Imagine a woman in her 60s with breast cancer who has undergone chemotherapy and taken bisphosphonates for months. She complains of persistent dry mouth, followed by jaw pain, an unpleasant odor, and eventually exposed bone in the oral cavity. This is not an ordinary complication—it is medication-related osteonecrosis of the jaw (MRONJ). The question researchers are now beginning to answer is whether changes in saliva during drug therapy could serve as an early marker—and potentially a contributing factor—of this serious condition.
This question prompted drg. Isti Rahayu Suryani, M.Biotech., Sp.RKG, Subsp.RDP(K), Ph.D., together with a research team from KU Leuven, Belgium, to conduct a systematic review published in Frontiers in Medicine in August 2023. The study was the first to specifically examine the relationship between drug-induced salivary changes and the risk of developing MRONJ.
Cancer Drugs, Dry Mouth, and Slowly Dying Bone
MRONJ is not a condition that can be easily overlooked. Clinically, it is defined as exposed necrotic bone in the maxillofacial region that persists for more than eight weeks in the absence of a history of radiotherapy. It is most commonly found in oncology patients taking antiresorptive drugs such as bisphosphonates and denosumab, antiangiogenic agents, immunomodulators, and immunosuppressants. Patients with multiple myeloma and osteoporosis are among those at greatest risk.
The research team searched four scientific databases—PubMed, Web of Science, Cochrane, and Embase—and identified 765 studies. After a rigorous selection process using standardized inclusion and exclusion criteria based on the PRISMA guidelines, only 10 articles met the criteria for qualitative analysis. Across these 10 studies, there were a total of 272 MRONJ cases: 35% were women, 32% were men, and the sex of the remaining patients was not reported. The mean age at diagnosis was 66 years.
Breast cancer was the most common primary disease, accounting for 57 cases, while hypertension was the most frequent comorbidity, reported in 107 cases. Bisphosphonates dominated the list of implicated medications, accounting for more than 85% of cases, followed by chemotherapy and corticosteroids.
When Saliva Changes, the Jaw Pays the Price
Saliva is more than simply a fluid that keeps the mouth moist. It is a biological defense system that maintains oral homeostasis: it remineralizes teeth, neutralizes acids, inhibits the growth of harmful microorganisms, and facilitates speaking and swallowing. When salivary production is disrupted, a cascade of consequences can follow.
The review identified two main pathways linking salivary changes to MRONJ. The first is reduced salivary flow, or hyposalivation. Patients taking bisphosphonates, steroids, chemotherapy, thalidomide, interferon, and hormonal therapy showed a significant association between reduced salivary flow rates and the occurrence of MRONJ. Xerostomia, the sensation of chronic dry mouth, is often associated with Sjögren's syndrome, which may occur as a drug-related adverse effect. In patients with this syndrome, the prevalence of dental caries is twice as high, while the risk of Candida albicans infection is ten times higher than in the general population.
The second, more complex pathway involves changes in salivary protein composition and biological profiles. Bisphosphonates, denosumab, and other bone-modifying agents have been shown to alter the salivary microbiome profile, increase pro-inflammatory cytokines such as IL-6, IL-1α, IL-1β, and TNF-α, and increase concentrations of matrix metalloproteinases (MMP-8 and MMP-9). In addition, the compound hypotaurine was found to be elevated in patients with MRONJ and may have potential as an early detection marker. Expression of the RBMS3 gene, which encodes an RNA-binding protein involved in collagen metabolism, was also significantly associated with MRONJ.
“Reduced salivary flow and changes in salivary protein concentrations are associated with the development of MRONJ. However, given the limited available evidence, the findings of this review should be interpreted with caution.” — drg. Isti Rahayu Suryani, M.Biotech., Sp.RKG, Subsp.RDP(K), Ph.D., and colleagues, Frontiers in Medicine, 2023
Polypharmacy: When Multiple Medications Make Everything Worse
One particularly striking finding was the role of polypharmacy—the concurrent use of five or more medications. This condition was identified as a significant predictor of xerostomia, regardless of the patient's age and sex. The prevalence of xerostomia and MRONJ among patients receiving polypharmacy was nearly three times higher than among those who were not taking any medications. Xerostomia was even reported as a side effect in 80–100% of patients in this group.
The mechanisms vary. Cytotoxic drugs can directly damage the salivary glands, anticholinergic drugs interfere with neural stimulation of salivary secretion, while diuretics promote systemic dehydration. Many medications also reduce salivary flow through vasoconstriction within the salivary glands themselves.
Diabetes mellitus further strengthens this chain of risk. Chronically elevated blood glucose levels impair parasympathetic function and salivary secretion. Hyperglycemic patients were found to have a significantly higher risk of MRONJ than those with normal glucose levels.
Saliva as a Diagnostic Window for the Future
The main strength of this review lies in an idea that has previously received limited attention: saliva, as an easily collected, non-invasive specimen, could serve as a diagnostic window for the early detection of MRONJ. With the development of the field of salivaomics, various salivary biomarkers have the potential to complement or even replace blood tests for monitoring disease progression.
The researchers recommend collecting saliva specimens before and after the development of MRONJ to validate the most reliable biomarkers. However, they also acknowledged several limitations of the review: the number of eligible studies remains very small, sample sizes are limited, and salivary collection methods varied across studies, making a meta-analysis impossible.
Many questions remain unanswered. Does temporarily discontinuing the causative medication—a drug holiday—actually reduce the risk of MRONJ? Current evidence remains contradictory. Comprehensive clinical guidelines on alternative treatment strategies are also not yet available.
One thing is certain: for patients with cancer or osteoporosis undergoing long-term therapy, persistent dry mouth is not a minor complaint that can simply be ignored. It may be the first signal of something much more serious. And saliva, a fluid we often take for granted, may hold some of the answers researchers have been looking for.
Source DOI: http://DOI 10.3389/fmed.2023.1164051
Authors: Anny Anggraini; drg. Achmad Zam Zam Aghasy, M.Kes.
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