The Prevention of Medication-related Osteonecrosis of the Jaw
; ; ;
Background: Medication-related osteonecrosis of the jaw (MRONJ) is a preventable complication of antiresorptive treatment. It arises in 1–20% of patients with bone metastases of solid tumors and hematologic malignancies and in 0.1–2% of patients being treated for osteoporosis with bisphosphonates. Depending on the underlying disease and medication dosage, the risk of MRONJ can be elevated even in the first year of antiresorptive treatment. The treatment of MRONJ is difficult and often involves surgery of the jaw.
Methods: We systematically reviewed publications retrieved by a selective search for literature on the prevention of MRONJ in the PubMed and Cochrane Library databases and with the aid of the Google Scholar search engine.
Results: 15 of 559 retrieved publications were included in the analysis. The quality of the evidence in the studies was generally moderate to low, with most of them being case series. In one case series of over 1200 patients with multiple myeloma, the incidence of MRONJ was lowered from 4.6% to 0.8% through regular dental checkups and improved oral hygiene. Tooth extraction, in particular, is associated with a high risk of MRONJ. In a retrospective study, 57% of patients who underwent tooth extraction without antibiotic prophylaxis developed MRONJ, compared to 0% with antibiotic prophylaxis.
Conclusion: Before antiresorptive medication is begun, oral hygiene should be improved. Moreover, it seems that perioperative antibiotic prophylaxis and adequate plastic wound closure can often prevent MRONJ. In view of the fact that bisphosphonates can persist in bone for more than 15 years, patients should be thoroughly informed of the risk that antiresorptive treatment can cause MRONJ, and the measures discussed should be initiated.
In Germany, 1.7 million of patients with osteoporosis are taking antiresorptive medication. Patients with multiple myeloma (MM) and underlying malignant diseases resulting in bone metastases are also treated with bisphosphonates (BP) or other antiresorptive medications (1, 2).
If the medication is administered orally, esophagitis is observed in many cases; if it is given intravenously, acute-phase reactions may occasionally be observed after the first administration. Furthermore, hypocalcemia and hypomagnesemia have been described, as has, in rare cases, acute renal failure (3). Severe adverse effects are less common, such as medication-related osteonecrosis of the jaw (MRONJ)—which can affect especially patients with malignancies in 1–20% of cases—or, rather more rarely, atypical femoral fractures (4–7). In addition to bisphosphonates, other drugs—for example, denosumab—can cause MRONJ (Tables 1 and 2).
The clinical finding in MRONJ is exposed bone in the oral cavity for a period of more than 8 weeks after prior therapy with bisphosphonates or other drugs that affect the bone metabolism (8) (Figure a–c, Box 1). Progression of the condition can lead to tooth loss and necrosis of entire sections of the jaw bone, including pathological fractures of the mandible.
Structurally, bisphosphonates resemble inorganic pyrophosphate and bind covalently to hydroxyapatite. They have different potencies and can be administered orally or intravenously (Table 1). Amino- and nitrogen-free bisphosphonates are taken up by osteoclasts during the bone resorption process and inhibit osteoclast-mediated bone resorption by means of toxic ATP analogues or through inhibition of farnesyl pyrophosphate synthase. Their tight binding and the release and re-deposition in the context of bone remodeling mean that they often remain in the bone for more than 15 years (9, 10).
The pathomechanism of the development of necrosis remains ultimately unexplained. The pH value, which is lowered as a result of the inflammatory response, triggers and biologically activates the bisphosphonate and results in a raised, locally toxic molecule concentration. The extent of the risk depends on:
- The indication for antiresorptive therapy (malignancy or osteoporosis)
- The administration route (intravenous or oral)
- The duration of the treatment.
The mean duration of treatment until MRONJ develops is 20 months in patients with malignant disease and 4.4 years in patients receiving oral treatment for osteoporosis (11, 12). Further risk factors include odontogenic infections and periodontal diseases, which are present in 71–84% of cases. Pressure sores from dentures double the risk ratio; in 62% of cases, dental extractions are the trigger (8, 13–15).
