Bisphosphonate-associated jaw osteonecrosis in the treatment of rheumatoid arthritis

Osteonecrose mandibular associada a bifosfonatos no tratamento de artrite reumatóide

ABSTRACT

This literature review aimed to raise the relationship between rheumatoid arthritis and mandibular osteonecrosis associated with bisphosphonates. The articles were collected in Pubmed, Bireme, Cochrane and Scielo between the years 2000 and 2023, the articles that contained hypotheses of correlation with the theme or that contained case reports (inclusion of publications between 2005 and 2019) where osteonecrosis appeared during treatment for rheumatoid arthritis were included. The survey allowed an assessment of the profile of the patient with rheumatoid arthritis, as well as the bone consequences of the use of oral methotrexate and bisphosphonates and treatment options; as well as the success of conservative and surgical techniques against mandibular osteonecrosis. Although the relationship between mandibular osteonecrosis and rheumatoid arthritis is not completely understood, we can conclude that the dental surgeon and the rheumatologist must always be in communication in order to treat mandibular osteonecrosis in the best possible way, as well as prevent its onset.

Indexing terms
Arthritis rheumatoid; Bisphosphonate-associated osteonecrosis of the jaw; Mandible

RESUMO

Esta revisão de literatura teve como objetivo levantar a relação da artrite reumatóide com a osteonecrose mandibular associada a bifosfonatos. Os artigos foram coletados no Pubmed, Bireme, Cochrane e Scielo entre os anos de 2000 e 2023, os artigos que continham hipóteses de correlação com o tema ou que continham relatos de casos (inclusão de publicações entre 2005 e 2019) onde a osteonecrose surgiu durante tratamento para artrite reumatóide foram incluídos. O levantamento permitiu uma avaliação do perfil do paciente com artrite reumatóide, bem como consequências ósseas frente uso de metotrexato e bifosfonatos por via oral e opções de tratamento; bem como sucesso de técnicas conservadoras e cirúrgicas frente uma osteonecrose mandibular. Embora a relação da osteonecrose mandibular e a artrite reumatóide não seja completamente compreendida podemos concluir que o cirurgião-dentista e o reumatologista devem estar sempre em comunicação a fim de tratar a osteonecrose mandibular da melhor forma possível, bem como prevenir seu aparecimento.

Termos de indexação
Artrite reumatoide; Osteonecrose da arcada osseodentária associada a difosfonatos; Mandíbula

INTRODUCTION

Rheumatoid arthritis (RA) is an autoimmune disease characterized by peripheral polyarthritis, which leads to the destruction of joints and bones through erosive processes [¹].

The clinical course of patients with the disease is variable, with acute and chronic periods. Treatment also includes a range of medications; among the most common are nonsteroidal anti-inflammatory drugs, glucocorticoids, opioids, folic acid and disease-modifying antirheumatic drugs [¹].

The treatment of RA is based on the use of methotrexate and bisphosphonates. Bisphosphonates (BFs) are medications that directly or indirectly induce osteoclast apoptosis and can also inactivate them, resulting in the maintenance of bone density [²].

In 2003, Marx published the first reports of bisphosphonate-related osteonecrosis of the jaw (BRONJ). These patients were polypharmacy patients for different diseases; the only thing they had in common was the consumption of bisphosphonates (BPs). Some patients developed osteonecrosis (ON) after dental intervention and others due to mucosal atrophy [³].

The possibility of RA being a cofactor for BRONJ opens up a new perspective, since the disease should be monitored in a multidisciplinary manner. Ideally, the patient should undergo a dental evaluation before starting to prescribe BPs. During this evaluation, the triggering factors for ON should be removed, the patient should be aware of the need to maintain good oral hygiene, and at the slightest sign of injury, the patient should see a dentist surgery (DS). In the case of ON, the approach should also be multidisciplinary. The physician may or may not suspend BPs, and the DS will choose between a conservative intervention or a surgical technique [⁴].

To conduct a literature review on the association of RA with medication-related mandibular ON.

Articles from PubMed, Bireme, Cochrane and Scielo were used. Publications occurred between the years 2000 to 2023. All articles that related RA, ON and BPs were included. The clinical cases included were reported between the years 2005 to 2018. Articles in English, Spanish and Portuguese were included. The literature review sought to organize the definition of ON, RA and BPs, and then correlate them. The keywords used in the search were: Bisphosphonate-associated osteonecrosis of the jaw; arthritis rheumatoid; Osteonecrosis of the jaw.

Rheumatoid arthritis and its pathology

RA is an autoimmune disease whose pathophysiology and etiology are still unknown. RA is characterized by erosive bone destruction, affecting large and small joints, and is generally associated with systemic manifestations such as weight loss, fatigue, morning stiffness, and disabling changes that interfere with the patient’s social life and activities [²].

From a cellular point of view, RA presents itself as a long-term immunological disorder involving persistent synovitis, systemic inflammation, autoantibody production, chronic pain and functional disability [⁵].

