Bisphosphonates and Osteonecrosis of the Jaw: A Retrospective Study

ObjectiveTo assess the prevalence of osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonate therapy and in those who were bisphosphonate naïve.MethodsWe undertook a retrospective review of medical records of patients at the New York Harbor Health Care System from 1999 through 2004. Charts were selected for review if patients had a Current Procedural Terminology (CPT) code suggestive of ONJ or if they had ever received bisphosphonate therapy.ResultsAmong 1,951 medical records reviewed, we identified 2 patients with ONJ who had received bisphos-phonates and 2 patients with ONJ who were bisphospho-nate naïve. Both patients treated with bisphosphonates had multiple myeloma and were receiving monthly infusions. They had initially received pamidronate before treatment was changed to zoledronic acid. In each case, ONJ was precipitated by a routine dental extraction. The prevalence of ONJ in our patient population receiving intravenously administered bisphosphonates was 1 in 71.5. Of the 2 cases of ONJ in bisphosphonate-naïve patients, osteora-dionecrosis was clearly incriminated in 1 patient and potentially the causative factor in the other patient as well. No patients receiving orally administered bisphosphonates had ONJ, nor did this complication occur in any patients receiving parenteral bisphosphonate therapy for disorders such as osteoporosis or Paget’s disease of bone.ConclusionBisphosphonates remain an important option for management of metabolic bone disease and complications of malignant disease. The overall prevalence of ONJ in patients receiving bisphosphonates seems to be very low; however, patients receiving intense parenteral therapy for an underlying malignant condition appear to have a uniquely elevated risk for the development of this complication. A causal relationship between bisphosphonates and ONJ remains to be proved and merits further investigation. (Endocr Pract. 2007;13:232-238)     

Bisphosphonate-associated osteonecrosis of the jaw: the rheumatologist's role

Several recent reports have described osteonecrosis of the jaws (ONJ) associated with the use of bisphosphonates. Rheumatologists treating bone diseases with bisphosphonate need, therefore, to be aware of this potential risk and plan the prophylaxis, early diagnosis and prevention of potential consequences. We review the literature on this newly described complication, with particular focus on systemic and local predisposing pathologies, preventive measures suggested before and during therapy with bisphosphonates, and the most frequent clinical presentation of the oral lesions. The expert panel recommendations for the management of care of patients who develop ONJ are summarized.     

Osteonecrosis of the jaw

The paper concerns osteonecrosis of the jaw (ONJ). It is a rare but serious clinical condition. It can develop in patients treated in oncologic doses with bisphosphonates but also with denosumab. In osteoporosis ONJ seems to be very rare. Definition, pathogenesis, risk factors, prevention and treatment, and the frequency of ONJ are presented.     

Platelet-rich plasma improves wound healing in multiple myeloma bisphosphonate-associated osteonecrosis of the jaw patients

Bisphosphonates are drugs used to treat various metabolic and malignant bone diseases. In the past 10 years intravenous bisphosphonates have been associated with increased risk of osteonecrosis of the jaw (ONJ). The aim of the present study is to evaluate platelet-rich plasma (PRP) wound healing benefits in multiple myeloma (MM) patients who developed ONJ after surgical tooth extraction. The study included 7 patients, 2 males and 5 females. All individuals had been taking zoledronate or pamidronate followed by zoledronate for an average of 5 years. Four subjects had only standard surgical debridement and sequestrectomy to treat the ONJ and three had additional autologous PRP. The patients were followed-up for 3 months. The use of PRP to enhance wound healing and reduce bone exposure seems to be a good treatment protocol in ONJ MM subjects.     

Impact of Bisphosphonate-related Osteonecrosis of the Jaw on Osteoporotic Patients after Dental Extraction: A Population-Based Cohort Study

Background and Aims

Little is currently known about the risk of developing bisphosphonate-related osteonecrosis of the jaw (BRONJ). This study sought to determine the incidence of BRONJ in osteoporotic patients. We also sought to identify the nature and types of risk factors of osteonecrosis of jaw (ONJ) related to the use of oral bisphosphonates (BPs).