The treatment of MRONJ is complex and often associated with inpatient stays and surgery.
Material and method
Our research question was formulated on the basis of the PRISMA guidelines: which available, scientifically-based approaches exist for the prevention of medication-related osteonecrosis of the jaw? In order to find an answer to this question, two of the authors (PP and PV) conducted a systematic literature search using the databases PubMed and the Cochrane Library, as well as the search engine Google Scholar. Because of the initial description of the disorder in 2003 (16) we restricted our search period to the time between January 2000 and November 2015. We used the following search terms: “Bisphosphonates OR Medication, OR Antiresorptive AND osteonecrosis AND jaw AND prevention”. We also searched for the MeSH term “Bisphosphonate-related osteonecrosis of the jaw AND prevention & control”. We included in our study publications on prevention strategies for MRONJ in patients with metastases originating from solid tumors and with osteoporosis. We did not include in the study articles that were in languages other than English or German, mere review articles, and animal models. We excluded studies in which medication-related osteonecrosis of the jaw had already occurred or been treated. The aim of our study was to identify approaches to preventing the disease. We excluded studies with fewer than 5 patients.
We extracted the following parameters from each article:
- Study design
- Number of patients
- Preventive method
- Success rate
- Mean follow-up period.
The electronic database search yielded 195 entries from PubMed, 148 entries from the PubMed MeSH term search, and 2 entries from the search of the Cochrane Library. The search with Google Scholar identified 214 sources. After eliminating duplicate entries, we excluded 105 review articles, animal models, and case reports, which left us with 67 potentially relevant publications. Of these, we excluded 28 as they contained existing or previously treated MRONJ. A further 13 publications were excluded after scanning the full text versions of the articles, because they did not pursue a preventive approach, or because the success rate or follow-up periods were not shown. Eventually we included 15 studies in our evaluation (eFigure, eTable 1) (17–30). We found no randomized controlled trials but case series with a high risk of bias. The evidence level of most of the studies was moderate because of the lack of randomization in most of them and therefore corresponded to level IIb, according to the classification system of the AWMF (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften [Association of the Scientific Medical Societies in Germany]) and the ÄZQ (Ärztliches Zentrum für Qualität in der Medizin [Medical Center for Quality in Medicine]). The evidence level of the described new preventive approaches was low at a value of III (eTable 2).
In a case series in which the risk was explained in detail, a dental exam took place before the start of treatment, oral hygiene was improved, and with 6-monthly checkups were performed in patients with multiple myeloma and solid tumors with bone metastases, the incidence of MRONJ in 1243 patients fell from 4.6% to 0.8% (28). Risk factors were detected by using radiographs, teeth that were beyond salvaging were extracted, conservative/restorative dental treatment was undertaken, and patients were informed about the importance of good oral hygiene.
General risk factors, such as smoking (odds ratio [OR] 3.0; 95% confidence interval [CI]: [0.8; 10.4]), alcohol consumption, or poorly controlled diabetes (OR 2.78; 95% CI [1.27; 6.07] were also treated.
After the initial examination, bisphosphonate therapy was started immediately in 36–48% of patients. Dental surgical measures delayed the start of treatment by 6–8 weeks. Patients receiving bisphosphonate therapy underwent professional dental hygiene treatments at regular intervals, with 6-monthly professional dental examinations, and annual x-ray exams. The recommendations in Box 2 are derived from these measures (18, 31–33).
Where teeth had been extracted, the exposure of bone in the oral cavity led to bacterial colonization of the modified bone. In 57% of patients receiving bisphosphonate treatment, MRONJ developed after dental extraction without perioperative antibiotic prophylaxis, whereas if such prophylaxis was given, no cases of MRONJ were seen (34).
