Successful transplant of mesenchymal stem cells in induced osteonecrosis of the ovine femoral head: preliminary results

PURPOSE: Evaluate the bone tissue recovery following transplantation of ovine mesenchymal stem cells (MSC) from bone marrow and human immature dental-pulp stem cells (hIDPSC) in ovine model of induced osteonecrosis of femoral head (ONFH). METHODS: Eight sheep were divided in three experimental groups. First group was composed by four animals with ONFH induced by ethanol through central decompression (CD), for control group without any treatment. The second and third group were compose by two animals, six weeks after ONFH induction received transplantation of heterologous ovine MSC (CD + oMSC), and hIDPSC (CD + hIDPSC), respectively. In both experiments the cells were transplanted without application of any type of immunosupression protocol. RESULTS: Our data indicate that both cell types used in experiments were able to proliferate within injured site providing bone tissue recovery. The histological results obtained from CD+hIDPSC suggested that the bone regeneration in such animals was better than that observed in CD animals. CONCLUSION: Mesenchymal stem cell transplant in induced ovine osteonecrosis of femoral head by central decompression technique is safe, and apparently favors bone regeneration of damaged tissues.

Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension.

The 3-year FREEDOM trial assessed the efficacy and safety of 60 mg denosumab every 6 months for the treatment of postmenopausal women with osteoporosis. Participants who completed the FREEDOM trial were eligible to enter an extension to continue the evaluation of denosumab efficacy and safety for up to 10 years. For the extension results presented here, women from the FREEDOM denosumab group had 2 more years of denosumab treatment (long-term group) and those from the FREEDOM placebo group had 2 years of denosumab exposure (cross-over group). We report results for bone turnover markers (BTMs), bone mineral density (BMD), fracture rates, and safety. A total of 4550 women enrolled in the extension (2343 long-term; 2207 cross-over). Reductions in BTMs were maintained (long-term group) or occurred rapidly (cross-over group) following denosumab administration. In the long-term group, lumbar spine and total hip BMD increased further, resulting in 5-year gains of 13.7% and 7.0%, respectively. In the cross-over group, BMD increased at the lumbar spine (7.7%) and total hip (4.0%) during the 2-year denosumab treatment. Yearly fracture incidences for both groups were below rates observed in the FREEDOM placebo group and below rates projected for a "virtual untreated twin" cohort. Adverse events did not increase with long-term denosumab administration. Two adverse events in the cross-over group were adjudicated as consistent with osteonecrosis of the jaw. Five-year denosumab treatment of women with postmenopausal osteoporosis maintained BTM reduction and increased BMD, and was associated with low fracture rates and a favorable risk/benefit profile.

Is rheumatoid arthritis a risk factor for oral bisphosphonate-induced osteonecrosis of the jaws?

Bisphosphonate-related osteonecrosis of the jaws is a relevant side-effect of these drugs that has been generating a great concern through increasing reports, worldwide, of this bone necrosis. Among several BRONJ hypothetical co-factors that could play a role in BRONJ pathogenesis, rheumatoid arthritis (RA) has been included as a relevant risk factor for BRONJ; however, until now the relationship between these diseases has not been fully explained. Thus, the purpose of this paper is to establish hypothetical factors that could link these two diseases, considering mainly inflammatory components and the organism effects of medicines used to treat RA, particularly steroids and methotrexate (MTX). (C) 2011 Elsevier Ltd. All rights reserved.

Epidemiological aspects of rheumatoid arthritis patients affected by oral bisphosphonate-related osteonecrosis of the jaws

This literature review aims to evaluate the epidemiologic profile of patients with rheumatoid arthritis (RA) that developed a bisphosphonate-related osteonecrosis that affect the jaws (BRONJ), including demographic aspects, as well as clinical and therapeutic issues. A search of PUBMED/MEDLINE, Scopus, and Cochrane databases from January 2003 to September 2011 was conducted with the objective of identifying publications that contained case reports regarding oral BRONJ in RA patients. Patients with RA who develop oral BRONJ are usually women above 60 years taking steroids and long-term alendronate. Most of them have osteoporosis, and lesions, triggered by dental procedures, are usually detected at stage II in the mandible. Although there is no accepted treatment protocol, these patients seem to have better outcomes with conservative approaches that include antibiotic therapy, chlorhexidine, and drug discontinuation.

