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Management of Radiation-associated Fractures

Cannon, Christopher P. MD; Lin, Patrick P. MD; Lewis, Valerae O. MD; Yasko, Alan W. MD, MBA

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Journal of the American Academy of Orthopaedic Surgeons: September 2008 - Volume 16 - Issue 9 - p 541-549
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Abstract

High-dose radiation (≥50 Gy) is used to treat a variety of disorders, including bone and soft-tissue sarcomas, lymphomas, gynecologic tumors, prostate cancer, rectal cancer, and, occasionally, benign bone and soft-tissue tumors (eg, giant cell tumor of bone and desmoid tumors, respectively).1-3 Radiation is known to have a deleterious effect on the surrounding tissues, including bone. The effect of radiation on bone has been labeled “radiation osteitis.”4 The pathogenesis of radiation osteitis is a combination of direct cell injury and radiation-induced vascular injury.5 Osteocytes, osteoblasts, osteoclasts, and dividing mesenchymal cells all can be injured or killed by radiation.5-7 Further, the small blood vessels of the Volkmann canals and haversian vessels may demonstrate endothelial injury, with eventual fibrosis of the vessels. Fibrosis of the periosteum and endosteum can also occur.5

The risk and severity of the effect of radiation on bone is dependent on several factors, in particular the total radiation dose, the dose per fraction, the total volume of tissue irradiated, and the schedule of treatment.8,9 The multiple factors involved in radiation-associated fractures make it difficult to discern a clear threshold dose of radiation that can result in bone fracture; however, clinically, fractures are seldom seen at doses <50 Gy.1-3

Management of fractures caused by radiation is generally considered to be difficult, and relatively little has been published on the subject. Lin et al10 reported on 12 femur fractures that occurred after irradiation. At a mean 37-month follow-up, only four fractures had healed; union was delayed beyond 12 months in all four cases. Helmstedter et al1 reported a 45% nonunion rate in a series of 20 radiation-associated fractures.1

Clinical Presentation

Most series report fractures occurring primarily with radiation doses >50 Gy.1-3 In their series of 20 radiation-induced fractures following radiation and surgery for soft-tissue sarcomas, Helmstedter et al1 reported a mean radiation dose of 58 Gy. In a series of nine femur fractures following surgery and radiation for soft-tissue sarcomas of the thigh, Lin et al3 reported a mean radiation dose of 56 Gy, although one fracture occurred with only 30 Gy radiation. In a series of 27 fractures following radiation and surgery for lower extremity soft-tissue sarcomas of the thigh, Holt et al2 reported that 24 of 27 fractures were sustained following ≥60 Gy of radiation (89%). The other three fractures occurred with 50 Gy radiation. Thus, most patients who present for treatment of a radiation-associated fracture will have been exposed to ≥50 Gy of radiation.

The time from radiation to fracture can vary widely. In one study, fractures occurred at a mean of 40.5 months following radiation.1 Similarly, Holt et al2 noted that fractures occurred at a median of 41 months, although the time to fracture ranged from 12 to 153 months. In their series of 12 radiation-induced femur fractures, Lin et al10 noted that fractures occurred at a median of 30 months (range, 4 to 229 months). In a series of five radiation-associated fractures, Cannon et al11 found that fractures occurred at a median of 5.2 years following radiation (range, 1.7 to 25 years). Although the specific time to fracture can vary widely, it generally occurs ≥1 year after completion of radiation treatment.

Radiation-associated fractures typically occur with minimal or no trauma.1-3,10,11 Additionally, unlike the situation with traumatic fractures, patients often report relatively little pain. The patient may not be aware that a fracture has occurred until it is detected radiographically.11

Proposed risk factors for the development of a radiation-associated fracture include periosteal stripping during resection of soft-tissue sarcomas, neoadjuvant chemotherapy, female sex, anterior thigh location of soft-tissue sarcoma, inadequate surgical margins, higher-dose radiation, and radiation to the entire circumference of the bone.1-3,11 Although some controversy exists regarding the specific risk factors associated with radiation-induced fractures, most investigators agree that higher-dose radiation and periosteal stripping constitute distinct risk factors.1-3,11 Also, any variable that is associated with lower bone mass (ie, female sex, adjuvant chemotherapy, osteoporosis) likely places the patient at higher risk for a fracture.1-3,11

