Potential Mechanisms for Localization of Osteonecrosis: Comparison
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Medication-related osteonecrosis of the jaw (MRONJ) has emerged as a complication of anti-resorptive medications. Many factors have been explored as possible localizing factors, including dental trauma, especially surgical extraction, periodontitis, impaired gingival healing, changes in oral bacteria biofilm profile, and impaired innate immune response specific to the oral cavity.

  • medication-related osteonecrosis of the jaw
  • osteoporosis medications
  • osteonecrosis

1. Dental Trauma

The incidence of MRONJ was highest with invasive dental trauma, such as tooth extraction, or minor oral or periodontal surgery (51–82%) [72,75,76,77,79,80,81,82,83][1][2][3][4][5][6][7][8][9]. While dental extraction seemed to top the list of risk factors for MRONJ [84][10], it could be argued that dental extraction was almost always preceded by chronic periodontitis, infection, or severe caries [80][6]. Indeed, some clinical data suggested that the rate of MRONJ actually decreased if the infected tooth was extracted, even without stopping anti-resorptive therapy [35,85][11][12]. However, many studies found that the risk of MRONJ with dental trauma was very high in association with local infection, abscesses, and poor oral hygiene [27,33,37,72,73,74,75,76,78,83,86,87,88,89][1][2][3][9][13][14][15][16][17][18][19][20][21][22]. Recent studies have shown that not only post-treatment implant placement but also the pre-existence of osseointegrated implants prior to therapy can be associated with MRONJ [90,91][23][24]. Posterior implants seemed to carry the highest risk [90[23][25],92], and the mandible was more susceptible than the maxilla [93][26]. Overall, as in the presented case report above, it seems that implants, whether new or preexisting, increase the risk of MRONJ. In patients undergoing tooth extraction after long-term anti-resorptive treatment, the risk of MRONJ varied between 1 and 5% [80][6]. The likelihood of MRONJ seemed to increase with subsequent extractions and with a longer duration of anti-resorptive use [33,79,82][5][8][14]. It is also worth noting that spontaneous MRONJ (without a history of any of the abovementioned risk factors) still occurred in as many as 35.1% of patients [5][27].

2. Chronic Inflammation in the Oral Cavity

In experimental animals, ligature-induced periodontitis and tooth extraction were widely used, separately or combined, to induce osteonecrosis in rats or mice treated with anti-resorptive medications. In these studies, dental extraction alone induced MRONJ lesions of various severity, while pre-existing pathologic inflammation increased the incidence and severity of MRONJ development following extraction with both Zol and Anti-RANKL treated animals [76,87,88,94,95][3][20][21][28][29]. It is now widely accepted that poor oral hygiene and chronic bacterial infection of the bone surface contributed to disease severity [27,33,80,96][6][13][14][30]. Since dental extraction is a standard treatment of chronic periodontitis, there is a confounding relationship between the two factors in MRONJ [27,80,89,97][6][13][22][31]. Chronic periodontal inflammation is associated with the suppression of bone healing through multiple mechanisms [41][32]. Evidence suggests that the jawbone may be more susceptible to chronic infection compared to other bones in the body due to its exposure to exponentially more bacteria [41,97][31][32]. In addition, MRONJ lesions invariably originated from the alveolar process of the jaw, which is frequently affected by odontogenic infections through the root tips or infected periodontal pockets [27][13].
The strong role of local inflammation in MRONJ has been supported by the presence of inflammatory cytokines at the site of necrosis [98][33]. In numerous studies, mice with experimentally induced rheumatoid arthritis demonstrated more severe MRONJ with larger areas of exposed bone and more severe necrosis [99][34]. The transplantation of peripheral blood mononuclear cells with anti-inflammatory properties reduced MRONJ prevalence and was associated with improved healing, decreased inflammatory cell infiltration, and enhanced vascularity [80][6]. On the other hand, anti-resorptive medications, such as bisphosphonates, were shown to enhance pro-inflammatory cytokine production and release, and therefore, sustain an inflammatory state [98,100][33][35].

