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Important aspects regarding the role of microorganisms in bisphosphonate-related osteonecrosis of the jaws

Archives of Oral Biology, 8, 59, pages 790 - 799

Highlights

 

  • Actinomyces is the most frequent microorganism found in BRONJ lesions.
  • Bacterial biofilm plays an essential role in BRONJ repercussion.
  • Treatment cannot ignore the different species found in BRONJ.

Abstract

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is an important side effect of bisphosphonates, whose etiopathogenesis has not been completely elucidated. Theories pointing to bone turnover and angiogenesis inhibition, as well as effects on epithelial cells of oral mucosa and the role of microorganisms have been reported. Nevertheless, the true contribution of each one of these factors to BRONJ is unknown. We present here a literature review focusing on important aspects regarding the role of microorganisms in BRONJ development. Knowledge about specific microbiota and its role in the etiopathogenesis of this disease can help the optimisation of preventive and therapeutic interventions in patients with or at-risk for BRONJ.

Keywords: Bisphosphonate, Osteonecrosis of the jaws, Infection, Actinomyces sp., Candida sp..

1. Introduction

Bisphosphonates are potent inhibitors of bone resorption that are widely used to treat osteogenesis imperfecta, osteoporosis and Paget's disease and also as adjuvant therapy in the management of multiple myeloma, bone metastases and complications of cancer, such as hypercalcemia.1, 2, 3, 4, 5, and 6 These drugs are classified according chemical structure into two main groups: non-nitrogen and nitrogen-containing, where the latter is far more potent. The potency can also vary according to the route of administration: oral or intravenous (IV). The non-nitrogen-containing bisphosphonates include etidronate (oral), tiludronate (oral),7, 8, and 9 and clodronate (oral and IV). 8 The major representatives of the nitrogen-containing group are alendronate (oral), risedronate (oral), ibandronate (oral and IV), pamidronate (IV) and zoledronic acid (IV). Etidronate and tiludronate are mostly prescribed to treat Paget's disease, whereas clodronate is more administered in patients affected by malignancies.7, 8, and 9 Alendronate, risedronate and ibandronate are primarily used to treat osteoporosis, whereas pamidronate and zoledronic acid are mostly for bone conditions related to malignancies.7, 8, and 9

Concentrations of bisphosphonates capable of inhibiting bone metabolism can also impair tissue healing after induced or physiological trauma, which has been associated with cases of necrotic bone exposure to the oral environment. 10 Bisphosphonate-related-osteonecrosis of the jaws (BRONJ), first recognised in 2003,11, 12, 13, and 14 is an important side effect of these drugs. 15 The condition is described as spontaneous bone exposure or non-healing wounds after tooth extraction, which may or may not involve infection and fistulisation. 16 Clinical features can also include pain, erythema and pathological jaw fracture.6 and 16 The lesions showing exposed and necrotic bone may remain asymptomatic for a long period, even years. However, they become symptomatic when surrounding tissues get inflamed or if there is clinical evidence of infection. 17 The disease shows some similarity to osteonecrosis of the jaw associated with radiation therapy, including poor response to treatment. 18 According to the literature, three conditions are needed to define a case of BRONJ: (a) current or previous therapy with bisphosphonates; (b) exposed necrotic bone in the maxilla or mandible lasting more than 8 weeks; and (c) absence of head and neck radiation therapy.2 and 19 Nevertheless, the occurrence of a nonexposed variant of osteonecrosis has recently been reported, where the most common findings are jaw bone pain, sinus tract, bone enlargement and gingiva swelling, which are not related to dental disease or another local or systemic disorder other than osteonecrosis. In such cases, radiological abnormalities can be either present or absent, and many patients develop subsequent bone exposure. 20 Differential diagnosis should consider clinical conditions such as alveolar osteitis, sinusitis, gingivitis/periodontitis, periapical pathology, and temporomandibular joint disorders. 17

