Serology and Comorbidities in Patients With Fracture Nonunion

A Multicenter Evaluation of 640 Patients

Joshua A. Shapiro, MD; Matthew R. Stillwagon, MD; Paul Tornetta III, MD; Thomas M. Seaver, MD; Mark Gage, MD; Jeffrey O'Donnell, MD; Keith Whitlock, MD; Seth R. Yarboro, MD; Kyle J. Jeray, MD; William T. Obremskey, MD; Andres Rodriguez-Buitrago, MD; Paul Matuszewski, MD; Feng-Chang Lin, PhD; Robert F. Ostrum, MD


J Am Acad Orthop Surg. 2022;30(18):e1179-e1187. 

In This Article

Abstract and Introduction


Introduction: This multicenter cohort study investigated the association of serology and comorbid conditions with septic and aseptic nonunion.

Methods: From January 1, 2011, to December 31, 2017, consecutive individuals surgically treated for nonunion were identified from seven centers. Nonunion-type, comorbid conditions and serology were assessed.

Results: A total of 640 individuals were included. 57% were male with a mean age of 49 years. Nonunion sites included tibia (35.2%), femur (25.6%), humerus (20.3%), and other less frequent bones (18.9%). The type of nonunion included septic (17.7%) and aseptic (82.3%). Within aseptic, nonvascular (86.5%) and vascular (13.5%) nonunion were seen. Rates of smoking, alcohol abuse, and diabetes mellitus were higher in our nonunion cohort compared with population norms. Coronary artery disease and tobacco use were associated with septic nonunion (P < 0.05). Diphosphonates were associated with vascular nonunion (P < 0.05). Serologically, increased erythrocyte sedimentation rate, C-reactive protein, parathyroid hormone, red cell distribution width, mean platelet volume (MPV), and platelets and decreased absolute lymphocyte count, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and albumin were associated with septic nonunion while lower calcium was associated with nonvascular nonunion (P < 0.05). The presence of four or more of increased erythrocyte sedimentation rate, C-reactive protein, or red cell distribution width; decreased albumin; and age younger than 65 years carried an 89% positive predictive value for infection. Hypovitaminosis D was seen less frequently than reported in the general population, whereas anemia was more common. However, aside from hematologic and inflammatory indices, no other serology was abnormal more than 25% of the time.

Discussion: Abnormal serology and comorbid conditions, including smoking, alcohol abuse, and diabetes mellitus, are seen in nonunion; however, serologic abnormalities may be less common than previously thought. Septic nonunion is associated with inflammation, younger age, and malnourishment. Based on the observed frequency of abnormality, routine laboratory work is not recommended for nonunion assessment; however, specific focused serology may help determine the presence of septic nonunion.


Fracture healing is a complex process that involves adequate mechanical stability, bony contact, blood supply, and appropriate endocrine and metabolic processes. When there is an insult to any of these areas, a solid union at the fracture site may not occur without additional intervention.[1] The overall incidence of nonunion is estimated at 5% to 10%.[2] Although the US Food and Drug Administration defines a nonunion as a fracture that is at least 9 months old and has not shown any signs of healing for 3 consecutive months,[3] Brinker and O'Connor define nonunion without an indication for temporality. Instead, they rely on the opinion of the treating physician to determine when there is no possibility of healing without additional intervention.[1]

The routine ordering of laboratory studies has become a standard of practice to evaluate for medically reversible causes of nonunion. Brinker et al[2] established an association between endocrine or metabolic abnormalities and nonunion through laboratory testing in 37 patients. Despite there being notable research into the area of nonunion, there remains many gaps in our knowledge, conflicting evidence, and few guidelines supporting the now routine ordering of laboratory studies.

Therefore, the goals of this study were to identify and compare rates of abnormal serology and medical comorbidities in patients with septic and aseptic nonunion, compare this to the general population, and develop a tool to predict septic nonunion through a large multicenter retrospective study. We hypothesized that serologic, metabolic, and endocrinologic abnormalities and medical comorbidities are seen commonly in nonunion and can be used to predict the presence of a septic nonunion.