Osteonecrosis of the Jaw or Maxilla after Intravenous Bisphosphonates for Multiple Myeloma and Breast Cancer: Long-Term Follow-Up Shows a Slow Rate of Healing.

Abstract Osteonecrosis of the jaw or maxilla (ONJM) is a rare but clinically significant disorder recently reviewed in a large retrospective study by our group (Hoff et al, 27th ASBMR Meeting 2005, Presentation #1218). A subset of the ONJM patients with breast cancer or myeloma was followed at the University of Texas M.D. Anderson Cancer Center (UTMDACC) dental clinic. This analysis describes the natural history of ONJM in this subset. Thirteen of 29 ONJM patients treated with intravenous bisphosphonates (IVBP) at UTMDACC and 1 ONJM patient treated elsewhere were evaluated in the dental clinic for more than 6 months (myeloma, n=7; breast cancer, n=7). Measurement of the maximum length of exposed bone was documented at each visit. Each patient received a standard regimen of conservative dental care with debridement only when indicated. All patients received zoledronic acid (mean cumulative dose 80mg; range 24–152mg) and 10 patients also received pamidronate (mean cumulative dose 1665mg; range 90–2700mg). This subset was followed for a median duration of 18.2 months (range: 7.1–67.3 months). The mean length of exposed bone at initial evaluation was 11 mm (range: 2–29 mm). The lesion from baseline to the most recent clinic visit progressed in 7 patients (50%), remained stable in 2 (14%), regressed in 2 (14%), and resolved in 3 (21%). Persistent ONJ was seen if IVBP was stopped (n=8), decreased in frequency (n=1), or continued at the same dose/frequency (n=2) (Graphs 1, 2). Complete resolution occurred in 3 multiple myeloma patients; IVBP was decreased in one and discontinued in 2 of the resolved cases (heavy lines on Graph 1). Our experience shows that ONJM is a disorder with slow resolution in most patients, lasting as long as 5 years. In the oncologic setting where there is clear benefit of bisphosphonate therapy, studies to optimize the dosing regimen may be needed. Graph 1. Myeloma (n=7) Graph 1. Myeloma (n=7) Graph 2. Breast Cancer (n=7) Graph 2. Breast Cancer (n=7)

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Osteonecrosis of the jaw: Long-term follow-up shows variable rate of healing

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.9061 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 9061-9061

Author(s):

M. I. Hu ◽

A. O. Hoff ◽

B. B. Toth ◽

K. Altundag ◽

V. Guarneri ◽

...

Keyword(s):

Breast Cancer ◽

Cumulative Dose ◽

Dental Care ◽

Healing Process ◽

Osteonecrosis Of The Jaw ◽

Cancer Center ◽

Dental Clinic ◽

Standard Regimen ◽

Exposed Bone ◽

Median Cumulative Dose

9061 Background: Osteonecrosis of the jaw (ONJ) is a rare but clinically significant disorder recently reviewed in a large retrospective study (Hoff et al, 42nd ASCO Annual Meeting 2006, Abstract #8528). A subset of the ONJ patients from that study with breast cancer or multiple myeloma (MM) was followed at the University of Texas M.D. Anderson Cancer Center (UTMDACC) dental clinic. This analysis describes the natural history of ONJ in this subset. Methods: Thirteen of 29 ONJ patients treated with intravenous bisphosphonates (IVBP) at UTMDACC and 1 treated elsewhere were evaluated in the dental clinic for > 6 months (MM, n=7; breast cancer, n=7). The maximum length of exposed bone was measured at each visit. Patients received a standard regimen of conservative dental care with debridement when indicated. Results: All 14 patients received zoledronic acid (median cumulative dose 72 mg; range 24–152) and 10 also received pamidronate (median cumulative dose 1,710 mg; range 90–2,700). They were followed for a median duration of 17.1 months (range: 7.1–67.3). The mean length of exposed bone at initial evaluation was 11 mm (SD: 8.4). Each patient demonstrated fluctuating clinical courses. The lesion from baseline to the last visit progressed in 7 patients (median increase of 13 mm), remained stable in 2, regressed in 2 and resolved in 3. Persistent ONJ was seen if IVBP was stopped (n=8), decreased in frequency (n=1) or continued at the same dose/frequency (n=2). Complete resolution occurred in 3 MM patients, where IVBP was discontinued, decreased in frequency or replaced by weekly oral alendronate. Conclusions: Our experience shows that ONJ resolved in 21% but persisted in the majority of patients with a duration of up to 5 years with conservative dental care. Further studies are needed to evaluate the pathogenesis and healing process of ONJ. No significant financial relationships to disclose.

