Orthopedics

Feature Article 

Radiation Therapy for Preventing Recurrence of Neurogenic Heterotopic Ossification

Cara Cipriano, MD; Stephan G. Pill, MD, MSPT; Jeffrey Rosenstock, MD; Mary Ann Keenan, MD

Abstract

Radiation therapy is commonly used to prevent heterotopic ossification, and the dose-dependent effects of this treatment have been well documented in patients after total hip arthroplasty (THA). However, the efficacy and dose requirement of radiation therapy to prevent heterotopic ossification of nonsurgical origin have not been studied. The purpose of this retrospective case-control study was to determine the effects of prophylactic radiation therapy on severe heterotopic ossification recurrence, postoperative range of motion (ROM), and wound healing in patients with heterotopic ossification secondary to neurologic deficits.

Selection was not blinded, and higher risk patients were generally assigned to the treatment group. Standard doses of radiation therapy did not adequately lower recurrence rates; in fact, there was a higher incidence of heterotopic ossification formation necessitating revision in the treatment group (15.0%) compared to the control group (5.1%). Moreover, patients who received radiation therapy were not more successful at maintaining intraoperative ROM over time. There was a similar incidence of delayed wound healing between groups (12.8% in the control group and 12.5% in the treatment group), and no other negative side effects or complications were observed.

These results suggest that the 700 cGy dose of radiation therapy typically used for the prophylaxis of heterotopic ossification associated with THA does not effectively prevent the recurrence of neurogenic heterotopic ossification in high-risk patients. Further studies are needed to determine whether higher doses of radiation therapy will provide more effective prophylaxis for heterotopic ossification.

Heterotopic ossification is the formation of bone in nonskeletal tissue, usually between muscle and joint capsule, which can lead to restricted motion and functional limitations.1 Nonhereditary heterotopic ossification can result from upper motor neuron lesions, traumatic injury, or surgery. Clinically, it presents with erythema, swelling, warmth, and loss of joint motion in the acute phase, and it may cause severe pain during formation. These nonspecific symptoms often mimic other inflammatory conditions such as infection, cellulitis, deep venous thrombosis, and osteomyelitis.

Radiation therapy is often used to prevent heterotopic ossification in patients at high risk following total hip arthroplasty (THA). Studies on heterotopic ossification in this patient population have established that a single dose of 700 cGy of local radiation administered in the first 4 postoperative days can effectively prevent its formation.2-8 Based on these findings, this dose has been applied to other populations at high risk for developing other forms of nonhereditary heterotopic ossification; however, the efficacy and dose requirement of radiation therapy may be different in patients with neurogenic heterotopic ossification. This retrospective case-control study evaluated the effects of this treatment on heterotopic ossification recurrence, postoperative range of motion (ROM), and wound healing in this patient population.

Between January 2003 and April 2006, 60 consecutive patients underwent surgical excision of heterotopic ossification at the institution of the senior author (M.A.K.; Table 1). A total of 72 joints were involved, including hips, knees, and elbows. The treatment group consisted of 30 patients with a total of 37 affected joints. Thirty-three cases of heterotopic ossification resulted from neurologic injury alone and 4 from concurrent local trauma. In this group, heterotopic ossification was excised from 29 hips, 3 knees, and 5 elbows; of these joints, 5 had undergone at least 1 prior resection. The group comprised 23 men and 7 women with an average age of 36.7 years at time of surgery.

The control group consisted of 30 patients with a total of 35 affected joints. Thirty cases of heterotopic ossification were secondary to isolated neurologic injury, while 7 had associated local trauma. In this group, 14 hips, 9 knees, and 12 elbows were affected; 2 of these joints had undergone prior heterotopic ossification…

Abstract

Radiation therapy is commonly used to prevent heterotopic ossification, and the dose-dependent effects of this treatment have been well documented in patients after total hip arthroplasty (THA). However, the efficacy and dose requirement of radiation therapy to prevent heterotopic ossification of nonsurgical origin have not been studied. The purpose of this retrospective case-control study was to determine the effects of prophylactic radiation therapy on severe heterotopic ossification recurrence, postoperative range of motion (ROM), and wound healing in patients with heterotopic ossification secondary to neurologic deficits.

