Delayed union and nonunion of tibial and femoral shaft fractures are common orthopedic problems. Numerous publications address lower extremity long bone nonunions. This review presents current trends and recent literature on the evaluation and treatment of nonunions of the tibia and femur. New studies focused on tibial nonunion and femoral nonunion are reviewed. A section summarizing recent treatment of atypical femoral fractures associated with bisphosphonate therapy is also included.
Key points
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Lower extremity nonunions, particularly of the tibia, have significant impact on both the patient and society.
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Radiographic union score for tibia fractures (RUST) is a method for more objectively describing fracture healing based on plain films.
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Fracture-specific and treatment-related risk factors have been associated with nonunion.
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Patient-related risk factors, both modifiable and nonmodifiable, have been associated with nonunion.
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Evaluating for the presence of infection is extremely important in the treatment of nonunion.
Demographics and economic impact
A retrospective review in the United States of 2006 managed care claims at 24 months after injury in 853 patients with tibial shaft fractures noted a 12% incidence of nonunion. This study also documented the increased costs of tibial nonunions for inpatient and outpatient services, as well as increased costs associated with narcotic usage ( Table 1 ).
| Tibial Nonunion | Tibial Union | |
|---|---|---|
| Inpatient | $7263.96 | $2868.56 |
| Outpatient | $1300.95 | $490.14 |
| Narcotics | $1,0300.95 | $605.44 |
According to one retrospective review of a prospective database collected by two level 1 trauma centers, patients with delayed union or nonunion also have significant lost productivity resulting in indirect costs. Records of 489 patients with 260 femur fractures and 282 tibia fractures were reviewed. Of the 423 patients who went on to known healing outcome, 138 (25%) experienced delayed union or nonunion. Seventy-two percent of patients with united fractures returned to work at 1 year, compared with 59% of patients with a delayed union or nonunion.
Definition
Fracture healing is assessed by a combination of clinical and radiographic criteria. Clinical markers of union include resolution of pain with weight bearing and radiographs that show progressive healing and cortical bridging of fracture lines.
The development of the radiographic union score for tibia fractures (RUST) is an attempt to objectively determine the extent of healing by scoring the degree of fracture healing from each of the 4 cortices, as viewed from anteroposterior and lateral radiographs. A recent modification of the initial scoring system differentiates bridging and nonbridging callus in an attempt to improve intraobserver agreement and the accuracy of predicting union ( Table 2 ). Use of the scoring system results in a score ranging from 4 (no callus any of 4 cortices) to 16 (complete remodeling of all 4 cortices). A summary of the initial findings comparing the readings of academic orthopedic traumatologists defines that healing corresponds to bridging callus on at least 3 cortices. However, these findings remain to be correlated with clinical outcomes.
| Score | Radiographic Description |
|---|---|
| 1 | No evident callus |
| 2 | Callus present |
| 3 | Bridging callus |
| 4 | Remodeling – no fracture visible |
The score for each individual cortex is summed yielding a score between 4 and 16.
In addition to the RUST, computed tomography is helpful for evaluating suspected nonunions.
A nonunion is generally defined as radiographic evidence of nonprogression of healing for at least 3 months, or lack of healing by 9 months since injury. Although the clinical and radiographic criteria discussed above are routinely used by most surgeons, there is a lack of consensus as to the real-time functional definition of nonunion. It can be agreed, however, that nonunion is the cessation of both endosteal and periosteal healing responses without bridging callus.
Classification
The classification of nonunions has not changed, and both the biological and mechanical characteristics must be evaluated for each case. The most important biological factor is the presence or absence of sepsis. Mechanical characteristics are frequently described as
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Hypertrophic-exuberant callous but not united, indicating a lack of stability but good biology;
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Atrophic-absent or minimal callous, which indicates a poor biological healing response;
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Oligotrophic-incomplete callous formation, which completes the spectrum between hypertrophic and atrophic.