Extending the antibiotic treatment to three days before dental extraction until 17 days afterwards did not confer any additional effect in terms of the development of MRONJ (20, 21). The extraction wound was covered with a mucoperiosteal flap in order to protect the bone from pathogens inside the oral cavity (19). Professional dental hygiene treatments, in which oral microorganisms may concentrate in the periodontal space, did not lead to an increase in MRONJ (34).
Atraumatic methods have been described as alternatives to surgical tooth extraction, in order to reduce pathogen load. Orthodontic elastic ligatures will eventually result in dental exfoliation, but the mean duration of treatment is 6 weeks (23). In one study, low level laser therapy during and after the extraction led to postoperative MRONJ in 2.5% of interventions, which healed when the laser treatment was continued (26). In another study, treatment with autologous plasma-rich growth factor in the setting of the tooth extraction as a means of covering the defect, without using plastic surgical wound closure, led to MRONJ in 2.3% of cases (eTable 1).
Since bisphosphonates were introduced to the market for the treatment of osteoporosis, a reduction in the rate of femoral head fractures of 24.5% has been documented (35). In patients with malignant disease, treatment with bisphosphonates prolongs the time interval before bone metastases develop, reduces the risk of skeletal related events (SRE) and bone pain, and improves quality of life. However, because of the higher dosage and frequency of application, treatment with bisphosphonates is associated with an increased risk for MRONJ (7, 36, 37).
In 2003, Marx et al. were the first to report occurrences of osteonecrosis of the jaw after intravenous administration of zoledronate and pamidronate in patients with multiple myeloma and metastatic breast cancer (16).
The German S3 guideline distinguishes different risk profiles in MRONJ. Patients with primary osteoporosis, who receive bisphosphonates orally or intravenously, have a low risk profile (prevalence 0.1%). The risk in therapy-induced osteoporosis, which is treated by means of 6-monthly intravenous bisphosphonate applications, is 2%. Patients who receive intravenous bisphosphonates on a monthly basis because of bone metastases or multiple myeloma are at high risk (prevalence 1–20%) (38).
Before initiating antiresorptive therapy, a systematic examination of the oral cavity by a dentist is a compulsory requirement. Patients should be informed about the risk of MRONJ. While undergoing antiresorptive treatment, patients need to maintain good oral hygiene, and regular checkups should be conducted at 6-monthly intervals (18). Before starting antiresorptive therapy, teeth and implants that are beyond salvaging should be removed, and pericoronal infections and entry points for pathogens should be eliminated. In this way, necroses can successfully be prevented from recurring (17, 38). If the underlying disorder permits this, the antiresorptive therapy should be delayed by 2–3 weeks until the extraction wounds have healed. However, MRONJ can also develop spontaneously or after small trauma. For this reason, it is important to ensure that dentures with mucosa contact are well fitted, in order to avoid pressure sores/mucosal ulcers. Surgical interventions should be undertaken in all patients receiving systemic antibiotic treatment at least one day before and 3 days after the intervention. Antiresorptive therapy should be restarted only once the bone has healed completely (8, 37) (Box 2).
For manifest osteonecrosis of the jaw, the guidelines of the American Association of Oral and Maxillofacial Surgeons (AAOMS) recommend a stage-appropriate approach, using primarily conservative therapeutic measures (8). Cure rates are 23% for exclusively conservative therapy using antibiotics and antibacterial rinses (39).
The German guideline of the AWMF favors early surgical intervention, so as to prevent progression of the lesion and in order to achieve cure rates of higher than 90% (38). In the context of surgical therapy, patients received prophylactic intravenous antibiotics perioperatively two days before and—depending on the extent of the necrosis—up to five days after the procedure. Under general anesthesia, the entire necrotically altered bone is ablated, sharp edges are smoothed, and the soft tissue is closed over the bone by plastic surgical techniques, using multiple-layer sutures (40). In order to be able to assess the extent of the necrosis during the operation, fluorescent marking can be used to expose non-vital bone (e10). To help the wound to heal, patients should ingest only liquid foods through a nasogastric tube (38).
