ReviewImportant aspects regarding the role of microorganisms in bisphosphonate-related osteonecrosis of the jaws
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, 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, 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, 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, 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, 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, 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, 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, 23 diabetes, 22, 24 tobacco use,22 trauma to oral tori25 or caused by prosthetic appliances, oral infection,26 poor oral hygiene, malnutrition27 and bone manipulation.28 Route of administration, type of bisphosphonate (nitrogen or non-nitrogen containing)2, 17 and treatment duration9, 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, 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, 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, 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, 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, 36 called osteoprotegerin (OPG).36, 37, 38, 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, 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, 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 mice41 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 hip44 and osteoradionecrosis of the jaw1, 45, 46 have led to the hypothesis that vascular disruption could also play a key role in the pathophysiology of BRONJ.22, 25, 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, 49
Still, there is strong evidence that infection is closely related to BRONJ etiopathogenesis,50, 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, 54 We present here a literature review focusing on important aspects related to the role of microorganisms in BRONJ etiopathogenesis.
Section snippets
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
Antimicrobial treatment of BRONJ
BRONJ management is a challenging problem, since up to now there is no efficacious therapy.21, 26, 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
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, 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
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.
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