The pathological mechanisms of RA are still unknown, but it is already possible to understand that it is a condition of osteochondral destruction in which there is an increase in inflammatory and immune cells, including neutrophils, monocytes and lymphocytes T and B, which culminates in an increase in pro-inflammatory mediators such as TNF-alpha, interleukin-1, interleukin-6 and matrix-degrading enzymes such as matrix metalloproteinase (MMPs) and cathepsin. There is also an increase in the activation of the nuclear factor kappa B (RANK-L) pathway induced by soluble mediators released by immune cells, which may stimulate the process of osteoclast maturation and differentiation [⁵].

RA has a preclinical manifestation phase that can last for many years with the emergence of autoantibodies in the absence of objective signs of joint inflammation. In the clinical picture of RA itself, there is a close interaction between cells and inflammatory mediators, progressive accumulation of multiple autoantibodies, dissemination of epitopes, and signal transduction pathways of the innate and adaptive immune systems [⁵,⁶].

Genetic Aspects of RA

Genome-wide association studies (GWAS) have sought to identify which genes could be related to susceptibility to RA, obtaining the response from the complex (MHC - Major Histocompatibility Complex). Within the MHC subdivision, it was found that the allele (HLA-DRB1 - amino acid sequence code of the gene) provides an important contribution to the risk of developing RA [⁷].

HLA-DRB1

This gene shares similar amino acid sequence at positions 70-74 in the HLA-DR beta chain, which is termed as shared epitope (SE). SE is prevalent in patients positive for anti-citrullinated protein antibodies (ACPAs) [⁷].

Citrullination

Protein citrullination is a post-translational modification (PTM) that can be physiological. A number of peptides can undergo PTM, but breaking the tolerance of citrullinated peptides can initiate the formation of anti-citrullinated protein antibodies (ACPAs). This production of ACPAs only occurs in predisposed individuals [⁸].

The citrullination process leads to the loss of positive charge and a slight change in the molecular mass of the protein. Its ability to bind to the hydrogen atom is impaired, as is its interaction with other amino acid residues. Thus, it is concluded that the citrullinated protein is very different from the original in terms of conformation and function [⁸].

ACPAs are highly reactive and bind to a number of citrullinated proteins such as enolase, fibrinogen, vimentin, collagen and histones. Studies have demonstrated the presence of citrullinated proteins in the synovial tissue of patients with RA [⁹].

Non-HLA Genes

A study in India revealed that polymorphisms in the promoter area of cytokine genes alter the expression of cytokines that contribute to susceptibility to RA. The polymorphism of the IL-1beta gene was investigated and it was found that it modulates inflammatory processes, destroys joints in RA and increases levels of anti-cyclic citrullinated peptide antibodies (anti-CCP). It was also found that the IL-10 gene has an immunoregulatory function, contributing to an anti-inflammatory action in rheumatoid synovitis [¹⁰].

Epigenetic studies in RA

Epigenetic studies are a branch of research that observes hereditary changes that modulate DNA, without altering its original sequence, but which can be influenced by environmental factors [¹¹].

In autoimmune diseases, there is epigenetic variability, and in the pathogenesis of RA, it is no different. Some epigenetic findings deserve to be highlighted:

• -Huntington’s disease signaling: specific protein 1 interacts with Huntington’s, modulating the ability of fibroblast-like synoviocyte (FLS) to remodel the bone matrix. Thus, anomalous methylation and alteration of histone lysine occur, which changes FLS gene expression, expanding and perpetuating the inflammatory and synovial remodeling picture in RA.

• - Changes in micro RNA expression have already been observed in patients with RA [¹²].

FcyR signaling

Osteoclast formation occurs through soluble mediators, such as the receptor ligand for nuclear factor K beta (RANKL or TNFSF-11), a factor that stimulates macrophage colonies (M-CSF), negative regulators (a decoy for RANKL), and osteoprotegerins. The bone resorption process itself releases growth factors that stimulate local immune cells and osteoblasts. The process of new bone formation occurs through the proliferation of stem cells that differentiate into osteoblasts that move to the bone matrix, where they are called osteocytes [¹³].

In RA, there is an immunological activation associated with bone tissue loss and hyperstimulation of osteoclasts. Humans have five FcyRs (Receptors for immunoglobulin G) that have different degrees of binding to immunoglobulin G (IgG). Activation of FcyRs generates calcium influx, antigen uptake, cellular activation, release of pro-inflammatory cytokines by immune cells and increased osteoclastogenesis [¹⁴].

Antibody glycosylation

IgG has a conserved area for Fc glycosylation (asparagine-297 CH2 domain). The glycosylation process needs to occur with maximum precision so that the binding between IgG and FcyR is regulated. Enzymatic deglycosylation or mutations of asparagine-297 to alanine cause the FcyR binding to be lost, and with this all effector functions are cut off [¹⁵].