The role of prophylactic internal fixation following combined surgical excision and radiation for soft-tissue sarcomas, typically in the form of an intramedullary (IM) nail, has been investigated. 1,3,11 The incidence of fracture following combined radiation and surgery for soft-tissue sarcomas ranges from 1.2% to 6.3%, although the likelihood is greater for patients with the aforementioned risk factors.1-3,11-13 Patients with several risk factors should be considered for prophylactic fixation with an IM nail when a long bone is involved.1,3,10

Clinical Evaluation

The soft tissues should be carefully examined. A patient may have evidence of radiation changes to the skin and soft tissue. These changes vary from mild hyperpigmentation of the skin to marked fibrosis of the entire soft-tissue envelope (Figure 1). Clinical evidence of prior radiation should alert the surgeon to the possibility of wound healing complications following surgery. Several studies have demonstrated high wound complication rates, ranging from 22% to 44%, associated with surgery following radiation.11,14-16

Figure 1
Figure 1:
Photograph of a 55-year-old man following preoperative radiation (50 Gy) and surgical resection of a medial arm soft-tissue sarcoma. Hyperpigmentation and fibrosis characteristic of mild radiation effects are evident.

From a radiologic standpoint, most radiation-associated fractures are the result of a low energy source and exhibit relatively minimal displacement1,10 (Figures 2 and 3). Most fractures have either a transverse or a short oblique pattern.1,10 In addition to the fracture, the bone typically demonstrates evidence of radiation osteitis (Figures 3 and 4). The radiographic hallmark of radiation osteitis is heterogeneous bone density with areas of osteolysis adjacent to thickened, coarse trabeculae.7,17

Figure 2
Figure 2:
Anteroposterior radiograph demonstrating a minimally displaced atraumatic subtrochanteric fracture in a 49-year-old woman. This image was taken 2 years after the patient was treated with preoperative radiation (50 Gy) and surgical resection for a large anterior thigh malignant fibrous histiocytoma.
Figure 3
Figure 3:
Lateral femoral radiograph demonstrating an incomplete diaphyseal fracture (arrow) in a 47-year-old woman who had been treated with preoperative radiation (50 Gy) and surgical resection 27 months earlier for a large malignant fibrous histiocytoma of the thigh. Mixed areas of sclerosis and osteolysis are also present, which are representative of radiation osteitis.
Figure 4
Figure 4:
Anteroposterior radiograph of the proximal femur in a 45-year-old woman with a history of a Ewing sarcoma of the femur that was managed with chemotherapy and radiation (60 Gy) 26 years previously. The radiograph demonstrates the coarsened trabeculae and mixed areas of sclerosis and osteolysis that are characteristic of radiation osteitis.

Management

Nonsurgical

In general, nonsurgical management of radiation-associated long-bone fractures is neither effective nor recommended.1-3,10,11 Although published series on nonsurgical management of these fractures are lacking, given the healing times of >1 year even with surgical intervention, it is presumed that nonsurgical management would require long periods of immobilization and restricted weight bearing before fracture healing could be expected to occur.1,10,11

However, fractures of the pelvis and sacrum are treated nonsurgically. 18-21 These fractures are known to occur following radiation for gynecologic, prostate, and rectal cancers.19-23 Fractures that occur as a result of normal physiologic stress on bone with deficient elastic resistance (secondary to prior radiation in this setting) have been termed insufficiency fractures.20 Recent published series have shown an incidence of pelvic insufficiency fractures following pelvic radiation ranging from 1.7% to 11.4% and occurring at a mean of 6 to 29 months following radiation.19-21,24

Some fractures are evident on plain radiographs; however, additional imaging is often required to establish the diagnosis.18,21,23,25-28 Magnetic resonance imaging is quite sensitive in detecting occult fractures and can also help distinguish between insufficiency fractures and metastatic bone disease18,25 (Figure 5). Computed tomography and bone scintigraphy also have been used successfully to establish the diagnosis of insufficiency fracture.23,26-28

Figure 5
Figure 5:
Imaging studies of a 70-year-old woman with pain in the low back and pelvis following treatment of cancer of the sigmoid colon with surgery and radiation (50 Gy) 2 years previously. A, Anteroposterior radiograph demonstrating evidence of osteopenia but no distinct fractures. B, Axial post-contrast fat-suppression T1-weighted magnetic resonance imaging scan of the sacrum demonstrating increased signal of the bilateral sacral ala, which is consistent with radiation-associated insufficiency fracture.

