Radiotherapy as Prophylactic or Sole Treatment of Heterotopic Ossifications-About Two Case Reports

Heterotopic ossification (HO) is a rare condition usually related to trauma or neurologic damage. It can affect all bone joints but is more frequent at the hip, particularly following total hip arthroplasty. This condition leads to significant impairment of life quality due to ectopic bone formation which causes functional loss. Here we describe two cases of patients presenting symptomatic HO classified as Brooker III following total hip replacement. One of them was treated prophylactically with external beam radiation, few hours before surgery for prosthesis revision. The other one, received radiotherapy as sole treatment with the intent of symptoms palliation. During the follow-up visits, the first patient didn’t show any HO recurrence and had a significant improvement of his symptoms, namely the claudication; the last one achieved a significant relief of pain and showed an improvement on his functional capability. These cases show the potential benefit of radiotherapy as prophylaxis or as sole treatment of symptomatic HO.


Introduction
Heterotopic ossification (HO) is an abnormal process that leads to the formation of lamellar bone in soft tissue, such as muscle, nerves or connective tissues [1][2][3][4]. There are some risk factors namely male gender, pre-existing ipsi-or contralateral HO, ankylosing spondylitis (Bekhterev's disease), disseminated idiopathic hyperostosis of the skeleton (Forestier disease), osteoarthritis and others [3,5]. Despite those, in general HO can be differentiated into three main categories: traumatic HO (eg. hip replacement, fracture, etc.), nontraumatic HO (mediated by genetic disorders like fibrodysplasia ossificans pregressiva), and neurologic HO (eg. myelitis; brain tumors) [1,6,7]. It has been postulated that HO pathogenesis is probably related to an inappropriate differentiation of mesenchymal stem cells into osteoblastic stem cells; however the definitive pathophysiologic causal factors remain uncertain. Although some authors identified some molecular and signaling pathways such as BMP-SMAD, Wnt/β-catenin, Hedge hog and HIF-1α, which can be activated by different stimuli like tissue damage, inflammation, hypoxia, central nervous injury or others and ultimately led to HO [8].
Regarding to clinical presentation, HO is usually asymptomatic and detected only as an incidental finding on a radiograph. The most prevalent location is hip, for which there are four severity grades according to Brooker classification as follows: a) Islands of bone within the soft tissues about the hip; b) Bone spurs in the pelvis or the proximal end of the femur with at least 1cm between the opposing bone surfaces;

c)
Bone spurs from the pelvis or proximal end of the femur with less than 1cm between opposing bone structures; d) Radiographic ankylosis. The latter two are clinically symptomatic leading to motion impairment at the involved joint, pain and rarely to inflammatory signs like warmth, swelling and local erythema [2,3,9]. When HO causes symptoms it may decrease patient's quality of life in a meaningful manner. The two major treatment options are nonsteroidal anti-inflammatory drugs (NSAIDs) like indomethacin and radiotherapy, and most reports use them as prophylactic agents before or after surgery in high risk patients [1,4,10,11].
External beam radiation therapy (EBRT) is frequently delivered in a single fraction of 700-800 cGy within 4h before surgery in the preoperative setting or within 72h from the end of surgery when applied postoperatively. Studies didn't find any difference on efficacy of prophylactic radiotherapy given before or after surgery, and rates of 77-90% of complete response has been reported [2,3,12,13]. DEGRO practical guidelines recommends a singlefraction dose of 700-800 cGy or fractionated radiation with five fractions of 350 cGy for HO prophylaxis [3]. Data [14]. In this article we describe two cases of HO where EBRT was used as prophylactic strategy before surgery (case 1) and as the only therapeutic approach for palliate HO symptoms (case 2).

