Heterotopic ossifications following implant surgery—epidemiology, therapeutical approaches and current concepts
The pathophysiology of heterotopic ossification (HO) is still ill-understood. Several risk factors such as osteoarthritis, male gender and injury patterns like traumatic brain injury and severe soft tissue damage have been described. Furthermore, the pathophysiology of local and systemic factors has been investigated leading to an extended knowledge especially on the molecular level. Knowledge of the involved cell types and mediators led to the now widely used prophylactic and therapeutic strategies to prevent heterotopic ossifications. Out of these findings, the beneficial effects of NSAIDs and radiotherapy on HO prophylaxis have been proven for a number of indications such as total hip arthroplasty and acetabular surgery. However, there is little information about the potential effects on heterotopic ossifications around the elbow. Surgical treatment may be considered in some cases, but there are only limited indications. Generally, only clinically relevant bone formations should be resected. Following surgical resection, beneficial effects on range of motion and pain relief has been described. An accurate perioperative regimen is crucial and includes prophylactic medication. In combination with radiotherapy, low recurrence rates were described but there are still controversies about the optimal timing for surgical resection.
KeywordsHeterotopic ossification Total hip arthroplasty Acetabular fracture Knee arthroplasty Posttraumatic complications
Heterotopic ossifications (HO) are defined as abnormal bone formations in soft tissue. The disease has been labelled with different names such as paraosteoarthropathy, myositis ossificans, ectopic ossifications or heterotopic bone formation but is now most appropriately described with the term HO . In general, there are three main entities of HO: genetic, neurogenic and traumatic. Concerning genetic factors, HO occurs in genetically associated disorders like fibrodysplasia ossificans progressiva or progressive osseus heteroplasia (POH). POH is associated with a defect in the GNAS1 gene which results in a dysfunction of the stimulatory G protein of adenylyl cyclase . Neurogenic HO occurs following traumatic brain injury , or spinal cord injury [4, 5]. Besides injuries, HO was diagnosed following meningitis and brain tumours [6, 7]. Traumatic HO is typically seen following fractures and operative procedures in orthopaedic surgery, such as hip arthroplasty. Hip arthroplasty was introduced in the late 1960s and led to a revolution in the surgical treatment of severe arthritis of the hip joint. As a result of improvements to surgical procedures and implants, short- and long-term results have been positively altered as shown in numerous publications. However, despite the advantages, a number of authors pointed out a recurrent phenomenon around the hip joints. They found bony formations in the soft tissue surrounding the prosthesis, namely HO, which led to clinical impairments like reduced range of motion (ROM), swelling and pain. Even total ankylosis has been reported [8, 9]. Since several surgeons were confronted with this entity, first classifications were implemented leading to today’s widely known and used Brooker classification [10, 11, 12]. Shortly thereafter, HO development has also been described following open reduction and internal fixation of acetabular fractures which led to even more studies investigating possible risk factors depending on patients’ and therapeutic characteristics [13, 14, 15, 16, 17]. Some authors also diagnosed HO in other regions like the knee or the elbow [18, 19]. Classifications were developed but a general classification for all joints is still missing .
The pathophysiology of HO is still not completely understood. However, there is profound evidence for local and systemic factors which are involved in the pathogenesis of HO. Especially the local inducing effects of bone morphogenetic protein (BMP) as well as the systemic influence of prostaglandine E2 (PGE2) have been described in some studies [21, 22, 23, 24, 25].
Prophylactic, as well as treatment options were investigated, reaching from drug therapy by nonsteroidal antiinflammatory drugs (NSAIDs) and corticoids, to radiotherapeutic approaches and surgical excisions .
This article describes the history and pathophysiology of heterotopic ossifications especially in the context of implant surgery. Strengths and limitations of prophylactical and therapeutical approaches in different localisations of HO as well as the contributing risk factors are described and based on an extensive review of current literature.
Heterotopic ossifications were first described by the German physician Riedel in 1883. After Riedel, it was Dejerne et al.  in 1918, who investigated the histopathological and anatomical details in servicemen following spinal cord injury and further specified HO as paraosteoarthropathy. The first reports about HO following traumatic brain injury (TBI) were published in the late 1960s. In these patients, bony formations around primary uninjured joints were found .
