Piezoeletric Surgery vs Conventional Surgery for Treatment of Medication-related Osteonecrosis of the Jaws: a Randomized Clinical Trial

Medicaiton-related osteonecrosis of the jaw (MRONJ) is defined as a drug-related adverse reaction characterized by progressive destruction and necrosis of the mandibular and/or maxillary bone in subjects exposed to treatment with drugs known to be at increased risk of disease, in the absence of previous radiation treatment. The first case of osteonecrosis was described in 2003 by Marx et al. in association with a specific group of drugs used in the treatment of skeletal system diseases: bisphosphonates, in particular the category of amino-bisphosphonates (i.e., zoledronate, pamidronate, alendronate) has been linked to the onset of MRONJ. However, from 2008, the first reports of MRONJ in association with other categories of drugs appeared: denosumab and targeted therapy as cancer treatment, such as bevacizumab, sunitinib, everolimus, etc. Bisphosphonates and denosumab are drugs used to treat osteometabolic (e.g. osteoporosis), oncological (e.g. bone metastases from solid tumors) and hematological diseases, available on the market in the form of oral or parenteral formulations (intravenous, intramuscular, subcutaneous). These drugs determine, through different mechanisms, an inhibition of osteoclastic activity and, consequently, an alteration of bone turnover. Target therapy are instead used only in the treatment of oncological diseases and mostly have an anti-angiogenic activity. The risk of onset of MRONJ varies mainly based on the type of drug administered, the administration route and the type of disease for which the intake was necessary; in particular, it has emerged that the risk is increased in case of intravenous administration and a higher cumulative dose, which is why cancer patients would seem to have a higher risk of developing MRONJ compared to subjects who use anti-resorbable drugs for osteo-metabolic diseases. The diagnostic process is complex and requires the integration of different clinical and radiological signs. In the past, the key element for the diagnosis of MRONJ was the presence of exposed necrotic bone inside the oral cavity, however in the literature it has emerged that a significant number of patients treated with these drugs present signs and symptoms, both in the initial and late phase, different from bone exposure alone. The diagnosis of MRONJ is structured according to the diagnostic work-up proposed by SICMF (Italian Society of Maxillo-Facial Surgery) - SIPMO (Italian Society of Oral Pathology and Medicine):

• Step 1: diagnostic suspicion deriving from the medical, dental and pharmacological history
• Step 2: differential diagnosis through identification of clinical signs (bad breath, odontogenic abscess, mandibular asymmetry, pain of dental and/or bone origin, exposure of necrotic bone, mucosal fistula, extra-oral fistula, hyperemia of the mucosa, failure to repair the alveolar mucosa after extraction, rapid onset of tooth mobility, preternatural mobility of the mandible, with or without preserved occlusion, paresthesia/dysesthesia of the lips, discharge from the nose, purulent discharge, spontaneous sequestration of bone fragments, trismus, swelling of the soft tissues), evaluation of pain and 1st level imaging (orthopantomography and/or intraoral radiography);
• Step 3: conclusive diagnosis through 2nd level imaging (CT Dentascan or Cone-Beam) These new diagnostic elements have allowed us to frame the pathology within a staging based on minor clinical signs and radiological signs. Reference is made to the staging proposed by SICMF - SIPMO. The importance of a correct diagnosis and therefore the inclusion of the pathology within a given stage lies in the variability and invasiveness of the therapeutic approach to MRONJ.

The treatment of MRONJ includes the possibility of medical and/or surgical therapy, although there is still no worldwide guidelines.

Medical therapy involves the use of drugs aimed at controlling the infection with the aim of stabilizing the clinical features by slowing the progression of the disease, but it is a very conservative approach that is unlikely to determine a complete resolution of the pathology. It consists of the association of an antiseptic therapy with chlorhexidine-based mouthwashes for disinfecting the oral cavity and an antibiotic therapy based on penicillins or in allergic patients quinolones, metronidazole, clindamycin and doxycycline.

Surgical therapy of MRONJ, however, remains the therapy of choice to date, although always in association with a medical approach. The surgical intervention, in fact, aims to stop the progression of the pathology through the removal of the tissue macroscopically involved in the disease until healthy bone tissue is reached.