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Prevalence of Medication-Related Osteonecrosis of the Jaw in Patients with Breast Cancer, Prostate Cancer, and Multiple Myeloma

Dentistry Journal ◽

10.3390/dj4040032 ◽

2016 ◽

Vol 4 (4) ◽

pp. 32 ◽

Cited By ~ 5

Author(s):

Petra Rugani ◽

Christian Walter ◽

Barbara Kirnbauer ◽

Stephan Acham ◽

Yvonne Begus-Nahrman ◽

...

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Multiple Myeloma ◽

Osteonecrosis Of The Jaw ◽

Cancer Prostate

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Conservative Treatment of Bisphosphonate-Related Osteonecrosis of the Jaw in Multiple Myeloma Patients

International Journal of Dentistry ◽

10.1155/2014/427273 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 14

Author(s):

Pelagia I. Melea ◽

Ioannis Melakopoulos ◽

Efstathios Kastritis ◽

Christina Tesseromatis ◽

Vasileios Margaritis ◽

...

Keyword(s):

Multiple Myeloma ◽

Median Time ◽

Management Strategy ◽

American Association ◽

Osteonecrosis Of The Jaw ◽

Major Surgery ◽

Inclusion Criteria ◽

Successful Management ◽

Intravenous Bisphosphonates ◽

Oral Antibacterial

The use of intravenous bisphosphonates (pamidronate or zoledronic acid) is the cornerstone for the management of multiple myeloma-(MM-) related bone disease. However, osteonecrosis of the jaw (ONJ) is a rare, but sometimes difficult to manage, adverse effect of bisphosphonates therapy. A retrospective review of all MM patients who were treated with bisphosphonates in our department, from 2003 to 2013, and developed ONJ was performed. According to inclusion criteria, 38 patients were studied. All these patients were treated as conservatively as possible according to the American Association of Oral and Maxillofacial Surgeons criteria. Patients were managed with observation, oral antibacterial mouth rinse with chlorhexidine, oral antibiotics, pain control with analgesics, nonsurgical sequestrectomy with or without simultaneous administration of antibiotics, or major surgery with or without antibiotics. Healing of the lesions was achieved in 23 (60%) patients who were treated with conservative measures; the median time to healing was 12 months (95% CI: 4–21). The number of bisphosphonates infusions influenced the time to healing: the median time to healing for patients who received <16 infusions was 7 months and for those with >16 infusions was it 14 monthsP=0.017. We conclude that a primarily nonsurgical approach appears to be a successful management strategy for bisphosphonate-related ONJ.

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Osteonecrosis of the Jaw in Multiple Myeloma Patients: Incidence and Characteristics in Korean Patients.

Blood ◽

10.1182/blood.v114.22.4956.4956 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4956-4956 ◽

Cited By ~ 1

Author(s):

Hyo Jung Kim ◽

Hyeok Shim ◽

Eunkyung Park ◽

Min Kyoung Kim ◽

Seok Jin Kim ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Retrospective Study ◽