Patient-related risk factors
Metabolic, Endocrine, and Other Systemic Factors
The importance of bone metabolism is increasingly recognized as a key component of fracture care. Brinker and colleagues examined the results of endocrinology referrals for 37 patients with nonunion. Criteria for referral included an unexplained nonunion without obvious technical error or other cause (26 patients), a history of multiple low-energy fractures with at least 1 progressing to a nonunion (8 patients), or nonunion of a nondisplaced pubic rami or sacral alar fracture (3 patients). They found that 31 of 37 patients (84%) who met screening criteria had a new diagnosis of a metabolic or an endocrine abnormality. Twenty-four patients (65%) had more than 1 metabolic or endocrine abnormality. Eight patients (22%) healed with medical treatment alone. Among the new diagnoses, 87% had a vitamin D deficiency or abnormal calcium regulation, 24% had thyroid dysfunction, 22% had reproductive hormone dysregulation, 13% had pituitary dysfunction, and 11% had parathyroid dysfunction.
25-Hydroxyvitamin D (25[OH]D) deficiency and insufficiency has been well documented in orthopedic trauma patients. Prevalence is high, as a majority (66%–86%) of patients have levels deemed insufficient (<30 ng/mL), whereas approximately half (40%–53%) are deficient (<20 ng/mL). Dark-skinned individuals are disproportionately affected, as are those between the ages of 18 and 60 years versus older or younger individuals.
The ramifications of insufficiency or deficiency on fracture healing and risk of nonunion are still unknown. A recent review notes that fracture may result in higher interosseous vitamin D metabolites and lower serum vitamin D metabolites; however, this finding is not consistent among studies. The prevalence of vitamin D deficiency in nonunion patients is also debated, as at least one small case-control study demonstrates higher prevalence of deficiency in nonunion patients, whereas another study seems to refute this. The effect of vitamin D supplementation on fracture healing is unclear; although animal studies demonstrate promising results, the few small human studies do not consistently demonstrate benefit. Thus, the role of vitamin D supplementation in fracture healing and nonunion treatment remains to be elucidated.
The medical comorbidities of the patients are correlated with increased risk of nonunion. Insulin-dependent and insulin-independent diabetes, as well as rheumatoid arthritis, have been linked to nonunion. HIV infection seems to correlate with nonunion, but data are limited.
Tobacco
Smoking may be the most well-documented modifiable patient factor correlated with nonunion and longer healing times. Meta-analysis of high-quality studies confirm the increased risk of nonunion for all fractures, but this seems to be particularly evident for open fractures and tibial fractures. Smoking is also associated with a trend toward increasing the time to union and increasing the rates of superficial and deep infections. These findings have been confirmed prospectively.
The potential for smoking cessation programs to improve fracture healing is unknown. The only published, prospective, randomized study demonstrated a trend toward lower superficial wound infections in the acute phase of postoperative fracture care but did not follow patients long enough to document the effect of smoking cessation on union rates. Of the 287 eligible patients who met the inclusion criteria, 182 (63%) declined to participate; thus patient compliance with smoking cessation programs in the setting of fracture care remains unknown. No studies have evaluated the isolated effect of smoking cessation on established nonunions.
Medications (Nonsteroidal Anti-inflammatory Drugs)
A link between nonsteroidal anti-inflammatory drugs (NSAIDs) and nonunion has been demonstrated in animal studies. This has been shown for both selective and nonselective cox inhibitors, although the effects may be reversible after short-term treatment. Human studies have been slow to follow. An association between NSAID use and nonunion has now been shown in a small retrospective study of femoral nonunion, a large retrospective level 1 trauma center study of long bone fracture nonunions, and a large retrospective national database review of both long- and small-bone fracture nonunions.
Treatment
Nonsurgical Treatment Adjuncts
Ultrasound
Few small randomized controlled trials of low intensity pulsed ultrasound (LIPUS) exist. One study demonstrated shorter healing times for conservatively treated acute tibia fractures, whereas another did not find any difference with acute tibias treated with reamed and statically locked intramedullary nailing. Use of LIPUS for established nonunion healing is purported to promote healing in 73% to 86% of cases ; however, these are retrospective studies without control groups, and no randomized trials exist.