Biopsy is generally not recommended because of the high probability of osteonecrosis and the low diagnostic efficacy.20,21,29,30 Nonsurgical management of pelvis and sacral insufficiency fractures generally consists of an initial period of enforced bed rest and analgesics (eg, nonsteroidal anti-inflammatory drugs) until the initial presenting symptoms subside.20-22,27 Mobilization may then commence, with limited weight bearing with a walker. Clinical symptoms (ie, pain, immobility) have been reported to resolve within 1 to 20 months.20,21

Surgical

Surgical management is indicated for most radiation-induced fractures. 1-3,10,11 However, these fractures remain difficult and problematic to treat. The nonunion rate is high in all series, generally >50%,1,10 and healing times are often quite long for the fractures that eventually unite. Lin et al10 were able to obtain union in only four of nine femur fractures, all of which required >12 months to heal. In the study by Helmstedter et al,1 mean time to union was 18 months for the femur fractures that eventually united. In addition, multiple procedures are often required, including supplemental bone grafting, vascularized fibula grafting, exchange nailing, and potential resection of the fracture site and conversion to a large oncologic endoprosthesis.1-3,10,11

Long-bone Fracture

Fractures of the long bones (ie, femur, humerus, tibia) generally should be treated with IM nailing.31 The entire bone can be protected with the use of an IM nail. Additionally, the IM nail is a load-sharing device that can be inserted through relatively small incisions. This is important when the soft-tissue envelope appears to be at high risk for a wound complication. Protection of the entire bone is important because even though the fracture may be limited to a small segment of bone, the area of compromised bone is often much larger.1,2 Plate fixation places the bone at risk for fracture outside the plate and requires a larger incision, with the attendant risk of wound complications. A large-diameter IM nail should be used when possible. Radiation-associated fractures often heal slowly; thus, the IM nail often will bear a significant amount of the load for a long period. A large-diameter nail reduces the risk of hardware failure. The IM nail should be left in situ. Even in the presence of fracture healing, the bone still has elements of the previous radiation injury and is at high risk for refracture.

A difficult decision is whether to use bone graft at the time of the index procedure or even proceed with a vascularized fibula graft (VFG). The nonunion rate is high enough to justify either autologous bone grafting or VFG at the index procedure. However, because of the increased surgical morbidity with these adjuvant procedures, most reported cases of surgical management of long-bone fractures describe an initial attempt at closed nailing, reserving supplemental bone grafting for patients in whom such treatment fails.1,10

Periarticular Fracture

Periarticular fracture, which includes fracture of the proximal humerus, femoral neck and proximal femur, and distal femur, generally should be treated with an arthroplasty procedure. Attempts at open reduction and internal fixation (ORIF) with plate fixation leave large portions of bone unprotected. Also, given the high nonunion rate of radiation-associated fractures, the risk of eventual plate failure is high. Most of the periarticular sites are amenable to an arthroplasty procedure that allows resection of some of the involved bone as well as protection of the rest of the bone with a long-stemmed component.

Proximal humerus fractures at or above the surgical neck can be treated with a conventional humeral head replacement. For fractures of the proximal humerus that are distal to the surgical neck, resection of the proximal humerus fragment and reconstruction with a proximal humerus oncologic endoprosthesis should be considered. Even though shoulder function is often limited following endoprosthetic reconstruction of the proximal humerus, the procedure provides excellent pain relief and preserves normal elbow and hand function.32 Similarly, radiation-associated fractures of the distal humerus and proximal ulna, although uncommon, should be treated with resection of the fracture fragment, reconstruction with a distal humerus or proximal ulna replacement, and total elbow arthroplasty (Figure 6).

Figure 6 A
Figure 6 A:
, Lateral radiograph demonstrating a radiation-associated fracture of the proximal ulna with significant radiation osteitis in a 78-year-old man who presented with elbow pain 43 months following surgery and radiation (60 Gy) for an antecubital fossa malignant fibrous histiocytoma. B, Lateral postoperative radiograph following resection of the proximal ulna and reconstruction with an oncologic total elbow arthroplasty. The patient obtained painless active range of motion of 10° to 120°.