Materials and Methods

Data from the National Health Insurance system of Taiwan. This cohort study included 19,399 adult osteoporosis patients received dental extraction in 2000-2010 (osteoporosis cohort) and 38,669 age and gender matched comparisons selected from dental extraction people without osteoporosis and osteonecrosis history (comparison cohort). All study subjects were followed from the date of their dental extraction (index date) to the development of ONJ and were included in the study up to 2011 or were lost to the study, whichever occurred first. Cox proportional hazard regression was used to estimate the hazard ratio and 95% confidence intervals for the two cohorts.

Results

Patients with osteoporosis had a significantly higher risk to develop ONJ than healthy persons (adjusted HR, 2.05; 95% confidence interval, 1.58–2.65). The risk of ONJ increased with the severity of osteoporosis, no matter whether patient with cancer or not. A cumulative effect of dental extraction frequency may increase the risk of ONJ.

Conclusions

We concluded that ONJ is caused by a number of factors. Osteoporosis and past dental history play the very important roles, while BPs play the synergistic effect.     

Dental implications of bisphophonate-related osteonecrosis

doi: 10.1111/j.1741‐2358.2012.00622.x
Dental implications of bisphophonate‐related osteonecrosis Objectives: The aim is to explore the current theories about clinical , pathological and dental management of bisphosphonate related osteonecrosis of the jaws. Also discussed are the actions of bisphosphonates, pathogenesis related to the susceptibility of jaws, the predisposing risk factors for the development of bisphosphonate‐related osteonecrosis of the jaws (BRONJ) and diagnostic criteria based on the literature review. Discussion: Osteoporosis is a disease that generally affects the mineral status of both cortical and trabecular bone in post menopausal women. Bisphosphonates are a group of drugs that preserve and increase bone mass. Bisphosphonate drugs are classified according to use and method of delivery. The bisphosphonates used for the treatment of osteoporosis are taken orally. Little is known about the side effects and dangers of the long‐term use of therapeutic doses of Bisphosphonates. A recent complication reported is osteonecrosis of jaws. The use of IV bisphosphonates for multiple myeloma and metastatic bone diseases suggests that dosage, length of treatment, and route of administration, as well as cofactors such as use of glucocorticoids and immunosuppressive agents, and dental surgery, could all be related to the incidence of BRONJ. This review provides an update on current knowledge about clinical, pathological and management aspects of BRONJ. Conclusions: Little evidence exists to direct the prosthodontic management of patients with a history of bisphosphonate use. Patients with active osteonecrosis related to bisphosphonate use have reduced tissue tolerance to function with removable prostheses and decreased potential for osseointegration of dental implants. Decisions should be based on clinical judgment tempered by the presenting conditions, medical profile, and patient needs. A better understanding would help in a dental setting to prevent any complication and help to improve the prognosis for those being treated for osteoradionecrosis.Until further evidence emerges regarding management of patients with active bisphosphonate‐ related osteonecrosis, conservative prosthodontic treatment is reasonable and prudent.     

Osteonecrosis of the jaw

This review looks at osteonecrosis in the stomatognathic system (mainly the jaws). Osteonecrosis of the jaw (ONJ) is a rare but serious clinical condition. It affects patients treated with bisphosphonates, and also with denosumab, mainly in oncological doses. In osteoporosis, it is a problem of relatively small significance. Article presents a thorough review of this phenomenon, including its definition, pathogenesis, risk factors, prevention and treatment methods, and its incidence rate.     