With increasing amounts of implants for total hip arthroplasty (THA), surgeons like Charnley, Harris and Brooker et al.  reported about a notable number of patients suffering from HO in the 1970s. They reported limited range of motion as well as pain and swelling to be the predominant complications. In the last three decades, heterotopic ossifications were described following implant surgery of acetabular fractures and other regions treated by plate osteosyntheses . Recently, first reports about HO following nail osteosynthesis and arthroplasty of the knee joint were published [18, 29, 30]. Within recent decades, the disease has been investigated in various settings, locations and outcome parameters. Altogether, the results led to today’s knowledge of risk factors and parts of the related pathophysiology.
Pathophysiology and risk factors
During normal bone development, pluripotential cells undergo a systematical process from migration to proliferation and finally bone formation. Current literature strongly supports the idea that this bony development is recapitulated in a pathological way during HO evolution. The newly formed ectopic bone shows differences compared to normal bone. Firstly, no periosteum is found in ectopic bone formations . Secondly, a higher number of osteoblasts and osteoclasts are found . However, the organised structure of HO is similar to normal bone. Bone of HO has been characterised as biologically highly active with high formation rates .
There is evidence that HO depends on the three entities osteogenic precursor cell, inducing agents and an appropriate environment .
Recent studies revealed the influence of local BMP, as an inducing factor in the development of HO. BMPs are important mediators during embryological osteogenesis and fracture healing. Furthermore, they regulate key steps like chemotaxis and differentiation in the osteogenic cascade. Increased local concentrations of these molecules may lead to HO [23, 24].
As HO was also frequently detected in patients with TBI and spinal cord injury as well as in burn injured patients , systemic inducing factors which pander the development of HO have been analysed. One possible systemic factor is circulating PGE2, which has been found in high concentrations in the urine of spinal cord injured patients. In the study of Schurch et al. , the investigators were able to demonstrate an association of the 24-h urinary excretion of PGE2 and HO development in these patients. PGE2 might therefore be a valuable marker for early detection of high risk patients.
It is also widely accepted, that the amount of soft tissue trauma and necrosis, (e.g. in hip surgery), seems to be a critical factor for the development of HO. Excessive muscle retraction, as well as surgical approaches with division or osteotomy of the greater trochanter, are leading to an appropriate environment and thus have been reported to correlate with high rates of HO [35, 36, 37, 38, 39].
Factors associated with heterotopic ossifications following implant surgery in different settings
Ahrengart and Lindgren 
Extensive osteoarthritis (including preexisting bone)
DeLee, Ferrari and Charnley 
History of HO in the ipsilateral or contralateral hip
Ritter and Vaughan 
Sundaram and Murphy 
Preoperative deformities around the knee joint
Dalury and Jiranek 
Preoperative osteophytes around the knee joint
Toyoda, Matsumoto, Tsuji et al. 
Harwin, Stein, Stern et al. 
Surgical fracture treatment
Zeckey, Hildebrand, Mommsen et al. 
Traumatic brain injury
Pape, Lehmann, van Griensven et al. 
Increased overall injury severity
Ghalambor, Matta and Bernstein 
Extensive surgical approach
Giannoudis, Grotz, Papakostidis et al. 
Hoffer, Brody and Ferlic 
Diagnostics and classifications
The clinical investigation provides essential information on the suspected HO. Clinical signs such as swelling, limited ROM, or increasing joint stiffness are leading symptoms of the newly formed bone. The diagnosis HO is mostly confirmed by plain X-rays. Typically, HO can be diagnosed as early as 6–12 weeks following trauma .
Ultrasound has been described as an inexpensive and fast performed examination, especially during the early phases of HO development around the hip joint . Thomas et al.  investigated 53 patients who underwent THA. In their study, the investigators were able to identify nearly 80% of the patients 1 week following surgery who would suffer from HO 2 weeks later. Thus, ultrasound might play an essential role in the early detection of HO and therefore, adapt or to initiate prophylactic treatment. However, up-to-date information is missing about the usefulness of ultrasound in detection of HO around other joints.
Bone scintigraphy can be useful in follow-up examinations. It is described as the most sensitive method to detect early HO. Moreover, viability of the newly formed bone can be assessed. Since most authors agree that surgical resection should take place in biologically low or inactive bone formations, bone scintigraphy can give useful information about the appropriate timing .
