Abstract
Simple SummaryMedication-related Osteonecrosis of the Jaw (MRONJ) is a significant complication mainly of antiresorptive medications used in the management of bone diseases. MRONJ development may be accompanied by pain, eating discomfort, self-consciousness, and other symptoms that overall disturb patients’ everyday life. Hence, MRONJ occurrence is of growing clinical concern and affects treatment decisions. Although MRONJ has been extensively studied since being first reported in 2003, the mechanisms of disease pathogenesis have not yet been determined and disease management is mostly empirical. Recent data investigate the effects of antiresorptive medications on immune system components including macrophages and introduce these cells as key players in MRONJ pathogenesis. Considering macrophage versatility, developmental plasticity, and its pivotal role in immune response, the current short review focused on the potential involvement of these multi-potential cells in MRONJ pathogenesis. Understanding the complex role of macrophages in MRONJ pathophysiology will add new valuable data on disease prevention and control.Antiresorptive agents such as bisphosphonates (BP) and denosumab are commonly prescribed for the management of primary bone malignancy, bone metastasis, osteoporosis, Paget disease, or other bone disorders. Medication-related osteonecrosis of the Jaws (MRONJ) is a rare but significant complication of antiresorptive medications. Duration, dose, and antiresorptive potency as well as concomitant diseases, additional medications, and local factors affect MRONJ incidence and severity. MRONJ pathophysiology is still poorly understood. Nevertheless, decreased bone resorption due to osteoclastic inhibition along with trauma, infection/inflammation, or blood supply inhibition are considered synergistic factors for disease development. In addition, previous data research examined the effects of antiresorptive medication on immune system components and introduced potential alterations on immune response as novel elements in MRONJ pathogenesis. Considering that macrophages are the first cells in the nonspecific immune response, it is not surprising that these multifaceted players attracted increased attention in MRONJ research recently. This current review attempted to elucidate the effects of antiresorptive medications on several aspects of macrophage activity in relation to the complex inflammatory microenvironment of MRONJ. Collectively, unravelling the mode of action and extent of macrophages’ potential contribution in MRONJ occurrence will provide novel insight in disease pathogenesis and potentially identify intrinsic therapeutic targets.
Highlights
Medication-related osteonecrosis of the jaws (MRONJ) is a rare but potentially severe adverse effect of antiresorptive and, more recently, antiangiogenic medications administered to patients with osteoporosis or bone malignancies [1,2]
Common antiresorptive agents largely involved in MRONJ are bisphosphonates and denosumab, a humanized monoclonal antibody against Receptor Activator of Nuclear Factor κB Ligand (RANKL)
In vivo animal studies indicated that BPs increase neutrophil numbers as well as related pro-inflammatory cytokines, including Tumor Necrosis Factor (TNF)-α, IL-1β, inducible nitric oxide synthase, NF-kβ, and IL-18 binding protein at MRONJ
Summary
Medication-related osteonecrosis of the jaws (MRONJ) is a rare but potentially severe adverse effect of antiresorptive and, more recently, antiangiogenic medications administered to patients with osteoporosis or bone malignancies [1,2]. Antiresorptive medications in conjunction with local instigating factors, such as gingival/periodontal disease or tooth extraction, increase MRONJ risk [11]. Tooth extraction is reported as the most common local instigating factor for MRONJ development [1], recently it was reported that after adjustment for confounders, tooth extraction does not increase MRONJ risk, suggesting that extraction of infected teeth in patients on antiresorptives should be performed to eliminate local infection [7,13]. BPs affected neutrophil activity and induced pro-inflammatory effects [19]. In vivo animal studies indicated that BPs increase neutrophil numbers as well as related pro-inflammatory cytokines, including Tumor Necrosis Factor (TNF)-α, IL-1β, inducible nitric oxide synthase (iNOS), NF-kβ, and IL-18 binding protein at MRONJ sites [17]. We focused our review on the existing evidence of the potential contribution of macrophages in MRONJ pathophysiology
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