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This article explores the potential side effect of osteonecrosis of the jaw (ONJ) associated with the use of bisphosphonates, medications used to treat bone diseases. The exact mechanism of how bisphosphonates contribute to ONJ is not fully understood, but it is believed to involve the inhibition of osteoclast differentiation and angiogenesis. The article suggests that local therapies targeting osteoclast differentiation in the jaw, such as inhibiting Glycogen synthase kinase-3 beta (GSK3b), administering geranyl-geraniol (GG), or using magnesium (Mg), may be potential treatments for ONJ. However, further studies are needed to explore these potential treatments. The article also mentions the potential use of teriparatide, a recombinant form of parathyroid hormone, in stimulating bone formation. Further research is needed to investigate these potential treatments for osteonecrosis of the jaw. [Extracted from the article]

Simple Summary: A number of skeletal disorders, all characterized by a metabolic or neoplastic loss of bone tissue, are cured with drugs called Bisphosphonates (BPs), which exert their therapeutic effect by suppressing cells named osteoclasts, normally mediating bone resorption. Unfortunately, these drugs can also provoke a dangerous side effect known as osteonecrosis of the jaw (ONJ), a bone infection localized in the oral cavity and characterized by gingival ulceration, sometimes accompanied by suppuration and pain. This condition, occasionally arising spontaneously, is more often started by a tooth extraction. The reduced number of osteoclasts, determined by BPs, is thought to favor the bacterial invasion of healthy bone and the incapacity to eliminate infected bone, that are in turn responsible for the appearance of ONJ. Here we show that Magnesium, used for decades as dietary supplement, can invert the effect of BPs, transforming them, through a sort of paradox effect, into powerful activators of osteoclast production. These results suggest that Magnesium might be used in a topical approach aimed to cure or prevent ONJ. Notably, the capacity of Magnesium to activate osteoclast production was even observed in absence of BPs, suggesting its application also in ONJ forms caused by agents distinct to BPs. Bisphosphonates (BPs) are successfully used to cure a number of diseases characterized by a metabolic reduction in bone density, such as Osteoporosis, or a neoplastic destruction of bone tissue, such as multiple myeloma and bone metastases. These drugs exert their therapeutic effect by causing a systemic osteoclast depletion that, in turn, is responsible for reduced bone resorption. Unfortunately, in addition to their beneficial activity, BPs can also determine a frightening side effect known as osteonecrosis of the jaw (ONJ). It is generally believed that the inability of osteoclasts to dispose of inflamed/necrotic bone represents the main physiopathological aspect of ONJ. In principle, a therapeutic strategy able to elicit a local re-activation of osteoclast production could counteract ONJ and promote the healing of its lesions. Using an experimental model of Vitamin D3-dependent osteoclastogenesis, we have previously demonstrated that Magnesium is a powerful inducer of osteoclast differentiation. Here we show that, surprisingly, this effect is greatly enhanced by the presence of Zoledronate, chosen for our study because it is the most effective and dangerous of the BPs. This finding allows us to hypothesize that Magnesium might play an important role in the topical therapy of ONJ. [ABSTRACT FROM AUTHOR]

Medication related osteonecrosis of the Jaws (MRONJ) is a severe complication of antiresorptive and anti-angiogenic medications. Osteoclast inhibition is central in MRONJ pathogenesis. Here, we investigated if local application of RANKL (a key molecule in osteoclast activation) could enhance osteoclast generation and improve extraction socket healing in the presence of bisphosphonates. Thirty Wistar-Han rats received one saline or 66 μg/kg zoledronate (ZA) i.p. dose before surgery. A week later, mandibular molars were extracted bilaterally. Collagen tapes infused with water or RANKL were placed in the extraction sockets of 60 hemimandibles of veh (veh/RANKL-, veh/RANKL+) or ZA treated rats (ZA/RANKL-, ZA/RANKL+). Rats were euthanized 3 or 12 days after surgery. Animals euthanized at 12 days received two additional veh or ZA injections. Clinical, radiographic and histologic assessments were performed. Visually, at the 3-day timepoint, no sockets demonstrated complete healing. At the 12-day timepoint, sockets of veh/RANKL- and veh/RANKL+ rats showed intact mucosa, while mucosal defects were noted in ZA/RANKL- rats. Importantly, ZA/RANKL+ sockets showed absence of bone exposure. RANKL delivery increased bone healing in the ZA/RANKL+ sites 12 days after extraction compared to the ZA/RANKL- sites. Histologically, at the 3-day timepoint, ZA/RANKL- sockets demonstrated extensive bone exposure and osteonecrosis. In contrast, ZA/RANKL+ rats showed granulation tissue coverage and significantly reduced osteonecrosis, similar to the veh groups. Importantly, in the ZA/RANKL+ group, osteoclasts attached to the bone surface and osteoclast numbers were higher compared to ZA/RANKL- sites. At the 12-day timepoint, persistent osteonecrosis and bone exposure were detected in the sockets of ZA/RANKL- animals. Contrary, ZA/RANKL+ rats demonstrated socket epithelialization and reduced osteonecrosis. Significantly more total and bony attached osteoclasts persisted in the ZA/RANKL+ vs the ZA/RANKL- group. We present a novel approach towards improving socket healing, in the presence of ZA, by enhancing osteoclastic numbers and attachment through local RANKL application. Our approach is clinically applicable and could improve treatment outcomes of patients on high-dose ZA therapy.