Because of its relatively short half-life, the therapeutic effect of the receptor activator of NF-κB Ligand (RANKL) antibody denosumab ceases within 6 months after administration of the substance has ended. By contrast, the covalent binding of bisphosphonates to hydroxyapatite ensures a half-life of several years’ duration in the bone, which leads to an extended therapeutic effect in spite of a treatment break (37, e11). The decision regarding a break from bisphosphonate treatment should be made individually for each patient after assessing their fracture risk (Table 3). There are currently no data on when antiresorptive therapy should be restarted. Bone density measurements or serum markers 2–3 years after the start of the break may provide indications of the residual activity of the bisphosphonate (36, e16).
As other substances—such as denosumab, which is also used to prevent fractures in malignancy and osteoporosis—are also associated with the occurrence of osteonecrosis of the jaw, the term bisphosphonate-associated osteonecrosis of the jaw was substituted by medication-related osteonecrosis of the jaw (8, e2). The incidence of MRONJ for denosumab in phase II and III clinical trials in patients with metastatic solid tumors is 2.0%, compared with 1.4% for zoledronate.
In the setting of osteoporosis treatment, similar incidence rates have been described for denosumab as for bisphosphonates (e17). The vascular endothelial growth-factor (VEGF) antibody bevacizumab, which is also used in tumor therapy, has also been associated with the occurrence of osteonecrosis of the jaw. So far, 11 case reports have been published for sole administration of bevacizumab. Combination treatment with bisphosphonates is associated with a 30-fold increase in the risk for developing MRONJ (e3, e5, e18). Four case reports are currently available for the tyrosine kinase inhibitor sunitinib, and the mechanistic target of rapamycin (mTOR) inhibitors everolimus und temsirolimus (2 case reports) are associated with a minimally increased risk for developing MRONJ; however, this risk rises substantially when the bisphosphonates are given as combination treatment (e5) (Table 2).
As the understanding of its pathogenesis is incomplete and biomarkers for identifying patients at risk of developing MRONJ are lacking, options for preventing and treating MRONJ are limited. Early dental examination and preventive treatment are crucial for preventing MRONJ. No scientific basis currently exists for a positive effect of interrupting antiresorptive therapy in tooth extractions or other procedures. Specialist societies recommend in high-risk patients a therapeutic break of 2 months before the planned procedure, as well as continuation of treatment only once wound healing is complete (8). In patients receiving intravenous bisphosphonate treatment, the preventive measures should have been taken before the treatment even starts. The short (compared with bisphosphonates) half-life of denosumab can be used to minimize risk. Denosumab is completely excreted by the body after 6 months. This is also the case for the substances bevacizumab and sunitinib, neither of which accumulates in the bone (8).
While antiresorptive medications improve patients’ quality of life by reducing tumor-related complications, this quality of life can be impaired by pain, exposed bone areas, and maxillary sinusitis—which accompany MRONJ (e19). Because of their increasingly widespread use and the extended indication for antiresorptive drugs, as well as the longer life expectancy of the population and tumor patients, the number of affected patients will increase in future (e20). Prophylaxis and early detection before, during, and after therapy in the context of general practice can, however, rather successfully prevent MRONJ (38).
Conflict of interest statement
The authors declare that no conflict of interest exists.
Manuscript received on 21 July 2016, revised version accepted on
9 November 2016.
Translated from the original German by Birte Twisselmann, PhD.