Effects of bisphosphonates on keratinocytes and fibroblasts having a role in the development of osteonecrosis of the jaw

Bisphosphonates (BPs) have became the treatment of choice for the prevention of skeletal complications in cancer patients with bone metastases as well as in patients suffering from osteoporosis, Paget's disease and rheumatoid arthritis. Osteonecrosis of the jaw (ONJ) is a recently described complication associated with the use of BPs in which the key finding is exposed necrotic bone in the oral cavity. Often, the precipitating event appears to be a dental invasive procedure. We recently provided evidence that ONJ is associated with dental extractions and use of dentures. It has been reported that the primary lesion lies in the bone and it is related to over-suppression of bone turnover, but it is unclear why such a lesion should present with loss of the soft tissue covering the jawbone. We propose that BP could be impairing molecular signalling not only of osteoblasts and osteoclasts but also of fibroblasts and keratinocytes, via cell to cell endocrine and paracrine interactions in a double manner. Such an impairment would result to fibroblast and keratinocyte impaired multiplication, proliferation and migration thereby leading to defective mucosal wound healing. This provides an open entry point for the oral flora to reach the underlying jawbone which is considered to have poor metabolic and immune properties when under BP treatment. We demonstrate that ONJ is associated with mucosal damage, which could be mediated via BP induced soft tissue toxicity. BPs have been reported to promote keratinocyte and fibroblast apoptosis and to impair various cellular activities like apoptosis, RANK, RANK-L and OPG signalling, bone morphogenetic protein signalling, growth factor signalling, immune homeostasis and wound healing. We discuss potential consequences of the above hypothesis for practitioners and investigators.     

Positive predictive value of the International Classification of Diseases, 10th revision, codes to identify osteonecrosis of the jaw in patients with cancer

Background: Osteonecrosis of the jaw (ONJ) is an important adverse event associated with therapies suppressing bone turnover, especially in patients with high-dose regimens of antiresorptive therapy, such as cancer patients. Danish health registries are an important resource for monitoring side effects of drugs. The International Classification of Diseases, 10th revision (ICD-10), currently used in Denmark, does not have a specific code for ONJ, making it difficult to monitor its occurrence. Objectives: To estimate the positive predictive value (PPV) for ONJ of currently used ICD-10 codes, suggested by Danish oral and maxillofacial surgeons, in order to assess feasibility of identification of ONJ cases among cancer patients in the Danish National Registry of Patients (DNRP). Methods: This study was conducted in northern Denmark (1.8 million inhabitants) among patients with a history of cancer. In Denmark ONJ cases are referred to hospital-based departments of oral and maxillofacial surgery (DOMS). In the DNRP, we identified patients with potential ONJ diagnosed at DOMS (as suggested by a series of ICD-10 codes) from 1 January 2005 to 31 December 2009. To confirm or rule out ONJ, we reviewed hospital records of these patients originating from DOMS. A confirmed ONJ case was defined by the presence of exposed maxillofacial bone for 8 weeks or more, in the absence of previous craniofacial radiation therapy. The PPV was the proportion of confirmed cases among all potential cases. Results: Among 85,910 eligible cancer patients, we identified 91 (0.11%) potential cases of ONJ, of which 18 were confirmed. The overall PPV was 20% (95% CI: 12–29%), ranging from 0% to50% for individual ICD-10 codes. Conclusions: A majority of cases identified by the suggested ICD-10 codes did not fulfill the criteria for ONJ, even though the potential cases were identified at DOMS. Therefore, reliance on ICD-10 codes, without hospital chart review, will lead to an overestimation of the occurrence of ONJ among cancer patients.     

Bisphosphonate-Associated Osteomyelitis of the Jaw: Guidelines for Practicing Clinicians

