Owing to their unique ability to inhibit bone resorption, bisphosphonates (BPs) have been used for several years for treating osteoporosis, Paget’s disease, and fibrous dysplasia. Recently, they have become part of chemotherapeutic protocols for managing bone invading tumours. The beneficial effects of BPs include significant reductions in pain, pathological fractures, osteolytic lesion size, and the need for subsequent bone surgery. A growing number of studies have recognized the crucial role of BPs in provoking heavy, chronic, therapy-resistant osteonecrosis of the jaws (ONJ). BPs are thought to influence ONJ by reducing bone metabolism, reducing osteoclast recruitment, inducing osteoclast-inhibiting factor production, and impairing angiogenesis.

Jaws are particularly subject to infection, due to their contact with the external environment, their susceptibility to trauma, their rich saprophytic flora, and the presence of teeth. The jaws are protected by a high rate of oral epithelium regeneration and a substantial blood supply. Serious bony complications are seldom triggered by potentially infectious conditions, such as open fractures, neglected teeth, periodontal abscesses, ill-fitting dentures, injuries to the mucosa, and facial wounds. The development of osteomyelitis and ONJ requires conditions that alter the healthy processes of immunity, blood supply, or cellular activity, and destroy natural defences. For example, diabetes mellitus, metabolic bone disorders, anti-cancer therapy, or neoplasmatic infiltration can contribute to the development of ONJ. Diabetes mellitus is associated with microvascular ischaemia, endothelial cell dysfunction, osteocyte apoptosis, and reduced bone turnover. Anti-cancer therapy, combined with cytostatics, corticosteroids, and stem cell transplantation, leads to general immunosuppression, bone marrow degeneration, vasculitis, reduced blood flow, and osteopenia. Multiple myelomas that develop in bone marrow and cancers that metastasise to the skeletal system (breast, prostate, kidney, lung) weaken bone structure by increasing osteoclast numbers and enhancing their resorptive activity. For example, in patients with multiple myelomas, A ndersen et al. demonstrated that osteolytic lesions contained 30% of malignant, hyperactive, polynuclear osteoclasts that originated from hybrid fusions between myeloma cells and normal osteoclasts.

Until recently, BPs were considered safe drugs with only a few side effects. BPs are pyrophosphate analogues, in which the oxygen atom in the basic chain (P–O–P) is substituted with carbon (P–C–P). BPs possess a high affinity for hydroxyapatite and are resistant to hydrolysis by bone phosphatases. This contributes to extended bone deposition, over several years. The mechanism of action underlying the antiresorptive potential of a BP is determined by whether it has a nitrogen molecule in the side chain. Non-nitrogen BPs (etidronate, clodronate, tiludronate) are phagocytosed by osteoclasts and metabolised to non-hydrolysable cytotoxic ATP analogues; this handicaps the mitochondrial function of the cell and results in apoptosis. In contrast, the more potent, nitrogen-containing BPs (aledronate, pamidronate, zoledronate, risedronate) can inhibit osteoclasts by interrupting the mevalonate pathway of cholesterol synthesis.

BPs were shown to exert a protective effect on bone tissue in avascular necrosis of the long bones and chronic sclerosing osteomyelitis of the jaws. Zoledronate had a beneficial influence on new bone formation during distraction osteogenesis. Several reports describe ONJ in patients who were treated for a long time with BPs due to bone metabolic disorders such as Paget’s disease or fibrous dysplasia.

These data raised the question of whether BPs might play a role in ONJ. To address this question, the authors undertook a retrospective analysis of a group of patients who had been treated with BPs for maxillary and mandibular osteomyelitis that did not have a directly associated pathological condition.