Bisphosphonates and Osteonecrosis of the Jaw: Advantages of a New Schedule.
Authors: Zappasodi Patrizia , Corso Alessandro , Varettoni Marzia , Klersy Catherine , Pica Gianmatteo , Mangiacavalli Silvia , Lazzarino Mario 
Published: October 2019

Abstract
Background: Bisphosphonates (Bi) have been proven to be effective in preventing or delaying skeletal complications in multiple myeloma (MM) with a significant improvement of the quality of life. The 2002 ASCO guidelines indicate that once initiated intravenous Bi should be continued until an evident substantial decline of performance status. Recently, osteonecrosis of the jaw (ONJ) has been reported as complication of intravenous Bi treatment, with an incidence ranging between 6 and 13% and a greater occurrence in patients (pts) receiving zoledronic acid (Zol) than in those treated with pamidronate (Pam).
Aim. In this retrospective study we evaluated the incidence of ONJ and of skeletal related events (SRE) in a cohort of MM pts divided in two groups according to the schedule of administration of Bi; group A: monthly administrations until tolerated (standard), group B: monthly administrations during the first year and then every 3 months (reduced).
Methods: One hundred and six MM pts (M: 63, F: 43) were included in this study: 51 pts received a standard treatment (group A) and 55 a reduced schedule (group B). Pam 90 mg i.v. was administered as a three hour infusion and Zol 4 mg i.v. as a 15 minutes infusion. SRE was defined as: pathologic fracture, radiation to bone, spinal cord compression with vertebral fracture, hypercalcemia.
Results: No difference was found between the two groups concerning pts characteristics at the onset: age, sex, extension of bone disease, status of the disease (progressive or responsive). Twenty pts received only Pam, 42 only Zol and 44 pts Pam followed by Zol. The distribution of the different type of Bi was not different in the two groups. ONJ occurred in 7 pts (6.6%) with a significant difference between the two groups: 6 pts in standard schedule (11.7%) and 1 in the reduced (1.8%), p=0.01, after a median time of 22.8 months in group A, and 37.8 months in the case of group B. Four of out 7 ONJ occurred during the second year of treatment (12–24 months): that period resulted significantly related (p=0.000) to the occurrence of ONJ with respect to the others (24–38 months, 40–100 months). All ONJ occurred in pts treated with Zol alone (5 pts) or with Zol after Pam (2 pts), whereas no cases were observed in Pam alone pts (p= 0.005). The median number of infusions was 20 with comparable results in the two groups (20 in group A, 19 in group B). SRE was observed in 38 pts (35.8%): 16 pts in group A and 22 pts in group B without statistical difference (p=0.6), after a median time of 9.8 months.
Conclusions: These results suggest that the reduced schedule of Bi is associated with a significant lower incidence of ONJ and, although the sample size is limited, the appearance of ONJ seems delayed with respect to the standard treatment. Moreover, the incidence of SRE is similar in the two groups. In conclusion, the reduced schedule, could be applied in order to combine the antiresorptive efficacy of Bi with a higher safety and a better compliance.