Bisphosphonates (BPs) are successfully used to cure a number of diseases characterized by a metabolic reduction in bone density, such as Osteoporosis, or a neoplastic destruction of bone tissue, such as multiple myeloma and bone metastases. These drugs exert their therapeutic effect by causing a systemic osteoclast depletion that, in turn, is responsible for reduced bone resorption. Unfortunately, in addition to their beneficial activity, BPs can also determine a frightening side effect known as osteonecrosis of the jaw (ONJ). It is generally believed that the inability of osteoclasts to dispose of inflamed/necrotic bone represents the main physiopathological aspect of ONJ. In principle, a therapeutic strategy able to elicit a local re-activation of osteoclast production could counteract ONJ and promote the healing of its lesions. Using an experimental model of Vitamin D3-dependent osteoclastogenesis, we have previously demonstrated that Magnesium is a powerful inducer of osteoclast differentiation. Here we show that, surprisingly, this effect is greatly enhanced by the presence of Zoledronate, chosen for our study because it is the most effective and dangerous of the BPs. This finding allows us to hypothesize that Magnesium might play an important role in the topical therapy of ONJ.

Rheumatoid arthritis (RA), an autoimmune inflammatory disorder, results in persistent synovitis with severe bone and cartilage destruction. Bisphosphonates (BPs) are often utilized in RA patients to reduce bone destruction and manage osteoporosis. However, BPs, especially at high doses, are associated with osteonecrosis of the jaw (ONJ). Here, utilizing previously published ONJ animal models, we are exploring interactions between RA and ONJ incidence and severity. DBA1/J mice were divided into four groups: control, zoledronic acid (ZA), collagen-induced arthritis (CIA), and CIA-ZA. Animals were pretreated with vehicle or ZA. Bovine collagen II emulsified in Freund's adjuvant was injected to induce arthritis (CIA) and the mandibular molar crowns were drilled to induce periapical disease. Vehicle or ZA treatment continued for 8 weeks. ONJ indices were measured by micro-CT (µCT) and histological examination of maxillae and mandibles. Arthritis development was assessed by visual scoring of paw swelling, and by µCT and histology of interphalangeal and knee joints. Maxillae and mandibles of control and CIA mice showed bone loss, periodontal ligament (PDL) space widening, lamina dura loss, and cortex thinning. ZA prevented these changes in both ZA and CIA-ZA groups. Epithelial to alveolar crest distance was increased in the control and CIA mice. This distance was preserved in ZA and CIA-ZA animals. Empty osteocytic lacunae and areas of osteonecrosis were present in ZA and CIA-ZA but more extensively in CIA-ZA animals, indicating more severe ONJ. CIA and CIA-ZA groups developed severe arthritis in the paws and knees. Interphalangeal and knee joints of CIA mice showed advanced bone destruction with cortical erosions and trabecular bone loss, and ZA treatment reduced these effects. Importantly, no osteonecrosis was noted adjacent to areas of articular inflammation in CIA-ZA mice. Our data suggest that ONJ burden was more pronounced in ZA treated CIA mice and that RA could be a risk factor for ONJ development. © 2016 American Society for Bone and Mineral Research.

Osteonecrosis of the jaw (ONJ) is a rare but serious adverse event associated with antiresorptive treatment. There is little evidence regarding the incidence of ONJ among patients with osteoporosis who are treated with denosumab versus bisphosphonates (BPs). The aim of this study was to determine the risk of ONJ in a real‐world population. Subjects who underwent at least one dual‐energy X‐ray absorptiometry (DXA) examination were included in the osteoporosis register of the Swiss Society of Rheumatology between January 1, 2015, and September 30, 2019. Statistical analyses included incidence rates, rate ratios, and hazard ratios for ONJ, considering sequential therapies and drug holidays as covariates. Among 9956 registered patients, 3068 (89% female, median age 69 years [63 to 76]) were treated with BPs or denosumab for a cumulative duration of 11,101 and 4236 patient‐years, respectively. Seventeen cases of ONJ were identified: 12 in patients receiving denosumab at the time of ONJ diagnosis and 5 in patients receiving oral or intravenous BP therapy. The diagnosis of ONJ was confirmed by independent and blinded maxillofacial surgeons, using the American Association of Oral and Maxillofacial Surgeons case definition of ONJ. The incidence of ONJ per 10,000 observed patient‐years was 28.3 in patients receiving denosumab and 4.5 in patients with BP‐associated ONJ, yielding a rate ratio of 6.3 (95% confidence interval [CI] 2.1 to 22.8), p < 0.001. Nine of 12 patients who developed ONJ during denosumab treatment had been pretreated with BPs, but none of the 5 patients with BP‐related ONJ had previously received denosumab. The risk of ONJ was higher in patients receiving denosumab therapy compared with BPs (hazard ratio 3.49, 95% CI 1.16 to 10.47, p = 0.026). Previous BP therapy before switching to denosumab may be an additional risk factor for ONJ development. © 2021 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Although osteonecrosis of the jaws (ONJ), a serious complication of antiresorptive medications, was reported a decade ago, the exact mechanisms of disease pathophysiology remain elusive. ONJ-like lesions can be induced in animals after antiresorptive treatment and experimental interventions such as tooth extraction or periapical or periodontal disease. However, experimental induction and manipulation of disease progression does not always reflect clinical reality. Interestingly, naturally occurring maxillofacial abscesses, inducing aggressive inflammation of the peri-radicular mucosa with significant osteolysis and alveolar bone expansion, have been reported in mice. Here, we aimed to explore whether osteonecrotic lesions would develop in areas of maxillary peri-radicular infections, in mice on antiresorptive medications with distinct pharmacologic action, thus establishing a novel ONJ animal model. Mice were treated with RANK-Fc or OPG-Fc that bind to RANKL or with the potent bisphosphonate zoledronic acid (ZA). Maxillae were assessed radiographically and histologically. μCT imaging of vehicle mice revealed several maxillae with altered alveolar bone morphology, significant ridge expansion and large lytic areas. However, in RANK-Fc, OPG-Fc and ZA treated animals the extent of bone loss was significantly less, but exuberant bone deposition was noted at the ridge periphery. BV and BV/TV were increased in the diseased site of antiresorptive vs. veh animals. Histologically, extensive inflammation, bone resorption and marginal gingival epithelium migration were seen in the diseased site of vehicle animals. Rank-Fc, OPG-Fc and ZA reduced alveolar bone loss, increased periosteal bone formation, and induced areas of osteonecrosis, and bone exposure that in many animals covered significant part of the alveolar bone. Collectively, our data demonstrate ONJ-like lesions at sites of maxillary peri-radicular infection, indistinguishable in mice treated with RAKL inhibitors vs. zoledronate. This novel mouse model of spontaneous ONJ supports a central role of osteoclast inhibition and infection/inflammation in ONJ pathogenesis and validates and complements existing animal models employing experimental interventions.