Conflicts Of Interest ◽

Previous History ◽

Clinical Manifestations ◽

Osteonecrosis Of The Jaw ◽

Korean Patients ◽

Dental Procedures ◽

Exposed Bone

Abstract Abstract 4956 Introduction Osteonecrosis of the Jaw (ONJ) is a potentially serious complication of bisphosphonate (BP) therapy in multiple myeloma (MM). Despite of current update about bisphosphonate related ONJ (BRONJ), only a few Asian BRONJ cases were reported and incidence of BRONJ in Asian MM patients has not yet been definitively estimated. The purpose of this study was to determine incidence and characteristics of BRONJ in Korean MM patients who were receiving BP therapy. Patients and Methods We invited 9 hospitals of Korean Multiple Myeloma Working Group (KMMWP) to participate in a retrospective multicenter study on BRONJ in MM patients. To defined BRONJ incidence, we reviewed the data from 130 MM patients treated with BP in one hospital. We also reviewed the medical records of MM patients with BRONJ treated in 9 hospitals to know the patterns of disease. We analyzed patient and disease characteristics, type and number of BP infusions, previous history of dental procedures, locations of osteonecrosis, clinical symptoms, treatment and outcome. ONJ was defined as clinical evidence of exposed bone in the jaw, which has been present for more than 8 weeks. Results Nine of 130 MM patients (6.9%) treated with BP developed BRONJ in the hospital. Twenty-two patients with MM developed BRONJ after a median number of 17 BP infusions (range 6 - 50) in all 9 hospitals. None of the patients had been irradiated to the jaw. There were 14 male and 8 female patients. The median age was 62 years (range 46 – 75). Median time from MM diagnosis to BRONJ was 2.8 years (range 0.6 – 15.6). The MM isotype was IgG in 9, IgA in 8, IgM in 1, light chain in 3 and non-secretory myeloma in 1 patient. BP therapy included zoledronate (n = 2) or pamidronate (n = 4) and both drugs as sequential treatment (n = 16). Fifteen patients had recent problems in oral cavity (72.7%) and 14 had prior dental procedures (63.6%). The mandible was involved in 14 patients (63.6%), the maxilla in 7 (31.8%), and both the maxilla and mandible in 1 (4.5%). Patients usually presented with pain and soft tissue swelling. ONJ staging (Khan et al. Canadian consensus practice guidelines of Bisphosphonate associated ONJ. J Rheumatol 2008;35:1391-7) was used to define the severity, there were 5 patients in stage I, 14 in stage II and 1 in stage III. Because of the limitation of retrospective study, the stage of 2 patients could not be confirmed. Management of these established cases were discontinuation of BP and medical treatment including antibiotics and pain killer. Surgical debridement of necrotic bone was performed in 12 patients. From onset of exposed bone in jaw, patients were followed for median 11 months (range 4.2 - 42). Wounds of 10 patients were healed at median 175 days (range 60 – 404) after bone exposure. In 8 patients, lesions had persisted over 154 days (range 66 – 425). Evaluation was impossible for 4 patients due to loss of follow up. Four patients were dead because of disease progression (n = 3) or concomitant infection. BRONJ was healed in 2 of them. Conclusions To the best of our knowledge, this is the largest retrospective study ever reported about BRONJ in Asian MM patients. The incidence of BRONJ in Korean MM patients was 6.9% and this is similar with data in western countries. Clinical manifestations and outcome of BRONJ in Korean patients were not different from previously reported data, but no risk factors could be definitively identified with our retrospective analysis. In the name of KMMWP, prospective trials are ongoing to define incidence and risk factors of BRONJ in Korean MM patients. Disclosures No relevant conflicts of interest to declare.

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Vertebral Fractures After Denosumab Discontinuation in Breast Cancer Survivors: A Single Institution Experience

HSS Journal ® ◽

10.1177/1556331621995846 ◽

2021 ◽

pp. 155633162199584

Author(s):

Michele Yeung ◽

Kaylee Ho ◽

Monica N. Fornier ◽

Azeez Farooki

Keyword(s):

Breast Cancer ◽

Bone Density ◽

Aromatase Inhibitors ◽

Vertebral Fractures ◽

Breast Cancer Survivors ◽

Retrospective Chart Review ◽

Fragility Fractures ◽

Osteonecrosis Of The Jaw ◽

Cancer Center ◽

Drug Discontinuation

Background: Denosumab is approved to prevent fragility fractures in patients with osteoporosis at high risk for fracture and to prevent bone loss in patients with breast and prostate cancer who receive endocrine therapy. The antiresorptive effect of denosumab rapidly dissipates when it is delayed or discontinued, but the risk for, and incidence of, multiple clinical vertebral fractures in patients with breast cancer after stopping denosumab is currently unclear. Question/Purposes: We sought to identify the incidence of clinical vertebral fractures in patients with breast cancer who received at least 2 doses of denosumab (60 mg) and then discontinued the medication. Methods: We conducted a retrospective chart review to identify patients with a history of breast cancer who were treated with denosumab between June 1, 2010, and July 18, 2018, at Memorial Sloan Kettering Cancer Center. We identified 335 postmenopausal women and 1 man with nonmetastatic breast cancer who received their final denosumab injection at least 6.5 months earlier. Data recorded included baseline bone density and the incidence of vertebral fractures after denosumab discontinuation. Results: The median age of patients was 62 years. Patients received between 2 and 13 denosumab doses before drug discontinuation. Most of the patients (310; 92.3%) were also treated with aromatase inhibitors. Of the 194 patients with baseline bone density data, 50 (25.8%) had normal bone density, 97 (50.0%) had osteopenia, and 47 (24.2%) had osteoporosis. The median follow-up duration from the last denosumab dose was 18.5 months. We identified 1 case of spontaneous vertebral fractures after denosumab stoppage. We found no cases of osteonecrosis of the jaw or atypical femur fracture. Most of the patients (88%) had a gap in denosumab dosing. Conclusions: Clinicians treating patients with breast cancer—especially those continuing to take aromatase inhibitors—should be aware of the possible risks of delaying doses of or discontinuing denosumab and should educate their patients accordingly. Prospective studies are needed to fully evaluate the risks of stopping or delaying denosumab.

