Long bone nonunion results in significant burden for the treating surgeon,1 cost to the health care system,2,3 and morbidity for the patient.4 Improvements in fracture management have prompted a decline in nonunion estimates of 30% since 1993.5 This improvement is multifactorial and can be attributed to advances in implant design, surgical technique, and postoperative management.6–12 Despite these improvements, nonunion continues to occur in 1.9% to 4.9% of all fractures.6,13
The cost of managing non-healing fractures cannot be overstated. Long bone injuries account for 10% of non-fatal injuries and are the number one category of injuries requiring inpatient expenditures.14,15 When nonunion is encountered, the management becomes involved, often requiring repeat procedures.1,7 Few recent studies have evaluated the economics of fracture nonunion. In 2007, Kanakaris and Giannoudis16 reviewed the literature and found an additional cost for humeral, femoral, and tibial nonunion of (pound equivalent) $21,023, $23,245, and $22,069, respectively. Antonova et al2 found that tibial nonunion can lead to more than double the cost of primary fixation ($25,556 vs $11,686). By continuing to modify any perioperative risk factors, surgeons will help to further decrease nonunion rates.
Risk factors for nonunion include type of fracture, method of fixation, and patient comorbidities.6–12,17 Of these, smoking has been well established as a risk factor for nonunion in certain fracture patterns.8,9,18 Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) has been controversial in its association with subsequent nonunion. Basic science, animal studies, and human clinical trials have all provided variable results regarding NSAID use and fracture healing.19–21 Many independent studies have found NSAID exposure to be associated with fracture nonunion.22–24 In contrast, meta-analyses have been mixed and other reports within the spine literature have revealed no risk.25–29
The purpose of this study was to evaluate the association of NSAID exposure with the risk of nonunion in operatively treated long bone fractures. Secondarily, the authors sought to evaluate the impact of nonunion reimbursement with the aim of providing guidance on NSAID use in the postoperative period. To the authors' knowledge, this is the first large database study to evaluate the risk of NSAID use and subsequent nonunion in long bone fractures treated operatively.
Materials and Methods
With the use of a large database of patients under the care of one private insurance provider (PearlDiver, Colorado Springs, Colorado), a retrospective cohort study was performed to assess for a relationship between the use of NSAIDs and nonunion rates in patients with operatively treated long bone fractures. The PearlDiver Humana database is a Health Insurance Portability and Accountability Act–compliant national database of more than 23.5 million orthopedic patients from 2007 to 2016 arranged by diagnosis and procedure codes. Because all patient data are deidentified, this study required no approval from an institutional review board. Patients with operatively treated humeral shaft, tibial shaft, and subtrochanteric femur fractures were identified using International Classification of Diseases, 9th and 10th revisions, and Current Procedural Terminology codes (Table A, available in the online version of the article).
Nonunion and NSAIDs
The patients were then divided into cohorts based on the use of NSAIDs. The data on NSAIDs were derived from Humana patient claims and originated from National Drug Codes on pharmacy claims. These data were further broken down into drug categories, out of which DRUG-CAT_1012 was used for NSAIDs. Patients who proceeded to nonunion were identified using the codes in Table A. Nonunion rates in NSAID users vs controls were then found. The study also investigated the temporal relationship between NSAID use and nonunion rate. Closed and open fractures were both analyzed.
Charlson Comorbidity Index and Cost
The Charlson Comorbidity Index (CCI) is a validated metric used to identify a patient's overall level of health and mortality risk. Several patient factors, including age, diabetes, renal disease, heart disease, and many other comorbidities, are used to calculate a patient's score. The lower the score, the lower the patient's comorbidity burden.30,31 The PearlDiver software also allows for cost analysis to be performed. The cost for patients who developed a non-union was compared with the cost for those who did not in the first year of treatment.
The relative risks and 95% confidence intervals of NSAID users compared with nonusers were calculated for association with nonunion. An unpaired t test was used to compare CCIs in the union and nonunion groups within the NSAID group and was also used to assess the cost associated with fractures with and without a diagnosis of nonunion. Finally, multivariate analysis was performed using logistic regression within the PearlDiver software to account for patient demographics (age, sex) and comorbidities (renal disease, tobacco use, diabetes, peripheral vascular disease, and obesity). Statistical significance was set at P≤.05 for all calculations.
