{"doi":"10.3389/fonc.2021.704722","title":"Prospective Observational Study of Bisphosphonate-Related Osteonecrosis of the Jaw in Multiple Myeloma: Microbiota Profiling and Cytokine Expression","abstract":"Purpose Define 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 Methods A 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. Results Over 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. Conclusion Periodontal 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.","journal":"Frontiers in Oncology","year":2021,"id":175511,"datarank":0.7759126500632456,"base_score":3.1354942159291497,"endowment":3.1354942159291497,"self_citation_contribution":0.47032413238937254,"citation_network_contribution":0.3055885176738731,"self_endowment_contribution":0.47032413238937254,"citer_contribution":0.3055885176738731,"corpus_percentile":74.06977643691498,"corpus_rank":3353,"citation_count":22,"citer_count":16,"citers_with_citation_signal":12,"citers_with_endowment":12,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.5942,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":4.1667,"fair_percentile":4.891470498318557,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":716661,"name":"Mariam Meddeb","orcid":"0000-0002-6922-1587","position":1,"is_corresponding":false},{"id":717372,"name":"Dianna Weikel","orcid":null,"position":2,"is_corresponding":false},{"id":717373,"name":"Sunita Philip","orcid":null,"position":3,"is_corresponding":false},{"id":717374,"name":"Todd Milliron","orcid":null,"position":4,"is_corresponding":false},{"id":437184,"name":"Rena Lapidus","orcid":null,"position":5,"is_corresponding":false},{"id":717375,"name":"Lisa Hester","orcid":null,"position":6,"is_corresponding":false},{"id":189570,"name":"Olga Goloubeva","orcid":null,"position":7,"is_corresponding":false},{"id":717376,"name":"Timothy F. Meiller","orcid":null,"position":8,"is_corresponding":false},{"id":238447,"name":"Emmanuel F. Mongodin","orcid":"0000-0003-3833-7437","position":9,"is_corresponding":false},{"id":641112,"name":"Ashraf Badros","orcid":"0000-0003-1690-0188","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-18T23:47:15.431199Z","pmid":"34249765","pmcid":"PMC8263936","fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":11.1111,"fair_a":18.75,"fair_i":0.0,"fair_r":16.6667,"fair_zscore":-1.1986,"fair_rationale":{"fair_score":4.17,"has_llm":true,"taxonomy_version":"fair_taxonomy_v5","dimensions":{"F":{"name":"Findable","score":11.11,"criteria":[{"key":"f_dataset_pid","label":"Persistent identifier for the data","kind":"llm","weight":2.0,"fraction":0.0,"verdict":"no","evidence":null,"grounded":false,"rationale":"No persistent identifier string (DOI, accession, etc.) is given for the data.","anchors":["RDA-F1-01D — FAIR Data Maturity Model: 'Data is identified by a persistent identifier' (priorit","RDA-F1-02D — FAIR Data Maturity Model: 'Data is identified by a globally unique identifier'","FsF-F1-02D — F-UJI/FAIRsFAIR: 'Data is assigned a persistent identifier'"],"scored":true,"signal":null},{"key":"f_repository_named","label":"Named repository","kind":"llm","weight":2.0,"fraction":0.0,"verdict":"no","evidence":null,"grounded":false,"rationale":"No repository is named; the holder is the corresponding author only.","anchors":["RDA-F4-01M — FAIR Data Maturity Model: metadata is offered so it can be harvested and indexed (","NIH DMS Policy Element 4 (NOT-OD-21-014) — name the repository where data will be archived","NSTC Desirable Characteristics of Data Repositories (2022) — 'Long-Term Sustainability', 'Reten"],"scored":true,"signal":null},{"key":"f_data_availability_statement","label":"Data-availability statement","kind":"llm","weight":2.0,"fraction":0.5,"verdict":"partial","evidence":"The raw data supporting the conclusions of this article is available on request.","grounded":true,"rationale":"The statement points to a person (Colavizza category 1), not to a repository record.","anchors":["Colavizza, Hrynaszkiewicz, Staden, Whitaker & McGillivray (2020), 'The citation advantage of li","Springer Nature research data policy — Data Availability Statements: standard statement templat","RDA-F3-01M — metadata clearly and explicitly includes the identifier of the data it describes"],"scored":false,"signal":null},{"key":"f_discovery_metadata","label":"Description of the dataset as an object","kind":"llm","weight":2.0,"fraction":0.0,"verdict":"no","evidence":"Microbiome profiling was performed on salivary samples collected after BP infusion every 3 months (seven time points) from 14 patients who developed BRONJ and compared with samples from patients who did not develop BRONJ (controls, n = 28).","grounded":false,"rationale":"The dataset is described in running prose, not in an itemised inventory. 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