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A Case of Bisphosphonate-Related Osteonecrosis of the Jaw in a Patient with Subpontic Osseous Hyperplasia

Case Reports in Dentistry ◽

10.1155/2017/9659761 ◽

2017 ◽

Vol 2017 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Chiaki Tsuji ◽

Hiroshi Watanabe ◽

Hidenori Nakayama ◽

Mitsuo Goto ◽

Kenichi Kurita

Keyword(s):

Osteonecrosis Of The Jaw ◽

Dental Clinic ◽

Histopathological Findings ◽

Exposed Bone ◽

Bony Lesion ◽

Bone Exposure

Subpontic osseous hyperplasia (SOH) is a growth of bone occurring on the edentulous ridge beneath the pontics of fixed partial dentures (FPDs). This report describes a case of bisphosphonate- (BP-) related osteonecrosis of the jaw (BRONJ) in a SOH patient followed by deciduation of the bony lesion. A 73-year-old woman visited a dental clinic after experiencing pain and swelling beneath the pontics of a FPD that had been inserted 15 years ago. The pontics were removed, but the symptoms persisted and she was referred to our hospital. There was an osseous bulge and gum swelling around the edentulous ridge of teeth 18 and 19, as well as bone exposure. As she had been taking an oral BP for 6 years, we diagnosed this case as stage 2 BRONJ. Following BP withdrawal, the bony lesion detached from the mandible. The tissue was diagnosed as sequestrum based on the histopathological findings. Two months after deciduation, epithelialization over the area of exposed bone was achieved and no recurrence has been observed.

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Osteonecrosis of the Jaw in Multiple Myeloma Patients (the IFM Registry).

Blood ◽

10.1182/blood.v110.11.4809.4809 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4809-4809

Author(s):

Jean Gabriel Fuzibet ◽

Marie Hélène Viellard ◽

Benoit B.R. Rossignol ◽

Chantal C.D. Doyen ◽

Cyril Hulin ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Risk Factor ◽

Osteonecrosis Of The Jaw ◽

Dental Extraction ◽

Purulent Discharge ◽

Adverse Side Effect ◽

Dental Infection ◽

Exposed Bone ◽

Extensive Surgery

Abstract PURPOSE: to describe the incidence, characteristics and risk factors for osteonecrosis of the jaw (ONJ) in multiple myeloma (MM). PATIENTS AND METHODS : retrospective review of 51 ONJ collected from the IFM centers. For MM, age at diagnosis, isotype, DS staging, nature of chemotherapy and number of Stem-Cell Transplantation were the same that expected. RESULTS: ONJ occurred predominantly in the mandible (70%). The median time of exposure to biphosphonates (BP) was 45 months (4 to 144 months). BP therapy included: zoledronate (85%), pamidronate (10%), clodronate (5%), all of the patients have received intravenous BP before, two patients have no BP at the time of diagnosis of ONJ. RISK FACTORS: dental extraction (59%) other dental care (5%), dental infection (24%), others (30%), no risk factor (10%). SYMPTOMS: pain (92%), purulent discharge (37%), presence of exposed bone (60%), fracture (2%). MANAGEMENT: BP discontinuation (84%), medical treatment (86%), removal of sequestra (51%), extensive surgery (20%). EVOLUTION: improvement (55%), chronical symptoms (70%). INCIDENCE: we have not the number of exposed patients but: 46 centers/73 reported no ONJ.The first report was march 2001. In the same period, 1695 patients where included in IFM trials and only 16 ONJ where observed. Year of diagnosis: before 2004: 5 cases; 2004: 11 cases; 2005:26 cases; 2006: 7 cases; 2007(6 months): 2cases. CONCLUSION: ONJ is an adverse side effect of amino BP therapy (zoledronate>pamidronate), is time dependant and often after dental extraction. Preventive recommandations applied in 2005 can explain the decreasing incidence of ONJ in our study.

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The Cumulative Dose But Not The Frequency Of Infusions Is a Risk Factor For The Development Of Osteonecrosis Of The Jaw (ONJ) In Myeloma Patients Who Receive Zoledronic Acid (ZA)

Blood ◽

10.1182/blood.v122.21.3196.3196 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3196-3196 ◽

Cited By ~ 1

Author(s):

Efstathios Kastritis ◽

Evangelos Terpos ◽

Ioannis Melakopoulos ◽

Pelagia Melea ◽

Despoina Kalapanida ◽

...