Fracture and Nonunion
Between 2007 and 2016, a total of 5310 tibial shaft fractures, 3947 humeral shaft fractures, and 8432 subtrochanteric femur fractures underwent operative fixation. Overall, operatively treated tibial shaft, humeral shaft, and subtrochanteric femur fractures had nonunion rates of 12.7%, 11.4%, and 5.3%, respectively (Table 1). Patients used NSAIDs in the first 90 days postoperatively in 900 tibial shaft, 694 humeral shaft, and 967 subtrochanteric femur fractures. In these patients, the rates increased to 18.8% in tibial shaft fractures, 17.4% in humeral shaft fractures, and 10.4% in subtrochanteric femur fractures. When no NSAIDs were used, the rates were 11.4%, 10.1%, and 4.6% for each fracture type, respectively (P<.05). In patients taking NSAIDs, subtrochanteric femur fractures had a 2.4 times higher risk of nonunion when calculating relative risk and both humeral shaft fractures and tibial shaft fractures had a 1.7 times higher risk of nonunion (P<.05).
Fracture and Nonunion Breakdown
Open Versus Closed Fractures
In open fractures, NSAID users had nonunions in 9 of 41 humeral shaft fractures, 52 of 216 tibial shaft fractures, and 3 of 23 subtrochanteric femur fractures. The rates in those who did not use NSAIDs were 13.5%, 19.1%, and 8.2%, respectively. These values were not statistically significant, possibly due to lower numbers of fractures (P>.05). Closed humeral shaft fractures had a nonunion rate of 17.3% in NSAID users, vs 9.9% in nonusers. This trend continued in tibial shaft (12.9% vs 3.2%) and subtrochanteric femur (10.4% vs 4.5%) fractures (P<.001). Overall, open fractures had nonunion rates of 15.1%, 20.2%, and 8.7% in humeral shaft, tibial shaft, and subtrochanteric femur fractures, respectively. These rates were much lower in closed injuries—11.2%, 4.8%, and 5.2%, respectively.
Intramedullary Nail Versus Open Reduction and Internal Fixation
To control for treatment strategy, fixations of tibia fractures were compared. A total of 3416 tibia fractures were treated with an intramedullary nail, and 1306 underwent open reduction and internal fixation. The intramedullary nail group had an 11.4% nonunion rate, vs 15.39% for open reduction and internal fixation (P<.001). When NSAIDs were taken into account, intramedullary nail patients who took NSAIDs had a nonunion rate of 18.7%, vs 9.9% in those who did not take NSAIDs (P<.001). Similar findings were encountered in the open reduction and internal fixation group. The NSAID users had a nonunion rate of 14.3%, vs 20.6% for nonusers (P<.001).
Effect of Timing and NSAID Use
Additionally, patients were placed into groups depending on when they took NSAIDs postoperatively. Patients who did so within 30 days of surgery were at the highest risk of nonunion when compared those who did so between 30 and 60 days and between 60 and 90 days. All groups were found to have a statistically significant increased risk of nonunion except for patients with humeral shaft fractures who took NSAIDs between 60 and 90 days after surgical fixation (Table 2).
Nonsteroidal Anti-inflammatory Drug Use and Nonunion Rate
Charlson Comorbidity Index
The CCI was used to assess overall comorbidity burden within the NSAID groups. For patients who used NSAIDs, no statistical significance was found in any of the fracture groups, meaning that the patients likely had a similar comorbidity burden. In all fracture groups for NSAID-naïve patients, the CCI was either the same as or even lower (humeral shaft nonunion) than that of the patients who went on to nonunion. Therefore, their comorbidity burden was similar to or even greater than that of patients with nonunions (Table 3).
Charlson Comorbidity Index in Union Versus Nonunion
In a further effort to ensure that the difference in fracture nonunion was not due to a confounding variable, multivariate analysis was performed using a logistic regression to control for comorbidities and demographics while assessing the impact of NSAID use. Odds ratios showed NSAIDs to be an independent risk factor for nonunion in all 3 groups, even when accounting for these other factors. Subtrochanteric femur fractures had an odds ratio of 1.50. Additionally, tibial shaft fractures were at increased risk of nonunion with NSAIDs (odds ratio, 1.42). Humeral shaft fractures had the lowest risk (odds ratio, 1.20). Infection was evaluated as well and had almost a 2-fold increased risk in all 3 fractures. Of note, tobacco use caused increased risk of nonunion in humeral shaft and tibial shaft fractures but not subtrochanteric femur fractures. Diabetes mellitus did not cause an increased risk in any of the 3 (Table 4).