Selection was not blinded, and higher risk patients were generally assigned to the treatment group. Standard doses of radiation therapy did not adequately lower recurrence rates; in fact, there was a higher incidence of heterotopic ossification formation necessitating revision in the treatment group (15.0%) compared to the control group (5.1%). Moreover, patients who received radiation therapy were not more successful at maintaining intraoperative ROM over time. There was a similar incidence of delayed wound healing between groups (12.8% in the control group and 12.5% in the treatment group), and no other negative side effects or complications were observed.

These results suggest that the 700 cGy dose of radiation therapy typically used for the prophylaxis of heterotopic ossification associated with THA does not effectively prevent the recurrence of neurogenic heterotopic ossification in high-risk patients. Further studies are needed to determine whether higher doses of radiation therapy will provide more effective prophylaxis for heterotopic ossification.

Heterotopic ossification is the formation of bone in nonskeletal tissue, usually between muscle and joint capsule, which can lead to restricted motion and functional limitations.1 Nonhereditary heterotopic ossification can result from upper motor neuron lesions, traumatic injury, or surgery. Clinically, it presents with erythema, swelling, warmth, and loss of joint motion in the acute phase, and it may cause severe pain during formation. These nonspecific symptoms often mimic other inflammatory conditions such as infection, cellulitis, deep venous thrombosis, and osteomyelitis.

Radiation therapy is often used to prevent heterotopic ossification in patients at high risk following total hip arthroplasty (THA). Studies on heterotopic ossification in this patient population have established that a single dose of 700 cGy of local radiation administered in the first 4 postoperative days can effectively prevent its formation.2-8 Based on these findings, this dose has been applied to other populations at high risk for developing other forms of nonhereditary heterotopic ossification; however, the efficacy and dose requirement of radiation therapy may be different in patients with neurogenic heterotopic ossification. This retrospective case-control study evaluated the effects of this treatment on heterotopic ossification recurrence, postoperative range of motion (ROM), and wound healing in this patient population.

Materials and Methods

Between January 2003 and April 2006, 60 consecutive patients underwent surgical excision of heterotopic ossification at the institution of the senior author (M.A.K.; Table 1). A total of 72 joints were involved, including hips, knees, and elbows. The treatment group consisted of 30 patients with a total of 37 affected joints. Thirty-three cases of heterotopic ossification resulted from neurologic injury alone and 4 from concurrent local trauma. In this group, heterotopic ossification was excised from 29 hips, 3 knees, and 5 elbows; of these joints, 5 had undergone at least 1 prior resection. The group comprised 23 men and 7 women with an average age of 36.7 years at time of surgery.

Table 1:  Patient Demographics

The control group consisted of 30 patients with a total of 35 affected joints. Thirty cases of heterotopic ossification were secondary to isolated neurologic injury, while 7 had associated local trauma. In this group, 14 hips, 9 knees, and 12 elbows were affected; 2 of these joints had undergone prior heterotopic ossification resection. The group comprised 24 men and 6 women with an average age of 35.9 years at time of surgery. The chronicity of the heterotopic ossification was variable, but all patients had been symptomatic for at least 1 year prior to operative intervention. Surgical indications included heterotopic ossification that significantly limited ROM or resulted in nerve impingement, causing interference with function or quality of life.

When assigning patients to the treatment or control group, risk of heterotopic ossification recurrence was taken into consideration. Overall, the treatment group had a greater number of preoperative risk factors, including more severe heterotopic ossification, which was assessed in terms of ROM. Five joints in the treatment group had undergone prior resection, compared to only 2 in the control group. The patients who received radiation therapy had more severe neurologic deficits in the affected limb. In the control group, local motor control was unaffected in 11 cases, impaired in 21, and absent in 3. In the treatment group, local motor control was unaffected in 8 cases, impaired in 15, and absent in 14. Finally, 26 of the patients receiving radiation therapy had some degree of residual cognitive impairment, while only 18 of the control patients were cognitively impaired.