Keyword(s):

Median Time ◽

Cumulative Dose ◽

Conflicts Of Interest ◽

Large Population ◽

Survival Rates ◽

Average Frequency ◽

Median Number ◽

Osteonecrosis Of The Jaw ◽

Dose Frequency ◽

Increased Risk

Abstract The administration of ZA in patients with symptomatic myeloma is associated with reduction of SREs and possible improvement of survival; its use however, is associated with increased risk of osteonecrosis of the jaw (ONJ). Longer exposure and more infusions of ZA have been associated with higher incidence of ONJ. It has been suggested that longer intervals between ZA infusions may reduce the risk of ONJ; however, this has not been proven. Since 2008, we have adopted a strategy in which ZA is discontinued in patients who remain in remission for more than 2 years, while ZA is administered every 8-12 weeks, after the first year, in patients who have achieved vgPR or CR. The aim of our analysis was to assess the incidence of ONJ in a prospectively studied population treated with ZA and to asses potential risk factors related to dosing and schedule of ZA. Since 2003, all patients in the Department of Clinical Therapeutics (Athens, Greece) undergo dental evaluation before ZA initiation and are instructed to avoid procedures that predispose to ONJ. Only patients who received ZA and survived at least 6 months post their first ZA infusion were included in the analysis. Relative dose frequency of ZA (RDF) was calculated as the average number of weeks between infusions of ZA (weeks between first and last infusion divided by the number of infusions). Time of exposure to ZA was calculated from the date of first infusion until the date of last infusion. Death due to myeloma and development of ONJ were treated as competing events. Between January 2000 and January 2013, 266 patients with symptomatic myeloma fulfilled the above criteria and were included in the analysis. Median age was 68 years (range 36-87 years) and 47% were males. Median follow up was 36 months and 35% of the patients have died. The median number of ZA infusions was 16 (range 1-107) and the median time of exposure to ZA was 29 months, corresponding to 9073 person-months of exposure. Median RDF was one infusion per 7.9 weeks (interquartile range (IQR) 5.8-11.4 weeks). ONJ developed in 26 (10%) patients. Median time from first ZA infusion to development of ONJ was 28 months (range 6-122 months). Accounting for death as a competing event, 1-year risk of ONJ was 1.2% (95% CI 0.3-3%), 2-year risk was 5% (95% CI 2.5-8.5%), 3-year risk was 8.5% (95% CI 5-13%), 4-year risk was 11.5% (95% CI 7.3-17%) and 5-year risk was 14% (95% CI 9-19%) (Figure). The respective survival rates were 93%, 84%, 76%, 65% and 56% at 1, 2, 3, 4 & 5 years. The median time of exposure to ZA was 28 months (IQR 22-46 months) for patients who developed ONJ vs. 24 months (IQR 11-42 months) for those who did not (p=0.2). However, the median number of ZA infusions was 23 for those who developed vs. 14 for those who did not develop ONJ (p=0.004). Increasing number of ZA infusions was associated with higher risk of ONJ: 2.3% of patients who received <10 infusions developed ONJ vs. 12% of patients who received 10-19 infusions vs. 15% of patients who received 20 or more ZA infusions (p=0.012). The incidence rate of ONJ for patients who started ZA before 2008 was 0.31 per 100 person-months vs. 0.26 per 100 person-months for those who started after 2008 (p=0.4). The incidence of ONJ at 3-years was 13.6% (95% CI 8-20%) for patients with an RDF <8 weeks vs. 2.6% (95% CI 0.5-8%) for patients with RDF of ≥8 weeks (p=0.018). However, after adjusting for RDF of ZA infusions, only the number of ZA infusions remained significant (p=0.03). The multivariate analysis showed that both the number and the frequency of ZA infusions were associated with a shorter time to ONJ development. More specifically, average frequency of infusion <8 weeks was associated with a 15-fold (95% CI 4-55, p<0.001) increase in the risk of ONJ, while for every infusion of ZA the risk of ONJ increased by 9% (95% CI 4-14%, p<0.001). In conclusion, our data, in a large population of consecutive unselected patients with symptomatic myeloma who received ZA, indicate that ONJ remains a frequent complication in patients who receive ZA for prolonged periods and the risk increases with the number of ZA infusions. More frequent infusions of ZA are associated with earlier development of ONJ, but the risk of ONJ is associated mainly with the cumulative dose of ZA. Prospective clinical trials should examine if less frequent administration of ZA can reduce the risk of ONJ without compromising its antiresorptive effect. Disclosures: No relevant conflicts of interest to declare.

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