Why osteonecrosis of the jaw after bisphosphonates treatment is more frequent in multiple myeloma than in solid tumors

Objective To determine the incidence of skeletal-related events among multiple myeloma patients who received chemotherapy without a bone-modifying agent (zoledronic acid and denosumab) versus those who received chemotherapy with a bone-modifying agent. The secondary objective was to determine the incidence of skeletal-related events in patients without any prior history of skeletal-related events and who were treated with zoledronic acid every four weeks versus those who received zoledronic acid at an extended interval of every twelve weeks. Additional secondary objectives included the incidence of nephrotoxicity, hypocalcemia and osteonecrosis of the jaw in all patients. Methods This institutional review board-approved, retrospective cohort study included patients 18 to 89 years old with a diagnosis of multiple myeloma, who were being treated with chemotherapy between July 1, 2016 and October 31, 2019. Safety and efficacy were assessed through analysis of pertinent data collected: patient demographics, baseline skeletal-related events, development of new skeletal-related events, number and type of bone-modifying agent doses administered, and drug-related toxicities such as nephrotoxicity, hypocalcemia, and osteonecrosis of the jaw. Results A total of 73 patients were included. New skeletal-related events occurred in 12 patients (27%) in the chemotherapy without a bone-modifying agent group and in 5 patients (17%) in the chemotherapy with a bone-modifying agent group (OR = 0.56, 95% CI [0.172–1.8]; P = 0.32). The incidence of skeletal-related events was similar among patients receiving zoledronic acid every four weeks versus every twelve weeks in patients without a prior skeletal-related event (N = 0 vs. N = 2 respectively; P = 0.47). There were no statistically significant differences observed in each of the three secondary safety endpoints: incidence of hypocalcemia, nephrotoxicity and osteonecrosis of the jaw. Conclusion Multiple myeloma patients receiving chemotherapy without a bone-modifying agent had higher rates of skeletal-related events compared to those being treated with chemotherapy and a bonemodifying agent. Our results highlight the benefit of utilizing bonemodifying agents for the prevention of skeletal-related events in all multiple myeloma patients being treated with chemotherapy.

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Recurrent Low-Energy Femoral Shaft Fractures and Osteonecrosis of the Jaw in a Case of Multiple Myeloma Treated With Bisphosphonates

Journal of Oral and Maxillofacial Surgery ◽

10.1016/j.joms.2008.11.005 ◽

2009 ◽

Vol 67 (3) ◽

pp. 645-649 ◽

Cited By ~ 19

Author(s):

Jonathan M. Grasko ◽

Richard P. Herrmann ◽

Samuel D. Vasikaran

Keyword(s):

Multiple Myeloma ◽

Femoral Shaft ◽

Osteonecrosis Of The Jaw ◽

Low Energy ◽

Femoral Shaft Fractures ◽

Shaft Fractures

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Dental pathologies in tumor patients with bone metastases or multiple myeloma scheduled for antiresorptive therapy

Future Oncology ◽

10.2217/fon-2020-1240 ◽

2021 ◽

Author(s):

Johannes Laimer ◽

Martin Hechenberger ◽

Daniela Müller ◽

Benjamin Walch ◽

Andreas Kolk ◽

...

Keyword(s):

Multiple Myeloma ◽

Oral Surgery ◽

Osteonecrosis Of The Jaw ◽

University Hospital ◽

Antiresorptive Therapy ◽

Jaw Cysts ◽

Dental Focus ◽

Antiresorptive Drugs ◽

The University ◽

Tooth Extractions

Background: Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe complication of mainly antiresorptive drugs. We evaluated the frequency of dentoalveolar pathologies in patients scheduled for antiresorptive therapy in a ‘real-world’ setting, also including patients with poor oral health potentially requiring tooth extractions and/or other dentoalveolar surgery. This approach is in contrast to the setting of recent randomized trials with restrictive exclusion criteria. Patients & methods: We prospectively included patients suffering from solid tumors with osseous metastases or multiple myeloma. Screening for dentoalveolar pathologies was done prior to initiation of antiresorptive therapy at the specialized MRONJ clinic of the University Hospital for Cranio-Maxillofacial and Oral Surgery, Innsbruck, Austria. Results: 119 subjects could be included. In 76 patients (63.9%), a dental focus was revealed including deep caries (24.4% of patients), chronic apical periodontitis (26.9%), periodontal disease (45.8%), root remnants (16%), jaw cysts (2.5%), partially impacted teeth (5.0%) and peri-implantitis (5.0%). Conclusion: Considering the high number of dentoalveolar pathologies (63.9%), systematic dental focus screening prior to initiation of antiresorptive therapy is of utmost importance to lower the risk for MRONJ.