ACPAs in the synovial fluid of patients with RA have a low sialic acid content, which contributes to the appearance of bone erosions. Glycosylation is relevant for the correct functioning of IgG and thus the reduction of antibody-mediated bone loss and the improvement of osteoclastogenesis [¹⁶].

TNF-alpha and Interleukin-6

TNF-alpha is among the most potent cytokines in osteoclastogenesis, inducing the expression of receptor activator of nuclear factor kappa beta (RANK) by osteoclast precursors, TNF-alpha and RANKL (receptor activator of nuclear factor kappa beta ligand) together can stimulate osteoclast formation; TNF-alpha indirectly regulates osteoclasts by stimulating stromal cells. Interleukin-6 (IL-6) is a potent molecule in inducing osteoclast differentiation [¹⁷].

Environmental factors

Smoking

Smoking causes changes in the inflammatory process and in bone neoformation, which influences the production of autoantibodies. Smoking causes tissue hypoxia, which induces inflammatory processes and angiogenesis, but also leads to citrullination of Fibroblast-like synoviocytes (FLS). Therefore, smoking contributes to and increases the chance of developing RA [¹⁸].

Obesity and diet

The activity of adipose tissue is mediated by adipokines. The most active adipokine in RA is leptin, since it has direct effects on the immune system, increasing circulating T cells, IL-6, IL-21 and IL-12 levels [¹⁹].

The Mediterranean diet consists of the healthiest eating habits, which positively influences the intestinal microbiota and indirectly modulates the immune system. Today, it has been proven that this type of diet is indicated for RA, as it involves a high consumption of antioxidant foods. The Mediterranean diet cited in the articles advocates the intake of vitamin C, retinol, omega-3 polyunsaturated fatty acids, monounsaturated fatty acids, and high consumption of fish, whole grains, fruits and vegetables [¹⁹].

Microbiota and mucosa

Sites lined with mucosa have mechanisms that serve as a physical and immunological barrier. Most mucosal surfaces have an epithelial barrier and a mucosal barrier that contains immunoglobulins, enzymes, neutrophils, and macrophages [²⁰].

Some studies have found that patients exposed to environmental factors, with a genetic history of HLA-DRB1, intestinal dysbiosis, infection by P. gingivalis or A. actinomycemcomitans generate protein alterations by citrullination. In predisposed individuals, a host response to citrullinated proteins occurs. Immune cells produce pro-inflammatory mediators such as interleukin, prostaglandins, tumor necrosis factors, and metalloproteases that aggravate the immune response. Patients with RA and chronic periodontitis (CP) have citrullination of their proteins. Patients with CP may have immune alterations that contribute to the onset of RA, and, in contrast, patients with RA have immune alterations that favor the onset of severe CP [²⁰].

Infections

In addition to the connection between arthritis and intestinal dysbiosis, severe viral and bacterial infections have been shown to favor the development of autoimmune diseases, such as RA. The Epstein-Barr virus (EBV) is currently the subject of research, but we can already say that serum and lytic EBV coincide with RA activity. EBV can be found in the synovial tissue of patients with RA and causes chronic joint inflammation that favors the onset of RA [²¹].

IMMUNE RESPONSE IN RA

Innate Immunity

The role of innate immunity is the non-specific recognition of microorganisms. Upon contact of immune cells with bacterial toxins, the phagocytosis process is activated and cytokines and chemokines are released at the infected site. Innate immune cells function with a series of specialized pattern recognition receptors, with Toll-like receptors (TLRs) being capable of recognizing microbial epitopes [²²].

Monocytes

Research shows that in RA, monocytes undergo an increase in turnover, migrating from the bone marrow to the bloodstream and heading towards the inflamed joint [²²].

Macrophages

Patients with RA have a 76% increase in the number of macrophages in adipose tissue and a greater amount of cytokines around dead adipocytes [²³].

Neutrophils

Neutrophils play an important role in the immune system, specifically in relation to RA, neutrophils represent 90% of the total cells found in the synovial fluid. Neutrophils release pro-inflammatory cytokines, reactive oxygen species (ROS), degradative enzymatic vesicles, neutrophil extracellular traps (NETs) that amplify tissue damage and the inflammatory response [²⁴].

Adaptive Immunity

A series of mediators and cellular components such as B and T lymphocytes may contribute to the pathogenesis of RA [²⁴].

A study conducted in rats demonstrated that animals treated with beta2 antagonists (an adrenergic receptor expressed by CDA+T lymphocytes) and PKA H-89 inhibitors (a blocker of the effects of the agonist terbutaline) were able to reduce Th17 cell differentiation, which consequently reduces the production of IL-17 and IL-22, inhibits the proliferation of CD4+T cells, resulting in an anti-inflammatory environment in the joints. Modulation of the beta2 receptor may help in the treatment of RA [²³,²⁴].

In some patients with RA, B lymphocytes produce anti-PAD4 antibodies, which may increase the action of PAD4 and, consequently, produce citrullinated antigens, since the requirement for calcium is reduced by enzyme inhibition [²⁵].