Multivariate Logistic Regression Analysis of Risk Factors for Fracture Nonunion
Results showed a large difference in cost for patients who went on to nonunion compared with those who did not. As seen in Figure 1, the average 1-year reimbursement associated with operatively treated subtrochanteric femur fractures was $22,435.05. In comparison, the reimbursement for patients with a diagnosis of nonunion with the same fracture was $35,968.19 (P<.001). Similar results were found for tibia fractures. Nonunion resulted in a reimbursement of $49,995.25, vs $28,077.04 for those without that diagnosis (P<.001). Finally, humeral shaft nonunions cost $31,746.91 at 1 year, vs $21,240.30 for humeral shaft fractures without nonunion (P<.001).
Cost (in dollars) of union vs nonunion.
In the current health care environment and with the goal of minimizing opiate analgesia during fracture management, NSAIDs play a key role in the control of patients' pain.32,33 However, these medications must not be used at the expense of fracture healing. Using the PearlDiver database, the authors identified 5310 tibial shaft fractures, 3947 humeral shaft fractures, and 8432 subtrochanteric femur fractures that underwent operative fixation. They chose fractures of the humerus, tibia, and subtrochanteric femur for analysis due to their increased incidence of nonunion and evaluation in prior literature.12,17,34
These data indicate that exposure to NSAIDs at any point within 90 days postoperatively is associated with subsequent fracture nonunion. Most importantly, the current study found an association between NSAID exposure during the immediate postoperative period (0 to 30 days) and subsequent nonunion. Significant risk of nonunion developed in all analyzed fractures: humeral shaft (19.5% vs 10.1%), subtrochanteric femur (11.2% vs 4.6%), and tibial shaft (20.0% vs 11.4%). Overall, NSAID exposure carried a relative risk of nonunion of 2.4 for subtrochanteric femur fractures, 1.7 for tibial shaft fractures, and 1.7 for humeral shaft fractures. The relative risk was highest 0 to 30 days following surgery—2.4, 2.0, and 1.9 for femur, tibia, and humerus fractures, respectively.
These results support prior literature, which found a risk with NSAID use. Jeffcoach et al34 retrospectively reviewed 1901 patients with long bone fractures at a single institution. Of these, 60 patients developed long bone nonunion. Postoperative use of NSAIDs resulted in an odds ratio of 2.17 for nonunion, and smokers were 3.19 times as likely to develop nonunion. However, this is in contrast to a 2005 database study by Bhattacharyya et al35 evaluating humeral shaft fracture. They found that opioid and NSAID exposure was associated with nonunion only during the 61 to 90 days period. They concluded that this was more likely associated with pain control of non-union than a causal relationship resulting in a protopathic bias.
As discussed previously, studies regarding NSAID use in spinal fusion procedures have tended to report no inhibitory effect and this may be the case, at least in the pediatric population.25,26 A 2010 meta-analysis by Dodwell et al22 analyzing 11 studies demonstrated an association between NSAID use and nonunion (odds ratio, 3.0). When only higher level studies were used, 7 spine fusion studies found no association.
Multivariate analysis was useful for assessing the effects of NSAIDs in fracture healing and taking into account possible confounders. In both subtrochanteric femur and tibia fractures, NSAIDs had a higher risk for nonunion than did renal disease, vascular disease, tobacco use, obesity, or diabetes. Only tobacco use and renal disease represented higher risks in humeral shaft fractures. Tobacco use did still pose significant risk for nonunion in humeral and tibia fractures. However, tobacco use was not found to be a risk factor in subtrochanteric fractures, which is consistent with previous literature.36 Interestingly, diabetes was not found to be a significant risk factor for any of the 3 fracture patterns, which does contrast with prior literature (Table 4).6
The nonunion rates found in the current analysis are consistent with those reported in prior studies. These data indicated total tibial shaft fracture nonunion of 12.7%, humeral shaft fracture nonunion of 11.4%, and subtrochanteric femur fracture nonunion of 5.3%. Rates were higher in open fractures than in closed fractures. Although the lack of a universally accepted definition of nonunion can affect outcome reporting,10,37 the current results are in accordance with prior literature.12 An evidence review by Tzioupis and Giannoudis12 found nonunion rates ranging from 2% to 13% for nonoperative humerus fractures and 2% to 7% for those treated with plate fixation. Intramedullary nailing had higher nonunion rates, ranging from 0% to 33%. Subtrochanteric fractures trended toward nonunion rates up to 5%. The nonunion rate for tibial fractures was 5% to 6.5% when using reamed nailing.12
In the subanalysis of cost, the data demonstrated that cost was substantially increased for all nonunion management, as expected and in accordance with prior studies.2,16 The current authors found that non-union of tibial shaft fractures had the greatest impact on cost, with standard healing having a reimbursement of $28,077.04, vs $49,995.25 with an associated nonunion. Significant cost increases were found in each of the other fractures as well.
