Imagine a breast cancer patient who has undergone a prolonged course of chemotherapy and then visits a dentist with exposed jawbone that refuses to heal. There is no history of bisphosphonate use and no history of radiotherapy. So where did the lesion come from?
This question prompted drg. Isti Rahayu Suryani, M.Biotech., Sp.RKG, Subsp. RDP(K), Ph.D., a lecturer in the Department of Dental Radiology, Faculty of Dentistry, Universitas Gadjah Mada, to investigate the relationship between non-antiresorptive medications and a condition known as medication-related osteonecrosis of the jaw (MRONJ). The systematic review she conducted with a team from KU Leuven, Belgium, was published in the prestigious journal Clinical Oral Investigations (Springer Nature) in January 2022.
Slowly Dying Jawbone: What Is MRONJ?
MRONJ is a condition in which jawbone tissue undergoes necrosis, or cell death, as a result of impaired blood supply. Bone that should remain living and continuously regenerate gradually dies, becomes exposed to the oral cavity, and fails to heal. The condition was first officially documented in 2003 in patients taking nitrogen-containing bisphosphonates, a class of drugs commonly used to treat osteoporosis and bone cancer.
Over the past two decades, scientific attention toward MRONJ has focused primarily on bisphosphonates and denosumab. However, as oncology has advanced, increasing numbers of patients have received other medications, including antiangiogenic agents, immunosuppressants, mTOR inhibitors, monoclonal antibodies, and long-term corticosteroids. Could these medications also trigger MRONJ? This was the central question addressed by drg. Isti and her team.
Screening 996 Articles and Identifying 867 Cases
To answer this question, the researchers conducted a systematic review and meta-analysis, one of the most rigorous methodologies in evidence-based medicine. They searched three major scientific databases—PubMed, EMBASE, and Web of Science—for studies published up to April 2021, with the search conducted between December 2020 and April 2021. Of the 996 articles identified, only 58 publications met the strict inclusion criteria, covering a total of 867 MRONJ cases.
The patient profile across this dataset was diverse: 55% were men and 33% were women, with a mean age at diagnosis of 61 years (range, 19–100 years). Interestingly, the mean interval between the initiation of medication and MRONJ diagnosis was only approximately 9.75 months—considerably shorter than for bisphosphonate-associated MRONJ, which may take more than two years to develop. Breast cancer was the most frequently reported primary malignancy (15%), followed by prostate cancer and multiple myeloma.
Anatomically, the mandible was the most frequently affected site (35% of cases), followed by the maxilla (14%). The most common clinical sign was exposed bone, followed by jaw pain, fistula formation, and pus discharge. Tooth extraction was the most frequently reported local precipitating factor, occurring in 245 cases.
Corticosteroids and Chemotherapy: The Two Main Suspects
The meta-analysis produced a striking finding. Among all categories of non-antiresorptive medications examined, corticosteroids and chemotherapeutic agents demonstrated the largest effect sizes for MRONJ.
“Patients with a history of corticosteroid use showed an effect size of 0.61 (95% CI, 0.39–0.82, p < 0.001), while patients with a history of chemotherapy showed an effect size of 0.59 (95% CI, 0.51–0.67, p < 0.001), both of which were statistically significant compared with the control group.”
Why can chemotherapy be harmful to the jawbone? These cytotoxic agents suppress the immune system while also inhibiting osteoclast formation, affecting cells that play an essential role in bone remodeling. Moreover, the antiangiogenic effects of some chemotherapeutic drugs interfere with bone vascularization, depriving tissue of vital nutrients.
Corticosteroids act through more complex pathways. Long-term use suppresses the production of vascular endothelial growth factor (VEGF), reduces the recruitment of osteoblasts and osteoclasts, and accelerates bone-cell apoptosis. As a result, the bone becomes less capable of repairing itself.
In addition, monoclonal antibodies (effect size 0.32) and immunomodulators (effect size 0.17) also demonstrated statistically significant associations, although the strength of the associations was lower.
What Does This Mean for Dentists?
These findings have concrete clinical implications. Until now, MRONJ prevention protocols in dental practice have largely revolved around one question: Is the patient taking bisphosphonates or denosumab? This research emphasizes that the assessment should be expanded to include a history of chemotherapy, long-term corticosteroid use, monoclonal antibodies, and tyrosine kinase inhibitors.
One potential therapeutic strategy highlighted by the study is the concept of a drug holiday—temporarily discontinuing medication before invasive dental procedures such as tooth extraction. Unlike bisphosphonates, which have a very long half-life in bone, most non-antiresorptive medications have shorter half-lives. Therefore, temporary discontinuation—of course, only with approval from the prescribing physician—could theoretically reduce the risk of MRONJ before dental procedures.
Nevertheless, the researchers caution that the available evidence remains limited. Most of the data come from case reports and retrospective studies rather than large-scale prospective clinical trials. The fact that many patients receive multiple medications simultaneously also makes it difficult to isolate the contribution of any single drug.
Funded by a doctoral scholarship from the Ministry of Education and Culture of the Republic of Indonesia, this research reinforces the idea that dental science does not exist in isolation. An oncology patient sitting in a dental chair brings with them the full complexity of their cancer treatment regimen. And dentists need to understand all of it—before picking up their first instrument.
Source DOI: https://doi.org/10.1007/s00784-021-04331-7
Authors: Anny Anggraini; drg. Achmad Zam Zam Aghasy, M.Kes.
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