Imprint cytology of osteosarcoma of the jaw: A case report

Introduction. Osteosarcomas are highly malignant bone-forming neoplasms that account for about 20% of all sarcomas. In light of their aggressive behavior, early diagnosis is crucial for determining adequate treatment. Dental professionals may be the first to detect jaw osteosarcomas in their initial stages. The aim of this case report is to draw attention to the possibility of diagnosing this tumor based on clinical, radiographical and cytological characteristics before confirmation by histology. Case presentation. A 24-year-old Afro-Brazilian man presented with swelling and pain on the left side of the mandible in the region of the third molar (tooth 38). Radiography showed a poorly delimited intraosseous lesion with radiolucent and radiopaque areas. The cytological aspects were consistent with the diagnosis of osteosarcoma, which was confirmed by biopsy. Conclusion. Imprint cytology was found to be a reliable, rapid and easy complementary examination. An early diagnosis of osteosarcoma of the jaw is fundamental to the early determination of an adequate treatment. © 2009 Cabral et al; licensee BioMed Central Ltd.

Effects of Maternal Pb2+ poisoning during pregnancy on the development of the jaw (Meckel´s Cartilage) of rat fetus

The purpose of this study was to investigate the effects of maternal lead poisoning during pregnancy on the development of the jaw (Meckel's cartilage) of rat fetuses by histologic and morphometric methods. Pregnant rats received a single intraperitoneal injection of 2.5 mg of lead acetate/100g body weight on the 10th day of pregnancy. Meckel's cartilage of fetuses of the lead-treated group showed smaller volume density and size of the lacunae, as well as modification of the lacunae shape. Moreover, the number density of lacunae and the volume density of the matrix increased significantly in the Meckel's cartilage in treated group fetuses. The results suggest that lead poisoning during the period of organogenesis can induce disturbances in the development and differentiation of the fetal stomatognathic system. Reducing the consumption of alcoholic beberages and smoking cessation by women in childbearing age, along with a strict policy of control of the environmental lead exposure can bring great benefits to the future generations of children.

Association of laser phototherapy with PRP improves healing of bisphosphonate-related osteonecrosis of the jaws in cancer patients: A preliminary study

The aim of this study was to compare retrospectively the effect of three different treatments on the healing outcome of bisphosphonate-related osteonecrosis of the jaws (BRONJ) in cancer patients. Twenty-two cancer patients were treated for BRONJ with one of the following protocols: clinical (pharmacological therapy), surgical (pharmacological plus surgical therapy), or PRP plus LPT (pharmacological plus surgical plus platelet rich plasma (PRP) plus laser phototherapy (LPT). The laser treatment was applied with a continuous diode laser (InGaAlP, 660 nm) using punctual and contact mode, 40 mW, spot size 0.042 cm(2), 6 J/cm(2) (6 s) and total energy of 0.24 J per point. The irradiations were performed on the exposed bone and surrounding soft tissue. The analysis of demographic data and risk factors was performed by gathering the following information: age, gender, primary tumor, bisphosphonate (BP) used, duration of BP intake, history of chemotherapy, use of steroids, and medical history of diabetes. The association between the current state of BRONJ (with or without bone exposure) and other qualitative variables was determined using the chi-square or Fisher's exact test. In all tests, the significance level adopted was 5%. Most BRONJ lesions occurred in the mandible (77%) after tooth extraction (55%) and in women (72%). A significantly higher percentage of patients reached the current state of BRONJ without bone exposure (86%) in the PPR plus LPT group than in the pharmacological (0%) and surgical (40%) groups after 1-month follow-up assessment. These results suggest that the association of pharmacological therapy and surgical therapy with PRP plus LPT significantly improves BRONJ healing in oncologic patients. Although prospective studies with larger sample sizes are still needed, this preliminary study may be used to inform a better-designed future study. (C) 2011 Elsevier Ltd. All rights reserved.

Clinical and image findings in bisphosphonate-related osteonecrosis of the jaws

Abstract: Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is characterized as exposed bone in the jaws for more than 8 weeks in patients with current or previous history of therapy with bisphosphonates (BPs) and no history of radiotherapy in the head and neck. We report a case series of 7 patients with BRONJ and analyze the variations of clinical and imaging signs, correlating them with the presence or absence of bone exposure. Among the patients, 6 were women and 1 was a man, aged 42–79 years. Five of the patients were using zoledronic acid and the other 2 alendronate. The use of BPs varied from 3 to 13 years. In 5 patients, tooth extraction was the triggering event of injuries. Panoramic radiographs and computed tomography (CT) were evaluated by a radiologist blinded to the cases. There were persistent unremodeled extraction socket even several months after tooth extraction in 3 of the cases that were consistent wit CT findings that also showed areas of osteosclerosis and osteolysis. Patients were treated according to the recommendations of the AAOMS, with surgical debridement and antibiotic coverage with amoxicillin in the symptomatic patients. The follow-up of these patients ranged from 8 to 34 months, with a good response to treatment. The image findings in this case series were not specific and showed no difference between each stages of BRONJ (AAOMS, 2009). The image features were similar in presence or absence of exposed bone.