Teriparatide
Teriparatide (rhPTH 1-34) has been demonstrated to result in clinically significant radiographic and functional healing of pelvic fractures in elderly women in a quasi-randomized clinical trial. Promising results for use in nonunion cases have been presented in case reports; however, no randomized trials exist to date.
Lee and colleagues presented a series of 3 nonunion cases, 1 femoral shaft fracture treated by previous intramedullary nail, 1 distal femur fracture treated by open reduction and internal fixation, and 1 femoral neck fracture treated by closed reduction and internal fixation with cannulated screws. All 3 cases were without any identifiable risk factors or infection, and all 3 achieved radiographic union with PTH and no further surgery within 3 months after start of treatment.
A similar case of an atrophic humeral shaft fracture nonunion, previously treated by flexible nails, has been presented. The only identifiable risk factor in that case was a 3-week course of NSAIDs during the early treatment. The fracture demonstrated complete healing within 3 to 5 months of PTH treatment without further surgery. This same group reported successful treatment of a previously nonoperatively treated atrophic humeral shaft nonunion in a smoker with multiple psychiatric disorders and poly-substance abuse. PTH treatment alone resulted in union after 4 months.
Preoperative Assessment
Once a nonunion has been identified, thorough assessment of possible causes should be performed. The first step is to assess the initial treatment. Assessment of the reduction, choice of fixation, fracture characteristics, and condition of soft tissues should be assessed in all nonunion cases. If the fracture was open, the adequacy of debridement and loss of soft tissues should be analyzed.
A thorough medical history should be obtained, particularly in diabetics who require blood sugar and A1C laboratory assessment. Their history should be explored for rheumatoid arthritis or other autoimmune disorders, HIV, renal, respiratory, or any other significant chronic disease.
The past medical history should include any previous history of wound problems; a history of bisphosphonate use or NSAIDs administration; and social factors including smoking and alcoholism; and social barriers that imply difficulty in access and follow-up to medical care.
All nonunion patients should have their vitamin D level assessed. Consideration should also be given to obtaining laboratory values of calcium, thyroid, parathyroid, and reproductive hormone, as these are also common abnormalities. Referral to an endocrinologist may be warranted.
The possibility of infection should be assessed, with the patient’s history and laboratory values, including white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels. Even with a negative history and laboratory workup, intraoperative cultures from multiple sites should be taken from all nonunion cases to detect occult infections. Limited data demonstrate that polymerase chain reaction (PCR) of intraoperative samples may be warranted when available to the operating surgeon.
The applicability and role of a trial of nonoperative treatment should be assessed and discussed with the patient. This may vary on a case-specific basis, and may include correction of risk factors such as diabetes, smoking, and endocrine abnormalities. The use of nonsurgical adjuncts such as ultrasound or PTH may also be applicable in certain cases either before or in conjunction with surgery.
Infection
Diagnosis of infection
For surgical planning purposes, the possibility of infection requires preoperative evaluation in all nonunion cases.
Inflammatory laboratory values
The use of the WBC count, the ESR, and the CRP levels are accurate predictors of infection in nonunions. Stucken and colleagues demonstrated that the likelihood of infection increases with each additional positive test. Based on their analysis, the predicted probabilities for 0, 1, 2, and 3 risk factors were 20%, 19%, 56%, and 100%, respectively. Their study also documented that expensive nuclear bone scans did not improve the predictive value of the WBC, ESR, and CRP.
Tissue culture
Intraoperative cultures remain the gold standard for diagnosing infections and the isolation of pathogenic organisms at the site of nonunions. Neither superficial swabbing nor needle biopsy is sufficient for the diagnosis or identification of pathogenic organisms. Perry compared intraoperative superficial swabs with intraoperative needle biopsy and found that swabbing of wounds and needle biopsy identified organisms in only 55% to 62% of cases. In 10 cases of tibial nonunion with latent infection, as identified by intraoperative cultures, needle biopsy failed to result in any organism in 9 (90%) cases.