3. Oral Mucosal Barrier

The oral mucosal barrier involves complex immune system components that constantly recognize and eliminate harmful exogenous organisms while maintaining commensals [101][36]. It has been hypothesized that bisphosphonates disrupt the local immune response through the inhibition of dendritic cell function [23,102][37][38]. One study found that bisphosphonate treatment led to increased oral bacterial load, accompanied by a significant decrease in antigen-presenting cells and decreased dendritic cell differentiation and activity [23][37]. It also found that dendritic cell-deficient mice contributed to an increased rate of MRONJ development [23][37]. Therefore, bisphosphonate-related disruption of the innate oral immune system can lead to colonization of the mucosa with pathogenic bacteria and perpetuate necrosis following dental trauma. Furthermore, bisphosphonates may be internalized by macrophages, impacting their phagocytic ability [20,103][39][40]. Macrophages treated with zoledronic acid have shown decreased protein expression and higher apoptotic rates which are furthered by LPS stimulation from gram-negative bacteria that have been implicated in MRONJ [103,104][40][41]. On the other hand, bisphosphonates enhance pro-inflammatory cytokine production and release, and therefore, sustain an inflammatory state [100][35]. Recent reports and ongoing studies demonstrated that T-cell dysregulation may play an important role in the pathogenesis of MRONJ [105][42].

4. Oral Bacteria

Interestingly, there is evidence that the depletion of indigenous oral microbes and the resulting dysbiosis could increase the risk of osteonecrosis induced by bisphosphonates following tooth extraction [33,76,106][3][14][43]. In other words, oral bacterial flora could play a role in the homeostatic mechanisms of the alveolar bone that are protective against osteonecrosis. Thus, a balance must be maintained between the management of infection and the preservation of the local oral flora [2,106][43][44]. This is especially relevant since the use of prophylactic antibiotics is a very common practice with invasive dental procedures. On the other hand, a sequestered bone from MRONJ lesions has consistently shown microbial biofilm formation, with Actinomycetes detected in 70% of samples [107,108][45][46]. Several studies have linked MRONJ to Actinomyces, especially Aggregatibacter Actinomycetemcomitans, which are common in patients with periodontitis, again linking MRONJ to the underlying prevalence of these bacteria [27,96,102][13][30][38]. It has been hypothesized that the mechanism of trauma-induced MRONJ simply includes creating access for pre-existing pathogenic bacteria [109][47], which is why MRONJ almost always started at the alveolar process of the jawbone. Gram-negative bacteria in particular are thought to produce toxic products, such as lipopolysaccharides that directly induce osteoclast differentiation and activity [107][45]. Other bacteria associated with MRONJ development included Prevotella and Fusobacterium [109][47].
Despite the concern about dysbiosis resulting from prophylactic antibiotics, mentioned above, studies have shown that the use of antibiotics could indeed help after MRONJ has already started, along with surgical debridement [110][48]. Therefore, antibiotics have become standard in patients with ongoing MRONJ.
As detailed in previous sections, bisphosphonate molecules accumulate in the bone, where they remain for many years after stopping treatment [26,79,111][5][49][50]. These deposits have been shown to increase the adhesion of different bacterial species and promote biofilm formation [27][13]. Experimental evidence showed that osteonecrosis could be induced following invasive trauma in long bones of zoledronate-treated animals, but only in the presence of pre-existing Actinomyces infection [71,76][3][51]. Therefore, deposited bisphosphonates, which have been shown to preferentially adhere to alveolar bone more than basal bone [112][52], maybe an attractive surface for bacterial colonization and formation of pathologic biofilm when bisphosphonate loaded surfaces are exposed, such as following invasive dental procedures [59][53].

5. Other Forms of Osteonecrosis

Finally, other forms of osteonecrosis have been described at different skeletal sites. For example, osteonecrosis occurs in the femoral head and is described as avascular necrosis, and it is not associated with anti-resorptive medications [80][6]. However, even though vascular impairment has been described in MRONJ, it seems to be only one aspect of a multifactorial process that starts primarily in the bone tissue itself. Indeed, MRONJ lesions show a decrease in vascularity during bone healing, which seems to be another effect of bisphosphonates [80,113][6][54]. When osteonecrosis occurs in the femur, it is not accompanied by bone exposure or infection. A similar difference exists between MRONJ and osteoradionecrosis.

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