A general classification system for all joints is still missing. Up-to-date, classification systems of the hip, elbow and also the knee joint were developed.
Classification system of HO around the hip joint according to Brooker 
Islands of bone within the soft tissues about the hip
Bone spurs from the pelvis or proximal end of the femur, leaving at least 1 cm between opposing bone surfaces
Bone spurs from the pelvis or proximal end of the femur, reducing the space between opposing bone surfaces to less than 1 cm
Apparent bone ankylosis of the hip
Classification system of HO around the elbow according to Hastings and Graham 
Radiologically demonstrable elbow and forearm HO without functional limitation
Radiologically demonstrable elbow and forearm HO with functional limitation in one or more planes of motion
(a) Limitation in elbow flexion/extension plane
(b) Limitation in forearm pronation/supination plane
(c) Limitation in both planes of motion (class 2a + 2b)
Complete ankylosis of the particular articulation
In some study populations, heterotopic ossifications were examined also at other joints than the hip, knee or elbow. Due to a missing general classification system for these joints, some studies described the pathology according to Brooker [46, 50]. As Brooker’s classification has been developed for the hip joint only, some investigators modified this classification system . Until now, these classification systems are not routinely used.
Heterotopic ossifications following total hip arthroplasty and surface replacement arthroplasty of the femoral head
Through fast pain relief and good clinical results, THA has become the surgical gold standard for severe pain and disabilities, caused by severe arthritis. The majority of THA result in a profound clinical improvement, but a number of patients report recurrent pain, swelling or limited ROM. Besides infections, poor surgical technique or other causes which lead to clinical restrictions, HO has been reported as a contributing factor for adverse outcome. Mainly located in the abductor compartment, the overall incidence of HO (Brooker grade 1–4) following THA has been reported ranging up to nearly 50% depending on sub-collectives and study design [8, 12, 40, 51, 52].
Beside the surgical approach, complications associated with the implantation technique might be evident. In case of THA, there are principally two options to achieve integration of the prosthesis: the uncemented and the cemented technique. Today, uncemented prostheses are usually used in younger and more active patients; meanwhile, cemented implants are more often used in older patients or in those with revision THA.
Due to the opening of the femoral canal as well as the preparation of the acetabular component, seeding of osteogenic bone debris is not always avoidable.
This fact led to a number of studies comparing both uncemented and cemented implants. Maloney et al.  investigated the effect of cemented femoral components as compared to patients receiving an uncemented implant in case of osteoarthritis. The acetabular cup was uncemented in both groups. The study demonstrated a significantly increased incidence and severity of the resulting HO following uncemented femoral components. Rockwood et al.  performed a study on 196 patients treated with uncemented THA and compared their results with the published literature. In contrast to the results of Puzas et al. , the investigators were not able to demonstrate an increased risk for HO in their uncemented study cohort.
Due to the different profiles in younger patients sustaining severe arthritis of the femoral head, new surgical techniques and implants have been developed. Surface replacement arthroplasty (SRA) of the femoral head is described as an excellent alternative, especially in younger patients offering the advantages of femoral bone conservation. In brief, parts of the femoral head and the femoral neck are preserved in SRA in order to safe bone for upcoming THA procedures. In THA, the femoral head and parts of the femoral neck need to be resected.
With rising amount of surgical-treated arthritis of the hip joint by SRA, a number of patients reported physical restrictions which forced some investigators to perform outcome studies following SRA. Within these reports, HO is also described in a limited number of studies and case series [55, 56, 57, 58, 59].
Rama et al.  compared the incidence and the severity of HO between THA and SRA in a randomised cohort study. At the 1-year follow-up, the investigators found evidence for an increased risk of HO following SRA as compared to THA. Furthermore, the size of HO according to Brooker was increased as compared to THA. However, the investigators also included more men in group SRA which might negatively affect the formation of HO towards higher Brooker grades. Thus, controlled randomised clinical studies, like matched-pair analysis should be focused on in further studies .