Diagnosis and Treatment of Rheumatoid Arthritis

To have RA, the patient must have at least 4 of the 7 criteria described; with a minimum duration of 6 weeks. The criteria are: morning stiffness, arthritis in at least 3 areas, soft tissue edema and joint effusion, arthritis of the joints of the hands, symmetrical arthritis, rheumatoid nodules, serum factor and radiographic changes of erosion or decalcification on hand and wrist radiographs [¹].

During the physical examination of the patient, the physician checks the duration of morning stiffness, the intensity of joint pain and limitation of movement. Inflamed, painful and swollen joints are counted; the presence of crepitus, instability, deformities, osteoporosis and extra-articular manifestations is checked [¹].

The laboratory tests that should be performed are complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein, renal function, liver enzymes, rheumatoid factor, analysis of synovial fluid and qualitative urine test. From a radiological point of view, it is necessary to perform X-rays of the hands, feet and areas that are clinically compromised [¹].

Patients with RA should attend regular medical appointments and undergo a thorough clinical examination; laboratory and imaging tests should be repeated at the physician’s discretion. The earlier the diagnosis and the earlier treatment is started, the more controlled the disease activity will be; it is worth mentioning that complete remission of RA rarely occurs [¹,²].

The therapeutic approach begins with educating the patient and their family. Periodic evaluation with a rheumatologist is recommended. The patient should practice physical exercises with the supervision of a physiotherapist, in order to protect and strengthen the joints and the cardiorespiratory system. Rest and a sedentary lifestyle accelerate joint degeneration [¹,²,⁴].

The most commonly prescribed medications to control pain and joint degradation are: nonsteroidal anti-inflammatory drugs, glucocorticoids, opioids, folic acid [¹] and disease-modifying antirheumatic drugs, such as hydroxychloroquine, sulfasalazine and methotrexate, which is considered the gold standard medication [²⁶]. Other medications include: leflunomide, azathioprine, cyclosporine, cyclosporine, etidronate, tiludronate, clodronate, pamidronate, ibandronate, risedronate, zoledronate and alendronate. More recently, genetically engineered biological agents have been indicated; in Brazil, TNF-alpha blockers (interleukin or tumor necrosis factor inhibitors or JAK inhibitors) such as infliximab, etanercept, adalimumab, denosumab and rituximab are used. Medications are combined in cocktails that aim to reduce periarticular inflammation and limit joint destruction, and contain a combination of bisphosphonates and methotrexate [⁵]. In some cases, treatment is surgical, with synovectomy, tendon correction, joint debridement, arthroplastic resection, arthrodesis and total arthroplasty procedures [¹].

Profile of Brazilians with rheumatoid arthritis

In 2007, a study was conducted to collect information on the demographic and clinical characteristics of patients with RA during laboratory monitoring at four reference university services in São Paulo, to verify the progression and stage of treatment. The results of the data collected from the medical records of 1,381 patients indicated a profile of patients with RA in which 86% were women, weighing an average of 65 kg, diagnosed with the disease less than 10 years ago (71%), aged between 40 and 59 years (55%); 71% were Caucasian, 65% complained of joint pain, only 30% were able to work formally and 85% used analgesics and anti-inflammatories. This Brazilian profile is not very different from what has been found in other countries [²⁷].

Oral complications in rheumatoid arthritis

RA is closely linked to moderate to severe periodontal and periradicular changes. Patients with RA are more likely to have periodontitis than healthy individuals; patients with periodontitis are more likely to have RA than patients without periodontal problems. RA negatively affects patients’ oral health, since it limits movement, especially of the hands; therefore, maintaining good oral hygiene becomes much more difficult, requiring biofilm control by a professional. If these patients have more periodontal problems, they also end up losing teeth; thus, edentulism is common in patients with arthritis. RA mainly affects the elderly; aging worsens the levels of fluoride circulating in saliva, which leads to caries lesions, which can also lead to teeth being extracted. If smoking is associated with RA, there may be a greater chance of developing periodontitis [²⁸].

Bisphosphonates

BPs are synthetic drugs derived from endogenous pyrophosphate that cause osteoclast apoptosis and their inactivation directly or indirectly, thus maintaining bone density and altering the entire bone turnover process, which reduces bone resorption [²⁹].

BP administered for a short period of time generates minimal side effects, as it is a well-accepted medication. However, prolonged use of BPs causes side effects, such as impaired renal function, pyrexia, bone pain, hypocalcemia, erosions and chronic ulcers in the oral cavity, esophagitis, esophageal stenosis, gastric ulcer, atrial fibrillation, atypical fracture, musculoskeletal pain and mandibular and maxillary ON, which is frequent when administered in high doses intravenously. However, patients who have been using BPs orally for a long time are also at risk and should be monitored. Patients with RA fall into this group [²⁹].