Dental extraction has often been described as the main trigger event of osteonecrosis of the jaws (ONJ). This longitudinal hospital-based study aimed to evaluate the outcome at 2 years of a standardized medical-surgical protocol for dental extraction, combined with platelet rich-plasma (PRP) application, compared with conventional protocol not combined with PRP or any other autologous platelet concentrate in cancer (ONC) and osteometabolic (OST) patients, at risk of bisphosphonate (BP)-related ONJ. Twenty patients were consecutively recruited: six received BPs for cancer skeletal-related events (34.17 ± 19.97 months), while fourteen received BPs for metabolic bone disease (74.5 ± 34.73 months). These patients underwent a standardized protocol for dental extraction, combined with autologous PRP application in the post-extraction socket. A total of 63 dental extractions were performed (24 and 39 in ONC and OST groups, respectively). As controls, historical cases, derived from the literature and including 171 ONC and 734 OST patients, were considered. The outcome of the surgical treatment was successful in all patients treated with PRP: two years after extraction, no patient had clinical or radiological signs of ONJ. When this datum was compared with historical controls, no statistically significant differences were found (p > 0.1). The combination of a standardized medical-surgical protocol with PRP application may contribute to limit the occurrence of BP-related ONJ, in both ONC and OST patients. Additional prospective studies with a larger patient sample are necessary to confirm this datum. [ABSTRACT FROM AUTHOR]

Summary: We investigated the association between bisphosphonate treatment and the risk of stroke using a large routine clinical dataset. We found no association between bisphosphonate treatment and risk of stroke, after adjusting for large number of clinical and demographic confounders. Introduction: There is conflicting evidence on the link between bisphosphonates and stroke with studies variously showing increased, decreased or unchanged risk. We investigated the association between bisphosphonate treatment and the risk of stroke using a large routine clinical dataset. Methods: We used a matched nested case-control study design analysing routinely collected electronic data from patients registered at primary care practices in England participating in the Royal College of General Practitioners Research and Surveillance Centre. Cases were patients aged 18 years or over, either living or dead, recorded as having had a stroke in the period 1 January 2005 to 31 March 2016. Each case was matched to one control according to age, sex, general practice attended and calendar time. Data were analysed using Stata, version 14.2. and RStudio, version 1.1.463. Conditional logistic regression was used to determine odds ratios for stroke according to bisphosphonate treatment and duration in cases compared with controls. We adjusted for disease risk groups, cardiovascular risk factors, treatments, smoking status, alcohol consumption, ethnicity, bisphosphonate types, fracture and socioeconomic status using IMD (Index of Multiple Deprivation). Results: We included 31,414 cases of stroke with an equal number of matched controls. Overall, 83.2% of cases and controls were aged 65 years or older, and there were similar proportions of females (51.5%) and males (48.5%). Bisphosphonate treatment was not associated with stroke after adjusting for the wide range of confounders considered (OR 0.86, 95% CI 0.62–1.19). Conclusions: We found no association between bisphosphonate treatment and risk of stroke, after adjusting for other confounders. [ABSTRACT FROM AUTHOR]

(1) Background: Multiple myeloma is a rare cancer that primarily affects the bone marrow. Osteoclasts are responsible for increased bone resorption and, therefore, bone destruction. Bisphosphonates are a class of drugs that can slow down bone resorption by reducing the number and action of osteoclasts. Intravenous injections of bisphosphonates (generally Zoledronic Acid) are administered to patients affected by Multiple Myeloma, but BRONJ is described as a serious side effect. This 5-year retrospective study aims to evaluate the efficacy of appropriate dental treatment protocols prior to initiating bisphosphonate therapy to prevent the development of BRONJ. (2) Methods: A total of 99 patients with symptomatic multiple myeloma were involved in this study (41–90 years, mean age 65 years, standard deviation 5 years). The data relating to the visits were tracked using a specific server and consulting the clinical reports. The AAOMS (American Association of Oral and Maxillofacial Surgeons) position was applied for both diagnosis and treatment. A total of 79 patients were examined before the administration of bisphosphonates (group A) and 20 after (group B). (3) Results: The entire sample required dental treatment: 23.2% underwent restorative therapy, 8% endodontic treatments, 44.4% tooth extractions. Periodontal disease was present in 41.4% of the patients. No osteonecrosis was observed in the first group, whereas BRONJ was found in five patients of the second one (25%) and two patients (10%) showed osteosclerotic areas under investigation [OR 0.026 (CI 0.0027 to 0.2454)]. (4) Conclusions: In the literature, there are no precise data about the prevalence of BRONJ. Despite the limitation of the present study, we point out that dental treatment before the treatment with intravenous bisphosphonates can help in reducing the incidence of BRONJ and good dental status is necessary for BRONJ prevention.

