A call for a randomized trial of prophylactic bisphosphonate for decreasing incidence of osteonecrosis in patients with acute lymphoblastic leukemia.Bruce C. Bostrom, MDPediatric Oncology, Children’s Minnesota, Saint Paul, Minnesota, USACorrespondence to:Bruce C. Bostrom, MD, 1162 Ivy Avenue East, Saint Paul, Minnesota 55106, USATel. 1-651-245-6244Email: Bruce.Bostrom@yahoo.comText word count: 485Abstract word count: 0Brief running title: Prevention of osteonecrosis with bisphosphonatesKey words: Osteonecrosis, Bisphosphonates, Acute Lymphoblastic Leukemia,Tables: 0Figures: 0Mattano et al. have demonstrated osteonecrosis is associated with a significant increase in survival due to a decrease in relapse (1). Must we accept this horrible life changing side effect in these patients? Is there something that may reduce the risk of osteonecrosis without impacting cure?Bisphosphonates, usually pamidronate, have been used for treatment of chemotherapy bone toxicities in ALL since 2002 (2). A recent review of published studies in ALL patients revealed no concerns about the safety of bisphosphonates but concluded there is insufficient evidence to recommend them for prevention of osteopenia or fractures (3). Bisphosphonates have proven useful to treat bone pain from osteonecrosis and also may prevent osteonecrosis progression in hips with mild disease (4). There are no published studies where therapeutic bisphosphonates prevented progression of severe joint osteonecrosis and the subsequent need for joint replacement (5).The only intervention that has resulted in a decrease incidence of osteonecrosis without compromising cure is intermittent dexamethasone during delayed intensification (6). I previously published as a letter to the editor in Pediatric Blood and Cancer results from a concurrent control study that showed prophylactic pamidronate significantly reduced the incidence of osteonecrosis in young adults (7). The publication has never been cited and therefore likely unknown to those who are in a position to perform a randomized trial of prophylactic bisphosphonates in ALL patients at high risk for osteonecrosis. In my study the incidence of symptomatic osteonecrosis was 16% with pamidronate versus 39% in concurrent controls (p=0.04). In addition, the only patients who developed osteonecrosis requiring a joint replacement were in the concurrent controls that did not receive pamidronate. Additional evidence in support of bisphosphonates can be found in a study of therapeutic alendronate for osteopenia in ALL, that showed a lower relapse rate in patients given 87 weeks of alendronate (7/69; 10%) vs. concurrent controls (19/89; 21%) (8).A very comprehensive in vivo study of murine and human leukemia cell lines demonstrated reduced osteonecrosis with prophylactic but not therapeutic zolendronate (9). Of concern, mice with murine leukemia treated with zolendronate and chemotherapy died from leukemia sooner than mice treated with chemotherapy alone (p=0.046). However patient derived leukemia cells only had a non-significant decrease in survival with zolendronate and chemotherapy (p=0.17). A corroborative in vitro study using multiple leukemia cell lines did demonstrate some antagonism of dexamethasone by zolendronate and pamidronate at five-fold peak plasma concentrations (10). No antagonism was seen with daunorubicin, 6-mercaptopurine, and pegylated asparaginase. There was no direct cytotoxic effect of zolendronate or pamidronate on leukemia cell lines.There have now been three calls for a randomized clinical trial to answer the question: “Does prophylactic bisphosphonate therapy reduce osteonecrosis without decreasing cure” (9,10,11). Given the much quicker administration time of zolendronate (5 minutes) vs. pamidronate (2 hours), zolendronate likely would be the bisphosphonate of choice. I sincerely hope this publication will lead to a randomized trial of bisphosphonate for osteonecrosis prevention.