This study had some limitations. First, this was a retrospective review of a database, which has inherent weaknesses and is dependent on International Classification of Diseases and Current Procedural Terminology coding. Studies have shown that databases, when used appropriately, can contribute to orthopedic research.38–40 The PearlDiver database has been used in numerous studies published in high impact journals.41–44 Databases do have a tendency to underreport complications.45 Individual patient factors could not be isolated and compared. Additionally, this study could have underestimated the cost of nonunion because the treating surgeon may have miscoded subsequent treatment. Although the period of NSAID use could be isolated, no determination was made regarding the specific type of NSAID or the exact duration, frequency, or dosages to establish a dose-dependent relationship. Finally, as data on NSAIDs were derived from Humana patient claims and originated from coding on pharmacy claims, over-the-counter NSAID use was not reported within the database.
Strengths of this study included its longitudinal nature, which allowed for patients to be followed over time and over a large number of providers. Additionally, the volume of patients improved the power of the study. The PearlDiver database has the ability to perform multivariate regression analysis, which can isolate, for instance, the impact of NSAIDs on nonunion when compared with many other risk factors. The use of the CCI also helped account for comorbidity burden.
This study indicated that NSAID exposure in the postoperative period was associated with fracture nonunion, given cross-sectional analysis of long bone fracture and nonunion across the United States. It provided a cost analysis comparing the 1-year reimbursement of the tested fractures with and without subsequent nonunion.
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Fracture and Nonunion Breakdown
|No. (N=8432)||No. of Nonunions (N=448)||Nonunion Percent (5.3%)||No. (N=5310)||No. of Nonunions (N=674)||Nonunion Percent (12.7%)||No. (N=3947)||No. of Nonunions (N=452)||Nonunion Percent (11.4%)|
Nonsteroidal Anti-inflammatory Drug Use and Nonunion Ratea
|NSAID Use POD||SFF||TSF||HSF|
|Nonunion Percent||Relative Risk (CI)||Nonunion Percent||Relative Risk (CI)||Nonunion Percent||Relative Risk (CI)|
|0–30||11.2||2.4 (1.8–3.3)||20.0||2.0 (1.6–2.4)||19.5||1.9 (1.5–2.4)|
|30–60||9.9||2.1 (1.5–3.0)||18.5||1.8 (1.4–2.4)||16.0||1.6 (1.1–2.2)|
|60–90||8.6||1.9 (1.2–2.8)||15.9||1.6 (1.1–2.2)||13.8||1.4 (0.9–2.2)b|
|0–90||10.4||2.4 (1.9–2.9)||18.8||1.6 (1.4–1.9)||17.4||1.7 (1.4–2.1)|
Charlson Comorbidity Index in Union Versus Nonunion
|Fracture Type/NSAID Use||Charlson Comorbidity Index||Pa|
| NSAID use||3.2||3.7||.16|
| No NSAID use||3.4||3.7||.06|
| NSAID use||2.4||2.3||.59|
| No NSAID use||2.1||2.2||.51|
| NSAID use||2.7||3.1||.11|
| No NSAID use||2.8||3.5||.01|
Multivariate Logistic Regression Analysis of Risk Factors for Fracture Nonunion
|Risk Factor||SFF Nonunion Risk||TSF Nonunion Risk||HSF Nonunion Risk|
|OR (95% CI)||Pa||OR (95% CI)||Pa||OR (95% CI)||Pa|
|NSAIDs||1.50 (1.24–1.84)||<.001||1.42 (1.19–1.69)||<.001||1.20 (1.00–1.46)||.05|
