Usability of surgical treatment in cases of bisphosphonate-related osteonecrosis of the jaw stage 2 with sequestrum.

OBJECTIVE: This retrospective study was conducted to reveal usability of surgical treatment in the cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ) stage 2 with sequestrum. PATIENTS AND METHODS: Study subjects included 18 patients having BRONJ stage 2 with sequestrum and 12 non-BRONJ patients with nearly equal clinical states of BRONJ stage 2. Patient characteristics, frequency of inciting factors of osteonecrosis, and treatment results were compared between BRONJ group and non-BRONJ groups. In addition, correlation between treatment methods (conservative therapy, sequestrum curettage, and sequestrectomy) and treatment results and correlation between the administration route of bisphosphonates (BPs) (oral or intravenous) and treatment results were examined statistically. The Student's t-test and Fisher's exact test were performed for statistical analysis.
RESULTS: Patient characteristics, frequency of inciting factors of osteonecrosis, and treatment results showed no significant differences between the two groups. In the BRONJ group, treatment result of sequestrectomy was significantly better than conservative therapy/sequestrum curettage (P < 0.001), however, no significant difference was observed in the non-BRONJ group. No significant difference was found in correlation between the administration route of BPs and treatment results in the BRONJ group.
CONCLUSION: Treatment outcome of sequestrectomy was better than conservative therapy/sequestrum curettage in BRONJ stage 2 cases with sequestrum.

INTRODUCTION

There has been considerable discussion regarding treatment methods for bisphosphonate-related osteonecrosis of the jaw (BRONJ) stage 2 cases. Regardless of disease stage, mobile segments of bony sequestrum should be removed without exposing uninvolved bone. Therefore, conservative therapy has been recommended by the American Association of Oral and Maxillofacial Surgeons (AAOMS).[1] However, little attention has been paid to the comparison of BRONJ with other osteonecrosis of the jaw that clinically-approximate to BRONJ. Therefore, usability of surgical treatment in BRONJ cases may not have been evaluated correctly. It is necessary that comparing treatment results between BRONJ stage 2 cases with sequestrum and non-BRONJ cases with sequestrum to confirm the usability of surgical treatment in BRONJ stage 2 cases. This study focuses on comparison of surgical treatment results between cases of BRONJ and cases of non-BRONJ.

PATIENTS AND METHODS

Study subjects were 30 patients who visited Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saitama Medical University, from January 1, 2009, to March 31, 2013. In this study, we classified patients diagnosed with BRONJ stage 2 using The AAOMS[1] as the BRONJ group. In this study, kinds of bisphosphonates (BPs) and administration period of BPs were not examined. Cases have nearly equal clinical states of BRONJ stage 2, without BP treatment, were classified as the non-BRONJ group. In addition, computed tomography was used to evaluate separation degree of sequestrum in all 30 cases. The BRONJ group included 18 cases (7 men and 11 women; mean age, 66.4 ± 11.9 years). The non-BRONJ group included 12 cases (7 men and 5 women; mean, 67.4 ± 12.7 years). In this group, 2 cases each had rheumatoid arthritis or multiple myeloma, 1 case was radio-osteonecrosis, and other 7 cases had no appreciable disease.

Regarding the inciting factors of osteonecrosis, ten cases in the BRONJ group were caused by tooth extraction, 8 cases were caused by other conditions (5 marginal periodontitis, 2 apical periodontitis, and 1 denture stomatitis). Seven cases in the non-BRONJ group were caused by tooth extraction, 5 cases were caused by other conditions (2 marginal periodontitis, 2 apical periodontitis, and 1 pericoronitis). Regarding the treatment method, conservative therapy (n = 3), sequestrum curettage (n = 6), and sequestrectomy (n = 9) were performed in the BRONJ group. Conservative therapy (n = 4), sequestrum curettage (n = 7), and sequestrectomy (n = 1) were performed in the non-BRONJ group. In this study, a treatment method which abrades the surface layer of inseparate sequestrum was defined as sequestrum curettage [Figure 1]. And a treatment method which removes separated sequestrum from normal bone with entire closed wound was defined as sequestrectomy [Figure 2]. In this study, all the cases with sequestrectomy were osteonecrosis cases had separated sequestrum in computed tomography.