ObjectiveTo evaluate the literature and discuss the risk factors, mechanisms, pathophysiologic aspects, and recommended management of bisphosphonate-associated osteomyelitis of the jaw (BAOMJ).MethodsMore than 350 published articles, case reports mentioning BAOMJ, and independent histology slides from BAOMJ lesions were reviewed critically. The most pertinent publications are cited and discussed.ResultsThe incidence of BAOMJ increases after extraction of teeth, dentoalveolar surgical procedures, or recent oral trauma leading to exposed maxillary or mandibular bone. Contributory factors include poor oral hygiene, oral infections, periodontal disease; recent or ongoing corticosteroid administration or chemotherapy; compromised immune status; diabetes or vascular insufficiency; old age; chronic diseases; and malignancies. On average, 1 of every 100,000 patients treated with bisphosphonates orally for osteoporosis or Paget disease of bone may develop BAOMJ-like lesions. Patients with cancer often receive bisphosphonate doses 10 times or higher, and also more frequently, than those used in patients with osteoporosis or Paget disease of bone. Therefore, greater frequency of administration of bisphosphonates, higher dosages, and prolonged use (that is, for more than 2 years) are likely to be factors triggering BAOMJ.ConclusionThe association of bisphosphonate therapy with BAOMJ is rare in noncancer patients and is likely to be a class effect that may occur with use of any bisphosphonate. Whether patients with cancer require such a high frequency of intravenously administered bisphosphonates needs to be investigated. Following established guidelines can decrease the risks of BAOMJ in vulnerable patients. Rather than necrotic bone, current evidence supports an infectious and perhaps immunologic underlying cause for BAOMJ. The estimated incidence of BAOMJ among noncancer patients receiving bisphosphonates is about 0.001%, whereas among patients with cancer receiving intravenous bisphosphonate therapy the incidence is between 0.5% and 4%, depending on the dose, frequency, and duration of therapy (on average, ~ 2%). Nevertheless, the benefits of bisphosphonates far outweigh the risks. (Endocr Pract. 2008;14:1150-1168)     

Bisphosphonate-related osteonecrosis of jaw (BRONJ): an anti-angiogenic side-effect?

ABSTRACT: Bisphosphonates are recommended in the treatment of osteoporosis and some cancers, in which case they prevent the appearance of bone metastasis. The patients taking bisphosphonates are at increased risk of developing bisphosphonate-related osteonecrosis of jaw (BRONJ) which is characterised by the presence of an un-healing wound after dental surgery. BRONJ might represent an anti-angiogenic side effect. However, the real number of patients with BRONJ might be higher than currently recorded. Considering the differential diagnosis which includes various primary and secondary cancers, a correct histopathological diagnosis is very important. The morphological criteria for diagnosis of BRONJ are highlighted in this material. Virtual Slides The virtual slide(s) for this article can be found here: http: //www.diagnosticpathology.diagnomx.eu/vs/1813972972323288.     

Oral status among seniors in nine nursing homes in Styria,Austria

doi:10.1111/j.1741‐2358.2009.00281.x
Oral status among seniors in nine nursing homes in Styria, Austria Objective: To investigate the oral state in participants cared for in residences for senior citizens in Styria, Austria. Materials and methods: Four hundred and nine participants in Styria from nine homes for senior citizens were examined employing parameters in accordance with those of Folstein’s Mini Mental Status (MMS), DMFT, basic periodontal examination, the modified oral hygiene index, pain experienced during the preceding year, the subjective and objective need for treatment, and also requirements involving surgical and prosthetic treatment. Furthermore, the habitual methods of maintaining oral hygiene were examined establishing by whom this was carried out – whether by the patient, the nurse, or by patient and nurse together. Results: Four hundred and nine participants were examined, 48.3% were found to have retained on average 4.9 of their own teeth while 69% were fitted with dentures; however, 81% of the participants required prosthetic treatment. 28.9% of the participants had experienced acute dental pain during the preceding year and surgical treatment was found to be necessary in 47.7% of those with original teeth. Eighty‐four per cent of the participants showed acute inflammation of the periodontium while the state of oral hygiene, measured on a scale of 0–4, reached an average of 2.43. Oral hygiene was carried out by the nurses in only 7.46% of the cases which showed an average MMS measurement of 18. Conclusion: The results compared with those reported in other recent surveys and our data show an urgent need in Austria to improve the standards in dental care for the hospitalised elderly. Regular dental checks, carried out in the actual home by a dental surgeon should be introduced, whilst the nursing staff should be made fully aware of the problems caused by insufficient oral care and receive regular support from specialised oral hygiene assistants. The results of this survey also suggest that nursing staff should be equipped with simple instruments in order to judge to the extent to which the patient is capable of carrying out oral care independently and then according to the results to supplement this with additional care.     

