Letters to the Editor Jaw avascular bone necrosis associated with long-term use of biphosphonates

Bisphosphonates are currently used to prevent bone complications and to treat malignant hypercalcemia in patients with multiple myeloma, or bone metastases from breast and prostate cancers [1]. Within the last year we observed 10 patients who developed jaw bone necrosis while on treatment with zoledronic acid (Zometa; Novartis) or pamidronate. All the patients had breast cancer with skeletal disease and received long-term treatment with bisphosphonates (range 14–48 months, median 30 months). Four patients developed this complication after tooth extraction or other odontostomatological procedures, and six had a spontaneous event. All patients but one had inferior mandibular necrosis. Patients started to complain of jaw pain, difficulty in masticating and in brushing teeth. The clinical appearance simulated dental abscesses or osteomyelitis. Biopsy of the involved area showed the presence of necrotic lacunae, with infiltration of lymphocytes and histiocytes. In six cases, histological or cytological diagnosis of suspicious osteomyelitis was done (Figure 1). This pathological feature, identified as ‘jaw avascular bone necrosis’, appears as a growing, painful, unilateral swelling of the jaw in patients receiving bisphosphonates [2–4]. Pain is frequently resistant to common anti-inflammatory drugs, causing severe impairment of quality of life. The definitive cure of avascular bone necrosis is controversial [4]. Surgical treatment and the use of hyperbaric oxygen seem to be partially effective. The removal of painful teeth may alleviate symptoms, but it eventually leads to further exposure of the bone [2]. In these cases discontinuation of bisphosphonates may be advocated, although the clinical benefit of this has not yet been proven. In our experience, four patients underwent curettage of the affected mandible, but in two patients the symptoms persisted. Subsequently, one patient experienced a mandibular fistula, with persistence of pain and purulent secretion, despite massive use of antibiotics. One patient with strong radiological suspicions of a jaw metastasis, was treated with local radiotherapy, but without clinical benefit. Afterwards, she developed a mandibular fistula. Another patient, after receiving hyperbaric oxygen therapy with no benefit, underwent wide resection of the affected bone, with no results. Another patient was treated with partial resection of the mandible, with a mild clinical improvement. Pamidronate and zolendronate are nitrogen containing bisphosphonates and bind preferentially to sites of active bone resorption, exerting direct effects on osteoclastic activity through different mechanisms, including cytoskeleton changes, decreased liposomal function and inducing osteoclast apoptosis [1, 4, 5]. Normal osteoclasis is vital to bone turnover, while its inhibition halts bone resorption, leading to the accumulation of non-vital osteocytes, microfractures of mineral matrix and bone necrosis. The selective appearance of this process in the jaw may be due to the specific anatomical pattern of harboring teeth, thus uniquely exposing this part of the skeleton directly to the open environment [2] and to continuous trauma due to mastication or to odontostomatological interventions. The antiangiogenic effect attributed to bisphosphonates might play a role, together with microtrauma and inflammation, in causing ischemic changes [1, 4, 5]. Understanding the precise mechanisms involved in the process may lead to the prevention of this skeletal complication. Long-term routine use of drugs should take into account the risk of this relatively uncommon event.