Epidemiological aspects of rheumatoid arthritis patients affected by oral bisphosphonate-related osteonecrosis of the jaws

This literature review aims to evaluate the epidemiologic profile of patients with rheumatoid arthritis (RA) that developed a bisphosphonate-related osteonecrosis that affect the jaws (BRONJ), including demographic aspects, as well as clinical and therapeutic issues. A search of PUBMED/MEDLINE, Scopus, and Cochrane databases from January 2003 to September 2011 was conducted with the objective of identifying publications that contained case reports regarding oral BRONJ in RA patients. Patients with RA who develop oral BRONJ are usually women above 60 years taking steroids and long-term alendronate. Most of them have osteoporosis, and lesions, triggered by dental procedures, are usually detected at stage II in the mandible. Although there is no accepted treatment protocol, these patients seem to have better outcomes with conservative approaches that include antibiotic therapy, chlorhexidine, and drug discontinuation.


Background
Bisphosphonates (BPs) are stable synthetic analogs of inorganic pyrophosphate that suppress osteoclastmediated bone resorption [1]. In this way, they have been widely used to stabilize bone loss in patients with rheumatoid arthritis (RA), especially those who develop osteoporosis, which is a common feature in this rheumatic disease [2]. However, since 2003, great concern has been generated regarding the side-effects of these drugs through increasing reports, worldwide, of a bisphosphonate-related osteonecrosis that affect the jaws (BRONJ).
There are many hypotheses regarding BRONJ pathogenesis, but none of them is completely accepted. Although there have been reports with no obvious co-morbidity factors [3,4], it is reasonable to believe that co-factors may play a relevant role in the development of these lesions, especially in patients taking oral BPs. Among these cofactors, RA has been included as a relevant risk factor for BRONJ; however, until now the relationship between these diseases has not been fully explained.
Due to the greater number of patients taking oral BPs for the treatment of RA and osteoporosis, it is very important for risks to be assessed. Thus, the purpose of this extended literature review is to evaluate relevant issues of patients with RA who developed oral BRONJ, including demographic, clinical, and treatment aspects, with the goal of establishing comparative associations with patients without RA who developed oral BRONJ.

Methods
We performed a computerized search to identify all papers published in English from January 2003 to September 2011 in PUBMED/MEDLINE, Scopus, and Cochrane databases. Case reports, case series, and retrospective studies were included, while short communications and letters to the Editor were excluded. The studies were approved by the Ethics in Human Research Committee and were in compliance with the ethical principles of the Helsinki Declaration. Literature reviews and systematic reviews also were considered with the objective of identifying cases already reported. The key MeSH (Medical Subject Headings) terms used were: diphosphonates, bisphosphonate, jaw osteonecrosis, rheumatoid arthritis, and rheumatologic.
The primary objective was to identify all articles containing clinical reports with the following inclusion criteria: • Diagnosis of RA and oral BRONJ • Patients with no prior history of radiation to the craniofacial region • Non-neoplasic patients • At least five areas of the specific demographics were collected, including gender, age, bisphosphonate type and length of exposure, concomitant medications, trigger event, clinical features, staging, lesion site, imaging and histological features, as well as management and outcomes. The stage of the lesions was retrieved directly from the papers or it was defined based on the available clinical data and according to the classification system by Ruggiero et al. [5].
• Papers published in English All titles and abstracts from the results of the literature search were reviewed by the authors for potential inclusion in our study. We also searched the related links of all relevant papers. Furthermore, all relevant papers were checked to avoid multiple inclusions of the same patients in this study.

Results
The search strategy yielded 1606 titles/abstracts from the databases analyzed. After title, abstract screening, and/or paper analyses, 331 potentially relevant studies were identified and screened for retrieval. Of these, 312 studies were excluded due to non-compliance with the inclusion criteria, one paper was excluded due to duplicity of one patient and, finally, 17 were included in the present review, consisting of 27 patients and 29 BRONJ lesions (Tables 1, 2, 3, and 4).