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Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis

Blood ◽

10.1182/blood-2008-04-147884 ◽

2008 ◽

Vol 112 (7) ◽

pp. 2709-2712 ◽

Cited By ~ 161

Author(s):

Maria E. Sarasquete ◽

Ramon García-Sanz ◽

Luis Marín ◽

Miguel Alcoceba ◽

Maria C. Chillón ◽

...

Keyword(s):

Multiple Myeloma ◽

Cytochrome P450 ◽

Genome Wide Association Study ◽

Osteonecrosis Of The Jaw ◽

Bisphosphonate Therapy ◽

Polymorphism Analysis ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Genome Wide ◽

A Genome

Abstract We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients under bisphosphonate therapy. A genome-wide association study was performed using 500 568 single nucleotide polymorphisms (SNPs) in 2 series of homogeneously treated MM patients, one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four SNPs (rs1934951, rs1934980, rs1341162, and rs17110453) mapped within the cytochrome P450-2C gene (CYP2C8) showed a different distribution between cases and controls with statistically significant differences (P = 1.07 × 10−6, P = 4.231 × 10−6, P = 6.22 × 10−6, and P = 2.15 × 10−6, respectively). SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni correction (P corrected value = .02). Genotyping results displayed an overrepresentation of the T allele in cases compared with controls (48% vs 12%). Thus, individuals homozygous for the T allele had an increased likelihood of developing ONJ (odds ratio 12.75, 95% confidence interval 3.7-43.5).

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Prospective Observational Study of Bisphosphonate-Related Osteonecrosis of the Jaw in Multiple Myeloma: Microbiota Profiling and Cytokine Expression

Frontiers in Oncology ◽

10.3389/fonc.2021.704722 ◽

2021 ◽

Vol 11 ◽

Author(s):

Ashraf Z. Badros ◽

Mariam Meddeb ◽

Dianna Weikel ◽

Sunita Philip ◽

Todd Milliron ◽

...

Keyword(s):

Multiple Myeloma ◽

Periodontal Disease ◽

Osteonecrosis Of The Jaw ◽

Cytokine Profile ◽

Rrna Gene ◽

Oral Microbiota ◽

Angiogenic Growth Factors ◽

Microbial Profiling ◽

Main Culprit ◽

Turnover Markers

PurposeDefine incidence and risk factors of osteonecrosis of the jaw (ONJ) and explore oral microbial signatures and host immune response as reflected by cytokine changes in saliva and serum in multiple myeloma (MM) patients on bisphosphate (BP) therapy.Patients and MethodsA single center observational prospective study of MM patients (n = 110) on >2 years of BP, none had ONJ at enrollment. Patients were followed every 3 months for 18 months with clinical/dental examination and serial measurements of inflammatory cytokines, bone turnover markers, and angiogenic growth factors. Oral microbiota was characterized by sequencing of 16S rRNA gene from saliva.ResultsOver the study period 14 patients (13%) developed BRONJ, at a median of 5.7 years (95% CI: 1.9–12.0) from MM diagnosis. Chronic periodontal disease was the main clinically observed risk factor. Oral microbial profiling revealed lower bacterial richness/diversity in BRONJ. Streptococcus intermedius, S. mutans, and S. perioris were abundant in controls; S. sonstellatus and S anginosus were prevalent in BRONJ. In the saliva, at baseline patients who developed BRONJ had higher levels of MIP-1β; TNF-α and IL-6 compared to those without BRONJ, cytokine profile consistent with M-1 macrophage activation. In the serum, patients with BRONJ have significantly lower levels of TGF beta and VEGF over the study period.ConclusionPeriodontal disease associated with low microbial diversity and predominance of invasive species with a proinflammatory cytokine profile leading to tissue damage and alteration of immunity seems to be the main culprit in pathogenesis of BRONJ.

