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Journal of Clinical Medicine Research

Original Article

Volume 5, Number 1, February 2013, pages 22-25

Histology of the Oral Mucosa in Patients With BRONJ at III Stage: A Microscopic Study Proves the Unsuitability of Local Mucosal Flaps

Bisphosphonates (BP) are a widely used class of drugs with known efficacy in the prevention and treatment of osteoporosis, Paget’s disease of bone, hypercalcemia of malignancy, osteolytic lesions of multiple myeloma and metastatic osteolytic lesion from breast, lung and other soft tissue tumours [1].

The development of BRONJ lesions appears to be associated with previous dental traumatic injury, like tooth extraction [2, 3], in the majority of cases. Spontaneous cases occur in less than 30% of patients especially localized in areas with very thin overlying mucosa [4]. BRONJ typically occurs in patients who are receiving intravenous BP treatment. However, an increasing frequency of osteonecrosis of the jaw has been reported recently in people who receive oral BPs.

Although numerous studies strongly suggest an association between BP and BRONJ, the true incidence, etiology, pathogenesis, and natural history of this condition have yet to be elucidated.

There are several pathogenic hypothesis about the mechanisms that cause the BRONJ [5]. BPs are thought to function by inhibiting at least one enzyme of the intracellular mevalonate pathway in osteoclasts [5, 6]. Inhibition of this pathway prevents the modification of important signaling proteins, which disrupts osteoclast function and leads to indirect apoptotic cell death. Antiangiogenic and antineoplastic properties have been attributed to BPs.

Most authors emphasize the role of BP in the inhibition of the osteoclastic activity as the drugs that lead to the beginning of osteonecrosis [7]. Bisphosphonate mediated inhibition of osteoclastic function leads to decreased bone resorption and inhibits normal bone turnover. Once incorporated into mineralized bone, BPs, stay in the bone for a long time and have a terminal half-life of many years. As a result, patients who discontinue BP therapy still may be at risk of developing BRONJ several years after they stop taking the drug.

However, this theory of the osteoclast inhibition does not explain the elective localization of the disease in maxillofacial area, supporting instead the hypothesis that other mechanisms determine the BRONJ. In reference to what was stated in literature about oesophageal mucosal and gastric lesions in patients treated with oral BP, some authors underlined that the BP given i.v. have a direct cytotoxic effect on oral mucosal keratinocytes because of a leakage of the drug on the overlying mucosa caused by the dental extractions or by some micro-traumatisms [8]. There is clear documentation of BP toxicity to gastrointestinal epithelia. For example, alendronate and risedronate inhibit cell proliferation in vitro by means of inhibition of farnesil-disphosphonate synthase, the same enzyme which is the target of BP in osteoclasts [8, 9]. The clinical effects of this phenomenon are well recognized in the form of upper gastrointestinal side effects from BP use, and also as ulceration occurring in patients who suck BP tablets [10]. Tooth extraction or other dental trauma result in local release of BP. If the local concentration of drugs is high enough, it inhibits proliferation of adjacent epithelial cells [11] and slows healing of the physical breach in the mucosa, BP uptake into bone is in direct proportion to the local rate of bone turnover and the alveolar ridges have high turnover [12]. This evidence could explain the elective localization in maxilla-facial region. In this anatomic area the alveolar ligament, the periosteum, the gingival mucosa and the dental neck are connected together: this peculiar structure may cause, also without any traumatic events, a contact between BP and the soft tissue [13, 14]. A direct cytotoxic effect on the mucosa epithelia cells could explain the necrosis of the flaps of the oral mucosa harvested to cover the bones in BRONJ stage II and III.

In some reports minimal surgical procedures such as sequestrectomy and coverage of the exposed bone with local mucosal flaps are preferred. The authors agree with the above-mentioned non-invasive procedure of demolition, but not with the use of the local mucosa flaps. In their experience the oral mucosa appears instable, prone to diastase and ulceration. Indeed, this type of reconstruction causes a high incidence of infections and relapses characterized by the bone exposure and let them prefer some other different treatments.

The Authors suggest: sequestrectomy and minimal invasive debridement of the necrotic bone and then reconstruction with microsurgical flaps.

Any procedures must be completed with 0.2% chlorhexidine mouthwash and antibiotic therapy.

Thanks to the histological analysis of the mucosa samples taken 2 cm around the osteonecrosis area and the mucosa over and close to the osteonecrosis, in 8 patients affected by BRONJ stage III, the authors highlighted the histopathological changes that underline the unsuitability of the mucosa flaps to fill in the losses of substance.

Mucosa tissue was taken from 8 patients, affected by BRONJ, III stage, which have been under treatment with BP i.v. (zolendronate) for at least 2 years. They either suffered from bone metastases caused by breast cancer and prostate cancer or from osteolytic lesions as a consequence of Multiple Mieloma.

Histological sampling was made at supralesion and perilesional seat (distance from the necrotic bone 2 cm max). The samples were fixed with formalin and an ematossilina-eosin dichromatic coloring was carried out.

Each preparation was subjected to morphological evaluation by optical microscopy. The taken parameters were: acanthosis, papillomatosis, histological architecture.

An inflammation of the mucosa with massive presence of plasma cells and granulocytes in the connective tissue was found in the samples taken from above the necrotic bone. The histo-architecture of the connective tissue and of the mucosa appears modified: stratification is visible only in some areas and the papillomatosis is clearly noticeable on the slide. The most superficial layers are made up of few mature cells and are characterized by phenomena of ulceration and fray. Also, a phenomenon of interstitial edema is evident. (Fig. 1A).

Click for large image

Figure 1. An inflammation of the mucosa with massive presence of plasma cells and granulocytes in the connective tissue was found in the samples taken from above the necrotic bone (A). (B) A conservation of the connective tissue isto-architecture and of deeper epithelial layers was found on the samples of the mucosa surrounding the osteonecrosis. The inflammatory infiltrate is poorly represented and small areas of cellular plasma densification are rarely noticeable. Despite the mucosa deep layers keep their original architecture, the superficial ones are characterized by the presence of swollen and hypereosinophilic cells with a picnotic nucleus, which represents the signs of pathognomonic cell suffering.

Source of Support

Nil.

Conflict of Interest

None declared.

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Journal of Clinical Medicine Research is published by Elmer Press Inc.