Reply to Letter to the Editor Regarding "Durability and Delayed Treatment Effects of Zoledronic Acid on Bone Loss After Spinal Cord Injury: A Randomized, Controlled Trial".

Abstract

To the Editors: We appreciate the compliments from Singhania and Bhattacharya regarding our recently completed randomized, controlled trial examining the efficacy of zoledronic acid to attenuate bone loss following spinal cord injury (SCI). Given their interest in the topic, Singhania and Bhattacharya have provided several comments related to our work that we are happy to respond to below. Of note, Singhania and Bhattacharya are mistaken when they mention our trial was conducted in “war veterans.” Participants were referred from admissions to the Shirley Ryan AbilityLab in Chicago, IL, USA, and as such, our sample represents a heterogenous group of individuals from the general public with common causes of acute SCI including motor vehicle accidents, falls, acts of violence, sports injuries and more. Singhania and Bhattacharya note that some 56% of our participants had cervical lesions, and given this distribution, suggest it may have been prudent to quantify changes to upper-extremity bone resulting from treatment. Of course, upper-extremity bone tends to be unaffected in individuals with paraplegia, but variably affected in those with quadriplegia, dependent in part on the degree of motor impairment.(1, 2) And although it may have been interesting to examine the efficacy of zoledronic acid to prevent bone loss in the upper extremities, most fractures after SCI occur in the lower extremities of individuals with paraplegia,(3, 4) likely owing to their increased independence and mobility. Upper-extremity factures represent less than 11% of fragility fractures after SCI,(5, 6) suggesting that lower-extremity bone loss, primarily that around the knee, is the most clinically relevant target for bone loss therapy. Our trial explored the timing and frequency of zoledronic acid infusion over 2 years of therapy following acute SCI. Singhania and Bhattacharya rightly point out that sublesional bone loss after SCI may continue to persist well beyond 2 years, and that a trial examining more than 2 years of zoledronic acid therapy would be desirable. We can only agree, and hope that the appropriate funding agencies and peer review systems concur with this statement. Follow-up beyond 2 years is desirable; however, as mentioned in our article, the slope of bone loss at the knee illustrated a steady decline even in participants that received two annual infusions of zoledronic acid. It is important to mention that our study was powered to examine Year 1 findings, with Year 2 findings being exploratory. We welcome additional studies examining the effects of zoledronic acid between 12 and 24 months and beyond, particularly because bone fractures after SCI tend to occur after 3 years of injury.(7) Singhania and Bhattacharya refer to the promising research taking place in the use of antiresorptive agents, such as zoledronic acid, in the management of knee pain.(8) It is our understanding this research is focused on management of knee osteoarthritis and thus a condition with a different pathogenesis from bone loss following SCI. Singhania and Bhattacharya acknowledge the important role of sclerostin in bone metabolism. The response of sclerostin associated with bone loss after SCI has been well characterized.(9) Our group is currently conducting a small trial in females with chronic SCI to examine the use of romosozumab, a monoclonal antibody that binds and inhibits sclerostin, for the treatment of bone loss after SCI (ClinicalTrials.gov Identifier: NCT04708886). We are enthusiastic to see there are several other active trials examining the efficacy of romosozumab after SCI (eg, NCT04597931 and NCT04232657). Last, Singhania and Bhattacharya acknowledge the high incidence of adverse events following infusion in our study; however, as was clearly stated in our article, there were no differences in adverse events between participants that received zoledronic acid versus placebo infusion apart from an increased incidence of an acute phase response in the zoledronic acid group. The presence of an acute phase response, though relatively higher than that observed in postmenopausal women,(10, 11) was expected. All acute phase responses were self-limited and without sequelae. Prophylaxis with acetaminophen or ibuprofen to lessen symptoms should be considered. We thank Singhania and Bhattacharya for their interest in our work and welcome additional discourse on these matters. We are committed to addressing the important issue of bone loss and the clinical sequela of fracture after SCI. W. Brent Edwards has received research funding and speaker fees from Amgen. Thomas J. Schnitzer has received research funding from Radius, Amgen, Eli Lilly, and Pfizer as well as consulting fees from Eli Lilly and Pfizer. Ifaz T. Haider, Narina Simonian, and Joana Barroso have no competing interests to declare.