Dental extraction has often been described as the main trigger event of osteonecrosis of the jaws (ONJ). This longitudinal hospital-based study aimed to evaluate the outcome at 2 years of a standardized medical-surgical protocol for dental extraction, combined with platelet rich-plasma (PRP) application, compared with conventional protocol not combined with PRP or any other autologous platelet concentrate in cancer (ONC) and osteometabolic (OST) patients, at risk of bisphosphonate (BP)-related ONJ. Twenty patients were consecutively recruited: six received BPs for cancer skeletal-related events (34.17 ± 19.97 months), while fourteen received BPs for metabolic bone disease (74.5 ± 34.73 months). These patients underwent a standardized protocol for dental extraction, combined with autologous PRP application in the post-extraction socket. A total of 63 dental extractions were performed (24 and 39 in ONC and OST groups, respectively). As controls, historical cases, derived from the literature and including 171 ONC and 734 OST patients, were considered. The outcome of the surgical treatment was successful in all patients treated with PRP: two years after extraction, no patient had clinical or radiological signs of ONJ. When this datum was compared with historical controls, no statistically significant differences were found (p > 0.1). The combination of a standardized medical-surgical protocol with PRP application may contribute to limit the occurrence of BP-related ONJ, in both ONC and OST patients. Additional prospective studies with a larger patient sample are necessary to confirm this datum.

This report describes an unusual and extreme case of osteonecrosis of the jaw (ONJ) affecting the entire mandible, which was attempting to self exfoliate. A 76‐year old male presented clinically with all aspects of the mandible, except the condylar heads, necrotic and exposed in the oral cavity. The mandible had elevated out of the mucosa and was attempting to exfoliate through the mouth. As it was obstructing his oral cavity, the necrotic mandible was sectioned posteriorly allowing the patient to speak and eat comfortably, as well regain an oral seal. The use of intravenous bisphosphonates for metastatic prostate cancer coupled glucocorticosteroids, diabetes mellitus and hyperlipidaemia are likely to have contributed this extensive medication related ONJ. This complication is well‐recognised in association with bisphosphonates, however, this case is unique due to its severity, its spontaneous occurrence and the oral cavity's natural response to manage it, through near complete self exfoliation. [ABSTRACT FROM AUTHOR]

No well-established evidence supporting safe use of bisphosphonates (BPs) or other antiresorptive agents prior, during, or after dentoalveolar surgery, are currently available; moreover, the real risk of osteonecrosis of the jaw (ONJ) development is still unknown. The aim of the present systematic review was to assess the scientific literature concerning the implants placement in antiresorptive agent users and the related risk of implants failure and ONJ development. English papers published from January 2003 until December 2014 were identified on the MEDLINE database. Titles and abstracts retrieved form electronic search were screened separately by 2 examiners; thus, original studies dealing with dental implants placement during or before bone antiresorptive agent therapy and the relative risk of implant failure or development of osteonecrosis were evaluated. Due to the heterogeneity of the included studies and the high risk of bias, there is no evidence of the safe use of oral antiresorptive agents prior or after dental implant surgery. Indeed, implant failure and ONJ development can occur and represent a devastating side effect that should be considered during treatment. Within the limitation of the present systematic review, high quality studies are needed to provide an adequate level of evidence regarding the safety of dentoalveolar surgery during or before bone resorption inhibition therapy and the increase predisposition to osteonecrosis of the jaw (ONJ) development. Therefore, antiresorptive agent therapy should be considered a risk factor until further evidence is prospectively obtained. [ABSTRACT FROM AUTHOR]

A known complication that can occur in patients using bisphosphonates (BPs) is osteonecrosis of the jaw (ONJ). ONJ features bone exposure that may be associated with severe pain, swelling, local infection, and pathological fracture of the jaw. Current literature indicates that a complex combination of factors is necessary to induce ONJ. Several hypotheses about the pathophysiology of ONJ were previously reported. Here, we review these hypotheses and introduce new ideas and suggestions on this topic, focusing on bone site-specific cells, and the effect that BPs and other anti-resorptive drugs have on those cells. Gaining more insight into bone site-specific effects may help to better understand the pathogenesis ONJ, and contribute to the development of new bone site-specific anti-resorptive drugs. [ABSTRACT FROM AUTHOR]