Bisphosphonates promote jaw osteonecrosis through facilitating bacterial colonisation

A specific chemical structure of bisphosphonates (BPs) determines their ability to inhibit bone resorption. Because of that they have been successfully used for several years to treat skeletal events in neoplasia, hypercalcemia of malignancy, osteoporosis, Paget's disease, osteogenesis imperfecta and fibrous dysplasia. Recently, bisphosphonate related osteonecrosis of the jaws (BRONJ) has been reported as a serious complication of therapy with these compounds. According to the currently recognised theory of its origin arrest of the osteoclast function not only reflects in diminished bone resorption, but also in reduced bone formation, both leading to decreased bone turnover and consequently to the bone necrosis.A novel hypothesis assumes that BRONJ results from increased bacterial adhesion to bone coated with BPs. It is mediated by proteins termed “microbial surface components which recognise adhesive matrix molecules” (MSCRAMM). It has been found that binding of Gram-positive strains was due to the amino-terminal domain of MSCRAMM structure and that this interaction played significant role in the pathogenesis of infection. The cationic amino group of nitrogen containing BPs may attract bacteria by direct electrostatic interaction, through a direct surface protein interaction or by providing an amino acid mimic on the surface of the bony hydroxyapatite which interacts with MSCRAMM component and mediates increased bacterial adhesion.Bone exposition during dental surgical procedures acts as a trigger opening the door for bacterial invasion. That is why a strong correlation between BRONJ and dental surgical procedures exists. The jaw bones are especially subjected to infection due to thin epithelial line coating their surface, susceptibility to trauma, and presence of teeth.     

Osteonecrosis of the Jaw Developed in Mice: DISEASE VARIANTS REGULATED BY γδ T CELLS IN ORAL MUCOSAL BARRIER IMMUNITY*

Osteonecrosis of the jaw (ONJ), an uncommon co-morbidity in patients treated with bisphosphonates (BP), occurs in the segment of jawbone interfacing oral mucosa. This study aimed to investigate a role of oral mucosal barrier γδ T cells in the pathogenesis of ONJ. Female C57Bl/6J (B6) mice received a bolus zoledronate intravenous injection (ZOL, 540 μg/kg), and their maxillary left first molars were extracted 1 week later. ZOL-treated mice (WT ZOL) delayed oral wound healing with patent open wounds 4 weeks after tooth extraction with characteristic oral epithelial hyperplasia. γδ T cells appeared within the tooth extraction site and hyperplastic epithelium in WT ZOL mice. In ZOL-treated γδ T cell null (Tcrd^−/− ZOL) mice, the tooth extraction open wound progressively closed; however, histological ONJ-like lesions were identified in 75 and 60% of WT ZOL and Tcrd^−/− ZOL mice, respectively. Although the bone exposure phenotype of ONJ was predominantly observed in WT ZOL mice, Tcrd^−/− ZOL mice developed the pustule/fistula disease phenotype. We further addressed the role of γδ T cells from human peripheral blood (h-γδ T cells). When co-cultured with ZOL-pretreated human osteoclasts in vitro, h-γδ T cells exhibited rapid expansion and robust IFN-γ secretion. When h-γδ T cells were injected into ZOL-treated immunodeficient (Rag2^−/− ZOL) mice, the oral epithelial hyperplasia developed. However, Rag2^−/− ZOL mice did not develop osteonecrosis. The results indicate that γδ T cells are unlikely to influence the core osteonecrosis mechanism; however, they may serve as a critical modifier contributing to the different oral mucosal disease variations of ONJ.     