Dr. med. Dr. med. dent. Philipp Poxleitner
Department für Zahn-, Mund- und Kieferheilkunde
Klinik für Mund-, Kiefer- und Gesichtschirurgie
79106 Freiburg im Breisgau, Germany
For eReferences please refer to:
Department of Medicine I: Hematology, Oncology, and Stem-Cell Transplantation, Medical Center—University of Freiburg: Prof. Dr. med. Engelhardt
|1.||Haussler B, Gothe H, Gol D, Glaeske G, Pientka L, Felsenberg D: Epidemiology, treatment and costs of osteoporosis in Germany— the BoneEVA Study. Osteoporos Int 2007; 18: 77–84 CrossRef MEDLINE|
|2.||Liu J, Huang W, Zhou R, et al.: Bisphosphonates in the treatment of patients with metastatic breast, lung, and prostate cancer: a meta-analysis. Medicine 2015; 94: e2014 MEDLINE MEDLINE PubMed Central|
|3.||Pazianas M, Abrahamsen B: Safety of bisphosphonates. Bone 2011; 49: 103–10 CrossRef MEDLINE|
|4.||Walter C, Al-Nawas B, Frickhofen N, et al.: Prevalence of bisphosphonate associated osteonecrosis of the jaws in multiple myeloma patients. Head Face Med 2010; 6: 11 CrossRef MEDLINE PubMed Central|
|5.||Kyle RA, Yee GC, Somerfield MR, et al.: American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 2007; 25: 2464–72 CrossRef MEDLINE|
|6.||Durie BG, Katz M, Crowley J: Osteonecrosis of the jaw and bisphosphonates. N Engl J Med. 2005; 353: 99–10 CrossRef MEDLINE|
|7.||Edwards BJ, Bunta AD, Lane J, et al.: Bisphosphonates and nonhealing femoral fractures: analysis of the FDA Adverse Event Reporting System (FAERS) and international safety efforts: a systematic review from the Research on Adverse Drug Events And Reports (RADAR) project. J Bone Joint Surg Am 2013; 95: 297–307 CrossRef MEDLINE PubMed Central|
|8.||Ruggiero SL, Dodson TB, Fantasia J, et al.: American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update. J Oral Maxillofac Surg 2014; 72: 1938–56 CrossRef CrossRef MEDLINE|
|9.||Licata AA: Discovery, clinical development, and therapeutic uses of bisphosphonates. Ann Pharmacother 2005; 39: 668–77 CrossRef MEDLINE|
|10.||Frith JC, Monkkonen J, Auriola S, Monkkonen H, Rogers MJ: The molecular mechanism of action of the antiresorptive and antiinflammatory drug clodronate: evidence for the formation in vivo of a metabolite that inhibits bone resorption and causes osteoclast and macrophage apoptosis. Arthritis Rheum 2001; 44: 2201–10 CrossRef|
|11.||Bamias A, Kastritis E, Bamia C, et al.: Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005; 23: 8580–7 CrossRef MEDLINE|
|12.||Lo JC, O’Ryan FS, Gordon NP, et al.: Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 2010; 68: 243–53 CrossRef MEDLINE|
|13.||Tsao C, Darby I, Ebeling PR, et al.: Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. J Oral Maxillofac Surg 2013; 71: 1360–6 CrossRef MEDLINE|
|14.||Vahtsevanos K, Kyrgidis A, Verrou E, et al.: Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 2009; 27: 5356–62 CrossRef MEDLINE|
|15.||Saad F, Brown JE, Van Poznak C, et al.: Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 2012; 23: 1341–7 CrossRef MEDLINE|
|16.||Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61: 1115–7 CrossRef|
|17.||Bonacina R, Mariani U, Villa F, Villa A: Preventive strategies and clinical implications for bisphosphonate-related osteonecrosis of the jaw: a review of 282 patients. J Can Dent Assoc 2011; 77: b147 MEDLINE|
|18.||Dimopoulos MA, Kastritis E, Bamia C, et al.: Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol 2009; 20: 117–20 CrossRef MEDLINE|
