{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T14:20:28Z","timestamp":1790086828082,"version":"4.0.1"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,1,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Nonunion is a rare yet serious complication in pediatric fracture healing that can lead to patient morbidity and economic burden. The administration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with an increased risk of fracture nonunion in adults, but data are lacking in the pediatric population. This study examines the relationship between postoperative ketorolac administration and nonunion in operatively managed pediatric long-bone fractures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>A retrospective cohort study was conducted with use of TriNetX, a research network that encompasses data from the United States, Canada, and Western Europe. A total of 462,260 patients from 52 health-care organizations met the inclusion criteria. Patients &lt;18 years old with operatively managed upper or lower-extremity long-bone fractures were included. The exposure of interest was ketorolac administration within 30 days postoperatively between 2003 and 2023. Nonunion was identified and verified with use of the pertinent medical codes. Absolute risks and hazard ratios (HRs) were calculated for both study groups. Significance was set at p &lt; 0.05.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>After propensity score matching, 48,778 patients were identified per group. The incidence of nonunion was 2.19% in the ketorolac group and 0.93% in the non-ketorolac group (HR, 2.71; 95% confidence interval [CI]: 2.46, 3.21; p &lt; 0.0001). Subgroup analyses demonstrated a higher risk of nonunion in patients with lower-extremity fractures (HR, 3.45; 95% CI: 3.14, 3.75; p &lt; 0.0001) than in those with upper-extremity fractures (HR, 2.11; 95% CI: 1.84, 2.32; p &lt; 0.0001). Among the fracture location subgroups, the greatest HR for nonunion was observed in patients with femoral fractures, followed sequentially by those with tibial and\/or fibular fractures, humeral fractures, and radial and\/or ulnar fractures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>To our knowledge, this is the largest study to date to explore postoperative ketorolac use and nonunion in the setting of operatively managed pediatric long-bone fractures. Nonunion in children was rare, occurring in &lt;1% of all included patients. Ketorolac administration was associated with a 2 to 3-fold increase in nonunion risks, with pronounced implications for patients with lower-extremity fractures, particularly those with femoral fractures. Clinicians should weigh the therapeutic advantages of non-opiate analgesia with ketorolac against the risk of nonunion in order to optimize postoperative pain management and recovery.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Level of Evidence:<\/jats:title>\n                    <jats:p>\n                      Therapeutic\n                      <jats:underline>Level III<\/jats:underline>\n                      . See Instructions for Authors for a complete description of levels of evidence.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.2106\/jbjs.23.01225","type":"journal-article","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T14:00:26Z","timestamp":1731420026000},"page":"66-72","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":14,"title":["Effect of Ketorolac Administration on the Rate of Nonunion of Operatively Treated Pediatric Long-Bone Fractures"],"prefix":"10.2106","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6356-9830","authenticated-orcid":false,"given":"Daniel E.","family":"Pereira","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Washington University School of Medicine, St. Louis, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3710-8037","authenticated-orcid":false,"given":"Caleb","family":"Ford","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Washington University School of Medicine, St. Louis, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8837-0396","authenticated-orcid":false,"given":"Mehul M.","family":"Mittal","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, UT Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0754-9157","authenticated-orcid":false,"given":"Tiffany M.","family":"Lee","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine, Houston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9583-9957","authenticated-orcid":false,"given":"Karan","family":"Joseph","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Washington University School of Medicine, St. Louis, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2622-0752","authenticated-orcid":false,"given":"Sabrina C.","family":"Madrigal","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Washington University School of