Radiation-associated fractures of the proximal femur should be managed with total hip arthroplasty (THA). Femoral neck fractures can be treated with a standard cemented stem. Because of the radiation injury to the bone, use of a porous ingrowth stem should be avoided.33 Intertrochanteric fractures are normally managed with a sliding hip screw device for nonpathologic fractures; however, they can be mobilized more quickly and safely with a calcar-replacing prosthesis, as has been shown in the salvage of failed intertrochanteric hip fractures.34,35

Management of the acetabulum following local radiation can be somewhat problematic. In patients in whom the acetabulum was in the radiation field, as is often the case, the bone will also exhibit radiation injury. In that setting, THA should be considered, rather than hemiarthroplasty. 36,37 The diseased acetabulum may not hold up to the stresses placed on it by the endoprosthesis, resulting in a >50% incidence of protrusio acetabuli.37 Failure rates of 44% to 52% have been reported in previous clinical series of both cemented and cementless acetabular components in irradiated hips.37-39 In a more recent study, however, no failures were shown in 66 THAs using cementless acetabular components in patients with a history of pelvis irradiation for prostate cancer. 40 Early experience with tantalum acetabular components seems to be favorable, with no failures reported in 12 THAs following pelvic irradiation at a mean follow-up of 31 months.41

Fractures of the subtrochanteric region of the proximal femur pose a treatment dilemma. More distal fractures may be well managed with a reconstruction nail. However, more proximal fractures with a short proximal fragment may be better managed with resection of the proximal femur and reconstruction with a proximal femoral oncologic endoprosthesis (Figure 7). Successful salvage of proximal femoral bone loss, recalcitrant nonunions, and radiation-associated fractures with a proximal femoral replacement has been described.35,42-44

Figure 7 A,
Figure 7 A,:
Anteroposterior (AP) hip radiograph demonstrating a displaced subtrochanteric fracture in a 70-year-old woman who had been treated with preoperative radiation (50 Gy) and surgical resection 41 months previously for a malignant fibrous histiocytoma of the proximal thigh. B, Postoperative AP radiograph following resection of the proximal femur and reconstruction with an oncologic endoprosthesis. The patient had painless hip motion postoperatively, although she ambulated with a walker because of hip abductor weakness.

Fixation of supracondylar fractures in the distal femur also can be challenging. Slightly more proximal fractures can be treated with a long antegrade IM nail to obtain distal interlock fixation. However, a fracture with only a very distal fragment remaining should be treated with resection of the distal fragment and reconstruction with a distal femoral replacement total knee arthroplasty. As with the proximal femur, endoprosthetic replacement has been reported to be a successful salvage technique for difficult distal femur fractures.35,45-48

Expendable Bones

Expendable bones (eg, fibula, clavicle, ribs) are those that can be resected and left unreconstructed without markedly compromising limb function.49 The clavicle is the bone most involved with radiation-associated fractures; it may receive significant radiation from treatment of head and neck tumors as well as of breast cancer. As with nonpathologic fractures, ORIF of the clavicle may be problematic. The soft-tissue envelope at this site is limited, and wound complications, symptomatic hardware, and nonunion are common.

Because of the difficulty in obtaining bony union in the clavicle, clinical series have recommended claviculectomy or resection of the pseudarthrosis site. Wang et al50 described partial claviculectomy for the treatment of an established nonunion secondary to a radiation-induced fracture in two patients. Following this simple procedure, both patients remained comfortable, with no further complaints. Similarly, Spar51 reported good clinical outcome following total claviculectomy for two radiation-associated pathologic fractures. This procedure is definitive, has a low complication rate (dictated mostly by the status of the soft-tissue envelope), and reliably produces good pain relief and function.50,51

Small clinical series also have described successful ORIF of radiation-induced clavicle fractures. Wera et al52 reported on ORIF of three clavicle fractures. Two fractures were managed with supplemental bone grafting, and the third, with supplemental bone cement. The two bonegrafted fractures progressed to union. The fracture managed with plating and cement did not appear to unite but showed no loss of reduction at 28 months. Fuchs et al53 described the use of free vascularized corticoperiosteal bone graft from the medial femoral condyle in conjunction with ORIF in three patients. All three fractures healed, with good clinical results.

Salvage of Recalcitrant Fractures

Even with appropriate management, the nonunion rate is high for radiation-associated fractures, and the treating surgeon often encounters challenges when managing these difficult nonunions. In general, atrophic nonunion is more common than hypertrophic nonunion. Radiation-associated fractures fail to heal because of the radiation damage to the bone and impaired vascularity. Assuming that adequate fixation has been performed, supplemental bone grafting is typically the next step, usually with autogenous bone graft. However, even supplemental autogenous bone graft does not ensure union.10

Another option for a persistent nonunion is a VFG. This can be performed either when autogenous bone grafting fails or as a primary procedure. Duffy et al54 reported the use of a VFG in conjunction with iliac crest bone grafting to treat 18 radiation-induced long-bone fractures. Sixteen of 18 fractures united at a mean of 9.4 months. The success of this procedure requires the skills of a microvascular surgeon. In general, donor site morbidity of fibula harvest is acceptably low, and free VFG has proved to be a useful tool in the management of these nonunions. However, even this procedure does not guarantee successful union. In the series by Duffy et al,54 two fractures did not unite, and one limb eventually required amputation. We also have encountered persistent nonunion following VFG (Figure 8).