|19.||Ferlito S, Liardo C, Puzzo S: Dental extractions in patient treated with intravenous bisphosphonates and risk of osteonecrosis of jaws: presentation of a preventive protocol and case series. Minerva Stomatol 2010; 59: 593–601 MEDLINE|
|20.||Heufelder MJ, Hendricks J, Remmerbach T, Frerich B, Hemprich A, Wilde F: Principles of oral surgery for prevention of bisphosphonate-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol 2014; 117: e429–35 CrossRef MEDLINE|
|21.||Lodi G, Sardella A, Salis A, Demarosi F, Tarozzi M, Carrassi A: Tooth extraction in patients taking intravenous bisphosphonates: a preventive protocol and case series. J Oral Maxillofac Surg 2010; 68: 107–10 CrossRef MEDLINE|
|22.||Mozzati M, Arata V, Gallesio G, Carossa S: A dental extraction protocol with plasma rich in growth factors (PRGF) in patients on intravenous bisphosphonate therapy: a case-control study. Joint Bone Spine 2011; 78: 648–9 CrossRef MEDLINE|
|23.||Regev E, Lustmann J, Nashef R: Atraumatic teeth extraction in bisphosphonate-treated patients. J Oral Maxillofac Surg 2008; 66: 1157–61 CrossRef MEDLINE|
|24.||Scoletta M, Arata V, Arduino PG, et al.: Tooth extractions in intravenous bisphosphonate-treated patients: a refined protocol. J Oral Maxillofac Surg 2013; 71: 994–9 CrossRef MEDLINE|
|25.||Vandone AM, Donadio M, Mozzati M, et al.: Impact of dental care in the prevention of bisphosphonate-associated osteonecrosis of the jaw: a single-center clinical experience. Ann Oncol 2012; 23: 193–200 CrossRef MEDLINE|
|26.||Vescovi P, Meleti M, Merigo E, et al.: Case series of 589 tooth extractions in patients under bisphosphonates therapy. Proposal of a clinical protocol supported by Nd:YAG low-level laser therapy. Med Oral Patol Oral Cir Bucal 2013; 18: e680–5 CrossRef MEDLINE PubMed Central|
|27.||Ripamonti CI, Maniezzo M, Campa T, et al.: Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol 2009; 20: 137–45 CrossRef MEDLINE|
|28.||Sim Ie W, Sanders KM, Borromeo GL, Seymour JF, Ebeling PR: Declining incidence of medication-related osteonecrosis of the jaw in patients with cancer. J Clin Endocrinol Metab 2015; 100: 3887–93 CrossRef MEDLINE|
|29.||Bramati A, Girelli S, Farina G, et al.: Prospective, mono-institutional study of the impact of a systematic prevention program on incidence and outcome of osteonecrosis of the jaw in patients treated with bisphosphonates for bone metastases. J Bone Miner Metab 2015; 33: 119–24 CrossRef MEDLINE|
|30.||Scoletta M, Arduino PG, Pol R, et al.: Initial experience on the outcome of teeth extractions in intravenous bisphosphonate-treated patients: a cautionary report. J Oral Maxillofac Surg 2011; 69: 456–62 CrossRef MEDLINE|
|31.||Kyrgidis A, Vahtsevanos K, Koloutsos G, et al.: Bisphosphonate-related osteonecrosis of the jaws: a case-control study of risk factors in breast cancer patients. J Clin Oncol 2008; 26: 4634–8 CrossRef MEDLINE|
|32.||Yarom N, Yahalom R, Shoshani Y, Hamed W, Regev E, Elad S: Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome. Osteoporos Int 2007; 18: 1363–70 CrossRef MEDLINE|
|33.||Molcho S, Peer A, Berg T, Futerman B, Khamaisi M: Diabetes microvascular disease and the risk for bisphosphonate-related osteonecrosis of the jaw: a single center study. J Clin Endocrinol Metab 2013; 98: E1807–12 CrossRef MEDLINE|