Medicine, St. Louis, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2086-5717","authenticated-orcid":false,"given":"David","family":"Momtaz","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, UT Health San Antonio, San Antonio, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0737-9271","authenticated-orcid":false,"given":"Beltran","family":"Torres-Izquierdo","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Washington University School of Medicine, St. Louis, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7146-664X","authenticated-orcid":false,"given":"Pooya","family":"Hosseinzadeh","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Washington University School of Medicine, St. Louis, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2024,11,12]]},"reference":[{"issue":"1","key":"bib2-20250101","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1302\/2058-5241.5.190037","article-title":"Nonunion - consensus from the 4th annual meeting of the Danish Orthopaedic Trauma Society","volume":"5","author":"Schmal","year":"2020","journal-title":"EFORT Open Rev."},{"issue":"Suppl 2","key":"bib3-20250101","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.injury.2020.11.029","article-title":"Fracture nonunion in long bones: A literature review of risk factors and surgical management","volume":"52","author":"Nicholson","year":"2021","journal-title":"Injury."},{"key":"bib4-20250101","article-title":"Guidance Document for Industry and CDRH Staff for the Preparation of Investigational Device Exemptions and Premarket Approval Applications for Bone Growth Stimulator Devices. Draft; Availability","author":"Archives","year":"1998","journal-title":"Federal Register."},{"issue":"6","key":"bib5-20250101","doi-asserted-by":"crossref","first-page":"410","DOI":"10.3928\/01477447-20090511-11","article-title":"Nonunion of fractures in pediatric patients: 15-year experience at a level I trauma center","volume":"32","author":"Shrader","year":"2009","journal-title":"Orthopedics."},{"issue":"31","key":"bib6-20250101","doi-asserted-by":"crossref","first-page":"e11691","DOI":"10.1097\/MD.0000000000011691","article-title":"Risk factors for nonunion of bone fracture in pediatric patients: An inception cohort study of 237,033 fractures","volume":"97","author":"Zura","year":"2018","journal-title":"Medicine (Baltimore)."},{"issue":"2","key":"bib7-20250101","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s00264-017-3734-5","article-title":"Diaphyseal long bone nonunions - types, aetiology, economics, and treatment recommendations","volume":"42","author":"Rupp","year":"2018","journal-title":"Int Orthop."},{"issue":"Suppl 2","key":"bib8-20250101","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.injury.2014.04.002","article-title":"Delayed union and nonunions: epidemiology, clinical issues, and financial aspects","volume":"45","author":"Hak","year":"2014","journal-title":"Injury."},{"key":"bib9-20250101","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/1471-2474-14-42","article-title":"Tibia shaft fractures: costly burden of nonunions","volume":"14","author":"Antonova","year":"2013","journal-title":"BMC Musculoskelet Disord."},{"issue":"4","key":"bib10-20250101","doi-asserted-by":"crossref","first-page":"221","DOI":"10.3928\/01477447-20200428-06","article-title":"The Effect of Postoperative Nonsteroidal Anti-inflammatory Drugs on Nonunion Rates in Long Bone Fractures","volume":"43","author":"Tucker","year":"2020","journal-title":"Orthopedics."},{"issue":"6","key":"bib11-20250101","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1359\/jbmr.2002.17.6.963","article-title":"Cyclo-oxygenase 2 function is essential for bone fracture healing","volume":"17","author":"Simon","year":"2002","journal-title":"J Bone Miner Res."},{"issue":"6","key":"bib12-20250101","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1152\/japplphysiol.00053.2013","article-title":"NSAID therapy effects on healing of bone, tendon, and the enthesis","volume":"115","author":"Su","year":"1985","journal-title":"J Appl Physiol("},{"issue":"2","key":"bib13-20250101","first-page":"70","article-title":"NSAID\/COX-2 Inhibitors Increase Nonunion after Fracture Surgery? Dilemma and Consideration in Use","volume":"11","author":"Do","year":"2022","journal-title":"J Orthop Traumatol Surabaya."},{"issue":"3","key":"bib14-20250101","first-page":"299","article-title":"Nonsteroidal anti-inflammatory drugs for pain relief in case of injuries: Is there a risk of bone metabolism disorders and nonunion of bone fractures? \u041d\u0430\u0443\u0447\u043d\u043e-\u041f\u0440\u0430\u043a\u0442\u0438\u0447\u0435\u0441\u043a\u0430\u044f \u0420\u0435\u0432\u043c\u0430\u0442\u043e\u043b\u043e\u0433\u0438\u044f","volume":"60","author":"Karateev","year":"2022"},{"issue":"5","key":"bib15-20250101","doi-asserted-by":"crossref","first-page":"309","DOI":"10.2165\/00002018-199716050-00003","article-title":"Ketorolac for postoperative pain management in children","volume":"16","author":"Forrest","year":"1997","journal-title":"Drug Saf."