Discussion
Until the present moment, there is no randomized, controlled, prospective clinical trial that assessed jaw osteonecrosis (ONJ) risk in patients with rheumatoid arthritis who were using oral BPs. In the absence of this data, the present paper performed a critical literature review to investigate the current status of the epidemiological aspects of patients with rheumatoid arthritis affected by BRONJ.
Considering the prevalence of BRONJ lesions in patients with RA, we considered only the raw number of oral BRONJ reports in RA patients, since the accurate number of non-neoplasic patients treated with oral BPs is unknown; therefore, the determination of the precise prevalence of BRONJ is extremely difficult but is possible to be estimated based on epidemiological studies. Two reviews published recently, reporting patients that presented BRONJ induced by the use of oral BPs, observed a very low prevalence of these lesions in patients with rheumatic diseases [22,23]. Other studies reported that the BRONJ prevalence in patients treated with oral BPs, ranges from 0.001% to 0.4% [17,[24][25][26][27]. These numbers give the idea that the prevalence of     BRONJ lesions in patients with RA is expected to be quite low, however it should be considered that the proportion of patients with rheumatic disease among all the population sampled in these studies is probably reduced as well. At the same time, it is reasonable to expect an increased tendency in the number of BRONJ lesions in RA patients considering that there is a lack of knowledge about this disease among rheumatologists in many countries and that BPs are among the most frequent prescribed drugs in rheumatologic practice [28]. This is due to the high efficiency of BPs in the prevention and treatment of osteoporosis, which is a common feature in RA [29].
There is a considerable discussion in the literature whether aging plays a significant role in BRONJ development. Some studies found no statistically significant correlation between aging and BRONJ [30,31]. Therefore, the advanced age of the patients with BRONJ observed in the studies [6,8,[10][11][12][14][15][16][18][19][20][21] may reflect nothing less than the increased BPs prescription to older patients compared with younger ones, since osteoporosis and RA are commonly seen in the elderly [29,32].
On the other hand, other authors include advanced age as a BRONJ co-factor [19,33,34], which could be related to the physiological effects of aging, including inflammatory issues [35], immune dysfunction [36], reduction of the blood flow and the remodeling ability [37,38], and increased oxidative stress [39]. In fact, these features are all implicated with BRONJ pathogenesis and could explain why this disease is not reported in young patients, even with other risk factors associated [40]. Paradoxically, BPs have been prescribed for the treatment of steroid-induced osteonecrosis of the joints in pediatric populations [41].
In spite of that, other authors reported a positive correlation between gender and BRONJ [19]. It has been speculated that estrogen therapy may play a role in this correlation, since hormonal reposition has been associated with an increased risk of BRONJ [43]. The concern is that hormonal replacement therapy is likely to occur in RA, since this disease is often worsened after estrogen delivery [44]. In fact, the association of BPs and estrogen reposition is especially possible in patients with no satisfactory outcomes associated with a single drug therapy or who have very low bone density with multiple risks [45]. Moreover, treatment with estrogen/ bisphosphonate conjugate drugs has also been described [46]. It is not surprising that osteoporosis was the most prevalent co-morbidity observed in the studies [4,[9][10][11][14][15][16][18][19][20][21], since this is a common feature in RA patients for several reasons, including: (a) postmenopausal women represent part of the main risk group for RA and are at risk for accentuated bone loss; (b) steroid therapy is often prescribed for the treatment of RA; (c) physical inactivity is characteristic of RA due to disease activity; and (d) bone loss due to inflammatory disease mechanisms, such as elevated levels of systemic cytokines [29].
It has been shown that there is a direct relation between BRONJ occurrence and BPs potency [13,33], which is supported by the high incidence of BRONJ in patients receiving intravenous BPs [47], as well as by faster lesion onset in these patients [24]. This assumption corroborates with the higher incidence of BRONJ in patients using alendronate, as seen in the studies revised here [4,[6][7][8][9]11,12,15,16,[18][19][20][21], since it is the most potent drug among the BPs [9].