|34.||Montefusco V, Gay F, Spina F, et al.: Antibiotic prophylaxis before dental procedures may reduce the incidence of osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates. Leuk Lymphoma 2008; 49: 2156–62 CrossRef MEDLINE|
|35.||Brauer CA, Coca-Perraillon M, Cutler DM, Rosen AB: Incidence and mortality of hip fractures in the United States. JAMA 2009; 302: 1573–9 CrossRef MEDLINE PubMed Central|
|36.||McClung M, Harris ST, Miller PD, et al.: Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am J Med 2013; 126: 13–20 CrossRef MEDLINE|
|37.||Saad F, Lipton A: Clinical benefits and considerations of bisphosphonate treatment in metastatic bone disease. Semin Oncol 2007; 34: S17–23 CrossRef MEDLINE|
|38.||Grötz K, Piesold JU, Al-Nawas B: Bisphosphonat-assoziierte Kiefernekrose (BP-ONJ) und andere Medikamenten-assoziierte Kiefernekrosen. AWMF Online 2012; AWMF Register-Nr. 007/091.|
|39.||Hoff AO, Toth BB, Altundag K, et al.: Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 2008; 23: 826–36 CrossRef MEDLINE PubMed Central|
|40.||Voss PJ, Joshi Oshero J, Kovalova-Muller A, et al.: Surgical treatment of bisphosphonate-associated osteonecrosis of the jaw: technical report and follow up of 21 patients. J Craniomaxillofac Surg 2012; 40: 719–25 CrossRef MEDLINE|
|e1.||Dunford JE, Thompson K, Coxon FP, et al.: Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 2001; 296: 235–42.|
|e2.||Hamadeh IS, Ngwa BA, Gong Y: Drug induced osteonecrosis of the jaw. Cancer Treat Rev 2015; 41: 455–64 CrossRef MEDLINE|
|e3.||Papapoulos S, Chapurlat R, Libanati C, et al.: Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res 2012; 27: 694–701 CrossRef MEDLINE PubMed Central|
|e4.||Papapoulos S, Lippuner K, Roux C, et al.: The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study. Osteoporos Int 2015; 26: 2773–83 CrossRef MEDLINE PubMed Central|
|e5.||Guarneri V, Miles D, Robert N, et al.: Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer. Breast Cancer Res Treat 2010; 122: 181–8 CrossRef MEDLINE|
|e6.||Smidt-Hansen T, Folkmar TB, Fode K, Agerbaek M, Donskov F: Combination of zoledron acid and targeted therapy is active but may induce osteonecrosis of the jaw in patients with metastatic renal cell carcinoma. J Oral Maxillofac Surg 2013; 71: 1532–40 CrossRef MEDLINE|
|e7.||Giancola F, Campisi G, Lo Russo L, Muzio LL, Di Fede O: Osteonecrosis of the jaw related to everolimus and bisphosphonate: a unique case report? Ann Stomatol (Roma) 2013; 4: 20–1.|
|e8.||Kim DW, Jung YS, Park HS, Jung HD: Osteonecrosis of the jaw related to everolimus: a case report. Br J Oral Maxillofac Surg 2013; 51: e302–4 CrossRef MEDLINE|
|e9.||Dickinson M, Prince HM, Kirsa S, et al.: Osteonecrosis of the jaw complicating bisphosphonate treatment for bone disease in multiple myeloma: an overview with recommendations for prevention and treatment. Intern Med J 2009; 39: 304–16 CrossRef MEDLINE|
|e10.||Pautke C, Bauer F, Otto S, et al.: Fluorescence-guided bone resection in bisphosphonate-related osteonecrosis of the jaws: first clinical results of a prospective pilot study. J Oral Maxillofac Surg 2011; 69: 84–91 CrossRef MEDLINE|
|e11.||Bonnick SL: Going on a drug holiday? J Clin Densitom 2011; 14: 377–83 CrossRef MEDLINE|
|e12.||Black DM, Schwartz AV, Ensrud KE, et al.: Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 2006; 296: 2927–38 CrossRef MEDLINE|