Figure 1

Sequestrum curettage (a) Nonbisphosphonate-related osteonecrosis of the jaw case with inseparate sequestrum (b) Curettage with cutting instrument

Figure 2

Sequestrectomy (a) Bisphosphonate-related osteonecrosis of the jaw case with free sequestrum (b) Removed sequestrum

Regarding treatment results, 11 cases in the BRONJ group were healed, 7 cases were not. 5 cases in the non-BRONJ group were healed, 7 cases were not. Healing status was considered to be successful when there was complete mucosal coverage without any exposed bone and any sign of infection. The patients were followed up for 3 months at our department after final healing was obtained. In the BRONJ group, the route of administration of BPs was oral in 7 cases and intravenous in 11 cases [Tables 1 and 2].

Table 1

Patient backgrounds of BRONJ group

Table 2

Patient backgrounds of Non-BRONJ group

In this study, we distinguished between cases receiving either conservative therapy or sequestrum curettage and cases receiving sequestrectomy. We statistically analyzed the average age, sex distribution, inciting factors of osteonecrosis, and postoperative results to reveal differences of patient background between the BRONJ and non-BRONJ groups. We divided the inciting factors of osteonecrosis into tooth extraction and not involving tooth extraction based on medical records. We divided treatment results into healing and nonhealing. In addition, the correlation between treatment methods and treatment results and that between the administration route of BPs (oral or intravenous) and treatment results were examined statistically for each group. The Student's t-test and Fisher's exact test (Ekuseru-Toukei 2010 for Windows) were used for statistical analysis. P < 1% were considered to indicate significant differences.

RESULTS

In Average age (P = 0.66), sex distribution (P = 0.25), frequency of inciting factors of osteonecrosis (P = 0.59), and treatment results (P = 0.25), no significant difference was noted between the two groups. In the BRONJ group, 7 out of 9 cases receiving conservative treatment or sequestrum curettage did not heal while 9 out of 9 cases receiving sequestrectomy healed. In contrast, in the non-BRONJ group, 1 out of 5 cases receiving conservative treatment or sequestrum curettage did not heal, whereas 4 out of 7 cases receiving sequestrectomy healed. In the BRONJ group, treatment result of sequestrectomy was significantly better than conservative therapy/sequestrum curettage (P = 0.001), however, no significant difference was observed in the non-BRONJ group (P = 0.25). In the BRONJ group, no significant difference was observed in the correlation between the route of administration of BPs and treatment results (P = 0.42).

DISCUSSION

BRONJ has been diagnosed as defined by the AAOMS: “Exposed bone in the maxillofacial region over a period of 8 weeks, current or previous treatment with BP, and no history of radiation therapy to the jaws.[2]” Although BRONJ has been classified as other osteomyelitis of the jaw, interrogation remains whether BRONJ is different from other osteonecrosis of the jaw in clinical aspects. Therefore, to clear the clinical differences between BRONJ and other osteomyelitis, we thought it is necessary to compare treatment methods and treatment results of these osteonecrosis of the jaws. The most commonly reported inciting factor for the initiation of BRONJ is tooth extraction.[3456] Odontogenic infection, dental implant surgery, denture stomatitis local, or spontaneous occurrences have been known as inciting factors.[17] In this study, 10 cases (55.6%) were caused by tooth extraction, which is in agreement with some reports.[89] However, in the BRONJ group, similar to non-BRONJ group, no significant difference was found between surgical procedure and nonsurgical procedures in inciting factors. In view of these results, to prevent BRONJ onset, it is necessary to pay attention to periodontitis, dentures ulcers, as well as for surgical procedures like tooth extraction.