Harvest of tissue from multiple culture sites of suspected or known infections is recommended. Patzakis and colleagues demonstrated the frequent polymicrobial nature of traumatic osteomyelitis in a series of 30 patients. Using aerobic, anaerobic, and fungal cultures of specimens harvested from the sinus track, purulent fluid, soft tissue, bone obtained from curettage, and the bed of the involved bone, multiple organisms were identified in 21 (70%) patients. Eleven patients (37%) had more than 3 organisms present.
Polymerase Chain Reaction
The role of biofilms has come to light in recent years, and this characteristic of pathogenic organisms, and the difficulty in culturing biofilm organisms may make even intraoperative cultures less reliable. In the near future, PCR of intraoperative tissue may become the standard of care. Palmer and colleagues compared intraoperative culture and molecular examination of harvested tissues via PCR of 34 nonunions. PCR assessed for the presence of bacterial 16S and 18S rDNA, and this was confirmed by fluorescent in situ hybridization. Eight cases (24%) were both culture positive and PCR positive, whereas 22 cases (65%) were culture negative and PCR positive. Only 4 cases (12%) were negative by both methods. Similar to the findings of Patzakis, 21 of 30 infected cases (70%) were PCR positive for multiple organisms. Although this method is highly sensitive, it is not routinely available to most surgeons.
Treatment of Infected Nonunions
Operative treatment of infected nonunions requires adequate debridement of the nonunion site, appropriate fracture stabilization, and bone grafting when necessary. Both single- and multiple-staged procedures have been proposed.
One case series reviewed the treatment of 42 infected long bone nonunions. The investigators recommended single-stage debridement and bone grafting for nondraining quiescent infections and staged debridement and bone grafting for active infections. They also recommended fixation and bone grafting for gaps up to 4 cm, with distraction osteogenesis for gaps over that threshold.
A review of published nonunion case series was unable to make recommendations for either single- or multiple-staged procedures. They found single-stage procedures to result in union in 70% to 100% of cases, with persistent infection in 0% to 55%. Similarly 2-staged strategies resulted in union in 66% to 100% of cases with persistent infection in 0% to 50%. They did, however, find that the use of an antibiotic-eluting device decreased persistent infection in planned staged debridement with secondary bone grafting. Cases with debridement and secondary bone grafting alone resulted in union in 75% to 100% of cases with 0% to 60% persistent infection, whereas in cases with debridement, antibiotic device placement and secondary bone grafting resulted in union in 93% to 100% of cases with 0% to 18% persistent infection. Thus, although it is unclear if single- versus multiple-staged procedures are superior, if delayed bone grafting is planned, interim placement of an antibiotic-eluting device is beneficial to both healing and persistent infection.
Bone grafting: iliac crest bone graft versus reamer irrigator aspirator
Although iliac crest bone graft (ICBG) is the traditional biological adjuvant, the reamer irrigator aspirator (RIA) has emerged as an alternative for autograft harvest. The device allows a method of bone graft harvest from the intramedullary canal of the femur or tibia that rivals the gold standard ICBG in terms of both volume and osteogenic potential, while potentially decreasing donor site morbidity. The potential for unique complications exist, including the risk of femoral neck fracture and shaft cut out with poor technique because of the sharp reamers. The risk of postoperative fracture seems to be increased when RIA is used in patients with thin cortexes or with overaggressive harvesting and/or reaming by the surgeon. Significant blood volume loss caused by prolonged aspiration has also been reported.
A recent review of the literature noted that RIA harvest has relatively low complication rates when there is adequate preoperative planning and a good technique is used. Four of 233 patients (1.7%) reported chronic pain. There were 4 fractures (1.7%) and 4 breaches of the anterior cortex (1.7%) that did not lead to other fractures, 1 violation of the knee joint, 1 vascular injury, but no nerve injuries. One episode of bradycardia and hypotension caused by prolonged aspiration led to a volume loss requiring transfusion. These investigators also noted that one case with excessive reaming of the femoral neck could have been avoided by use of a lateral entry point rather than via the piriformis. A review of ICBG from the anterior iliac crest (AIC) and posterior iliac crest (PIC) in that same article noted 204 of 3180 (6.4%) and 164 of 1909 (8.6%) of AIC and PIC patients reported chronic pain, respectively. Sensory disturbances surrounding the harvest site were the second most common complication with 5.2% and 7.3% of AIC and PIC patients reporting them, respectively.
