Osteonecrosis of the Jaw Associated with Chronic Bisphosphonates Therapy: An Italian Experience.
Authors: Cafro Anna M. , Barbarano Luciana A. , Andriani Alessandro , D’Avanzo Giovanna , Nichelatti Michele , Gaglioti Domenico , Taroni Alberto , Gargantini Livio , Draisci Michela G. , Morra Enrica 
Published: April 2020

Abstract
Background. Pamidronate (P) and Zoledronate (Z) are new generation bisphoshonates (BS) used for treatment of bone lesions in patients (pts) with multiple myeloma (MM), solid tumors and no oncologic diseases. They are monthly administered for prolonged periods of time and they are generally well tolerated. Recently, severe osteonecrosis (ON) of the jaw has been reported as an adverse effect of treatment. Avascular bone necrosis has been often observed after major dental procedure. In site of lesion, occasionally, Actinomyces spp were recovered from culture. The aetiology is not understood, although it has been postulated to be secondary to the antiangiogenic effect of BS.
Patients. We performed a review of pts of the two hematologic departments treated in the last two years with monthly intravenous BS therapy (Pamidronate 90 mg and /or Zoledronate 4 mg). Overall, 118 patients were studied: 48 males, 70 females; 104 presented MM, 8 severe osteoporosis, 4 iperparathyroidism, 1 Paget disease and 1 breast carcinoma. All patients with a neoplastic disease had received at least one line of chemotherapy.
Results. Fourteen pts presented ON (13 with MM and one with severe osteoporosis). The median doses of BS therapy were: 560 mg (range 0–6480 mg) for P, 80 mg (range 0–308 mg) for Z. Five pts had an important exposed jawbone and 11 pts developed ON after a previous tooth extraction. Mandible was involved in 9 pts and maxilla in 5. Diagnosis was made with oral inspection, X-ray, TC and histology. Actinomyces spp were recovered in only one patient.
Statistical Analysis. All variables were analyzed for descriptive statistics and to check their distribution by Shapiro-Wilk test. The median values of cumulative dosage were used as cut-off points, and a score 0 was attributed to all dosages lower or equal to median dose, whereas a score 1 was attributed to all dosages grater than median doses. The presence and absence of the event were respectively coded as 1 and 0, and then logistic regression analysis was carried out. The significance for the whole univariate and multivariate models was set at p&lt; 0.05 for the regressors: the odds ratio (OR) was also calculated together with its CI 95%.. At univariate analysis, the significant contributor to oral lesions was only the dosage of pamidronate above or below median value (p=0.021). At multivariate analysis, significant regressors proved to be the female sex (p=0.032; OR 0.142)) and the score of cumulative dosage of drugs (p=0.005; OR 3.977; CI 95%.(OR) 1.517–10.424)
Conclusions. Oncologists should pay attention to ON occurrence in long survivors in chronic therapy with BS. Major debridement surgeries are to be avoided if at all possible. Our preliminary data in these pts showed that the lesions are more probable in females than in males and that the administration of more than 560 mg of Pamidronate and of more than 80 mg of Zoledronate is significantly associated with ON lesions.