不同颌间牵引结合可吸收内固定材料在下颌骨骨折的重建研究

目的:下颌骨骨折患者采用可吸收内固定材料进行固定,同时结合牙弓夹板或自攻钛钉进行术后颌间牵引固定,探讨两种牵引方式对患者口腔情况和术后咬合关系恢复的促进作用。方法:对65例下颌骨骨折病例在完成骨折坚固内固定的基础上分别应用牙弓夹板和自攻钛钉进行颌间牵引,14 d后拆除颌间牵引,术后3-6月进行复查,对患者术后及复查期间口腔情况和咬合关系进行评估,采用两组间t检验进行统计学分析。结果:所有35例患者伤口均一期愈合。两种技术相结合,即使全面部骨折和陈旧性骨折都获得了良好的疗效,不同颌间牵引结果显示采用自攻钛钉治疗更加简便,口腔卫生情况明显好于采用牙弓夹板的患者;复查显示两组患者咬合关系恢复理想,两者骨折愈合、张口度及咬合关系无明显差异。结论:采用可吸收材料进行颌骨固位是一种较先进的坚固内固定方法,颌间自攻钛钉是恢复及维持咬合关系较为理想的治疗方法,两者结合可以获得满意的效果,值得临床推广。     

Intravenous rehydration for diarrheal dehydration of eutrophic children: survey of protocols provided at Colombian medical schools

Introduction. In all cases of severe dehydration from diarrhea, WHO recommends rapid rehydration. If oral rehydration in children is contraindicated, intravenous rehydration is recommended for immediate administration. However, methods of intravenous rehydration appear to be inadequately addressed in the medical schools of Colombia. Objective. Current approaches to oral rehydration were summarized, and instructors were informed concerning current WHO recommendations. Materials and methods. A survey was designed for pediatric instructors in Colombian medical schools. Direct questions about rehydration methods were included as well as presentation of theoretical clinical situations with dehydrated children. The survey also asked for the conditions necessary for intravenous rehydration and method of administration (volume, solution, concentration and speed of infusion). Results. Forty-one surveys were included (82% of medical schools in Colombia). Inadequate contraindications for oral rehydration therapy were made in 41%. Rapid and slow intravenous rehydration was recommended in 71% and 29%, respectively; 57% recommended fluid bolus to rehydrate. Adequate volumes were recommended by less than half of the respondents and adequate sodium concentration was recommended by 85%. In 56% of medical schools, glucose was not included in solutions and 66% use Ringer lactate. Normal saline solution, dextrose solution with electrolytes and polyelectrolytes solutions are also used. Conclusions. Misconceptions are common concerning the contraindications to oral rehydration therapy. One-third of medical schools promote a slow therapy despite the superiority of the rapid therapy. Uniformity for rapid therapy schemes is lacking. Bolus rehydration is commonly advocated despite the fact that this method is unsupported by the literature. Concepts about rehydration must be updated in medical schools and a national guide for intravenous rehydration is recommended.     

Paget's disease of bone: early and late responses to three different modes of treatment with aminohydroxypropylidene bisphosphonate (APD).

Early and late responses to treatment with either oral (600 mg/day) or intravenous (20 mg/day) (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (aminohydroxypropylidene bisphosphonate; APD) were studied in 142 patients with Paget''s disease of bone who had not previously been treated with bisphosphonate. The efficacy of three therapeutic regimens was compared: (a) oral aminohydroxypropylidene bisphosphonate given continuously until six months after the serum alkaline phosphatase activity had returned to normal (long term); (b) oral aminohydroxypropylidene bisphosphonate given until urinary hydroxyproline excretion had returned to normal (short term); (c) intravenous aminohydroxypropylidene bisphosphonate for 10 days. With either oral or intravenous treatment the decrease in urinary hydroxyproline excretion was rapid and always preceded the fall in serum alkaline phosphatase activity. Normal urinary hydroxyproline excretion is essential for return of the serum alkaline phosphatase activity to normal. Complete biochemical remission, defined as return of the serum alkaline phosphatase activity to normal, was obtained in 129 patients (91%). The median duration of remission as assessed by actuarial analysis was 2.7 years. This study found no difference in the long term among the three modes of treatment, suggesting that for most patients with Paget''s disease a short course of intravenous aminohydroxypropylidene bisphosphonate will produce longlasting, complete remission without need for maintenance treatment.