BRONJ affects the maxilla and mandible with preference for the latter, 21 and has related-risk factors such as tooth extractions,22 and 23 diabetes, 22 and 24 tobacco use, 22 trauma to oral tori 25 or caused by prosthetic appliances, oral infection, 26 poor oral hygiene, malnutrition 27 and bone manipulation. 28 Route of administration, type of bisphosphonate (nitrogen or non-nitrogen containing)2 and 17 and treatment duration9 and 21 are also important risk factors. Duration of bisphosphonate exposure is positively correlated to developing BRONJ, 9 and nitrogen-containing bisphosphonates are more associated with BRONJ than are non-nitrogen ones. Among the nitrogen-containing drugs, those administered intravenously such as pamidronate and especially zoledronic acid, represent significantly more risk. The estimated cumulative incidence of BRONJ for patients taking IV bisphosphonates for malignancies ranges from 0.8 to 12%,2 and 17 whereas for oral bisphosphonates, it ranges from 0.01 to 0.04%. 29 Mavrokokki et al. 29 reported 72% of cases occurring in patients with bone malignancy, where the main trigger was tooth extraction (73%). Assaf et al. 30 reported that 8.9% (n = 15) of patients with malignancy developed BRONJ, where the majority of them (60%) received zoledronic acid. According to Ruggiero et al., 9 the two greatest risk factors for BRONJ are IV bisphosphonate exposure and dentoalveolar procedures.

The theories that try to explain BRONJ etiopathogenesis are basically related to three mechanisms: inhibition of bone remodelling, inhibition of angiogenesis, and infection. 22 The most popular one is the bone remodelling cessation theory,22 and 31 where osteoclasts are the main cellular target of bisphosphonates. 32 These drugs have an affinity for bone mineral matrix, and it is believed that they inhibit bone resorption by inducing osteoclast apoptosis and/or inhibiting osteoclast function. The inhibition of osteoclast function can also impair normal bone turnover. Consequently, local micro damage from normal mechanical loading or injury cannot be repaired, which in turn can result in bone necrosis.17 and 31 Bisphosphonates are not metabolised by bone, where they can remain unchanged for many years. During bone remodelling they are released from hydroxyapatite crystals and internalised by osteoclasts. Non-nitrogen-containing bisphosphonates are metabolised in the osteoclast cytoplasm into non-hydrolyzable ATP analogues, which are cytotoxic compounds that lead to cell death. Nitrogen-containing bisphosphonates, in turn, disrupt the mevalonate pathway, a biosynthetic pathway needed for cholesterol and isoprenoid lipid synthesis, leading to inhibition of protein prenylation, which determines osteoclast apoptosis.33 and 34 Also, there are speculations of some effects on osteocyte life span and osteoblast physiology. 22 It has been demonstrated in vitro that bisphosphonates stimulate osteoblasts to produce an inhibitor of osteoclast differentiation,35 and 36 called osteoprotegerin (OPG).36, 37, 38, and 39 All such effects impair the homeostatic cycle of bone remodelling and repair, especially in the jaws, which have more intense metabolic activity than other skeletal bones.25 and 33 In inflammatory processes of the oral cavity, bisphosphonate-impregnated alveolar bone cannot be resorbed because of osteoclast inhibition, which leads to bone exposure to an environment rich in bacterial toxins, inflammatory cytokines and oxidative stress. This environment is highly toxic to bone cells, which can result in osteonecrosis. 40

There is also evidence that bisphosphonates have marked antiangiogenic properties.41, 42, and 43 It has been observed that zoledronic acid inhibits in vitro proliferation of human endothelial cells and modulates their adhesion and migration, and reduces vessel sprouting. Besides, it has been shown to inhibit the angiogenesis induced by subcutaneous implants impregnated with basic fibroblast growth factor (bFGF) in mice 41 and reduces VEGF circulating levels in patients. 43 Fournier et al. 42 observed in vitro that bisphosphonates reduced endothelial cell proliferation, induced their apoptosis and reduced formation of capillary tubes, whereas in vivo zoledronic acid, ibandronate and, to a lesser extent, clodronate inhibited ventral prostate revascularisation in castrated male rats under testosterone stimulation. 42 These antiangiogenic effects of bisphosphonates along with the known role of disruption of the vasculature under conditions such as necrosis of the hip 44 and osteoradionecrosis of the jaw1, 45, and 46 have led to the hypothesis that vascular disruption could also play a key role in the pathophysiology of BRONJ.22, 25, and 42