},{"issue":"5","key":"bib16-20250101","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1097\/01241398-199909000-00027","article-title":"The role of ketorolac in decreasing length of stay and narcotic complications in the postoperative pediatric orthopaedic patient","volume":"19","author":"Eberson","year":"1999","journal-title":"J Pediatr Orthop."},{"issue":"1","key":"bib17-20250101","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2165\/00003495-199753010-00012","article-title":"Ketorolac. A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management","volume":"53","author":"Gillis","year":"1997","journal-title":"Drugs."},{"issue":"suppl_3","key":"bib18-20250101","doi-asserted-by":"crossref","first-page":"140","DOI":"10.2106\/JBJS.F.00454","article-title":"Nonsteroidal Anti-Inflammatory Drug-Induced Fracture Nonunion: An Inhibition of Angiogenesis?","volume":"88","author":"Murnaghan","year":"2006","journal-title":"J Bone Joint Surg Am."},{"issue":"3","key":"bib19-20250101","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1159\/000028236","article-title":"Effects of ketorolac on bone repair: A radiographic study in modeled demineralized bone matrix grafted rabbits","volume":"57","author":"Ho","year":"1998","journal-title":"Pharmacology."},{"issue":"2","key":"bib20-20250101","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1177\/1556331621998634","article-title":"The Effect of Nonsteroidal Anti-inflammatory Drugs and Selective COX-2 Inhibitors on Bone Healing","volume":"17","author":"White","year":"2021","journal-title":"HSS J."},{"issue":"14","key":"bib21-20250101","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.2106\/JBJS.19.01415","article-title":"Risk of Nonunion with Nonselective NSAIDs, COX-2 Inhibitors, and Opioids","volume":"102","author":"George","year":"2020","journal-title":"J Bone Joint Surg Am."},{"issue":"15","key":"bib22-20250101","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.2106\/JBJS.20.01663","article-title":"Do Nonsteroidal Anti-Inflammatory or COX-2 Inhibitor Drugs Increase the Nonunion or Delayed Union Rates After Fracture Surgery?: A Propensity-Score-Matched Study","volume":"103","author":"Kim","year":"2021","journal-title":"J Bone Joint Surg Am."},{"issue":"3","key":"bib23-20250101","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s00223-010-9379-7","article-title":"NSAID exposure and risk of nonunion: a meta-analysis of case-control and cohort studies","volume":"87","author":"Dodwell","year":"2010","journal-title":"Calcif Tissue Int."},{"issue":"9","key":"bib24-20250101","doi-asserted-by":"crossref","first-page":"815","DOI":"10.2106\/JBJS.J.01743","article-title":"The Effect of Nonsteroidal Anti-Inflammatory Drug Administration on Acute Phase Fracture-Healing: A Review","volume":"94","author":"Kurmis","year":"2012","journal-title":"J Bone Joint Surg Am."},{"issue":"2","key":"bib25-20250101","doi-asserted-by":"crossref","first-page":"ooad035","DOI":"10.1093\/jamiaopen\/ooad035","article-title":"A global federated real-world data and analytics platform for research","volume":"6","author":"Palchuk","year":"2023","journal-title":"JAMIA Open."},{"issue":"2","key":"bib28-20250101","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/s41390-022-02264-9","article-title":"Improving child health through Big Data and data science","volume":"93","author":"Vesoulis","year":"2023","journal-title":"Pediatr Res."},{"issue":"9","key":"bib29-20250101","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1001\/jamadermatol.2021.2856","article-title":"Validity of Using Billing Codes From Electronic Health Records to Estimate Skin Cancer Counts","volume":"157","author":"Anand","year":"2021","journal-title":"JAMA Dermatol."},{"issue":"1","key":"bib30-20250101","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1055\/s-0040-1721012","article-title":"Coronary Artery Disease Phenotype Detection in an Academic Hospital System Setting","volume":"12","author":"Joseph","year":"2021","journal-title":"Appl Clin Inform."},{"issue":"10","key":"bib31-20250101","doi-asserted-by":"crossref","first-page":"e0276299","DOI":"10.1371\/journal.pone.0276299","article-title":"Healthcare Claims-Based Lyme Disease Case-Finding Algorithms in the United States: A Systematic Literature Review","volume":"17","author":"Nam","year":"2022","journal-title":"PLoS One."},{"issue":"6","key":"bib32-20250101","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1159\/000527805","article-title":"Predictive Value of Pediatric Stroke Diagnoses in Administrative Data: A Systematic Literature Review","volume":"56","author":"Bindslev","year":"2022","journal-title":"Neuroepidemiology."},{"issue":"2","key":"bib33-20250101","doi-asserted-by":"crossref","first-page":"43","DOI":"10.13078\/jsm.18004","article-title":"The Association between Serotonin Reuptake Inhibitors and Obstructive Sleep Apnea in People with Epilepsy-A Retrospective Analysis","volume":"15","author":"Cheng","year":"2018","journal-title":"J Sleep Med."