ON associated with bisphosphonates and Treatment Modalities

Some authors disregard ON as an adverse effect of BP therapy, as there are still no studies proving such a relationship in bones. Despite this, the clinician must evaluate the dose administered, the time of administration and the route of administration. The incidence in patients with non-malignant diseases is lower and directly related to prolonged periods of medication use [³⁰].

BRONJs are considered when the patient presents bone necrosis in the jaw or maxilla region, being present for a period of more than 8 weeks, without healing, and without a history of radiotherapy, osteolysis, jaw tumor, bone metastasis, or even exposure due to more serious periodontal problems [³⁰].

The patient at risk is the one who uses BPs, but clinically does not present bone exposure; patients who actually have ON are staged as:

• Stage 1 - ON with bone exposure, asymptomatic and without signs of infection;

• Stage 2 - ON with bone exposure with clinical signs of infection and generally without drainage of purulent secretion;

• Stage 3 - ON with signs of infection, with the presence of bone sequestration, paresthesia, pathological fracture or extraoral fistula [³⁰].

BRONJs can be observed after dental manipulations, such as control of established periodontal diseases, patients with bacterial plaque accumulation, tooth extractions, implant placement and osseointegration. Patients who use corticosteroids or those who consume antiangiogenic drugs are at greater risk. Clinically, it is observed that patients with infectious foci, established periodontal disease, traumatic lesions, lesions infected by bacteria and who have undergone surgical interventions are more susceptible to BRONJs, but it can also appear spontaneously [³¹].

There is no consensual treatment protocol. Some authors advocate surgical intervention, while others advocate preservation and local measures. In the case of bone necrosis, surgical removal of the sclerotic bone or fixation may be performed in patients with pathological fractures; in the postoperative period, local antimicrobial solutions and prophylactic and therapeutic antibiotics are necessary, as well as close monitoring by a professional. Conservative measures may be chosen, including antibiotics, chlorhexidine mouthwashes, superficial debridement, and pain control medication. For both surgery and preservation, there are studies that advocate the temporary suspension of BPs, known as drug holidays, which would improve the bone repair process. Studies show the success and failure of both approaches. It is up to the DS to choose what best suits the patient’s situation, considering their general health status. Currently, there are innovative therapeutic modalities that aim to improve the patient’s necrosis in a less invasive way, such as, for example, the prescription of parathyroid hormone, especially in patients with RA and osteoporosis, the association of platelet-rich plasma in debridement and extirpation, the use of low-power laser or Photo Dynamic Therapy (PDT) to decontaminate the area and accelerate healing, and ozone therapy. Periodic consultations every 6 months are also recommended after an episode of ON, as well as good levels of oral hygiene [³¹,³²].

ON can occur in the jaw or maxilla, but there is a predilection for the jaw due to the lower blood flow that supplies this bone. Since BPs inhibit angiogenesis and the jaw frequently suffers microtraumas, ON is more easily installed. After the sixth decade of life, the risk of ON in the jaw increases, since the jaw blood supply decreases even further, due to the appearance of stenosis of the inferior alveolar artery and decreased collateral circulation of the jaw due to peripheral vascular disease (thrombosis and atherosclerosis) [³²].

RA treatment and angiogenesis

Angiogenesis is a process that involves the migration, differentiation and growth of endothelial cells, so that blood vessels can be formed. For this process to occur, a connection between the signaling molecules Vascular endothelial growth factor (VEGF) and the endothelial cell receptors is necessary. Some authors also argue that there is a connection between VEGF and nitric oxide, stimulating the synthesis of endothelial cells and mobilizing endothelial progenitor cells. ON is defined as avascular necrosis, with interference in angiogenesis [³²,³³].

There are some diseases and medications that can interfere with angiogenesis. Among these diseases, we can mention arterial hypertension, diabetes mellitus and hyperlipidemia. RA, in turn, exposes the patient to the risk of developing ON due to the continuous use of anti-resorptive medications and BPs [³³].

Inhibition of the VEGF molecule causes the antiangiogenic effect. It is known that the gold standard medication in the treatment of RA is methotrexate, which, in combination with steroids, acquires anti-angiogenic properties. The cocktail of BPs, steroids and methotrexate can suppress angiogenesis excessively and, thus, favor the appearance of mandibular ON. Bone exposure also occurs due to poor healing of the mucosa and submucosa in the face of traumatic injuries; methotrexate has a toxic effect on the mucous membranes, increasing the patient’s chance of developing ON and healing problems [³³].

BRONJ in patients with rheumatoid arthritis and taking BPs

There is still no scientifically proven correlation between RA and mandibular ON. Arthritis is an autoimmune disease with oral repercussions and drug therapy that favors the appearance of ON. The main link between the manifestations is the inflammatory condition resulting from RA and, at the same time, the systemic effects resulting from methotrexate, BPs and anti-inflammatories [³⁴].

Systemic inflammation negatively affects bone tissue and can stimulate bone resorption and necrosis processes through the release of pro-inflammatory mediators [³⁴,³⁵].