Ex-vivo transcriptional and histologic analysis has demonstrated similar expression of osteogenic genes and stem cell populations between RIA and ICBG samples. A randomized controlled trial of RIA-harvested graft versus AIC or PIC-harvested ICBG demonstrated similar union rates and statistically, but likely not clinically, significant increased volume of bone graft and reduced harvest time with RIA compared with ICBG. Patients also reported less pain at the donor site with RIA compared with ICBG.
Bone grafting: bone morphogenetic protein
Although recombinant human bone morphogenetic protein-2 (BMP-2) may provide a benefit in terms of reduced need for bone grafting or secondary procedures for acute Gustilo-Anderson type-III open tibial fractures, it may not have a substantial role in nonunion treatment. A retrospective review has demonstrated that ICBG autograft results in a nonstatistically significant trend toward improved healing in established nonunion, compared with BMP-2 combined with allograft cancellous bone chips (85.1% vs 68.4%, respectively). According to one retrospective review of a prospective database, there is no apparent advantage for use of BMP-2 with ICBG autograft versus ICBG autograft alone in treatment of established nonunion. Thus, there is likely no role for BMP-2 when a suitable high-quality autograft such as ICBG or RIA graft is available.
In a single randomized controlled trial, recombinant human osteogenic protein-1 (rhOP-1 or BMP-7) demonstrated results equivalent to autograft (type not specified) (81% vs 85%) in terms of radiographic and clinical healing at 9 months, and with a similar need for further surgical treatment (5% vs 10%). The BMP-7 group consisted of a higher proportion of atrophic nonunion than the bone graft group (65% vs 41%). A small prospective nonrandomized comparative study of the direct medical costs associated with BMP-7 versus ICBG noted higher initial costs associated with BMP-7 treatment, in large part because of the cost of BMP-7.
Specific Treatment of Tibial Shaft Fractures
Tibial nail dynamization and exchange nailing
Exchange nailing and nail dynamization are two common methods for treating aseptic nonunion of the tibia. Dynamization is performed by removing the interlocking bolts that are most distant from the fracture site, and it relies on weight bearing to compress the fracture site; theoretically this stimulates union by mechanical compression. Exchange nailing involves reaming the intramedullary canal and using a larger nail. The reaming is believed to biologically stimulate fracture healing by depositing the reamings as a local bone graft and also by generating a revascularization of the fracture site. In addition, insertion of a larger nail improves the stability of the fracture site. Two recent studies have re-addressed these techniques. Litrenta and colleagues retrospectively compared a series of 194 tibial nonunions treated with either dynamization (97 patients) or exchange nailing (97 patients). High union rates were achieved in both groups with dynamization and exchange nailing resulting in 83% and 90% union, respectively. The investigators noted that gaps of greater than 5 mm were associated with a 78% union rate compared with a 90% union rate with no gap at the fracture site. Because this was a retrospective study, the indications for dynamization or exchange nailing were based on the preferences of the treating surgeons and do not clearly establish either the indications or the benefits of one procedure over the other.
Swanson and colleagues treated 46 tibial nonunions with exchange nailing and achieved a success rate of 98%. This protocol included reaming, increasing the nail diameter by at least 2 mm, static interlocking, and low incidence of fibulectomy. Achieving cortical contact with a minimum of 50% cortical contact was an important inclusion criterion in this series. All cases were statically locked, but other series have recommended dynamic locking at the time of exchange nailing, so no conclusions can be made regarding the benefits of static versus dynamic interlocking at the time of exchange nailing.
Although dynamization and exchange nailing can be effective in the treatment of delayed and nonunion, waiting to intervene is also important. The SPRINT trial (Study to Prospectively Evaluate Reamed Intramedullary Nails in Patients with Tibial Fractures) documents that nonunion rates and secondary events are significantly reduced by allowing a minimum 6-month postoperative period for tibial fractures to heal after intramedullary nailing. With this protocol, the trial observed only a 4.6% rate of exchange nailing or bone grafting for treating nonunions. Although the study was initially designed to compare the relative merits of reamed versus nonreamed nailing techniques for closed and open fractures, the greatest benefit seems to be establishing that, by avoiding “fracture site gaps” at the time of intramedullary nailing, most fractures will progress to union, with a slight advantage for reamed nailing in closed tibia fractures.