Heterotopic ossifications following total knee arthroplasty
As THA gained profound attention due to the excellent clinical results, total knee arthroplasty (TKA) has been developed some years later. Beside excellent results following arthritis, complications like fracture, failure of the extensor apparatus or infection have been reported. Furthermore, some authors also noted HO. The incidence of HO following TKA has been described by a number of investigators ranging from 4% up to 42% [18, 29]. However, only a limited number of patients with HO are symptomatic. HO around the knee joint mostly appears anterior to the distal femur, adjacent to the periosteum and around the quadrizeps expansion. In case of TKA, periostal trauma due to notching or stripping is believed to be a contributing factor for HO development. Therefore, extensive periostal trauma and stripping should be avoided, unless absolutely necessary for exposure or alignment considerations . Furthermore, preoperative deformities are believed to be an independent risk factor. Especially patients with a combined deformity (flexion plus valgus or varus) of greater than 15° are at increased risk of forming HO . Toyoda et al.  examined 63 TKA with a median follow-up of 1 year. The investigators found some correlations like extensive preoperative osteophytes or press-fit fixation of the tibial component and the postoperative incidence of HO. In contrast, perioperative ligament release has not been described as a contributing factor.
A significantly reduced range of motion was found only during early postoperative phases in patients suffering from HO, no significant difference were described at the follow-up . This result has been confirmed by the study of Hasegawa et al. . In their investigation, no restrictions concerning range of motion or late clinical outcome were found in patients sustaining HO. Dalury and Jiranek  performed a prospective analysis of 500 patients following TKA, some of them bilaterally. In their study, only 1% of the patients developed a critical size of HO leading to a slight decreased ROM in the 1- and 2-year follow-up. No changes concerning progress of the new formed bone formation has been observed in the second year after TKA. Rader et al.  retrospectively examined a series of 615 knees following TKA. The authors found very few cases in which surgical resection has been needed due to severe limitations of ROM or painful events, however, the investigators recommended a new graduation system to evaluate critical sizes of the HO after TKA.
Taken together and in contrast to HO around the hip joint, HO following TKA is believed to be a self-limitating process requiring neither prophylaxis nor specific therapy. Evidence suggests that HO around the knee joint following TKA has a substantially better prognosis than around other joints .
Heterotopic ossifications following acetabular fracture care and long bone fractures
Surgical management of dislocated fractures of the acetabulum remains one of the greatest challenges in fracture care. As acetabular fractures in young patients are frequently the result of high energy trauma, additional injuries like long bone shaft fractures are common. During the clinical course of these often multiply injured patients, additive and contributing factors to sustain HO have been revealed . Current literature strongly supports a correlation between ventilation time and HO. Furthermore, traumatic brain injury especially in combination with plate osteosynthesis of the acetablum but also of long bones has been shown to be crucial in different settings [46, 62, 63].
The main goal in the treatment of acetabular fractures is to achieve anatomic joint reconstruction. Beside conservative treatment options in non-displaced fractures followed by secondary joint congruence, open reduction and internal fixation is often necessary. As acetabular surgery is frequently accompanied or followed by complications like osteoarthritis, accidental nerval lesions and vascular injuries, accurate preoperative planning is necessary. However, besides joint restoration and a crucial postoperative regimen, the responsible surgeon has to be aware of heterotopic bone formation, which has been described in numerous studies following acetabular surgery and consecutive plate osteosynthesis . The risk to sustain HO following open reduction and internal fixation of the acetabulum ranges from 7% to 58%, depending on study design and population . A meta-analysis described an overall risk to sustain HO of 25.6%, significant HO (Brooker grade 3 or 4) occurred in 5.7% .
Despite known factors like traumatic brain injury, male gender, previous history of HO, or extensive osteoarthritis (Table 1), the role of the surgical approach has been discussed. In acetabular fracture care, there are different types of surgical approaches, depending on type of fracture and personal experience. The Kocher–Langenbeck, ilioinguinal and iliofemoral approaches are mainly used to perform osteosyntheses . However, there are still controversies regarding the best surgical approach to achieve optimal exposure and lowest soft tissue damage which has been shown to be a predominant factor in the development of HO . There is evidence of a higher risk for developing HO Brooker grade 3/4 using the iliofemoral approach (24.6%). The Kocher–Langenbeck was associated with an incidence of 11.6% and for the ilioinguinal approach it was 1.5%. Furthermore, high overall injury severity scores and delays of surgical fixation are related to higher rates of HO [14, 15, 16].
The elbow and heterotopic ossifications
The function of the elbow has a profound influence on the function of the upper limb. Movements like extension and flexion but also the sometimes less considered but highly important pronation and supination are related to a precise articulation process involving the humerus, radius and the ulna. The complex anatomy and the precise articulation of the distal humerus with the radial head and the olecranon fossa underlines the importance but also the complexity of the elbow joint.