In contrast, Kos and Luczak [48] found no correlation between the type of BPs and BRONJ incidence, which reinforces the assumption that it can be only a coincidence. In fact, over the last decade, alendronate was among the most used drugs in the USA as first-line therapy for the prevention or treatment of osteoporosis [49], both in non-neoplasic BRONJ patients without RA [6,9,14,16] and in patients with RA [32]. Furthermore, it is reasonable to understand why ibandronate, a potent nitrogen-containing bisphosphonate (N-BPs) [7] that is much less prescribed compared with alendronate, is not associated with large-series cases of BRONJ [23].
It has been discussed that one of the most critical factors for BRONJ is the duration of oral BPs therapy [9,33]. It is believed that there is an increased incidence of oral BRONJ in patients treated with oral BPs for more than 3 years [5,9], which is in agreement with the findings of the studies revised here [4,6,9,12,[15][16][17][19][20][21]. In fact, longerterm use of oral BPs may have a dose-equivalence effect, potentially approximating BPs levels in bone thought to be achieved only through high-dose intravenous delivery [16], and the total dose administered over a long period of time is important for the magnitude of the bone turnover reduction [50].
An interesting observation is that it has been suggested a trend of early-onset lesions due to steroids therapy [9]. However, this tendency was not confirmed in the patients of the studies revised in this paper, since the mean duration of BP therapy in steroid-treated patients was similar to patients that have not been treated with this drug. Furthermore, some authors reported early-onset lesions in patients with RA and no history of steroids [3,19].
Most of the lesions in the studies were diagnosed in lower jaw at stage II or III [4,[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] with the most common clinical findings being bone exposure, pain, edema, and purulent discharge. In fact, it also represents the same clinical aspects found in patients with no RA [6,9,14,16]. This evidence brings to light the lack of knowledge and attention about early clinical features that include nonspecific signs and symptoms in the oral cavity, including no clinical evidence of bone exposure. The concern is that lesions can progress rapidly, and, in advanced stages, paresthesia, fistula formation, and pathologic fracture can also occur, even in RA patients [6].
The typical imaging finding in all groups of patients with BRONJ is the association of osteolysis and sclerosis aspects. Within this context, when it is considered that bone sclerosis is often detected in the initial stages of BRONJ [51], this sign can also be maintained in advanced stages; indeed, we observed in the studies that bone sclerosis was reported in six patients, all classified in advanced stages [7,12,17,19,21]. Therefore, a careful dental examination could allow an early diagnosis and intervention and assist the patients in responding more promptly to stagespecific treatment regimens for BRONJ.
Regarding the management and outcomes of BRONJ lesions in patients with RA, there is no widely accepted treatment protocol to BRONJ. Some authors believe that surgical procedures are not effective in patients with BRONJ and have led to further bone exposure, worsening of symptoms, and a greater risk of pathologic fracture, indicating conservative approaches as the best choice, including antibiotics, oral rinses with chlorhexidine, and 'drug holidays' [47]. In contrast, other authors believe that surgical procedures may achieve better outcomes in non-neoplasic patients [14].
In fact, the management of BRONJ lesions is a great challenge, which reinforces the necessity of an adequate oral care through routine dental examinations, education and motivation of the patients to adopt preventive measures in order to maintain a good oral hygiene and [52].

Conclusion
The main characteristics of BRONJ patients with RA are generally similar to those with no RA. This critical review highlights a serious concern regarding the delayed diagnosis of BRONJ lesions, since most of these patients were diagnosed in stage II/III. It is clear that the rheumatologist needs to be aware of the potential risk of their patients developing BRONJ and must work together with the dentist to prevent and detect the lesions as soon as possible.
Authors' contributions NCN analyzed the records, reviewed all patients' data. ASB drafted the manuscript and helped in writing the text. RACM and EMJ drafted the manuscript and reviewed it critically. All authors read and approved the final manuscript.
Authors' information NCN is a PhD student from Implantology program at Araraquara School of Dentistry and ASB is a PhD student from Periodontology program at Araraquara School of Dentistry. EMJ and RACM are professors and chairmen of the Department of Diagnosis and Surgery, Division of Periodontology at Araraquara School of Dentistry.