Bisphosphonate-related osteonecrosis of the jaw in metastatic breast cancer patients: a review of 25 cases

Currently, breast cancer is an increasing cause of cancer-induced deaths in the world [1]. Multimodality treatment strategies have been proposed for eradicating breast cancer, but still, many patients with breast cancer are in multiple threats to their lives [2]. The bone is the most vulnerable site for breast cancer metastasis. Bone microenvironment has a significant role in harboring disseminated tumor cells and a source of late relapse [3]. Therefore, agents that affect bone metabolism might provide meaningful reductions in the risk of metastasis as well as prevent the development of bone lesions [4]. Malignancy and cancer treatment-induced bone loss can make bone mineral reserves decrease, and patients would face risks of skeletal-related events (SREs) such as pathologic fracture and spinal cord compression [3].

Breast cancer cells usually metastasize to the bone by secreting factors that enable tumor cells to be gathered inside of the bone tissues. Tumor cells produce cytokines that induce osteoclast formation and bone resorption such as interleukin-8 and parathyroid hormone-related protein [2]. Osteoclast would increase both osteolysis and the release of tumor-promoting growth factors from the bone matrix. Using antiresorptive agents to cease osteolysis should make the bone microenvironment difficult for cancer stem cell survival and growth [2].

In patients with bone metastases or multiple myeloma, bisphosphonates are part of the standard treatments [2, 5]. Bisphosphonates are analogs of inorganic pyrophosphates, commonly used for the management of metastatic bone disease such as breast cancer, prostate cancer, and multiple myeloma. Bisphosphonates are capable of localizing metastatic lesions and inhibiting osteoclastic function [6–8]. Because bisphosphonates bind strongly to exposed bone mineral around resorbing osteoclasts, high levels of bisphosphonate in the resorption lacunae would remain even after several years. Within the bone, bisphosphonates are not metabolized and these high concentrations will be held for long periods of time [6]. Although whole mechanism of this bisphosphonate-related osteoclast inhibition has not been completely explained, it has been considered that these compounds affect bone turnover at various levels [9]. On a cellular level, the bisphosphonates target the osteoclasts and may inhibit their function as follows: hindering the osteoclast recruitment; reducing the osteoclast life span [10, 11]. At a molecular level, it has been supposed that bisphosphonates regulate osteoclastic function by interacting with a cell surface receptor or an intracellular enzyme [12]. About 300,000–500,000 cancer patients were prescribed intravenous (IV) bisphosphonates in 2004 [13].

The metastatic breast cancer patients who need for bisphosphonate therapy should be relieved from the bone pain and hypercalcemia and improve quality of life [6]. Bisphosphonate therapy has shown dramatic effect on reducing the risk of SREs by reducing this risk by nearly one third, and because of this reason, intravenous bisphosphonates are commonly used in the oncology practice [14, 15]. Zolendronate, the most potent bisphosphonate, is the second-generation bisphosphonate and approved for patients with metastatic breast cancer, multiple myeloma, hypercalcemia of malignancy, or Paget’s disease of bone and for patients with documented bone metastases from any solid tumor (i.e., prostate cancer, lung cancer) [6]. In comparison with other bisphosphonates, zolendronate is crucially more effective in reducing the risks of SREs and controlling hypercalcemia of malignancy [16].

It has been reported that the incidence of BRONJ with intravenous bisphosphonates is more frequent than that with oral bisphosphonates [23]. The incidence of BRONJ with intravenous bisphosphonates has been reported 0.8–1.2 % on average, increasing up to 21 % after injection of bisphosphonate for 3 years or more [5, 24, 25]. Bisphosphonates bind to bone hydroxyapatite for almost 10 years, and because of this reason, discontinuation of bisphosphonate administration before dental treatment is still disputable [26]. Cancer patients who have high risks for bone pain, hypercalcemia, or pathological fracture could effectively benefit from intravenous bisphosphonates. However, BRONJ could happen during treatment [3, 19–21]. When BRONJ is suspicious, it is highly recommended to stop using them. In this study, 24 patients stopped taking bisphosphonates after consulting with an oncologist. However, it could not be discontinued in one patient who had suffered from multiple bone metastases with hypercalcemia.

The relatively high percentage of the maxilla (12 of 25 patients) involvement of BRONJ in this study is uncommon because the maxilla is provided with rich vascular supply. This finding is distinguished from other studies which reported dominant involvement of the mandible [27–30]. It may be related to the mechanism by which bisphosphonates would not only inhibit the angiogenesis but also affect in other way [18]. One of the most frequent initiations of BRONJ is a dental extraction. In our case series, dental extraction was more frequent in the maxilla than the mandible.

The potent inhibition of osteoclast proceeds to reduce bone resorption and interrupt normal bone turnover remodeling, resulting in reduction of some mechanical properties in skeletal health [31]. As bone resorption occurs, cytokines and growth factors would be released into the surrounding matrixes that are significant for regulating new bone development. The inhibition of new bone formation would lead to degrade bone quality during growth and fracture healing [6]. Systemic conditions of patients involving diabetes mellitus or coagulopathy have also been reported as a risk factor for BRONJ [18, 32]. In the present study, three of the patients had diabetes mellitus.

Bisphosphonate therapy should be delayed until all necessary dental treatments have been performed, except life-threatening hypercalcemia [18]. In this report, dental extraction was the most common etiology for BRONJ initiation. Other surgical procedures such as dental implant surgery and preprosthetic surgical treatment could be the causes of BRONJ [33]. During bisphosphonate therapy, patients should manage their oral hygiene. Invasive dental procedures should be avoided during bisphosphonate therapy, if that is possible. Bacterial infection was observed in all the present cases, therefore, antibiotic treatment should be ensured on BRONJ patients [23].

Recent studies have reported that surgical debridement might have benefited in eradicating necrotic bone in comparison with conservative treatment [27, 34–36]. If invasive dental procedure is determined, a systemic perioperative antibiotic treatment is recommended. Surgical debridement should be done for those patients who complained symptoms. Obtaining a surgical margin with viable bleeding the bone is significant in surgery, and primary closure for wound healing should be served by using mucosal flaps for bone coverage [3]. It is recommended that bisphosphonate administration should be withheld for 6–8 weeks before and after dental procedures [3, 18]. After complete wound healing is achieved, bisphosphonate therapy could be reinitiated because the risk of SREs would still exist and increase during the course of disease [37]. Despite the several efforts for setting guidelines, the optimum treatment for BRONJ remains unclarified. It is necessary to accumulate further clinical data to make the standard for effective treatment in BRONJ patients.

Prevention of the BRONJ is critical in metastatic breast cancer patients. Dental extraction is the main etiology for BRONJ. Conservative treatment to reduce pain, discomfort, and infection is recommended for the initial therapy. However, if there is a sequestrum which is separated from the basal bone of the jaw, surgical debridement and primary closure is the key to treat the BRONJ.