Some factors associated with the RA state that predispose to ON include the proliferation of T-gamma-delta cells that play a cytotoxic role in oral tissues, leading to ulceration of the epithelium; ulcers are entry points for microorganisms, which can reach the underlying bone tissue, favoring the emergence of ON [³⁴,³⁵]; decreased vitamin D stimulates the proliferation of T-gamma-delta cells, which contributes to the onset of the inflammatory process [³⁵]; nitrogen-derived BPs used in the treatment of RA can induce the release of pro-inflammatory cytokines, such as interleukin-1 and TNF-alpha, which can induce different inflammatory processes and necrosis [³⁶]; pro-inflammatory cytokines in RA are produced by synovial tissues, but this does not prevent them from coming into contact with the bloodstream; ON usually has a predilection for the jaw; considering that arthritis can affect the TMJ (temporomandibular joint) and that patients with RA usually develop moderate to severe periodontal disease, the bone at greatest risk is the jaw [³⁶], both RA and ON affect more elderly people due to the high production of inflammatory mediators and exhibit immunological impairment, excessively immunosuppressed patients are susceptible to ON and RA, steroid-induced ON, diabetes mellitus, hypertension, cancer, periodontal disease, oral ulcers and other oral diseases generate intense oxidative stress [³⁷].

Prevention of ON should be carried out by a multidisciplinary team. Ideally, before the rheumatologist prescribes BPs, the patient should see a dentist surgery (DS) so that infectious foci can be eliminated and further damage can be avoided. If the patient needs surgery, the DS should talk to the rheumatologist, as it may be necessary to suspend the medications. If the patient develops ON, the DS should decide whether or not to undergo surgical treatment, and follow-up should be done every six months [³⁸].

Studies report that it would be possible to request highly sensitive and specific clinical biomarkers for bone resorption. Among the biomarkers we can mention degradation of the C-terminal telopeptide of type I collagen (CTX), N-telopeptide (NTX), bone-specific alkanine phosphatase (BAP), osteocalcin (OCN), parathyroid hormone (PTH), receptor activator of nuclear factor kappa beta ligand (RANKL), osteoprotegin (OPG), triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH) and vitamin D, which in a not too distant reality could be requested before patients using BPs undergo surgical interventions. The different values of these biomarkers would show when the patient would be at greater or lesser risk of BRONJs. It should be noted that little scientific evidence supports the use of biomarkers for the diagnosis and prognosis of BRONJs in an effective manner and even preventively for DS [³⁹].

Reported clinical cases

Table 1
Mandibular ON associated with BFs in patients with RA.