Osteonecrosis of the jaw ( ONJ) is a severe complication of bisphosphonate treatment. Purpose A detailed characterization of sampled peri-necrotic jawbone from bisphosphonate-treated patients was performed at tissue and cellular level (histological analyses and gene expression). Materials and Methods Alveolar bone samples were collected from patients with (n = 5) and without ONJ (n = 5). Healthy patients served as controls (n = 10). Results The histological analysis demonstrated low to moderate inflammation, displaying areas of inflammatory infiltrate in the bone marrow. Multinuclear giant cells and osteoclasts were found in both groups. Markers of bone formation (alkaline phosphatase, Col1a1, and osteocalcin), bone resorption (receptor activator of NF-kappa B ligand [ RANKL], osteoprotegerin [ OPG], tartrate-resistant acid phosphatase, and cathepsin K), inflammation (tumor necrosis factor-alpha, interleukin [ IL]-1β, and IL-6), angiogenesis (vascular endothelial growth factor A), and apoptosis ( Casp3, Casp8, p53, and Smac) were evaluated. Nonparametric statistical tests were used to identify differences between the groups. In patients with ONJ, the expression level of the proinflammatory marker IL-1β was strongly up-regulated compared with controls (p = .040). Conclusions A down-regulated expression of Casp8 compared with controls was observed (p = .014) in patients treated with bisphosphonates. The RANKL/ OPG ratios were similar in the three groups. The results indicate a need to further investigate the molecular mechanisms involved in the course of ONJ related to antiresorptive treatment. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Summary: Objectives: Bisphosphonates are associated with osteonecrosis of the jaw. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) may be treated conservatively or by surgery. Patients and methods: 108 patients underwent surgery and 88 patients were followed for a mean period of 337days. Age, gender, dental procedures, underlying disease, and the role of bisphosphonate treatment in the success of surgery were evaluated retrospectively. Results: Surgical treatment improved the stage distribution from 19% stage I, 56% stage II and 25% stage III to 59% intact mucosa, 19% stage I and 13% stage II and 8% stage III. The improvement in the stage of disease achieved by surgery was statistically significant. Further relevant parameters that favor a positive outcome of surgery were the event triggering the outbreak of BRONJ (p =0.05) and the underlying disease (p =0.05). BRONJ in the maxilla necessitated repeat surgery significantly earlier than did BRONJ in the mandible (p =0.03). Conclusion: Effective surgery might improve the outcome of BRONJ, although prevention still is the most important aspect of this condition. [ABSTRACT FROM AUTHOR]

Abstract: Osteonecrosis of the jaw (ONJ) is an uncommon condition noted to occur in patients who are receiving osteoclast-targeted antiresorptive therapy. The incidence of ONJ in patients taking oral antiresorptives for the management of osteoporosis is low (approximately 1:100,000), whereas it is higher (∼10%) in patients taking intravenous bisphosphonates for the treatment of metastatic bone diseases. The etiology and pathophysiology of ONJ is unclear. No established preventive or treatment modalities are currently available. Although ONJ is a rare condition, it is imperative for oral care providers to have updated knowledge, as a large number of patients on antiresorptives are seeking oral care. In this comprehensive review, we focus on ONJ and bisphosphonate therapy and dissect the currently available evidence to establish a clinical approach to assess risk, preventive measures, and management of ONJ. [Copyright &y& Elsevier]

Abstract: Introduction: Osteonecrosis of the jaw (ONJ) is a serious side-effect of intravenous nitrogen-containing bisphosphonate therapy frequently used in the treatment of malignant diseases. Despite numerous case series published so far studies with detailed investigations into risk factors, the precise localization of ONJ and impact of ONJ on the oncological treatment remain sparse. Patients and methods: This single-centre study collated medical records (2003–2009) of all patients that suffered from ONJ within the Department of Oral and Maxillofacial Surgery, Ludwig-Maximilians-University of Munich, Germany. In total, 126 patients fulfilled the case criteria of ONJ and were examined clinically. The complete medical history including detailed questionnaires was collected of 66 patients, focussing in particular on the identification of underlying risk factors, clinical features, ONJ localization as well as the impact on the oncological treatment. Results: The majority of ONJ cases occurred in patients suffering from malignant diseases (n =117; 92.8%), in particular breast cancer (n =57; 45.2%), multiple myeloma (n =37; 29.4%) and prostate cancer (n =13; 10.3%), all received nitrogen-containing bisphosphonates intravenously. ONJ was also diagnosed in 9 patients (7.1%) suffering from osteoporosis or rheumatoid arthritis. The most prevalent clinical feature was exposed necrotic bone (93.9%) in the oral cavity which was accompanied in 78.8% of cases by pain. A predilection for the mandible and in particular for molar and premolar regions in both jaws was shown. Although no recommendation concerning the oncologic treatment was made, the manifestation of ONJ resulted (in a significant proportion of the patients) in a change of medication and schedule. The most frequent co-medications were steroids and anti-angiogenetic drugs, such as thalidomide. Discussion: The predilection for mandibular molar and premolar regions, and the infectious conditions that often precede the onset of ONJ support recent pathogenesis theories stating that local inflammation and associated pH-changes may trigger the release and activation of nitrogen-containing bisphosphonates ultimately resulting in necrosis. Conclusion: The development of ONJ has a multi-factorial aetiology and the clinical presentation can vary markedly. ONJ cannot only impair the quality of life but also the treatment of the underlying disease. [Copyright &y& Elsevier]