Patients in the treatment group received a single 700 cGy dose of radiation therapy at an average of 1.18 days (range, 0-4 days) following heterotopic ossification excision. All patients were followed for an average of 12.7 months (range, 6-33 months). They were closely monitored for wound-healing complications, as well as for clinically significant heterotopic ossification recurrence, which was measured in terms of ROM and functional outcome. Severe recurrence was defined as heterotopic ossification at least as limiting as prior to the initial resection and therefore necessitating revision surgery.

Results

Severe heterotopic ossification recurrence was observed in 6 joints (15%) treated with radiation therapy and in only 2 joints (5.1%) that were not treated. In the treatment group, the mean range of hip flexion-extension was 4.23° preoperatively, 87.2° intraoperatively, and 67.2° at most recent follow-up. In the control group, these ranges were 32.5°, 112.1°, and 73.0°, respectively. Knee ROMs were 81.3° preoperatively, 137.5° intraoperatively, and 117.5° at follow-up in the treatment group, and 84.2° preoperatively, 146.7°, and 146.7° at follow-up in the control group. In the treatment group, flexion-extension at the elbow was 4° preoperatively, 132.0° intraoperatively, and 92.0° postoperatively, while in the control group, these values were 66.0°, 150.0°, and 140.0°, respectively.

Figure A: Patient preoperative, intraoperative, and follow-up of hip ROM
Figure B: Patient preoperative, intraoperative, and follow-up of knee ROM
Figure C: Patient preoperative, intraoperative, and follow-up of elbow ROM

Figure: Patient preoperative, intraoperative, and follow-up of hip (A), knee (B), and elbow (C) ROM. Patients who received radiation therapy following resection of heterotopic ossification from the hip did not have greater ROM losses at follow-up. Patients who received radiation therapy following resection of heterotopic ossification from the knee or elbow had significantly greater ROM losses at follow-up.

Patients in the treatment group lost an average of 20.0° of ROM (22.9% of the intraoperative range) at the hip, 20.0° (14.5%) at the knee, and 40.0° (30.3%) at the elbow, while patients in the control group lost 40.1°(3.8%), 0° (0%), and 10° (6.67%), respectively, at these joints (Table 2). Thus, the patients who received radiation therapy were generally less successful at maintaining their intraoperative ROMs over time (Figure). In addition, the incidence of heterotopic ossification recurrence necessitating revision was significantly greater in the treatment group (15.0%) compared to the control group (5.1%). Finally, a comparable incidence of delayed wound healing was observed in the treatment (12.5%) and control (12.8%) groups, and no other treatment-related complications were observed.

Table 2: Average ROM

Discussion

A significantly higher incidence of recurrence necessitating revision was found in the treatment group (15.0%) compared to the control group (5.12%). This suggests that the 700 cGy dose of radiation therapy typically used for the prophylaxis of heterotopic ossification associated with THA does not effectively prevent the recurrence of neurogenic heterotopic ossification in high-risk patients. These results imply that this patient population is distinct from patients postarthroplasty, and the dose of radiation therapy may need to be tailored accordingly.

Several studies have shown that a single dose of 600 to 800 cGy prevents heterotopic ossification formation in patients considered to be at high risk following THA.2-8 In addition, radiation has effectively prevented heterotopic ossification in patients following acetabular fracture8,9 and spinal cord injury.10 Smaller case series have also documented successful inhibition of heterotopic ossification formation at the elbow11 and knee.12 Radiation-induced sarcoma has been reported as a rare but serious complication of this treatment,13,14 and a theoretical risk exists that radiation therapy may contribute to osteonecrosis as well, although to our knowledge this has not been described.

The dose-dependent effects of radiation therapy prophylaxis were demonstrated in a retrospective study by Healy et al.5 They reviewed 107 hips in patients at high risk for developing heterotopic ossification following THA who were treated with either 550 or 700 cGy. Sixty-three percent of patients receiving low-dose radiation therapy and 10% of patients receiving high-dose radiation therapy developed heterotopic ossification (P=.03). Moreover, Brooker class 3 or 4 heterotopic ossification was seen in 4 patients receiving 550 cGy and only 2 patients receiving 700 cGy. These results suggest a dose-dependent effect of radiation therapy in heterotopic ossification prophylaxis.5

Based on studies like this, 700 cGy is generally accepted as the standard dose of prophylactic radiation therapy following THA. Higher doses have typically not been used due to the potential complications. Finally, while the timing of radiation therapy varies slightly between trials, a large study on patient acetabular fractures by Childs et al9 demonstrated no significant increase in the incidence of heterotopic ossification formation when radiation therapy was administered on postoperative day 1, 2, 3, or 4.