Reference	Study	Gender	Age (years)	Comorbidities	Medication/ Time in use	Stage BRONJ /Trigger Event	Treatment	Results
Marunick et al. [40]	CR	F	59	RA OST	STE+MTX+SA (3 years)	II- tooth extraction	ATB +Washmouth +SEQ	Not heal
Yarom et al. [41]	RS	F	76	RA SAH HCOL Arrhythmia	SA (1,5 years)	III-tooth extraction	ATB+CURET +DEB +RESEC	Partial Healing
Yarom et al. [41]	RS	F	73	RA SAH	STE+MTX+SA+ Infliximab (7 years)	III-tooth extraction	ATB+CURET +DEB +RESEC	Not heal
Khamaisi et al. [42]	RS	F	73	RA DM	SA (6 months)	II-oral surgery	NI	NI
Marx et al. [43]	CR	F	NI	RA OST	STE+MTX+SA (3 years)	I-spontaneous	CLX + SM	Complete healing
Marx et al. [43]	CR	F	NI	RA OST	STE+MTX+SA (3,3 years)	II- spontaneous	CLX + SM	Complete healing
Hamada [44]	CR	F	68	RA OST	STE + risedronate (4 years)	II- spontaneous	Conservative treatment	Partial Healing
Mavrokki et al. [45]	RS	NI	NI	RA OST	SA+MTX+PRED (4,3 years) SA (5,8 years) Accumulated dose of SA 9060 mg	NI	NI	NI
Junqueira et al. [46]	CS	M	73	RA	MTX-15mg/week (5years) PRED-5mg/day SA-70mg/week (3,8 years)	II-tooth extraction	ATB Amoxicillin 4g/day Clavulanate 250mg/day Fluconazole 100mg/day CLX Recurrence- SEQ+ tooth extraction+SM	Complete healing, with recurrence of the condition 1 month later
Mehanna & Goddard [47]	CR	F	55	RA	STE+BPs per oral Route +leflunomide (1 year)	II-spontaneous	ATB+drainage +SM	Complete Healing
Lo et al. [48]	RS	NI	NI	RA	BPs per oral route (4,8 years)	II-tooth extraction	ATB+CLX+SM +SEQ+DEB	Not heal
Lo et al. [48]	RS	NI	NI	RA OST of hip	STE+BPs (2,6 years)	II-tooth extraction	ATB+CLX+SM	Not heal
Park et al. [49]	CS	F	68	RA OST	SA+STE (5 years)	II-implant instalation	ATB+SM +CURET+CLX	Satisfactory healing
Park et al. [49]	CS	F	70	RA OST SAH	STE+SA (6 years)	III-spontaneous	ATB+SM+CLX	Satisfactory healing
Manfredi et al. [39]	CS	F	68	RA DM OST SAH	SA (4,25 years)	III- spontaneous	SM	NI
Manfredi et al. [39]	CS	F	65	RA OST SAH	SA (5 years)	II-spontaneous	ATB+SM +Laser therapy	Partial healing
Manfredi et al. [39]	CS	F	79	RA OST	SA (4 years)	II-spontaneous	ATB+Laser therapy	Partial Healing
Manfredi et al. [39]	CS	F	57	RA OST DM SAH	SA (>3 years)	II-tooth extraction	ATB	Partial healing
Conte-Neto et al. [50]	CR	F	58	RA	SA-70mg/week (4 years)	II-spontaneous	CLX-4X/day ATB Clindamycin 300mg 2 tablets/day for 10 days DEB +SEQ+SM	Complete healing in 8 months with normal sérum CTX test value
Conte-Neto et al. [50]	CR	F	68	RA Smoker	MTX-2,5mg 6x/week for 7 years SA-70mg/week STE (20 years)	II-spontaneous	CLX+SM+CTX test with abnormal value (33pg/ml)+DEB ATB Clavulanate 500mg 3x/day	Complete healing after 2 months
Malden & Lopes [51]	CS (4 cases)	NI	NI	RA	MTX+SA	NI	NI	NI
Lescaille et al. [52]	CS	F	51	RA Sjögren Syndrome	MTX +risedronate (2 years) Accumulated dose 3360mg	II-tooth extraction	mouthwash +ATB Amoxicillin 1g +clavulanate 125mg ou clindamycin 600mg +metronidazole - 2x/day	Without clinical monitoring
Lescaille et al. [52]	CS	F	59	RA SAH	Risedronate Accumulated dose 8400mg Leflunomide +PRED +Fluindione	II-tooth extraction	Mouthwash +ATB Amoxicillin1g +clavulanate 125mg ou clindamycin 600mg +metronidazole - 2x/day Surgical procedures (SEQ+ALVEO)	Complete healing after 2 years
Lescaille et al. [52]	CS	M	56	RA Arrhythmia	Zoledronate (3 years) Accumulated dose 48mg Pamidronate (1 year) Accumulated dose 18 mg Fluindione Bisoprolol PRED	II- spontaneous	Mouthwash+ATB Amoxicillin1g +clavulanate 125mg ou clindamycin 600mg +metronidazole - 2x/day	Complete healing after 6 months
Lescaille et al. [52]	CS	M	39	RA Kidney failure	Hydroxychloroquine +MTX +PRED+SA (3 years) Accumulated dose 10080mg	II- tooth extraction	Mouthwash +ATB Amoxicillin1g +clavulanate 125mg ou clindamycin 600mg +metronidazole - 2x/day Surgical procedures (SEQ e ALVEO)	Without clinical monitoring
Lescaille et al. [52]	CS	F	82	RA Coronary artery disease	SA (1 year) Accumulated dose 180mg Ibandronate (18 months) Accumulated dose 270mg Ramipril Clopidogrel Furosemide Atenolol PRED	III- tooth extraction and jaw fracture	Mouthwash +ATB Amoxicillin1g +clavulanate 125mg ou clindamycin 600mg +metronidazole - 2x/day Surgical procedures (SEQ e ALVEO)	Complete healing after 13 months
Skare et al. [53]	CR	F	74	RA (severe) OST	Risedronate 35mg/week Infliximab 400mg intravenous every 68 weeks (3 years) MTX 15mg/week (4 years) PRED 5mg/day (4 years) Ibuprofen 1800mg/day Pantoprazole 40mg/day Vitamin D3 2x/day	III-tooth extraction	ATB+SEQ Recurrence-prophylaxis +RESEC+ Titanium reconstruction + progression to septic respiratory symptoms culminating in death	Complete healing with recurrence after 16 months
Longato et al. [54]	CR	F	73	RA (severe) diagnosed 36 years ago	Gold salts+MTX+ Leflunomide+STE+ SA 70mg/week+ calcium+ vitamin D3(10 years)	III- poorly healed tooth extraction, evn with cleaning of the surgical wound and ATB (Amoxicillin)	SM and replacement with strontium ranelate +SEQ +ATB (Fluconazole+ Amoxicillin) +CURET with ultrasound	Complete healing
Manzon et al. [55]	CR	F	68	RA diagnosed 22 years ago	Gold salts +MTX+ Leflunomide +calcium PRED+vitamin D3(22 years) Ibandronic Acid 150mg/month (during 10 years)	III- tooth extraction and temporal abscess	ATB Amoxicillin 875mg+ Clavulanate 125mg + surgical hygiene+ Absces Drainage Surgery was not sutured, it was irrigated with sodium hypochlorite and hyaluronic acid gauze 2x/week e ATB de Meropenem 2g + Metronidazole 500mg/day	Complete healing after 3 months
Aiex et al. [56]	CR	F	83	RA SAH DM type 2 Obesity Dyslipidemia Mild Chronic renal failure Duodenal ulcer Glaucoma	Enalapril Hydrochlorothiazide Glicazide Metformin Simvastatin Omeprazole Topical Timolol Paracetamol Transdermal Fentanyl Ibandronic Acid 150mg/month Calcium Cholecalciferol	II- It appeared after a 2 year episode of dental infection (ATB-Amoxicillin, Anti-inflammatory e CLX)	SEQ+biopsy +SM+ Calcium Supplements +age appropriate physical activity	NI
Mori et al. [57]	CR	F	69	RA OST SAH	MTX 6mg/week Folic Acid 5mg/week Brotizolam 0,25mg/day PRED 3mg/day Meloxicam 10mg/day Amlodipine 5mg/day Doxazosin 1mg/day Alfacalcidol 0,5ug/day Minodronate 50mg/month (18 months)	Initial stage- Imaging finding in magnetic resonance	SM+minodronate replacement by recombinant human parathyroid hormone 20ug/day	Jaw bone was not exposed
Furuya et al. [58]	RS	F	79	RA diagnosed 17 years ago SAH	Minodronate (7years)+PRED 5mg/day	NI-tooth extraction	NI	NI
Furuya et al. [58]	RS	F	65	RA diagnosed 33 years ago DM SAH	Risedronate (8 years)+PRED 6mg/day	NI-tooth extraction	NI	NI
Furuya et al. [58]	RS	F	77	RA diagnosed 27 years	AS (5 years) PRED 5mg/day	NI-tooth extraction	NI	NI
Furuya et al. [58]	RS	F	79	RA diagnosed 22 years ago Chronic kidney disease	BPs(1 year)	NI-tooth extraction	NI	NI
Aghaloo & Tetradis [59]	CS	F	66	RA SAH Anemia Gastroeso- phageal reflux	PRED+ Hydrochlorotiazide+ hydroxychloroquine +SA(2 years)+ adalimumab +etanercept	III- Unsuccessful tooth extration requiring drainage, SM e ATB (Cephalexin). Presence of extra-oral fistula	Local intra and extra oral treatment with CLX	Partial healing without active infection
Hayashi et al. [60]	RS	M	63	RA	MTX 2mg/day PRED 5mg/day	NI- multiple extration of 8 teeth	NI	Delayed complete healing