},{"issue":"1","key":"bib34-20250101","doi-asserted-by":"crossref","first-page":"18090","DOI":"10.1038\/s41598-019-54075-4","article-title":"An electronic medical records-based approach to identify idiosyncratic drug-induced liver injury in children","volume":"9","author":"Sandritter","year":"2019","journal-title":"Sci Rep."},{"key":"bib36-20250101","first-page":"43","article-title":"Epidemiology Of Hepatocellular Carcinoma In Nonalcoholic Fatty Liver Disease","volume":"5","author":"Moriguchi","year":"2019","journal-title":"Hepatoma Research."},{"issue":"5","key":"bib37-20250101","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1177\/1079063212469060","article-title":"Quantifying the relative risk of sex offenders: risk ratios for static-99R","volume":"25","author":"Hanson","year":"2013","journal-title":"Sex Abuse."},{"issue":"116","key":"bib38-20250101","doi-asserted-by":"crossref","first-page":"3511","DOI":"10.1182\/blood.V116.21.3511.3511","article-title":"Allogeneic Hematopoietic Cell Transplantation For Acute Lymphoblastic Leukemia In First Complete Remission: a Systematic Review And Meta-analysis","volume":"21","author":"Pidala","year":"2010","journal-title":"Blood."},{"key":"bib39-20250101","doi-asserted-by":"crossref","first-page":"101061","DOI":"10.1016\/j.eclinm.2021.101061","article-title":"Cerebral venous thrombosis and portal vein thrombosis: A retrospective cohort study of 537,913 COVID-19 cases","volume":"39","author":"Taquet","year":"2021","journal-title":"EClinicalMedicine."},{"issue":"2","key":"bib40-20250101","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/S2215-0366(20)30462-4","article-title":"Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA","volume":"8","author":"Taquet","year":"2021","journal-title":"Lancet Psychiatry."},{"issue":"7","key":"bib41-20250101","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1097\/BPO.0b013e3181efb8b4","article-title":"Complications of ketorolac use in children undergoing operative fracture care","volume":"30","author":"Kay","year":"2010","journal-title":"J Pediatr Orthop."},{"issue":"9","key":"bib42-20250101","first-page":"821","article-title":"NSAID Use and Effects on Pediatric Bone Healing: A Review of Current Literature","volume":"8","author":"Choo","year":"2021","journal-title":"Children (Basel)."},{"issue":"1","key":"bib43-20250101","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S1529-9430(02)00446-1","article-title":"Use of ketorolac tromethamine in children undergoing scoliosis surgery. an analysis of complications","volume":"3","author":"Vitale","year":"2003","journal-title":"Spine J."},{"issue":"4","key":"bib44-20250101","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s11832-013-0521-8","article-title":"The risk of non-union per fracture in children","volume":"7","author":"Mills","year":"2013","journal-title":"J Child Orthop."},{"issue":"12","key":"bib45-20250101","doi-asserted-by":"crossref","first-page":"755","DOI":"10.5435\/00124635-201212000-00003","article-title":"Perioperative pain control in pediatric patients undergoing orthopaedic surgery","volume":"20","author":"Nowicki","year":"2012","journal-title":"J Am Acad Orthop Surg."},{"issue":"6","key":"bib46-20250101","doi-asserted-by":"crossref","first-page":"e447","DOI":"10.1097\/BPO.0000000000001345","article-title":"Perioperative Ketorolac for Supracondylar Humerus Fracture in Children Decreases Postoperative Pain, Opioid Usage, Hospitalization Cost, and Length-of-Stay","volume":"39","author":"Adams","year":"2019","journal-title":"J Pediatr Orthop."},{"issue":"1","key":"bib47-20250101","doi-asserted-by":"crossref","first-page":"11","DOI":"10.5312\/wjo.v13.i1.11","article-title":"Regional anesthesia for orthopedic procedures: What orthopedic surgeons need to know","volume":"13","author":"Kamel","year":"2022","journal-title":"World J Orthop."},{"issue":"10","key":"bib48-20250101","doi-asserted-by":"crossref","first-page":"e923","DOI":"10.1097\/BPO.0000000000001956","article-title":"What\u2019s New in Pain Management for Pediatric Orthopaedic Surgery","volume":"41","author":"Johnson","year":"2021","journal-title":"J Pediatr Orthop."}],"container-title":["Journal of Bone and Joint Surgery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.2106\/JBJS.23.01225","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T13:53:01Z","timestamp":1787752381000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.2106\/JBJS.23.01225"}},"subtitle":["A Matched Cohort Analysis"],"short-title":[],"issued":{"date-parts":[[2024,11,12]]},"references-count":44,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025]]}},"URL":"https:\/\/doi.org\/10.2106\/jbjs.23.01225","relation":{},"ISSN":["0021-9355","1535-1386"],"issn-type":[{"value":"0021-9355","type":"print"},{"value":"1535-1386","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,12]]}}}