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, 24–27]. 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 . This is due to the high efficiency of BPs in the prevention and treatment of osteoporosis, which is a common feature in RA .
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, 10–12, 14–16, 18–21] 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 , immune dysfunction , reduction of the blood flow and the remodeling ability [37, 38], and increased oxidative stress . 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 . Paradoxically, BPs have been prescribed for the treatment of steroid-induced osteonecrosis of the joints in pediatric populations .
Controversial aspects have also been discussed regarding gender as a BRONJ co-factor. Some studies found no statistically significant correlation between gender and BRONJ [33, 34]. Therefore, we observed that the large proportion of female patients from the studies [4, 6–11, 13–16, 18–21] can represent only a coincidence, since women take oral BPs more frequently than males, especially because RA and osteoporosis are more common in women .
In spite of that, other authors reported a positive correlation between gender and BRONJ . 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 . The concern is that hormonal replacement therapy is likely to occur in RA, since this disease is often worsened after estrogen delivery . 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 . Moreover, treatment with estrogen/bisphosphonate conjugate drugs has also been described .
It is not surprising that osteoporosis was the most prevalent co-morbidity observed in the studies [4, 9–11, 14–16, 18–21], since this is a common feature in RA patients for several reasons, including: (a) post-menopausal 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 .
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 , as well as by faster lesion onset in these patients . This assumption corroborates with the higher incidence of BRONJ in patients using alendronate, as seen in the studies revised here [4, 6–9, 11, 12, 15, 16, 18–21], since it is the most potent drug among the BPs .
In contrast, Kos and Luczak  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 , both in non-neoplasic BRONJ patients without RA [6, 9, 14, 16] and in patients with RA . Furthermore, it is reasonable to understand why ibandronate, a potent nitrogen-containing bisphosphonate (N-BPs)  that is much less prescribed compared with alendronate, is not associated with large-series cases of BRONJ .
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, 15–17, 19–21]. In fact, longer-term 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 , and the total dose administered over a long period of time is important for the magnitude of the bone turnover reduction .
An interesting observation is that it has been suggested a trend of early-onset lesions due to steroids therapy . 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].
The literature indicates a strong association of BRONJ with dental surgical procedures in all groups of patients [3, 5, 9]. Although we also observed this tendency in the large number of lesions triggered by teeth extractions and dental implants in the studies that were retrieved [4, 5, 7–9, 12, 14, 17–20], it is relevant to state that spontaneous occurrence of BRONJ lesions was observed in a significant proportion of individuals in several studies [9, 10, 12, 13, 15, 19–21].
Most of the lesions in the studies were diagnosed in lower jaw at stage II or III [4, 6–21] 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 non-specific 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 .
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 , 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 stage-specific 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'. In contrast, other authors believe that surgical procedures may achieve better outcomes in non-neoplasic patients .
In the papers that we revised, the lesions were treated either by conservative therapy (48%) or its association with surgical procedures (52%). Overall, this literature review showed that most of the lesions were treated with conservative approach [9, 10, 12, 14, 17, 19, 20] and were associated with the most positive outcomes including the complete healing of the lesions (33.3%) and no healing in only one patient (8.33%)  (Table 4). However, in other studies [4, 6, 7, 12, 13, 15–19, 21] the association of conservative and surgical therapy showed more diverse outcomes, with complete healing in only three lesions (25%) [13, 21].
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 .