• Note: BRONJ- Bisphosphonate-related osteonecrosis of the jaw; CR-Case report; F- Feminine; RA- Rheumatoid Arthritis; OST-Osteoporosis; STE- Steroids; MTX-methotrexate; SA- Sodium alendronate; ATB- Antibiotic therapy; SEQ-Sequestrectomy; RS-Restrospective study; SAH- Systemic arterial hypertension; HCOL-Hypercholesterolemy;CURET-Curettage; DEB-Debridation; RESEC- Jaw resection; DM-Diabetes Mellitus; NI- Not informed; CLX-Chlorrhexidine; 0,12%; SM- Suspension of medication; PRED- Predinisone; CS- Case series; M- Masculine; BPs-Biphosphonates; CTX- C-terminal telepeptide of type I collagen; ALVEO-alveolectomy.

CONCLUSION

It was believed that only high doses of intravenous BPs were capable of causing bone problems, but the cumulative effect of oral BPs can also trigger bone sclerosis. More prospective studies are needed to define the correlation between BRONJ and RA, so that it can be investigated whether only the medication or the autoimmune inflammatory condition itself are risk factors for bone necrosis. For health professionals, we can issue a warning: when it is necessary to introduce BPs, we must perform a prior dental evaluation, so that all infectious foci are removed before the medication acts on the bone matrix. In patients with RA, the dentist should be attentive to hygiene, periodontal disease, opportunistic infections, smoking, ulcers and bone changes. If the patient has an episode of BRONJ, the rheumatologist and the dentist should consider a conservative or surgical approach, associated or not with the temporary suspension or drug holiday of BPs. Consultations should be periodic, for biofilm control, calculus and biannual control after an episode of BRONJ.

How to cite this article

• Santos GDS, Corrêa L, Carvalho DLC. Bisphosphonate-associated jaw osteonecrosis in the treatment of rheumatoid arthritis. RGO, Rev Gaúch Odontol. 2024;72:e20240038.http://dx.doi.org/10.1590/1981-86372024003820230074

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Edited by

• Assistant editor: Luciana Butini Oliveira

Publication Dates

• Publication in this collection
  11 Nov 2024
• Date of issue
  2024

History

• Received
  21 Sept 2023
• Reviewed
  04 June 2024
• Accepted
  09 Aug 2024