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Following the Guidelines for Reducing Osteonecrosis of the Jaw associated with Bisphosphonate therapy in Symptomatic Multiple Myeloma - Experience of a District General Hospital

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2015.07.436 ◽

2015 ◽

Vol 15 ◽

pp. e199

Author(s):

J. Page ◽

S. Moore

Keyword(s):

Multiple Myeloma ◽

General Hospital ◽

District General Hospital ◽

Osteonecrosis Of The Jaw ◽

Bisphosphonate Therapy

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Tooth Extraction Locally Stimulates Proliferation of Multiple Myeloma in a Patient with Mandibular Localizations

Acta Haematologica ◽

10.1159/000481425 ◽

2017 ◽

Vol 138 (4) ◽

pp. 201-207 ◽

Cited By ~ 4

Author(s):

Jean-Daniel Kün-Darbois ◽

Léonie Quenel ◽

Smaïl Badja ◽

Daniel Chappard

Keyword(s):

Multiple Myeloma ◽

Tooth Extraction ◽

Soft Tissues ◽

Plasma Cells ◽

Osteonecrosis Of The Jaw ◽

Surgical Trauma ◽

Osteolytic Lesions ◽

X Ray ◽

Extraction Site ◽

The Right

Objectives: Multiple myeloma (MM) is characterized by the occurrence of osteolytic lesions. MM treatment usually involves antiresorptive drugs (mainly bisphosphonates). Case Report: A patient with an MM presented osteolytic lesions of the mandible. Extraction of teeth 45 and 46 was performed 5 years after the diagnosis of periodontitis. Four months later, osteonecrosis of the jaw (ONJ) was diagnosed at the extraction site. X-ray showed an extension of osteolytic lesions on the right side, close to the extraction site, without modification of the lesions on the left side. Two months later, a curettage was performed because of a painful bone sequestration. X-ray showed an extension of the osteolytic lesions on the right side. Results: Histological analysis found a vascularized plasmacytoma of the soft tissues around the ONJ. Analysis of the bone showed mixed lesions with osteonecrotic areas and living bone resorbed by active osteoclasts surrounding a plasmacytoma. The surface area of the osteolytic foci has considerably increased only close to the extraction site. Conclusions: Tooth extraction triggered an ONJ associated with bisphosphonate treatment. However, it also seemed to induce a considerable proliferation of plasma cells at the extraction site; we hypothesize that it is due to the increase in bone remodeling related to the surgical trauma.

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Altered Long Noncoding RNA Expression Profile in Multiple Myeloma Patients with Bisphosphonate-Induced Osteonecrosis of the Jaw

BioMed Research International ◽

10.1155/2020/9879876 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Alessandro Allegra ◽

Manuela Mania ◽

Angela D’Ascola ◽

Giacomo Oteri ◽

Enrico Nastro Siniscalchi ◽

...

Keyword(s):

Multiple Myeloma ◽

Metabolic Pathways ◽

Noncoding Rna ◽

Protective Action ◽

Noncoding Rnas ◽

Osteonecrosis Of The Jaw ◽

Base Pairs ◽

Osteolytic Lesions ◽

Ctrl Group ◽

Rna Molecules

Bisphosphonates (BPs) are inhibitors of osteoclast-mediated bone resorption used for the treatment of multiple myeloma (MM) patients with osteolytic lesions. Bisphosphonate-induced osteonecrosis of the jaw (BONJ) is an infrequent drug-caused adverse event of these agents. Long noncoding RNAs (lncRNAs) are a set of more than 200 base pairs, noncoding RNA molecules, which are critical posttranscriptional regulators of gene expression. Our study was aimed at evaluating 17 lncRNAs, whose targets were previously validated as key elements in MM, bone metabolism, and angiogenesis in MM subjects without BONJ (MM group), in MM subjects with BONJ (BONJ group), and a group of healthy controls (CTRL group). Our results demonstrated a different lncRNA profile in BONJ patients compared to MM patients and controls. Two lncRNAs (DANCR and MALAT1) were both downregulated compared to controls and MM, twelve (HOTAIR, MEG3, TP73-AS1, HOTTIP, HIF1A-AS2, MANTIS, CTD-2201E18, CTD1-2003C8, R-471B22, RP1-43E13, RP11-553L6.5, and RP1-286D6) were overexpressed in MM with BONJ, and one (H19) was upregulated compared with only MM. Two lncRNAs (JHDMD1 and MTMR9LP) had higher expression, but these differences were not statistically significant. The examined lncRNAs target several genes and metabolic pathways. An altered lncRNA signature could contribute to the onset of BONJ or have a protective action. Targeting these lncRNAs could offer a possibility for the prevention or therapy of BONJ.

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