Immune Biomarkers of Medication (bisphosphonates) Related Osteonecrosis of the Jaws (MRONJ)

Background:

Medication related osteonecrosis of the jaws (MRONJ), previously known as bisphosphonate (BP) related osteonecrosis of the jaws (BRONJ) is a debilitating bone disease that has been associated with antiresorptive medications such as BPs. BPs remained the most commonly prescribed medication for both osteoporosis and cancer patients and subsequently the most common cause of osteonecrosis of the jaw or MRONJ. The pathophysiology of the linkage of BP to MRONJ has eluded many researchers. Studies have shown that Nitrogen-containing BPs can activate a subset of adaptive T-cells. Our research group have demonstrated that an altered immune homeostasis induced by BPs, in part by suppressing the adaptive regulatory T-cell (Treg) and suppressing the ratio of Treg/Th17 ratio has been established as the pathogenesis of BP-related ONJ in murine model; however such linkage has not been established or confirmed in humans.

Purpose:

We propose that the altered immune homeostasis, regulated by suppressed Treg, contributes to the pathophysiology of BP-associated MRONJ disease in humans. Treg levels and associated pro-inflammatory cytokines can potentially serve as determinants of MRONJ risk in BP treated patients.

Methods:

This is a cross-sectional, case-controlled study using two well-defined groups: cancer patient being treated with chemotherapy and BP use >1 year, presenting with diagnoses of MRONJ; and 2) patients being treated with BP without MRONJ. Immune profile and cytokines were evaluated in the BP treated cancer or osteoporosis patients with MRONJ (n=38) and compared to the control group without MRONJ (n=25). The case and controlled group were matched for age, sex ethnicity, and disease type; and both were compared to healthy subjects (n=57) with no history of chemotherapy and BP use. Additional outcomes were evaluated regarding comorbidities (diabetes), dental health status (periodontitis and caries) and their additional risk factors related to incidence of MRONJ.

Results:

The study groups included MRONJ (n=38), non-MRONJ (n=25), healthy control, or non-exposed subject (n=57). BP exposed group (n=63) included subjects who have been exposed to any form of BP, oral and IV, and was composed of both MRONJ and non-MRONJ subjects. The major oral BPs included Fosamax and Actonel and the IV BP was Zometa. The majority of cancer patients were diagnosed with breast cancer, prostate cancer, lung cancer, and multiple myeloma. We measured and compared the immune profile and cytokines. When compared to control or drug-naïve group, the BP-exposed patients with and without active MRONJ demonstrated significant elevated Th17 cell and suppressed Treg/Th17. The cytokine panel, including IFNγ, IL-4, IL-17, IL-10, TGF-β, and other inflammatory cytokines such as IL-6, IL-1β, and TNF-α were elevated in BP-exposed patients as compared to healthy controls.

Conclusion:

It is likely that the multiple immunosuppressant drugs given to patients undergoing chemotherapy alters their immune profile and makes them more susceptible to developing Bp related MRONJ. Elevated Th17 and suppressed Treg/Th17 ratio have potential use as immune biomarkers for human MRONJ.

References:

1. Ruggiero SL, Dodson TB, et al: Medication-Related Osteonecrosis of the Jaw—2014 Update. J Oral Maxillofac Surg 72(10):1938-56, 2014

2. Kalyan S, Quabius ES, et al: Can peripheral blood γδ T cells predict osteonecrosis of the jaw? An immunological perspective on the adverse drug effects of aminobisphosphonate therapy. J Bone Miner Res Apr;28(4):728-35, 2013