osteoclastic activities disturb bone remodeling, resulting in greater mineral density and greater compressive strength; therefore, bone fracture is a major physical symptom of osteopetrosis. Osteomyelitis of the maxilla or mandible is a common and well-documented complication of osteopetrosis. Local infection, such as odontogenic infection, is more likely to lead to osteomyelitis, and treatment strategies can be challenging. However, detailed ultrastructural analyses of bone from patients with osteopetrosis and odontogenic infection are limited. This report describes a case of osteomyelitis of the maxilla and mandible secondary to osteopetrosis in an adult patient and presents ultrastructural data of alveolar bone tissue analyzed by contact microradiography, electron probe microanalysis, and x-ray diffraction. Cases of osteomyelitis of the jaw secondary to osteopetrosis also are reviewed.

Management of central giant cell granuloma of the jaws with intralesional steroid injection and review of the literature.

PURPOSE: We report the results of the intralesional steroid injections for the management of central giant cell granuloma (CGCG) of the jaws. METHODS: Seven CGCGs were treated with intralesional injection of corticosteroids. To accomplish this, 3.5 mL of triamcinolone and 3.5 mL of 0.5 % marcaine with 1/200,000 epinephrine (total 7 mL) were mixed. An adequate amount of steroid was injected into different areas of the lesion. This procedure was repeated on a weekly basis for 6 weeks. RESULTS: Clinical and radiological examination showed complete resolution and ossification of the lesions in four patients. Partial recovery was achieved in two patients. One patient did not respond to the treatment and underwent surgical curettage. CONCLUSIONS: We suggest that intralesional steroid injection is safe and effective for the treatment of CGCG, especially in non-aggressive lesions.

[Osteomyelitis of the jaws - review of the literature and a case report].

Osteomyelitis (OM), is a rare disease in developed countries. It is defined as a progressive inflammation of the bone and the bone marrow, and characterized by formation of necrotic bone. This disease is more common in the lower jaw, which resembles the structure of a long bone. However, there are histologic and microbiologic characteristics that constitute important factors in the etiology and pathogenesis of the disease and therefore it is not possible to make an analogy from OM of long bones to OM of the jaws. The diagnosis of OM is based on a detailed anamnesis, clinical findings, laboratory tests and imaging. The treatment of OM consists of surgical treatment, which is considered the mainstay of the treatment, and antibiotic treatment, parenteral and oral which is considered as complementary therapy. There are several surgical procedures, according to the extent of the lesion, which include: drainage, curettage, sequestrectomy, saucerization, decortications and resection. A case of osteomyelitis of the lower jaw after dental treatment is presented. The patient underwent segmental resection and reconstruction.

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.

Prospective biomarker evaluation in patients with osteonecrosis of the jaw who received bisphosphonates.

Bone biomarkers have been suggested for the risk assessment for osteonecrosis of the jaw, a serious complication associated with bisphosphonate (BP) use; however, no consensus has been reached. This study investigated the possible associations between bone biomarkers and the development of bisphosphonates-related osteonecrosis of the jaw (BRONJ). This is a case-control study of 37 patients with BRONJ (age, 73.6±11.2years) who had at least 1 sample available at diagnosis, out of which, 35 were taking BPs for osteoporosis and 2 patients for bone metastasis. Age- and gender-matched 37 patients who had been exposed to BPs for >24months and had no evidence of BRONJ after dentoalveolar surgery served as control group. The association between biomarkers (osteocalcin [OC], deoxypyridinoline [DPD], C-terminal telopeptide of collagen I [CTX], N-terminal telopeptides [NTX], bone-specific alkaline phosphatase [BAP], and parathyroid hormone [PTH]) and BRONJ development, the effects of BP discontinuation on biomarkers, and the performance of biomarkers for risk assessment were investigated. In our study, the PTH levels were found to be significantly higher in BRONJ patients compared to controls (P<0.05). But the OC, DPD, CTX, NTX, and BAP levels were not significantly different between the 2 groups (P>0.05). The CTX level in reference to a 150pg/mL cutoff was also not significant for BRONJ development (P>0.05). Among BRONJ patients who discontinued BP, in a linear mixed model, only CTX showed a significant increase over time (ß=0.002, P=0.007). The cutoff PTH level was >41.52pg/mL (AUC=0.719, P=0.009), and that of CTX was ≤0.094ng/mL (AUC=0.619, P=0.069). In conclusion, there is insufficient evidence for the risk prediction for BRONJ of current bone biomarkers; additional research is necessary.