Considering that epithelialisation is an essential step in wound healing, 22 other studies defend the idea that bisphosphonates accumulated in the bone have direct toxic effects on the oral epithelium and inhibit normal healing of soft tissue lesions caused by either dental intervention or some other trauma thereby favouring the persistence of bone exposure and BRONJ development.47, 48, and 49

Still, there is strong evidence that infection is closely related to BRONJ etiopathogenesis,50 and 51 especially regarding the constant findings of Actinomyces sp. colonies in histological examinations of the lesions. 52 In patients taking bisphosphonates, the site of tooth extraction favours infection because of (a) less inflammatory response and vascularisation of the tissues, (b) increased bacterial adhesion to bisphosphonate-coated bone, and (c) persistence of exposed bone to oral cavity consequent to inhibition of both bone resorption and epithelial covering, which can provide a substrate for bacterial growth. 50 The participation of microorganisms in the etiopathogenesis of these lesions was at first classified as secondary, but the possibility of a major role of microbial agents has been suggested.6, 22, 28, 52, 53, and 54 We present here a literature review focusing on important aspects related to the role of microorganisms in BRONJ etiopathogenesis.

2. Biofilm in BRONJ

In the oral cavity, bone can be easily exposed to the abundant bacterial and fungal microbiota, which has the potential of causing biofilm-mediated diseases. 55 Although routinely exposed to oral microorganisms that include over 750 recognised bacteria, 56 the jaws are generally resistant to colonisation. Therefore, for colonisation to occur, it is necessary to have a combination of patient susceptibility and the presence of potentially pathogenic microorganisms, such as Actinomyces sp., which predominates either in BRONJ cases or in jaw osteomyelitis. 55

Biofilms are complex microbial communities attached to surfaces, which can harbour single or multiple microbial populations or microcolonies. Microbial cells are incorporated in a matrix of extracellular polymeric substance they produce to be linked to and to communicate with each other and with the environment. 57 Such bacterial communities play an important role in BRONJ pathogenesis. It is probable that biofilm development in these lesions results from their chronic course and local environment, even though it could be favoured by the presence of bisphosphonates on the bone surface. 52 The presence of microorganisms compatible with Actinomyces sp. and yeast colonies in contact with necrotic bone and within empty lacunae in BRONJ lesions58 and 59 suggests an essential role of infectious agents in BRONJ pathogenesis. 6

Saia et al. 51 evaluated 60 patients at high risk for osteonecrosis, who were being treated with nitrogen-containing bisphosphonates and who were subjected to surgical tooth extractions. The inclusion criteria were (a) metastatic bone disease and multiple myeloma treated with high-dose intravenous nitrogen-containing bisphosphonate or non-malignant bone disease treated with oral bisphosphonate for at least 3 years; (b) one or more unsalvageable teeth requiring extraction; (c) lack of bone exposure and of clinical and radiologic signs related to bisphosphonates in the jaw where dental extraction was required; (d) absence of previous radiation therapy of the jaws; and (e) lack of clinical and radiologic evidence of jaw bone metastases. The patients stopped bisphosphonate therapy for 1 month after tooth extraction and were evaluated at 3, 6 and 12 months. Biopsies of alveolar bone were performed during the tooth extraction procedure, and 54 patients showed normal bone architecture and vascularisation on histopathological examination, whereas 6 patients showed baseline osteomyelitis. No sign of bone necrosis was detected at this moment in any specimen. Nevertheless, three months after tooth extractions, four out of the six patients with baseline osteomyelitis developed osteonecrosis and, one more at six months follow-up. Because osteonecrosis developed only in patients who had osteomyelitis prior to surgery, the authors believed that it was unlikely that trauma from tooth extraction was responsible for the lesion. Moreover, as bone necrosis was not detected in any specimen at the moment of tooth extraction, the hypothesis that BRONJ is an infectious disease and that the oral microbiota plays an important role in its pathogenesis was reinforced.