|ESRD||1.14 (0.88–1.45)||>.1||0.90 (0.68–1.18)||>.1||1.52 (1.16–2.00)||.01|
|Tobacco||1.04 (0.86–1.26)||>.1||1.45 (1.23–1.70)||<.001||1.37 (1.14–1.65)||<.001|
|PVD||1.33 (1.10–1.62)||<.01||1.37 (1.12–1.67)||<.001||0.97 (0.78–1.19)||>.1|
|Obesity||1.29 (1.05–1.58)||<.05||1.22 (1.02–1.45)||<.001||1.28 (1.05–1.55)||.05|
|DM||1.00 (0.82–1.21)||>.1||0.89 (0.74–1.07)||>.1||0.85 (0.70–1.03)||.1|
|Infection||2.09 (1.63–2.68)||<.001||2.67 (2.20–3.23)||<.001||1.93 (1.45–2.54)||<.001|
|Subtrochanteric Femur Fracture||ICD-9 CODES: 820.22, 820.32
ICD-10 CODES: S72.21XA, S72.21XC, S72.22XA, S72.22XB, S72.23XA, S72.23XB, S72.23XC, S72.24XA, S72.25XA, S72.26XA|
|Tibial Shaft Fracture||ICD-9 CODES: 823.20, 823.22, 823.30, 823.32
ICD-10 CODES: S82.201A, S82.201B, S82.201C, S82.202A, S82.202B, S82.202C, S82.209A, S82.209B, S82.209C, S82.221A, S82.221B, S82.221C, S82.222A, S82.222B, S82.222C, S82.223A, S82.224A, S82.225A, S82.231A, S82.231B, S82.231C, S82.232A, S82.232B, S82.233A, S82.234A, S82.235A, S82.241A, S82.241B, S82.242A, S82.242B, S82.242C, S82.243A, S82.244A, S82.245A, S82.245B, S82.246A, S82.251A, S82.251B, S82.251C, S82.252A, S82.252B, S82.252C, S82.253A, S82.254A, S82.254B, S82.255A, S82.261A, S82.261B, S82.261C, S82.262A, S82.262B, S82.264A, S82.265A, S82.291A, S82.291B, S82.291C, S82.292A, S82.292B, S82.299A|
|Humeral shaft Fracture||ICD-9 CODES: 812.21, 812.31
ICD-10 CODES: S42.301A, S42.301B, S42.302A, S42.302B, S42.309A, S42.309B, S42.311A, S42.312A, S42.321A, S42.321B, S42.322A, S42.323A, S42.324A, S42.325A, S42.331A, S42.332A, S42.333A, S42.334A, S42.335A, S42.341A, S42.342A, S42.343A, S42.344A, S42.345A, S42.351A, S42.351B, S42.352A, S42.352B, S42.353A, S42.354A, S42.355A, S42.355B, S42.356A, S42.361A, S42.362A, S42.363A, S42.364A, S42.365A, S42.366A, S42.391A, S42.391B, S42.392A, S42.392B, S42.399A, S42.399B|
|Subtrochanteric Femur Fracture Fixation||ICD-9-CODES: 79.15, 79.35
ICD-10-CODES: 0QH606Z, 0QH636Z, 0QH646Z, 0QH706Z, 0QH736Z, 0QH746Z, 0QH634Z, 0QH644Z, 0QH704Z, 0QH734Z, 0QH744Z
CPT CODES: 27244, 27245
|Tibial Shaft Fracture Fixation||ICD-9-CODES: 79.16, 79.36
ICD-10-CODES: 0QHG04Z, 0QHG06Z, 0QHG34Z, 0QHG36Z, 0QHH04Z, 0QHH06Z, 0QHH34Z, 0QHH36Z, 0QHH46Z, CPT-27756
CPT CODES: 27758, 27759|
|Humeral Shaft Fracture Fixation||ICD-9-CODES: 79.11, 79.31
ICD-10-CODES: 0PHF04Z, 0PHF06Z, 0PHF34Z, 0PHF36Z, 0PHF46Z, 0PHG04Z, 0PHG06Z, 0PHG34Z, 0PHG36Z
CPT CODES: 24515, 24516|
|Subtrochanteric Femur Nonunion||ICD-9 CODES: 73382
ICD-10 CODES: S72.21XK, S72.22XK, S72.22XM, S72.23XK, S72.24XK, S72.25XK|
|Tibial Shaft Nonunion||ICD-9 CODES: 73382
ICD-10 CODES: S82.201K, S82.201M, S82.201N, S82.202K, S82.202M, S82.202N, S82.209K, S82.221K, S82.221M, S82.222K, S82.222M, S82.224K, S82.225K, S82.231K, S82.231M, S82.231N, S82.232K, S82.235K, S82.241K, S82.242K, S82.245K, S82.251K, S82.251M, S82.251N, S82.252K, S82.261K, S82.261M, S82.261N, S82.264K, S82.291K, S82.291M, S82.292K|
|Humeral Shaft Nonunion||ICD-9 CODES: 73382
ICD-10 CODES: S42.301K, S42.302K, S42.309K, S42.321K, S42.322K, S42.325K, S42.331K, S42.332K, S42.341K, S42.342K, S42.351K, S42.352K, S42.361K, S42.364K, S42.391K, S42.392K, S42.399K|