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious adverse drug reaction. We conducted a genomewide association study to search for genetic variants with a large effect size that increase the risk for BRONJ. Methods. We ascertained BRONJ cases according to the diagnostic criteria of the American Association of Oral and Maxillofacial Surgeons. We genotyped cases and a set of treatment-matched controls using Illumina Human Omni Express 12v1 chip (733,202 markers). To maximize the power of the study, we expanded the initial control set by including population and treatment-tolerant controls from publicly available sources. Imputation at the whole-genome level was performed to increase the number of single nucleotide polymorphisms (SNPs) investigated. Tests of association were carried out by logistic regression, adjusting for population structure. We also examined a list of candidate genes comprising genes potentially involved in the pathogenesis of BRONJ and genes related to drug absorption, distribution, metabolism, and excretion. Results. Based on principal component analysis, we initially analyzed 30 white cases and 17 treatment-tolerant controls. We subsequently expanded the control set to include 60 genetically matched controls per case. Association testing identified a significant marker in the RBMS3 gene, rs17024608 (p-value < 7 × 10-8); individuals positive for the SNP were 5.8× more likely to develop BRONJ (odds ratio, 5.8; 95% confidence interval, 3.1-11.1). Candidate gene analysis further identified SNPs in IGFBP7 and ABCC4 as potentially implicated in BRONJ risk. Conclusion. Our findings suggest that genetic susceptibility plays a role in the pathophysiology of BRONJ, with RBMS3 having a significant effect in the risk. [ABSTRACT FROM AUTHOR]

Abstract: Bisphosphonates are one of the most well studied groups of medications and they are bone specific. This tissue specificity is a rare property for a drug introduced into clinical practice as long as 40years ago. Over the years, the therapeutic boundaries of bisphosphonates were explored and their safety profile has withstood the challenges of the harsh clinical reality and widespread use. Certainly, the esophageal or gastric irritation caused by the oral preparations is an established adverse effect, the risk of which can be reduced by the recommended routine of taking the medication. From the other reported associations with adverse events, osteonecrosis of the jaw (ONJ) and subtrochanteric fractures have attracted most of the attention mainly because their pathophysiology remains unclear. However, overall, only a very small proportion of patients treated with bisphosphonates, especially with the oral formulations, experience adverse events and the overall benefits have consistently outweighed their potential risks. Furthermore, bisphosphonates improve the quality of life in patients with metastatic bone cancer and delay the development of adverse skeletal effects. This article is part of a Special Issue entitled Bisphosphonates. [Copyright &y& Elsevier]

Osteonecrosis of the jaw (ONJ) has been hypothesized to result in part from a relative 'oversuppression' of normal physiologic bone remodeling at the jaw brought about by bisphosphonate therapy. Biochemical markers of bone turnover give readily measurable information on integrated systemic bone remodeling activity, as measured by blood and urine assays. The intra- and interassay variability of most currently available assays is less than 10%, although many biological factors can influence levels of bone turnover markers. Bone turnover markers may show a dynamic response to changes in clinical status for a given disease state. Elevated bone turnover on and off treatment appears to predict adverse clinical consequences in both osteoporosis and cancer. Bisphosphonates effectively decrease the level of the bone turnover markers with a pattern depending on the marker, the bisphosphonate, the dose regimen, and the disease. However, long-term (10-year) treatment with bisphosphonates for osteoporosis does not appear to result in a progressive decline in bone turnover, as measured by markers and bone histology. The effects of long-term (greater than 2 years) treatment with monthly intravenous bisphosphonates on bone turnover markers in cancer are unknown. Discontinuation of bisphosphonate therapy appears to allow a recovery of bone turnover, which is related to the bisphosphonate, the duration of therapy, and the disease being treated. At this time, data are limited with regard to the utility of bone turnover markers in assessing risk for ONJ and whether bone marker-directed bisphosphonate holidays would be useful in prevention or treatment of ONJ. [ABSTRACT FROM AUTHOR]

Bisphosphonates are widely used in the management of metastatic disease to bone and in diseases of altered bone turnover. Recently, multiple-case series and retrospective studies have established a relationship between necrotic bone lesions localized to the jaw and the use of chronic bisphosphonate therapy. This condition has been named bisphosphonate-related osteonecrosis of the jaw (BRONJ). To evaluate the potential risks associated with this new and emerging complication, stage-specific management strategies and guidelines have been developed. In view of the widespread use of chronic bisphosphonate therapy, the observation of an associated risk of osteonecrosis of the jaw should alert practitioners to monitor for this previously unrecognized complication and to reevaluate the indications for and the duration of bisphosphonate therapy in patients with osteopenia/osteoporosis and cancer. Morbidity associated with BRONJ might be prevented or reduced by implementing prevention strategies and establishing early diagnostic procedures. The current widespread use of bisphosphonates as an inhibitor of bone resorption is directly attributable to their efficacy in improving the quality of life for patients with metastatic bone cancer, osteoporosis, and Paget's disease. [ABSTRACT FROM AUTHOR]

Bisphosphonates are used in the treatment of hypercalcemia of malignancy, skeletal complications associated with metastastic bone disease, Paget's disease, and osteoporosis. Osteonecrosis of the jaw (ONJ) is a recently described clinical condition that has been associated with the use of nitrogen-containing bisphosphonates. Reports describing this entity first appeared in the literature in 2003. While there have been significant numbers of case reports and a limited number of retrospective and prospective studies examining risk factors associated with ONJ, the pathophysiology of this condition remains elusive. In this review, we explore proposed mechanisms underlying ONJ development and identify potential areas for future investigation. [ABSTRACT FROM AUTHOR]