T-786C polymorphism of the endothelial nitric oxide synthase gene and neuralgia-inducing cavitational osteonecrosis of the jaws.

OBJECTIVE: We hypothesized that, similar to idiopathic hip osteonecrosis, the T-786C mutation of the endothelial nitric oxide synthase (eNOS) gene affecting nitric oxide (NO) production was associated with neuralgia-inducing cavitational osteonecrosis of the jaws (NICO). DESIGN: In 22 NICO patients, not having taken bisphosphonates, mutations affecting NO production (eNOS T-786C, stromelysin 5A6A) were measured by polymerase chain reaction. Two healthy normal control subjects were matched per case by race and gender. RESULTS: Homozygosity for the mutant eNOS allele (TT) was present in 6 out of 22 patients (27%) with NICO compared with 0 out of 44 (0%) race and gender-matched control subjects; heterozygosity (TC) was present in 8 patients (36%) versus 15 control subjects (34%); and the wild-type normal genotype (CC) was present in 9 patients (36%) versus 29 controls (66%) (P = .0008). The mutant eNOS T-786C allele was more common in cases (20 out of 44 [45%]) than in control subjects (15 out of 88 [17%]) (P = .0005). The distribution of the stromelysin 5A6A genotype in cases did not differ from control subjects (P = .13). CONCLUSIONS: The eNOS T-786C polymorphism affecting NO production is associated with NICO, may contribute to the pathogenesis of NICO, and may open therapeutic medical approaches to treatment of NICO through provision of L-arginine, the amino-acid precursor of NO.

Accurate Approach in the Treatment of Oral Bisphosphonate-Related Jaw Osteonecrosis

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is not completely understood and difficult to treat. Even though the occurrence of BRONJ is mainly related to the therapy with intravenous bisphosphonates (BPs), this article reports a case of long-term oral BP use and BRONJ occurrence. In addition, a literature review provides some additional information about BPs, BRONJ, and also a guideline for the prevention and treatment of BRONJ stages. A 79-year-old patient presented intense and persistent pain, purulent secretion, and exposed bone at the right side of the lower jaw. Thus, she was submitted to anamnesis, radiologic and tomographic examinations, and bacterial culture and sensitivity tests. These procedures were followed by surgical debridement of the bone and surrounding tissues/cyst and antibiotic prescription and histopathologic analysis of the fragments. Together, the examinations performed showed the occurrence of stage 2 BRONJ. Moreover, the antibiotic prescription, discontinuation of oral BP, and surgical procedures ensure that the patient had no more symptoms. Therefore, considering the presented case, we believe that an accurate approach is promising to diagnose and treat stage 2 BRONJ and other associated pathologic findings.

The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension.

CONTEXT: The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension is evaluating the long-term efficacy and safety of denosumab for up to 10 years. OBJECTIVE: The objective of the study was to report results from the first 3 years of the extension, representing up to 6 years of denosumab exposure. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, international, open-label study of 4550 women. INTERVENTION: Women from the FREEDOM denosumab group received 3 more years of denosumab for a total of 6 years (long-term) and women from the FREEDOM placebo group received 3 years of denosumab (crossover). MAIN OUTCOME MEASURES: Bone turnover markers (BTMs), bone mineral density (BMD), fracture, and safety data are reported. RESULTS: Reductions in BTMs were maintained (long-term) or achieved rapidly (crossover) after denosumab administration. In the long-term group, BMD further increased for cumulative 6-year gains of 15.2% (lumbar spine) and 7.5% (total hip). During the first 3 years of denosumab treatment, the crossover group had significant gains in lumbar spine (9.4%) and total hip (4.8%) BMD, similar to the long-term group during the 3-year FREEDOM trial. In the long-term group, fracture incidences remained low and below the rates projected for a virtual placebo cohort. In the crossover group, 3-year incidences of new vertebral and nonvertebral fractures were similar to those of the FREEDOM denosumab group. Incidence rates of adverse events did not increase over time. Six participants had events of osteonecrosis of the jaw confirmed by adjudication. One participant had a fracture adjudicated as consistent with atypical femoral fracture. CONCLUSION: Denosumab treatment for 6 years remained well tolerated, maintained reduced bone turnover, and continued to increase BMD. Fracture incidence remained low.