Nerve palsy is a dreaded complication of HO around the elbow. The ulnar nerve is affected most commonly by HO. Nerve palsy may occur several months or years after the initial formation of HO. In some cases, complete nerve palsy may result [68, 69]. Thus, a neurologic evaluation in patients suspected for HO should be performed.
Concerning the range of motion, some authors state that an elbow spanning of extension/flexion 0/30/110° is not functionally impaired . Morrey et al.  performed a biomechanical analysis concerning required ROM of the elbow for daily activities. The investigators demonstrated that most activities of daily living can be accomplished with 100° of flexion (30–130°) and 100° of forearm rotation (50° of pronation and 50° of supination). Thus, the authors concluded that interventions should only be promoted in severe restrictions due to HO.
There is some uncertainty in current literature about the influence of passive range of motion and rehabilitation procedures following injuries and surgical interventions on the development of HO at the elbow. Some authors described forced motions to be a contributing factor to sustain HO. However, others did not confirm these findings [72, 73]. Today, postoperative concepts include the early mobilisation as early as 48 h following surgery to avoid shortening of muscles and soft tissue contractures. Thereby, early mobilisation is believed to inhibit fibroblasts and consequently preventing muscle contractures [34, 70]. However, when the range of motion 6 weeks postoperatively remains significantly reduced, closed mobilisation of the joint in anaesthesia should be considered. Radiation therapy has been revealed to be beneficial in case of early stages of HO [49, 74].
However, in severe HO of the elbow, surgery is frequently required. To achieve optimal treatment results, indications for surgical procedures have to be critically discussed. Indications for surgical excision of the formation are nerval compression syndromes, impaired range of motion affecting daily activities (less than extension/flexion 0/30/130°, pronation/supination 50/0/50°) or painful HO .
Prophylaxis and treatment of heterotopic ossifications—general considerations
Sufficient management of prophylaxis as well as treatment of HO requires a precise collaboration between surgeons and physical therapists. Moreover, systemic therapy or external radiation should be promoted in many cases. The correct indications but also the limits or even contraindications have to be considered to achieve optimal results.
Although the incidence of symptomatic and high grades of HO remains relatively low, there are a number of studies reporting severe restrictions due to HO during the posttraumatic course . Due to the high incidence of THA and the correlated high risk of HO around the hip joint, most studies describing the effects of NSAIDs on HO prophylaxis were performed in this field. However, there are also are number of reports concerning the effectiveness of prophylactic treatment following acetabular surgery. Additionally, the beneficial effects of radiation therapy following total hip arthroplasty or open reduction and internal fixation of acetabular fractures have been revealed in a number of studies which will be discussed below.
In contrast, only a very limited number of studies are available concerning the effectiveness of NSAIDs in case of HO around the elbow. Although literature providing this data is lacking, most authors recommend prophylactic treatment with NSAIDs, sometimes even in combination with radiation therapy in these cases .
Surgical excision is only required in highly symptomatic HO, independent of the location. When indicated, accurate preoperative planning and perioperative management is crucial. Preoperative planning includes exact localisation and visualisation by X-ray, CT and sometimes MRI. Especially in case of compression syndromes of nerval structures, MRI may provide crucial information. Beside surgical resection, perioperative management (analgetic treatment, NSAIDs treatment), has been found to be essential for the clinical outcome.
Effect of NSAIDs on HO—prophylaxis or treatment?
Overview of non-surgical prophylactic and therapeutic approaches to prevent heterotopic ossifications
Total hip arthroplasty
Lower Brooker grade
Cella et al. 
Total hip arthroplasty
Indomethacin and radiation
Lower Brooker grade
Knelles et al. 
Total hip arthroplasty
No effect on HO development
Knelles et al. 
Postoperative and gastrointestinal bleeding
Total hip arthroplasty
Celecoxib vs. indomethacin
Comparable Brooker grade
Romano et al. 
comparable incidence of HO
Total hip arthroplasty
Lower Brooker grade
Fransen et al. 
Improved clinical outcome
Total hip arthroplasty
NSAIDs vs. radiation
Radiation slightly more effective to prevent Brooker grades 3/4
Pakos et al. 