The clinical management of BRONJ remains controversial. In BRONJ group, healing rate was more than 60% while the rate of non-BRONJ group was <50%. However, in comparison of both groups, no significant difference was showed, it seems right to presume that osteomyelitis of the jaw including BRONJ is an intractable disease.

In the initial reports and some studies of BRONJ, the results were observed that surgical therapy could not provide complete healing to BRONJ treatment.[10111213] Therefore, the assumption that patients should undergo palliative therapies rather than pursue complete healing with more aggressive interventions was led. According to these results, the treatment guidelines of AAOMS recommend conservative therapy for cases of BRONJ stage 2. However, acute inflammation and recurrence of symptoms occur in some cases following conservative therapy or a palliative procedure like sequestrum curettage. Therefore, some reports indicate that surgical treatment like sequestrectomy is a useful method for these cases.[1415] To confirm whether surgical therapy should be avoided for patients with BRONJ stage 2, we thought the comparison between BRONJ stage 2 cases involved sequestrum, and clinically-approximated osteomyelitis of the jaw cases was needed. In this study, we indicate that surgical therapy gave much better results than conservative therapy or sequestrum curettage for the BRONJ group. It seems right to presume that sequestrectomy is a radical treatment for cases of BRONJ stage 2 with sequestrum. Kobe et al.[16] reported that four of seven cases of BRONJ stage 2 showed healing with sequestrectomy, whereas only one of nine cases showed healing following conservative therapy. Abu-Id et al.[17] also observed that surgical therapy was the only treatment method for not only symptom improvement but also complete recovery. Critical surgical treatment taking lesion off clearly has been effective for the cases with separated sequestrum from peripheral bone obviously.[1819] Free sequestrum should be removed without exposing normal bone.[20] In contrast, it is difficult to remove the direct factors of non-BRONJ cases such as radio-osteonecrosis or cryptogenic osteomyelitis. Therefore, some radical surgical therapies have been used for these cases. Though, radical debridement, removing inseparate sequestrum and marginal normal bone en bloc, is disadvantageous as the excision range may become slightly large. As a general rule, normal bone should be scraped to the point of bleeding when removing inseparate sequestrum following curettage surrounding bone under the sequestrum, such as saucerization with sequestrectomy. However, it is difficult to define bleeding as a mark to set the excision range in many cases of BRONJ, as the entire jaw becomes ischemic due to BPs. Thus, taking this into account, it is seems natural to conclude that some cases of BRONJ stage 2 with separation of sequestrum that occurred due to discontinuation of BPs could be operated on with sequestrectomy, and other cases without separation of sequestrum involving progression of osteonecrosis of the jaws could be operated on with radical debridement or saucerization with sequestrectomy.

In patients with cancer, intravenous BPs have higher binding affinity and potency, probably resulting in greater remodeling suppression compared with oral BPs. For absorption from the gastrointestinal tract, in oral BPs, its absorption rate is <1% of the administered dose. However, in intravenous BPs, more than 50% of the dose is taken into bone tissue.[21] Therefore, other studies indicating that the prevalence of BRONJ is much lower in patients on oral BPs than in patients treated with intravenous BPs.[22] However, in treatment results, comparison between oral and intravenous BPs showed no significant differences. Because of the potential for the deficiency of the number of the cases, we are planning to carry out the study by amassing more cases.

It is not to say that if surgical therapy leads any BRONJ stage 2 cases to successful treatment outcome. This study was not conducted under substantially similar conditions in the separation of sequestrum and taking situation of BPs. However, it is evident from the present study that as far as BRONJ stage 2 cases with sequestrum is concerned, discontinuation of BPs can develop separation of sequestrum, and sequestrectomy could result in successful treatment. The most important finding in this study is that BRONJ, as well as other osteomyelitis, is a disease that would be cured with appropriate treatment method. It is hoped that the findings that have been presented in this paper will contribute to a better selecting mark of surgical treatment in BRONJ stage 2 cases.

CONCLUSION

Treatment outcome of sequestrectomy was better than conservative therapy or sequestrum curettage in BRONJ stage 2 cases with sequestrum.