To our knowledge, our study is the first to investigate the effects of radiation therapy on neurogenic heterotopic ossification recurrence. One limitation to the study design is that patients were not randomized into treatment groups. The assignment of patients to the treatment group was done according to the senior author’s experience, with patients believed to be at high risk for recurrence after resection being assigned to receive radiation therapy. As a result, differences existed between patients in the treatment and control groups, including preoperative ROM, prior heterotopic ossification resection, local motor control, and neurologic deficits. Another limitation is that 17 patients in the treatment group and 10 in the control group received bisphosphonates postoperatively. Since bisphosphonates are also known to effect heterotopic ossification recurrence, this may serve as a confounding variable. Neither the selection bias nor the potentially confounding variable, however, negates our conclusion that standard doses of radiation therapy may not provide adequate prophylaxis for heterotopic ossification recurrence in our high-risk population.

It is also possible that follow-up ROMs may have been limited by muscle spasticity and soft tissue contractures in addition to bone formation. We attempted to minimize this effect through careful attention to our measurement process: in order to document the maximum extension at each joint, ROMs were recorded by experienced staff only after significant stretching of soft tissues.

Heterotopic ossification most commonly develops during the first 2 months after the causative event (surgery, injury, or neurologic damage). Therefore, we feel that our follow-up was sufficient to capture the majority of postoperative recurrence. If additional cases of heterotopic ossification developed after the follow-up period, this would support our present findings that 700 cGy of radiation therapy does not provide sufficient prophylaxis for heterotopic ossification recurrence in our study population. Our length of follow-up allowed us to monitor for immediate complications of radiation therapy; however, long-term complications such as radiation-induced malignancy would not be immediately evident. Few studies have attempted to monitor patients beyond the immediate postoperative period, and those that have struggled with loss of follow-up.15 Moreover, long-term sequelae may not manifest for decades. Thus, while there appeared to be no increase of radiation therapy–related complications in the early postoperative period, we are unable to comment on the potential long-term risks of this treatment.

Due to the low prevalence of neurogenic and injury-related heterotopic ossification compared to heterotopic ossification secondary to THA, our study population consisted of only 63 patients. Nevertheless, this represents the largest study that has yet been done on this patient population. Recruiting a large number of patients is difficult; however, larger-volume studies should be attempted if feasible.

Conclusion

Radiation therapy has largely been assumed to be effective in many patient populations based on literature involving patients following THA. This study suggests that the typical dose of radiation therapy used for THA does not effectively prevent the recurrence of neurogenic heterotopic ossification in high-risk patients. In addition, a greater complication rate was not related to radiation therapy. Based on these findings, increased amounts of radiation may be indicated.

Finally, given the recurrence rate of 5.12% in the relatively low-risk patients with neurogenic heterotopic ossification who did not receive prophylaxis, these patients would likely benefit from radiation therapy as well. Further randomized controlled studies are needed to determine whether higher radiation doses, more frequent administration, or a combination with other treatments such as nonsteroidal anti-inflammatory drugs may provide effective prophylaxis against heterotopic ossification in this patient population.

References

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Authors

Dr Cipriano is from the Department of Orthopedic Surgery, Rush University, Chicago, Illinois; and Drs Pill and Keenan are from the Department of Orthopedic Surgery, Hospital of the University of Pennsylvania, and Dr Rosenstock is from Pennsylvania Hospital, Philadelphia, Pennsylvania.

Drs Cipriano, Pill, Rosenstock, and Keenan have no relevant financial relationships to disclose.

This study was approved by the University of Pennsylvania Institutional Review Board.

Correspondence should be addressed to: Mary Ann Keenan, MD, Department of Orthopedic Surgery, University of Pennsylvania, 3400 Spruce St, 2 Silverstein, Philadelphia, PA 19104.

DOI: 10.3928/01477447-20090728-33

10.3928/01477447-20090728-33

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