Osteonecrosis of the jaw (ONJ) in patients on long-term bisphosphonate Therapy (BPT) has been reported with increasing frequency in literature over the past 4 years. Therapy for this condition is still a dilemma. Temporary suspension of BPT offers no short-term benefits; hyperbaric oxygen has no proven efficacy and therefore is not recommended. Intermittent or continuous antibiotic therapy with surgical debridement can be beneficial to palliate the symptoms. Er:YAG laser can be used to eliminate necrotic bone portions by partial or total resection as an alternative to conventional rotary devices. In our study, 91 patients affected by ONJ-BP lesion, for a total of 115 ONJ sites were observed between January 2004 and May 2008 (Department of Odontostomatology, University of Parma). Fifty-five ONJ sites were considered for this study in four different groups, retrospectively identified on the basis of treatment performed (G1–G4). G1: 13 ONJ-BP sites were treated with medical therapy (amoxicillin 1gr x 3/ die per os with metronidazole 250 mg x 2/ die per os) for at least 2 weeks; G2: 17 ONJ-BP sites received medical treatment in association with cycles of low-level laser therapy (LLLT) applications performed using an Nd:YAG laser (1,064 nm) once a week for 2 months; G3: 13 ONJ-BP sites were surgically treated (sequestrectomy of necrotic bone, debridement, corticotomy/surgical removal of alveolar and/or cortical bone); G4: 12 ONJ-BP sites were treated with surgical therapy performed using an Er:YAG laser (2,940 nm) in association with LLLT. Clinical success has been defined for each treatment performed as: (a) complete mucosal healing free from signs and symptoms (classified as stage “0”) or (b) transition from a higher to a lower stage (Ruggiero staging) for at least 3 months. All the ONJ-BP sites treated with Er:YAG laser (G4 group) had a clinical improvement (100%) and 87.5% of sites had a complete mucosal healing with a mean follow-up of 13 months. The result obtained in the G4 is extremely significant in comparison with those obtained by medical treatment alone or in a traditional surgical approach. Thanks to the high degree of affinity of this wavelength for water and hydroxyapatite, both soft and bone tissues can be easily treated. This technique can also be used for conservative operations whereby necrotic bone is vaporized until healthy bone is reached. In addition, an additional advantage of the Er:YAG laser is its bactericidal and possible biostimulatory action, accelerating the healing of both soft tissues and bone tissues, in comparison to conventional treatments. In conclusion, from our experience, it is possible to observe that an early conservative surgical approach with Er:YAG laser associated with LLLT, for BP-induced ONJ could be considered as more efficient in comparison with medical therapy or other conventional techniques. [ABSTRACT FROM AUTHOR]

To identify potential risk factors for the development of osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates, we conducted a MEDLINE search. We identified 44 English-language published case reports and case series describing 481 patients with bisphosphonate-related ONJ. Our review of these reports indicated that ONJ occurs more frequently in patients receiving intravenous bisphosphonates (453 patients [94.2%]) than in patients receiving oral bisphosphonates (28 patients [5.8%]). Most patients who developed ONJ had cancer (451 patients [93.8%]), with multiple myeloma being the most common diagnosis, followed by breast, prostate, and lung cancers. Nearly one third of patients had a history of glucocorticoid use. The inciting event (reported in 449 patients) preceding the diagnosis of ONJ was a tooth extraction or other surgical or invasive dental procedure in 309 patients (68.8%), whereas 93 patients (20.7%) developed ONJ spontaneously. Guidelines for the prevention and treatment of bisphosphonate-associated ONJ have been developed but are largely based on anecdotal evidence. Patients receiving bisphosphonates must be counseled on the risks and benefits of therapy. Further studies will help to elucidate the pathophysiology, frequency, and risk factors for development of bisphosphonate-associated ONJ. [ABSTRACT FROM AUTHOR]

Summary: Introduction: Bisphosphonates (BPs) have transformed our ability to treat certain malignancies, osteoporosis and hypercalcaemia. This class of drug is assumed to be well tolerated by most. There are some important caveats to this assumption, however, one of the significances being the risk of osteonecrosis of the jaw (ONJ). Material and methods: This multi-centre retrospective study examined the role of different BPs on the development of ONJ, its clinical presentation and the efficacy of various treatment modalities, comparing these findings with the available literature. Results: A total of 78 patients from 17 centres were identified with ONJ. A majority of patients identified with ONJ had used Pamidronate or Zoledronate (93.6%) intravenously. 94.9% of patients had received BP in the course of treatment for malignancies and a majority had also received prior chemotherapy or exogenous steroids. 82.1% of patients had received BP for more than 1 year. The mean time from the introduction of BP to the development of ONJ in 24 patients from our department was 31.8 months. Conclusions: The most common intraoral manifestation was exposed necrotic jawbone. Tooth extractions and oral surgical intervention appear to place patients on BP therapy at risk of ONJ, especially after intravenous BP treatments. ONJ proved in this study to be remarkably refractory to treatment, with radical resection being the only curative approach. We recommend that all patients receive necessary dental treatment prior to commencing BP therapy. [Copyright &y& Elsevier]

Abstract: Background: Bisphosphonates are commonly used as standard care in the management of patients with advanced-stage cancer involving bone. There has recently been growing concern that the use of bisphosphonates is associated with osteonecrosis of the jaw (ONJ). Methods: Between 2001 and 2005, five patients with ONJ associated with pamidronate and zoledronate therapy were diagnosed at our department. The patients had breast cancer, renal carcinoma, mesothelioma, and multiple myeloma, all involving bone. The literature was reviewed. Results: The duration of bisphosphonate therapy before presentation of ONJ ranged from 21 to 36 months. The lesions were localized to the mandible (n =3) and maxilla (n =2). All of the patients presented with pain and exposed bone; in two of them, symptoms began after tooth extraction. A review of the literature through March 2006 identified more than 250 reported cases of ONJ. Conclusions: The findings in our patients, combined with the literature review, suggest that: (1) the most common clinical presentation of ONJ is pain and exposed bone of the mandible or maxilla; (2) for patients who develop ONJ, conservative, non-surgical treatment is strongly recommended; (3) clinical dental examination and a panoramic jaw radiograph should be performed before patients begin bisphosphonate therapy; (4) dental treatment and other oral procedures should be completed before initiating bisphosphonate therapy; (5) patients should be informed and instructed on the importance of maintaining good oral hygiene and having regular dental assessment; and (6) the medical community needs to be aware of the association between bisphosphonate usage and ONJ so that unnecessary and harmful surgical procedures can be avoided. [Copyright &y& Elsevier]

Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse event affecting patients with cancer and patients with osteoporosis who have been treated with powerful antiresorptives (pARs) or angiogenesis inhibitors (AgIs). pARs, including nitrogen-containing bisphosphonates (N-BPs; e.g., zoledronic acid, alendronate) and anti-RANKL antibodies (e.g., denosumab), are used to manage bone metastases in patients with cancer or to prevent fragility fractures in patients with osteoporosis. Though significant advances have been made in understanding MRONJ, its pathophysiology is still not fully elucidated. Multiple species have been used in preclinical MRONJ research, including the rat, mouse, rice rat, rabbit, dog, sheep, and pig. Animal research has contributed immensely to advancing the MRONJ field, particularly, but not limited to, in developing models and investigating risk factors that were first observed in humans. MRONJ models have been developed using clinically relevant doses of systemic risk factors, like N-BPs, anti-RANKL antibodies, or AgIs. Specific local oral risk factors first noted in humans, including tooth extraction and inflammatory dental disease (e.g., periodontitis, periapical infection, etc.), were then added. Research in rodents, particularly the rat, and, to some extent, the mouse, across multiple laboratories, has contributed to establishing multiple relevant and complementary preclinical models. Models in larger species produced accurate clinical and histopathologic outcomes suggesting a potential role for confirming specific crucial findings from rodent research. We view the current state of animal models for MRONJ as good. The rodent models are now reliable enough to produce large numbers of MRONJ cases that could be applied in experiments testing treatment modalities. The course of MRONJ, including stage 0 MRONJ, is characterized well enough that basic studies of the molecular or enzyme-level findings in different MRONJ stages are possible. This review provides a current overview of the existing models of MRONJ, their more significant features and findings, and important instances of their application in preclinical research. [ABSTRACT FROM AUTHOR]

(1) Background: Multiple myeloma is a rare cancer that primarily affects the bone marrow. Osteoclasts are responsible for increased bone resorption and, therefore, bone destruction. Bisphosphonates are a class of drugs that can slow down bone resorption by reducing the number and action of osteoclasts. Intravenous injections of bisphosphonates (generally Zoledronic Acid) are administered to patients affected by Multiple Myeloma, but BRONJ is described as a serious side effect. This 5-year retrospective study aims to evaluate the efficacy of appropriate dental treatment protocols prior to initiating bisphosphonate therapy to prevent the development of BRONJ. (2) Methods: A total of 99 patients with symptomatic multiple myeloma were involved in this study (41–90 years, mean age 65 years, standard deviation 5 years). The data relating to the visits were tracked using a specific server and consulting the clinical reports. The AAOMS (American Association of Oral and Maxillofacial Surgeons) position was applied for both diagnosis and treatment. A total of 79 patients were examined before the administration of bisphosphonates (group A) and 20 after (group B). (3) Results: The entire sample required dental treatment: 23.2% underwent restorative therapy, 8% endodontic treatments, 44.4% tooth extractions. Periodontal disease was present in 41.4% of the patients. No osteonecrosis was observed in the first group, whereas BRONJ was found in five patients of the second one (25%) and two patients (10%) showed osteosclerotic areas under investigation [OR 0.026 (CI 0.0027 to 0.2454)]. (4) Conclusions: In the literature, there are no precise data about the prevalence of BRONJ. Despite the limitation of the present study, we point out that dental treatment before the treatment with intravenous bisphosphonates can help in reducing the incidence of BRONJ and good dental status is necessary for BRONJ prevention. [ABSTRACT FROM AUTHOR]

Abstract: Bone metastases and skeletal events related to bone loss are common complications of prostate cancer and its treatment with androgen deprivation therapy. Skeletal-related events, particularly fractures, reduce functional independence and overall survival. Strategies to prevent cancer-related bone loss and restore or maintain bone integrity are thus critical in managing patients with prostate cancer. Management of bone metastases includes radiotherapy, surgery, vertebroplasty, kyphoplasty, and pharmacotherapy with bisphosphonates. Intravenous pamidronate and zoledronic acid are among the bisphosphonates that have been most extensively studied in the treatment of bone metastases. Toxicities associated with bisphosphonates include acute-phase reactions, nephrotoxicity, and osteonecrosis of the jaw. Targeted therapies for prostate cancer–related bone metastases are rapidly being developed. Agents in early stages of clinical development include denosumab, odanacatib, atrasentan, and other mediators of osteoclast activity. Increased use of androgen deprivation therapy for prostate cancer and at earlier stages in the disease course requires that clinicians understand the implications for greater bone loss and monitor patients appropriately. Skeletal morbidity has become an increasing concern, as men survive this disease for longer periods of time. In the absence of any drug treatments specifically approved for the prevention of bone loss from cancer treatment, management is guided by available data from studies showing reduced bone loss with the use of bisphosphonates and selective estrogen-receptor modulators, as well as with emerging agents in patients receiving androgen deprivation therapy. [Copyright &y& Elsevier]