Sedghizadeh et al. 58 observed by means of scanning electron microscopy the presence of biofilm in bone specimens of four patients with BRONJ who had been subjected to surgical bone debridement and sequestrectomy. Bone specimens revealed large areas occluded by biofilm that comprised predominantly bacteria and occasionally some yeasts incorporated in the extracellular polymeric substance. Bacteria identified in all bone samples comprised Gram-positives and Gram-negatives and also included aerobes, even though the majority were anaerobes or facultative anaerobes. Species of Fusobacterium, Bacillus, Actinomyces, Staphylococcus, Streptococcus, Selenomonas and three different morphological variants of spirochetes were observed in the biofilms. Fungal morphotypes compatible with Candida sp. were also evident in all cases. The organisms identified were compatible with normal oral microbiota, particularly with that involved in periodontal, pulpal, periapical (bacterial) and mucosal (fungal) diseases. The authors observed that, when the specimens were cut in cross-section, bacteria were evident on all internal surfaces, indicating the presence of bacterial biofilm in deep bone cavities and not only on its surface exposed to the contaminated oral cavity. Moreover, all specimens showed bone regions where host eukaryotic cells were adjacent to or trapped within the biofilm. Nevertheless, no eukaryotic cell was observed in or near resorption pits. Therefore, considering that bone resorption was evident in all samples despite the absence of osteoclasts within or adjacent to resorption pits, Sedghizadeh et al. 55 concluded that resorption had probably been caused by microbial biofilms. According to the authors, the fact that patients were taking bisphosphonates, which are antiresorptive drugs, supports this hypothesis. Also, all cases exhibited large surface areas occluded by well-developed biofilms, which comprised microbial organisms embedded in the extracellular polymeric substance. Both osteomyelitis and osteonecrosis cases showed multispecies microbial biofilms on internal and external surfaces along the depth of the excised bone.

Actinomyces israelii can be found in dental biofilm and calculus, advanced periodontitis, infected dental root canals and periapical infections. 60 This microorganism and many pathogenic bacteria of the oral cavity, which are associated with osteonecrosis, have the ability to invade jaw bones causing destruction through direct and indirect mechanisms. 61 Among these mechanisms are: (a) destruction of non-cellular components of bone through the release of acids and proteases; (b) induction of cellular processes that stimulate bone degradation; and (c) inhibition of bone matrix synthesis. 61 In addition, bacteria can invade osteoblasts, producing functional disturbances and apoptosis, which leads to dysregulation of bone remodeling 62 ( Fig. 1 ).

gr1

Fig. 1 Mechanisms of jaw bones destruction by oral pathogenic bacteria. (A) Destruction of non-cellular components of bone caused by acids and proteases release; (B) induction of cellular processes that stimulate bone degradation; (C) inhibition of bone matrix synthesis.

Chemical mediators of bone resorption produced by bacteria include proteins such as porins61 and 62 and collagen-degrading enzymes such as collagenases. Through this process, amino acids required for bacterial growth are obtained and anaerobic niches are created in bone, which favours bacterial growth and spread. 63 In most cases of chronic inflammation associated with infection, Gram-negative bacteria and their products have been implicated. Moreover, Gram-negative bacteria show lipopolysaccharides, which, like interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha), can directly induce osteoclastogenesis. 64 It is known that osteoblasts regulate osteoclastogenesis by receptor activator of NF-κB ligand (RANKL), which can also be induced by bacteria, favouring bone loss in chronic inflammation. 64 Eventually, it is important to emphasise in this context that classically the expression bone resorption refers to a process of bone degradation performed by osteoclasts, even though, some authors22, 58, and 61 have reported that bone resorption could also be performed by other agents, such as bacteria.