While waiting to intervene in many tibia fractures may be appropriate, this approach may cause some patients unnecessary and prolonged morbidity. Yang and colleagues have shown that experienced orthopedic trauma surgeons can use mechanism of injury and radiographic parameters at 3 months to determine patients who will ultimately proceed to nonunion. It is to be hoped that future investigation will clarify the fracture, treatment, and patient characteristics that predict nonunion and lead to early effective intervention.
Specific Treatment of Femoral Shaft Fractures
Nonunion of femoral shaft fractures treated by intramedullary nailing is uncommon. Union rates as high as 98% to 99% have been reported with reamed intramedullary nailing, which is the standard of care for closed fractures of the femoral shaft. Nonunion has been associated with open fractures and delayed weight bearing, as well as Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association (AO/OTA) fracture classification.
Femoral Exchange Nailing
Exchange nailing seems to be successful in the treatment of femoral nonunions. Swanson and colleagues recently reported 100% union rate with exchange nailing of aseptic nonunions. This technique was used even with atrophic nonunions (7/50) and bone grafting was not used. Treatment was focused on increasing the stability of the construct by placing an intramedullary nail at least 2 mm larger than the original one. The method of intramedullary nail placement (antegrade vs retrograde) was also chosen to optimize stability in meta-diaphyseal fractures with short segments, as 6 exchange nailings were performed in the opposite direction of the original intramedullary nailing.
Plating/Bone Grafting over a Nail
Exchange nailing may not be as successful with meta-diaphyseal nonunions. Hakeos and colleagues have recently described, in a very small series, open plating of proximal and distal meta-diaphyseal fractures while leaving the intramedullary nail in place. These investigators report a 100% union rate with this technique. Bone grafting was used with this technique of open plating. A second small series (7/11 nonunions were of the femur) also demonstrated a 100% union rate with plating and bone grafting around an intramedullary nail. Unfortunately, neither of these small studies had a comparison group, so determining the effectiveness of the plating and bone grafting individually is impossible.
Atypical Femoral Fractures and Bisphosphonates
Osteoporosis was believed to be a risk factor for delayed healing and nonunion; however, early studies were not age matched. Osteoporosis and decreased bone density are not risk factors for nonunion when matched for age and sex. These findings are confirmed in a large retrospective national database review of both long- and small-bone fracture nonunions. Thus, it seems that nonunion in advanced age is more significantly related to the healing capacity of bone, which declines with age, rather than trabecular density.
Bisphosphonates are a major treatment of osteoporosis and prevent bone loss by inhibiting osteoclastic mediated bone resorption. However, this effect also inhibits the osteoclastic activity during normal bone healing and seems to increase the risk of nonunion. In one study of 17 femur fractures in 15 patients treated with bisphosphonates for an average of 7.8 years, 7 of 12 (58%) subtrochanteric and midshaft femoral fractures treated with intramedullary nailing required secondary surgery. Revisions varied from dynamization, to exchange nailing, to conversion to blade plate. Another study of 41 atypical femur fractures treated by intramedullary nailing in 33 patients with a history of bisphosphonate treatment for an average of 8.8 years demonstrated that, although 98% of patients appeared to have radiographically united, only 66% of patients were pain free at the fracture site at 1 year. A third retrospective study of 33 consecutive female patients presenting with atypical subtrochanteric femur fractures after bisphosphonate therapy demonstrated 6.7 months to full weight bearing, 10.9 months to radiologic union, a revision rate of 38%, and an implant failure rate of 29% in 21 patients treated with extramedullary implants, versus 8.2 months to full weight bearing, 7.7 months to radiologic union, 22% revision rate, and 11% implant failures in 9 patients treated with intramedullary implants ( Table 3 ).
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