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Original Investigation
November 16, 2016

Epidemiology of Fracture Nonunion in 18 Human Bones

Author Affiliations
  • 1Department of Orthopaedic Surgery, Duke University Medical Center, Durham, North Carolina
  • 2Department of Statistics, North Carolina State University, Raleigh
  • 3Department of Orthopaedic Surgery, New York University Langone Medical Center, New York
  • 4Department of Orthopaedic Surgery, Saint Louis University School of Medicine, St. Louis, Missouri
  • 5Department of Orthopaedic Surgery, University of North Carolina, Chapel Hill
  • 6Department of Orthopaedics and Sports Medicine, Wright State University, Dayton, Ohio
  • 7Department of Orthopaedic Surgery, University of Missouri, Columbia
  • 8Department of Orthopaedic Surgery, Hospital of the University of Pennsylvania, Philadelphia
  • 9Department of Orthoapaedic Surgery, Indiana University, Indianapolis
  • 10Medical Affairs, Bioventus LLC, Durham, North Carolina
JAMA Surg. 2016;151(11):e162775. doi:10.1001/jamasurg.2016.2775
Key Points

Question  Which patient-specific risk factors other than injury severity increase risk of nonunion of fractures?

Findings  In an inception cohort study of a payer database in which 309 330 fractures in 18 bones were analyzed, only 5 patient-specific risk factors significantly increased the risk of nonunion more than 50% across all bones: multiple concurrent fractures, prescription nonsteroidal anti-inflammatory drug and opioid use, open fracture, anticoagulant use, and osteoarthritis with rheumatoid arthritis.

Meaning  The probability of fracture nonunion can be determined from patient-specific risk factors at presentation.


Importance  Failure of bone fracture healing occurs in 5% to 10% of all patients. Nonunion risk is associated with the severity of injury and with the surgical treatment technique, yet progression to nonunion is not fully explained by these risk factors.

Objective  To test a hypothesis that fracture characteristics and patient-related risk factors assessable by the clinician at patient presentation can indicate the probability of fracture nonunion.

Design, Setting, and Participants  An inception cohort study in a large payer database of patients with fracture in the United States was conducted using patient-level health claims for medical and drug expenses compiled for approximately 90.1 million patients in calendar year 2011.The final database collated demographic descriptors, treatment procedures as per Current Procedural Terminology codes; comorbidities as per International Classification of Diseases, Ninth Revision codes; and drug prescriptions as per National Drug Code Directory codes. Logistic regression was used to calculate odds ratios (ORs) for variables associated with nonunion. Data analysis was performed from January 1, 2011, to December 31, 2012,

Exposures  Continuous enrollment in the database was required for 12 months after fracture to allow sufficient time to capture a nonunion diagnosis.

Results  The final analysis of 309 330 fractures in 18 bones included 178 952 women (57.9%); mean (SD) age was 44.48 (13.68) years. The nonunion rate was 4.9%. Elevated nonunion risk was associated with severe fracture (eg, open fracture, multiple fractures), high body mass index, smoking, and alcoholism. Women experienced more fractures, but men were more prone to nonunion. The nonunion rate also varied with fracture location: scaphoid, tibia plus fibula, and femur were most likely to be nonunion. The ORs for nonunion fractures were significantly increased for risk factors, including number of fractures (OR, 2.65; 95% CI, 2.34-2.99), use of nonsteroidal anti-inflammatory drugs plus opioids (OR, 1.84; 95% CI, 1.73-1.95), operative treatment (OR, 1.78; 95% CI, 1.69-1.86), open fracture (OR, 1.66; 95% CI, 1.55-1.77), anticoagulant use (OR, 1.58; 95% CI, 1.51-1.66), osteoarthritis with rheumatoid arthritis (OR, 1.58; 95% CI, 1.38-1.82), anticonvulsant use with benzodiazepines (OR, 1.49; 95% CI, 1.36-1.62), opioid use (OR, 1.43; 95% CI, 1.34-1.52), diabetes (OR, 1.40; 95% CI, 1.21-1.61), high-energy injury (OR, 1.38; 95% CI, 1.27-1.49), anticonvulsant use (OR, 1.37; 95% CI, 1.31-1.43), osteoporosis (OR, 1.24; 95% CI, 1.14-1.34), male gender (OR, 1.21; 95% CI, 1.16-1.25), insulin use (OR, 1.21; 95% CI, 1.10-1.31), smoking (OR, 1.20; 95% CI, 1.14-1.26), benzodiazepine use (OR, 1.20; 95% CI, 1.10-1.31), obesity (OR, 1.19; 95% CI, 1.12-1.25), antibiotic use (OR, 1.17; 95% CI, 1.13-1.21), osteoporosis medication use (OR, 1.17; 95% CI, 1.08-1.26), vitamin D deficiency (OR, 1.14; 95% CI, 1.05-1.22), diuretic use (OR, 1.13; 95% CI, 1.07-1.18), and renal insufficiency (OR, 1.11; 95% CI, 1.04-1.17) (multivariate P < .001 for all).

Conclusions and Relevance  The probability of fracture nonunion can be based on patient-specific risk factors at presentation. Risk of nonunion is a function of fracture severity, fracture location, disease comorbidity, and medication use.