Kos and Luczak 65 defend the hypothesis that bisphosphonates promote jaw osteonecrosis by facilitating bacterial colonisation. According to these authors, bone necrosis and osteomyelitis that occur during bisphosphonate administration result from the more intense bacterial adhesion to bone coated with this drug. This promotes bone surface colonisation predominantly by Gram-positive strains, including Actinomyces, which creates favourable conditions for the development of chronic infection with a polymicrobial ecosystem more resistant to therapy. Actinomyces perpetuate the adherence of other microflora, which results in a heterogeneous population of bacteria primed for the development of infection. 22 Such bacterial adhesion to bone surface would occur by direct electrostatic interaction with the amino-cationic group of nitrogen-containing bisphosphonates, through direct interaction between surface proteins or by providing an amino acid mimic on the surface of bone hydroxyapatite, which interacts with microbial surface components that recognise adhesive matrix molecules (MSCRAMM) mediating increased bacterial adhesion. Bone exposure during surgery or tooth extraction works as a triggering factor that opens the door for bacterial invasion. This would explain the strong correlation between BRONJ and dental surgeries. Also, the higher susceptibility of jaws to infection, when compared to other bones, reinforces this hypothesis. Jaw bones easily come in direct contact with the external environment because of the thin layer of overlying mucosa, constant exposure to trauma and presence of teeth. 65 According to Kos and Luczak, 65 the confirmation of this theory of infection could indicate the need for more rational antibiotic therapy, with a special reference to the efficient system of application of antibiotics to the hypovascular and hypocellular bone. That is, it should be taken into account that systemic antibiotic therapy may have a limited efficacy on the bacterial population associated with BRONJ lesions. 27

BRONJ cases exhibit numerous microbial morphotypes, whereas bisphosphonate-non-related osteomyelitis cases show a higher prevalence of monospecies with a predominance of Actinomyces sp. In the former, bone becomes more susceptible to being colonised by various microorganisms that usually do not, such as superficial fungal organisms (Candida albicans) and some of the more benign bacterial morphotypes found in osteonecrosis. 55

A microbial variety has been identified in BRONJ, where Actinomyces sp. colonies in contact with non-vital bone are a consistent histological finding.1, 66, and 67 These colonies were observed in all BRONJ and osteoradionecrosis cases studied by Hansen et al. 1 The authors used histological samples subjected to haematoxylin and eosin (H&E), Grocott, Gram and periodic-acid Schiff (PAS) staining. Bacteria were observed in greater amounts at sites of necrotic bone, which differed from other bone regions by notable signs of erosion and numerous irregularly shaped contours. Also, bacterial filaments were interspersed with some inflammatory cells, especially neutrophilic granulocytes. Other microorganisms were not observed, except in one case of BRONJ that showed fungal spores superficially located, compatible with Candida spp.

The bacterial profile in soft tissues in BRONJ lesions has been analysed by means of polymerase chain reaction (PCR). 27 Samples were collected from five patients under antibiotic therapy and five patients under no treatment. The results indicated that Parvimonas and Peptostreptococcus were more prevalent in the group treated with antibiotics, whereas Fusobacterium, Atopobium, and Streptococcus existed predominantly in the non-treated group. Both groups showed a high number of Actinomyces, which was attributed to the fastidious nature of the bacteria and not to its association with BRONJ. 27

Hansen et al. 68 evaluated archived material from 45 patients with actinomycosis of the jaws, and found that 42 had malignancy treated by head and neck radiation therapy or by bisphosphonate and that 3 had no malignancy. All patients, with or without malignancy, exhibited similar histological features: (a) Actinomyces colonies in direct association with bone; (b) mixed inflammatory infiltrate in bone marrow spaces with variable amount of osteoclasts; and (c) pseudoepitheliomatous hyperplasia in up to 60% of cases. Actinomyces sp. colonies were principally adhered to bone without inflammatory cells. In 3 out of the 45 cases, fungi forming non-septated hyphae and spores were also observed, which probably corresponded to Candida sp. In contrast to Actinomyces, mycotic filaments were always broader showing a double-linear lining.

Merigo et al. 69 reported four cases of BRONJ that occurred without previous dental extraction, in patients using pamidronate and zoledronic acid. According to the authors, Candida albicans was observed in two cases, whereas one case showed Actinomyces within the bone lesion on microbiological and histopathological examinations. Diego et al., 3 in turn, found necrotising osteitis associated with bacterial colonies in all 10 cases of zoledronic acid-associated osteonecrosis evaluated by histopathological examination. Also, histopathology was available in 30 out of 101 cases of BRONJ reported by Lazarovici et al., 70 where 93% showed Actinomyces colonies identified by Gram and PAS staining. Senel et al. 71 reported one case of osteonecrosis related to the use of oral clodronate during 5-year treatment of multiple myeloma. Histopathology of the infected bone exhibited dense infiltrate of plasma cells, polymorphonuclear leukocytes and lymphocytes as well as numerous Actinomyces colonies. Badros et al. 72 investigated BRONJ cases in multiple myeloma patients. On histological examination, they observed osteomyelitis and areas of acellular necrotic bone, whereas the microbiological examination showed filamentous microorganisms compatible with Actinomyces in 7 out of 20 patients.