|e13.||Watts NB, Chines A, Olszynski WP, et al.: Fracture risk remains reduced one year after discontinuation of risedronate. Osteoporos Int 2008; 19: 365–72 CrossRef MEDLINE|
|e14.||Curtis JR, Westfall AO, Cheng H, Delzell E, Saag KG: Risk of hip fracture after bisphosphonate discontinuation: implications for a drug holiday. Osteoporos Int 2008; 19: 1613–20 CrossRef MEDLINE PubMed Central|
|e15.||Gallagher AM, Rietbrock S, Olson M, van Staa TP: Fracture outcomes related to persistence and compliance with oral bisphosphonates. J Bone Miner Res 2008; 23: 1569–75 CrossRef MEDLINE|
|e16.||Bonnick SL, Shulman L: Monitoring osteoporosis therapy: bone mineral density, bone turnover markers, or both? Am J Med 2006; 119: S25–31 CrossRef|
|e17.||Qi WX, Tang LN, He AN, Yao Y, Shen Z: Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials. Int J Clin Oncol 2014; 19: 403–10 CrossRef MEDLINE|
|e18.||Whitaker M, Guo J, Kehoe T, Benson G: Bisphosphonates for osteoporosis--where do we go from here? N Engl J Med 2012; 366: 2048–51 CrossRef MEDLINE|
|e19.||Wardley A, Davidson N, Barrett-Lee P, et al.: Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration. Br J Cancer 2005; 92: 1869–76 CrossRef MEDLINE PubMed Central|
|e20.||Miksad RA, Lai KC, Dodson TB, et al.: Quality of life implications of bisphosphonate-associated osteonecrosis of the jaw. Oncologist 2011; 16: 121–32 CrossRef MEDLINE PubMed Central|
|e21.||Scoletta M, Arata V, Arduino PG, et al.: Tooth extractions in intravenous bisphosphonate-treated patients: a refined protocol. J Oral Maxillofac Surg 2013; 71: 994–9 CrossRef MEDLINE|
Cancer Treatment–Induced Bone Loss (CTIBL): State of the Art and Proper Management in Breast Cancer Patients on Endocrine TherapyCurrent Treatment Options in Oncology, 202110.1007/s11864-021-00835-2
Evaluation of Preventive Treatment Protocols for Patients under Antiresorptive Therapy Undergoing Tooth Extraction at a Swiss University ClinicInternational Journal of Environmental Research and Public Health, 202110.3390/ijerph18189924
Actual problems in dentistry, 202010.18481/2077-7566-2019-15-4-103-108
Journal of Oral Science, 202110.2334/josnusd.21-0016
Efficacy of Adjunctive Photobiomodulation in the Management of Medication-Related Osteonecrosis of the Jaw: A Systematic ReviewPhotobiomodulation, Photomedicine, and Laser Surgery, 202210.1089/photob.2022.0084
Success Rate and Safety of Dental Implantology in Patients Treated With Antiresorptive Medication: A Systematic ReviewJournal of Oral Implantology, 202110.1563/aaid-joi-D-19-00088
Kazan medical journal, 202010.17816/KMJ2020-226
Osteonecrosis of the Jaws in Patients Receiving Anti-Angiogenic Drugs and Chemotherapeutics: Literature Review and Case ReportsActa Medica Bulgarica, 201910.2478/amb-2019-0019
Ural Medical Journal, 202210.52420/2071-5943-2022-21-3-30-37
An impossible choice: MRONJ vs ORN? The difficulties of the decision-making process for head and neck cancer patients on long-term anti-angiogenic medicationBritish Dental Journal, 202010.1038/s41415-020-2276-1
Medication-Related Osteonecrosis of the Jaw in Dental Practice: A Retrospective Analysis of Data from the Milan CohortDentistry Journal, 202210.3390/dj10050089
Journal of Cancer Prevention & Current Research, 202210.15406/jcpcr.2022.13.00505
Balkan Journal of Dental Medicine, 202110.2478/bjdm-2020-0034
Journal of the American Geriatrics Society, 202310.1111/jgs.18414