Case 1
Male patient with 83 years of age, with history of total hip replacement 3 years ago, presenting HO Brooker III of the ipsilateral hip ( Figure 1). He presented with pain and claudication.
He underwent a single fraction of 750 cGy few hours before

Case 2
Male patient with 67 years of age, with previous total hip replacement 7 months ago. His comorbidities were osteoporosis, heart valve replacement and diabetes induced kidney injury. One

Discussion
HO is a well described condition, first reported in 1883 by Reidel, which leads to functional impairment and significant decrease in quality of life when symptomatic [15]. It may be caused by multiple factors such as traumatic injury, neurologic damage or burns that act as triggers to bone formation at ectopic sites. Most often it occurs at the hip after total arthroplasty, and there is a classification to grade the severity of HO based on radiograph findings. Typically Brooker III-IV HO are clinically relevant and symptomatic [1,9].
Both of our cases are classified as Brooker III of the hip and both developed following total hip arthroplasty. Treatment options include radiotherapy and NSAIDs or a combination of both.
When performed EBRT tend to take place immediately before or The difference between the groups was statistically significant (p<0.05), but the authors stated that this difference was unapparent when comparing patients who preoperatively had Brooker grades 0-2 [16]. On another randomized study, Gregoritch, compared the results of 122 patients that received 700-800 cGy in one fraction either before or after surgery and concluded that the preoperative and postoperative regimens are similar in efficacy [17]. Nowadays, prophylactic radiotherapy can be used before or after surgery, although some authors prefer the preoperative setting advocating that on postoperative setting there may be some obstacles related to transport difficulties and maneuver due to pain and the need to keep the mobilization of the joint minimized immediately after surgery [1].Regarding fractionation, several studies have been done in order to establish the optimal dose. Liu, randomized 147 high risk patients to receive either 400 cGy or 700 cGy on a single fraction one or two days after total hip arthroplasty. They found that 700 cGy was superior to 400 cGy in preventing HO formation following surgery [11] Similarly, Healy, examined single dose irradiation with 700 cGy in comparison to 550 cGy and concluded that the later dose is not sufficient for HO prophylaxis [18]. In an editorial about a systematic review published by Milakovic, Roos and Smith also defended that if EBRT is the chosen strategy for HO prophylaxis, treatment with a single 700-800 cGy fraction pre-or postoperatively seems optimal [4,10]. On the other hand, compared to fractionated treatments, single fraction have the advantages of causing less pain and risk of dislocation if given post-operatively or, in the pre-operative setting, RT can be completed a few hours immediately before surgery. One of the cases we report here, received a single fraction of 750 cGy immediately before surgery and there were none postoperative complications related to wound healing and the patient didn't experience local failure and a significant improvement of his life quality was achieved. In fact, according to DEGRO guidelines for the radiotherapy of non-malignant disorders, prophylactic radiotherapy is well tolerated and impaired wound healing has not been reported [3]. Pohl, also obtained excellent radiographic and functional outcomes after a single fraction of 700 cGy administered before surgery [19].
Redda, retrospectively analyzed 30 patients after pre-or postoperative EBRT and obtained complete responses in 23 patients with excellent results in terms of joint mobility (the majority of patients received single fraction EBRT of 700 cGy) [2]. The use of radiotherapy as a prophylactic strategy is well established on the literature, and seems an efficient way of preventing the re-formation of ectopic bone, when delivered immediately before or after surgery. However its role on the treatment of this condition without surgery is less known. Morcos, studied the effect of late radiotherapy (delivered > 6 weeks after surgery) on HO radiographically proven in 9 patients. They found that 89% of patients demonstrated no further progression in the amount of bone formed after EBRT treatment.13 This study contradicted the previously held belief that there were no role for radiotherapy in the management of HO more than 72h after total hip arthroplasty. In fact several studies had demonstrated that EBRT after 72h is ineffective for HO prophylaxis, but radiotherapy can be successfully used to prevent significant progression of the already forming HO [5,20,21].
Kantor, also achieved no further HO progression after EBRT treatment in patients with significant HO diagnosed more than 6 weeks after surgery [22]. Based on this postulated, we report a case of a patient treated only with single fraction of 800 cGy for a Brooker III hip HO, 6 months after surgery and he had a significant improvement of his pain and mobility, which ultimately led to On both of the cases that we described, testicular shielding was not used because the patients manifest no concerns regarding sperm count or infertility.

Conclusion
HO impairs quality of life causing several functional limitations.
Radiotherapy can successfully be used to prevent its recurrence after surgery on the prophylactic setting, or to palliate symptoms on non-operative setting. One single fraction of 700-800 cGy can be delivered either before or after surgery, as well as the sole treatment of symptomatic HO, with satisfactory results in terms of pain control and joint motion.