Maahs et al. 23 analyzed the tooth extraction sites in rats treated with bisphosphonates. They observed that 80% of the animals treated with zoledronic acid showed osteonecrosis with high prevalence of microorganisms, most of them compatible with Actinomyces. On the other hand, the alendronate group did not have any case of osteonecrosis and had low prevalence of microorganisms, with no significant difference from controls for this variable. According to the authors, the high prevalence of microorganisms in the zoledronic acid group resulted from the osteonecrotic lesion.

Jacobsen et al. 21 reported the clinical and histological features of 110 cases of jaw osteonecrosis associated with bone resorption-inhibiting drugs, such as bisphosphonates and RANKL inhibitors. Seventy-four percent of patients showed clinical bone exposure, and in 23% a fistula was observed with only radiographic evidence of affected bone. Pain was the major concern in 75% of patients, where 100% showed signs of infection at the site of the affected bone, with pus discharge, abscesses or inflammation of surrounding soft tissue. Histological analysis was performed in 64 specimens, where all of them showed necrotic bone (acellular bone, without osteocytes, osteoclasts or osteoblasts) with signs of acute and chronic inflammation, besides bacterial colonisation. Plaques of Actinomyces were specifically described in 72% of the cases.

Fourteen BRONJ patients who received intravenous bisphosphonate to treat bone metastases and hypercalcemia were diagnosed by Dannemann et al. 73 Clinically, the most prevalent finding was exposed necrotic bone, occurring in 13 patients. Eleven patients reported discomfort or strong acute pain. Six patients showed hypoesthesia of the inferior alveolar nerve. Inflammatory signs were observed in all cases and four out of them showed soft tissue abscess. Histopathological examination of necrotic bone fragments revealed acute and chronic inflammatory alterations with bone marrow fibrosis, plasma cell infiltration, and colonisation by pathogens. Microbiological analysis was performed in six cases and showed fungal and bacterial colonisation with pathogens of normal oral microbiota such as Actinomyces, Lactobacillus, Candida glabrata and other microorganisms determining aggressive infection of the bone and surrounding soft tissues. According to the authors, such results suggest that bisphosphonates are not an isolated cause of osteonecrosis. However, they play an important role in the pathogenesis of the lesion if associated with other synergistic factors such as oral microbiota. The authors believe that infection plays a major role in BRONJ pathogenesis. They found that even after a very successful surgery, some patients had bone dehiscence later on. Nevertheless, symptoms were completely alleviated after subjecting patients to antibiotic therapy, including antibiotics and antimicrobial rinsing.

Badros et al. 72 observed species of Peptostreptococcus, Streptococcus, Eikenella, Prevotella, Porphyromonas and Fusobacterium in 9 out of 20 BRONJ patients evaluated. According to the authors, the contribution of these microorganisms to soft tissue infection and osteomyelitis is unknown. Wongchuensoontorn et al. 74 reported three cases of BRONJ that progressed to pathological fracture. Microbiological culture showed Streptococcus intermedius, Peptostreptococcus spp. and Bacteroides melaninogenicus in the first patient, Actinomyces israelii and Bacteroides fragilis in the second, and Enterococcus faecalis and Bacteroides fragilis in the third.

O’Ryan and Lo 75 reported 30 cases of patients treated with oral bisphosphonate that developed BRONJ after tooth extraction or oral trauma or spontaneously. The cases subjected to histopathological examination showed Actinomyces spp. as a common feature. Most patients with oral trauma history also showed the presence of Streptococcus spp., Prevotella and Klebsiella, as well as Pseudomonas in those who had had tooth extraction.