Figure 8
Figure 8:
A 45-year-old woman presented with a proximal femur fracture following treatment of a Ewing sarcoma with chemotherapy and radiation 26 years previously. Initial treatment with intramedullary nailing was unsuccessful. A, Anteroposterior (AP) radiograph of the proximal femur 3 months after attempted salvage with a vascularized fibula graft. B, AP radiograph of the proximal femur 3 years later demonstrating healing of the vascularized fibula to the lateral aspect of the femur. However, there is still no evidence of healing at the actual fracture site.

Another salvage procedure involves resection of the involved area of bone and reconstruction with an oncologic prosthesis. This is a good option for primary reconstructions at periarticular sites. It also can be used as a salvage procedure for sites in which arthroplasty would not normally be considered.42-48,55 Fractures of the diaphyseal or metaphyseal femur or humerus can be resected, much like for a tumor, followed by reconstruction with a large endoprosthesis (Figure 9). Oncologic prosthesis reconstructions of the distal femur are typically quite effective, with achievement of excellent function.56 Replacement of the proximal humerus and proximal femur is somewhat more problematic because of loss, respectively, of the rotator cuff and hip abductor attachments. However, even in the presence of residual weakness and limited active range of motion, pain relief is usually excellent. 32,57,58 Also, because the diseased bone is resected, nonunion is no longer an issue. The complication rate is also relatively low.

Figure 9
Figure 9:
A 71-year-old woman who was treated with resection and radiation (65 Gy) 25 years previously for synovial sarcoma of the thigh presented with a distal femur fracture. The fracture was initially treated with a closed retrograde femoral nail at an outside facility. A, Anteroposterior (AP) radiograph of the distal femur 5 months postoperatively, demonstrating persistent nonunion. The patient had significant pain, minimal knee motion, and was unable to ambulate. The painful nonunion was salvaged with resection of the distal femur and reconstruction with a distal femoral replacement total knee arthroplasty. B, AP radiograph of the distal femur 4 years after placement of the endoprosthesis. The patient was reportedly pain free and fully ambulatory without assistive devices.

Infection

A relatively high infection rate has been reported in most series of radiation-associated fractures. Helmstedter et al1 reported a 20% deep infection rate. Lin et al10 reported one wound infection and one deep infection in their series of 12 femur fractures. Duffy et al54 reported four infections in their series of 17 patients managed with a VFG for a radiation-associated fracture. The combination of necrotic bone, diminished vascularity secondary to radiation, a potentially compromised soft-tissue envelope, and multiple surgeries places patients at higher risk for infection than do similar procedures in patients who have not been treated with radiation therapy.

Infection can be a devastating complication. Active infection often precludes the use of needed fixation devices. Eradicating infection in necrotic bone can be extremely difficult because of the reduced blood supply. When an infection cannot be cleared with irrigation, generous bony débridement, and intravenous antibiotics, amputation may be necessary. Prevention is key, and preventive measures should include gentle soft-tissue handling, prophylactic antibiotics, and the involvement of a plastic surgeon for performing wound coverage. Several studies have shown that vascularized tissue transfer for wound coverage in irradiated tissue leads to improved wound healing and lower complication rates.53,59-61

Summary

Radiation-associated fractures remain difficult to treat, with long healing times and high nonunion rates. However, adherence to specific treatment guidelines will maximize the chance for success. Long-bone fractures should be treated with an IM nail. A low threshold should exist for adding supplemental bone graft. Fixation should not be removed at a later date because the likelihood of refracture is high. Refractory nonunions should be treated with either a VFG or with resection of the fracture fragment and reconstruction with an oncologic endoprosthesis. Periarticular fractures should be treated with an arthroplasty procedure to eliminate the risk of nonunion and allow earlier mobilization and weight bearing. The fracture site should be resected in the patient with painful nonunion of the expendable bones, such as the clavicle or rib. The soft tissues are frequently fibrotic and have impaired healing. Careful soft-tissue handling during the surgical procedure is essential.

References

Evidence-based Medicine: Reference 15 is a level I randomized controlled study. Level III/IV casecontrol and cohort studies include references 1-3, 10-14, 16, 18-26, 28-46, 48, and 50-61. The remainder are level V (expert opinion).

Citation numbers printed in bold type indicate references published within the past 5 years.

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