Osteonecrosis of the jaw - prevention and treatment strategies for oral health professionals.

Patients diagnosed with multiple myeloma and metastatic breast, prostate and renal cancers have a better opportunity for longer survival due to a myriad of chemotherapies regimens that attempt to manage disease progression while decreasing treatment-related side effects. Osteonecrosis of the jaws (ONJ) is a known side effect of bisphosphonates and other anti-neoplastic drugs. This complication can lead to oncologic treatment interruptions as well as diminished quality of life. Most recommendations for treatment of ONJ are based on position papers and case reports, while evidence-based treatment paradigms are lacking. With cancer survivorship on the rise, long-term chemotherapeutic side effects are becoming more prevalent and attention to untoward oral complications cannot be understated. In this review, the accepted recommendations for dental clearance prior to head and neck chemo-radiation therapy are put forth as a means of possibly preventing and treating drug induced ONJ.

Osteonecrosis of the jaw and oral health-related quality of life after adjuvant zoledronic acid: an adjuvant zoledronic acid to reduce recurrence trial subprotocol (BIG01/04).

PURPOSE: In patients with early breast cancer, adjuvant zoledronic acid (zoledronate) may reduce recurrence and improve survival. However, zoledronate is associated with the occasional development of osteonecrosis of the jaw (ONJ). We report on the frequency of ONJ and investigate oral health-related quality of life (Oral-QoL) in a large randomized trial (Adjuvant Zoledronic Acid to Reduce Recurrence [AZURE]). PATIENTS AND METHODS: Three thousand three hundred sixty women with stage II or III breast cancer were randomly assigned to receive standard adjuvant systemic therapy alone or with zoledronate administered at a dose of 4 mg for 19 doses over 5 years. All potential occurrences of ONJ were reported as serious adverse events and centrally reviewed. Additionally, we invited 486 study participants to complete the Oral Health Impact Profile-14 (OHIP-14) to assess Oral-QoL around the time the patients completed 5 years on study. Multivariable linear regression was used to calculate mean scores and 95% CIs in addition to identifying independent prognostic factors. RESULTS: With a median follow-up time of 73.9 months (interquartile range, 60.7 to 84.2 months), 33 possible cases of ONJ were reported, all in the zoledronate-treated patients. Twenty-six cases were confirmed as being consistent with a diagnosis of ONJ, representing a cumulative incidence of 2.1% (95% CI, 0.9% to 3.3%) in the zoledronate arm. Three hundred sixty-two patients (74%) returned the OHIP-14 questionnaire. Neither the prevalence nor severity of impacts on Oral-QoL differed significantly between zoledronate patients and control patients. CONCLUSION: Adjuvant zoledronate used in the intensive schedule studied in the AZURE trial is associated with a low incidence of ONJ but does not seem to adversely affect Oral-QoL.

The effects of adjunctive parathyroid hormone injection on bisphosphonate-related osteonecrosis of the jaws: an animal study.

Bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) is a serious and challenging complication of chronic BP uptake in patients with osteoporosis who require management of skeletal-related events. The efficiency of adjunctive parathyroid hormone (PTH) injection was evaluated after chronic BP administration that was followed by tooth extraction. BRONJ was not observed in any of the subjects in the control groups, while BRONJ was observed in 66% and 22% of the subjects in the tooth extraction group and the tooth extraction with PTH injection group, respectively. In addition the presence and severity of inflammation was lower in the PTH injected group than in the tooth extraction group, but the difference was not statistically significant (P>0.01). In conclusion, the administration of 30µg/kg/day PTH during a period of 8 weeks had positive effects on the resolution of BRONJ, but further studies are required to verify the effectiveness of PTH in the treatment of BRONJ.