3. Antimicrobial treatment of BRONJ

BRONJ management is a challenging problem, since up to now there is no efficacious therapy.21, 26, and 76 Depending on the clinical conditions and type of bisphosphonate used, surgical treatment can be recommended, 21 but there is no agreement about the adequacy of this therapeutic option. 76 In this context, biofilm organisms have been the clinical target for the prevention and treatment of the disease, aiming to reduce morbidity and costs associated with it. 6 Mouth rinses with antimicrobial substances such as 0.12% chlorhexidine and hydrogen peroxide, three to four times daily have been recommended as local therapy to reduce bacterial colonisation.26, 69, 77, 78, and 79 Systemic antibiotics associated with mouth rinses are recommended for more advanced cases. Even though antibiotic regimen should be established according to the antibiogram, 73 some protocols are in current use. As most of the microorganisms isolated from BRONJ lesions are sensitive to penicillin, oral amoxicillin at 1.5–3 g daily has been the therapeutic choice. 70 Quinolones, metronidazole, clindamycin, doxycycline and erythromycin have been used in patients allergic to penicillin. These drugs must be administered over a long-term period, which can vary from several months to more than a year. Intravenous antibiotics should be used when lesions do not respond to oral route.2 and 70 Chlorhexidine has been beneficial in the control of surface bacteria, which can help the recovery of bone-exposed regions in BRONJ. 80

It is important to recall that, besides bacteria, fungi, especially Candida spp., have also been found in BRONJ lesions,1, 58, 59, 68, 69, and 73 which deserves attention when deciding on antimicrobial therapy. Among the protocols applied in BRONJ treatment, chlorhexidine seems to be the main tool against fungal agents. Malhotra et al. 81 evaluated the efficacy of six different mouth rinses against Streptococcus mutans, Lactobacillus and Candida albicans. The rinses were (a) 0.12% chlorhexidine digluconate, (b) 0.2% sodium fluoride, (c) propolis mouth rinse and (d–f) combinations of these three substances. Among the mouth rinses, chlorhexidine was the most efficacious against Streptococcus mutans and Lactobacillus. In all test groups the smallest inhibition zone occurred for Candida albicans, even though chlorhexidine was the mouth rinse with the highest inhibition against it. At low concentrations, chlorhexidine is bacteriostatic, whereas at high concentrations it is bactericidal. 82 These effects are based on its ability to impair the integrity of bacterial membranes. 83 At low concentrations, it increases the permeability of bacterial cell membranes with leakage of intracellular components. At high concentrations, it induces the precipitation of the bacterial cytoplasm and consequently causes cell death. 81 Besides a broad spectrum of antimicrobial activity, chlorhexidine has an antifungal effect particularly efficient against Candida albicans. 84 The lower antifungal than antibacterial activity is related to the basic differences in the external cellular structure of bacteria and fungi, as the latter have a rigid external wall of chitin. 81 Despite showing lower antifungal than antibacterial activity, chlorhexidine has proved efficacy against Candida albicans, 84 which seems to be the major yeast found in BRONJ lesions.

4. Final considerations

BRONJ etiopathogenesis has not been completely elucidated, even though there are many theories trying to explain it. Some of them point to infection as the major and not just a secondary event.6, 50, 51, and 73 There are authors who defend the idea that bone impregnated with bisphosphonate is less resistant to bacterial infection and colonisation than normal bone, serving as an ideal incubator for periapical and periodontal bacteria, which stimulate a chronic inflammatory immune response. 85 There are also speculations suggesting an electrostatic interaction between nitrogen-containing bisphosphonates and Gram-positive bacteria, which would favour bone infection by these microorganisms. 65 Moreover, although Actinomyces sp. is the most frequent microorganism found in BRONJ lesions, there are many other bacterial and fungal species of the oral microbiota that are also found in the affected bone ( Table 1 ).

Table 1 Reports on microorganisms involved in bisphosphonate-related osteonecrosis of the jaws (BRONJ).

Microorganisms n of positive cases/total n (%) Bisphosphonate Method Reference
Actinomyces spp 8/8 (100%) Pamidronate, zoledronic acid, ibandronate Clinical study, histopathology (H&E, PAS, Gram, Grocott) Hansen et al. 1
Candida spp 1/8 (12.5%)
Actinomyces spp 46/64 (72%) Zoledronic acid, pamidronate, alendronate, ibandronate, risedronate Clinical study, histopathology Jacobsen et al. 21
Actinomyces spp. 10/10 (100%) Zoledronic acid In vivo study (rats), histopathology (H&E) Maahs et al. 23
Actinomyces spp 4/10 (36.4%) Alendronate
Fusobacterium, Bacillus, Actinomyces, Candida spp., Staphylococcus, Streptococcus, Selenomonas, Treponemas 4 a Pamidronate (1), zoledronic acid (1), alendronate (2) Clinical study, histopathology (H&E), SEM Sedghizadeh et al. 58
Actinomyces spp 13/13 (100%) Zoledronic acid, alendronate, risedronate, ibandronate Retrospective study, histopathology, SEM Lee et al. 59
Yeast colonies Common finding a
Actinomyces spp 26/26 (100%) Zoledronic acid, pamidronate Clinical study, histopathology (H&E, Grocott, Gram, PAS, Goldner or Elastica-van Gieson)

PCR, SEM
Hansen et al. 68
Actinomyces israelii 7/7 (100%)
Candida spp 3/26 (11.54%)
Actinomyces spp. 1/4 (25%) Pamidronate and zoledronic acid (n = 2) Zoledronic acid (n = 2) Clinical study, histopathology (H&E, PAS) and microbiology Merigo et al. 69
Candida spp 2/4 (50%)
Actinomyces spp 28/30 (93%) Pamidronate, zoledronic acid, alendronate, risedronate, clodronate Clinical study, histopathology (Gram and PAS) Lazarovici et al. 70
Actinomyces spp 1/1 (100%) Clodronate Clinical study, histopathology: (H&E) Senel et al. 71
Actinomyces spp 7/20 (35%) Zoledronic acid, pamidronate Clinical study, histopathology Badros et al. 72
Peptostreptococcus, Streptococcus, Eikenella, Prevotella, Porphyromonas, Fusobacterium 9/20 (45%)   Culture  
Actinomyces, Lactobacillus, Candida glabrata and other microorganisms 6 a Zoledronic acid, pamidronate Clinical study, microbiology Dannemann et al. 73
Streptococcus intermedius, Peptostreptococcus spp, Bacteroides melaninogenicus 1/3 (33.3%) Zoledronic acid, alendronate Clinical study, culture Wongchuensoontorn et al. 74
Actinomyces israelii, Bacteroides fragilis 1/3 (33.3%)
Enterococcus faecalis, Bacteroides fragilis 1/3 (33.3%)
Actinomyces spp, Streptococcus spp, Prevotella, Klebsiella, Pseudomonas 12 a Alendronate, ibandronate, etidronate Retrospective study, histopathology O’Ryan & Lo 75

a Without other specification.

H&E, haematoxylin and eosin; PAS, periodic acid-Schiff; SEM, scanning electron microscopy.

In fact, even if bacterial biofilm does not directly cause the development of BRONJ, it indeed plays an essential role in the clinical repercussion of the disease. 6 In this way, regardless of having a major or secondary role in BRONJ etiopathogenesis, microorganisms are up to now important determinants of the therapeutic measures in this disease. Therefore, BRONJ treatment cannot ignore the different species found in the lesions, including fungal ones. Further studies aiming to classify and quantify all these diverse microorganisms are needed. The strict relationship between microorganisms and the type of bisphosphonate used, as well as the possible electrostatic interactions between nitrogen-containing bisphosphonates and bacteria must be investigated.

Funding

None.

Competing interests

None declared.

Ethical approval

Not required.

Acknowledgment

We thank Dr. A. Leyva (U.S.A.) for English editing of the manuscript.

References

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Footnotes

Postgraduate Program, Dental College, Pontifical Catholic University of Rio Grande do Sul – PUCRS, Brazil

lowast Corresponding author at: Serviço de Estomatologia, Hospital São Lucas PUCRS, Av Ipiranga, 6690, sala 231, CEP 90610-000 Porto Alegre, RS, Brazil. Tel.: +55 51 33203254; fax: +55 51 33203254.


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