Lower Brooker grade, decreased incidence of HO
McLaren et al. 
Comparable incidence of HO
Matta et al. 
Not effective in preventing ectopic bone formation
Reduced Brooker grade
Indomethacin vs. radiation
Comparable Brooker grade
Moore et al. 
NSAIDs combined with radiation vs. radiation and NSAIDs alone
Decreased incidence of HO
Piatek et al. 
Best results in combination
Decreased recurrence rate, improved clinical function
Heyd et al. 
Improved clinical outcome
McAuliffe et al. 
Since gastrointestinal lesions are mainly associated with inhibition of cyclooxygenase-1, selective COX-2 inhibitors were developed. Out of the findings of prior studies, a number of investigators examined the effectiveness of selective COX-2 inhibitors on HO development following THA. Romano et al.  performed a study in 150 patients receiving celecoxib as compared to 250 patients receiving indomethacin. No differences were found regarding HO development and size of the HO. However, a significant reduction of gastrointestinal lesions has been shown in the celecoxib group. Saudan et al.  compared celecoxib with ibuprofen in a blinded study of 250 patients. They found no differences concerning side effects but a significant reduction of the respective Brooker grades in the celecoxib group. Due to cardiovascular side effects, especially in patients with coronary heart disease, the standardised usage of COX-2 inhibitors has to be critically discussed and further research is needed.
In summary, the type of NSAID used for prevention has to be adapted to the patients risk profile and the surgeons experience. Indomethacin and diclofenac are the best investigated and most commonly used drugs. Therefore, there seems to be evidence for the effectiveness of prophylactic treatment with these NASIDs in combination with a mucoprotective drug. Side effects like renal failure or gastrointestinal lesions have to be considered during treatment with NSAIDs.
Regarding acetabular fractures, results of NSAID medication on HO development remain controversial. One of the first reports about the influence of indomethacin on HO development following surgically treated acetabular fractures was performed by McLaren et al. . The investigators described a beneficial effect of indomethacin not only regarding the incidence of HO but also with regard to the severity of HO according to the Brooker classification.
In contrast, Matta et al.  did not find a beneficial effect of indomethacin. In their respective randomised study, the investigators examined 107 patients nearly 8 months following open reduction and internal fixation of acetabular fractures using the ilioinguinal, Kocher–Langenbeck and extended iliofemoral approach. Karunakar et al.  investigated the effect of indomethacin on the development of HO following acetabular fractures and consecutive surgical treatment. Using the Kocher–Langenbeck approach, the investigators were also not able to demonstrate beneficial effects of indomethacin as compared to placebo when administered for 6 weeks once daily (75 mg).
As NSAIDs are known to induce delayed fracture healing, the influence of prophylaxis of HO on fracture healing in additional long bone fractures has been investigated. Burd et al.  studied 112 patients who underwent open reduction and internal fixation of the acetabulum and sustained a concomitant long-bone fracture. In their report, they found a significant increase of non-unions in the indomethacin group. Thus, prophylaxis of HO following open reduction and internal fixation of acetabular fractures should be critically discussed.
Is there a role for radiation therapy in prophylaxis of heterotopic ossifications?
In addition to the effectiveness of NSAIDs in the prevention of HO following THA, the effect of radiation has been studied in a number of clinical trials. According to the clinical findings of the Mayo Clinic during the 1970s, it was Coventry  who first described the application of radiation in high-risk patients following THA. During HO development, it is assumed that mesenchymal stem cells are stimulated and differentiate to osteoblastic cells which results in osteid and finally in bone tissue. Radiation interferes with this process leading to a decreased amount of osteoblastic cells and, therefore, reduced ectopic bone. Due to the potentially cancerogenity of the external beam therapy, subsequent studies were performed to find optimal dosage and timing of prophylaxis [91, 92]. Furthermore, different settings were investigated using fractionated or single dose radiation therapy. In summary, a single dose of 7–8 gray (Gy) seems to be efficacious and safe for the patient. Despite the beneficial effects on HO development, possible negative effects on ingrowth in cementless prostheses have been described. Therefore, effective shielding of cementless implants as well as osteotomy sites seems to be necessary [91, 93].
Various studies were performed to demonstrate possible superior effects of either NSAID or radiation following THA. However, a great diversity with regard to study concepts and designs has to be considered when comparing the results. To compare the published reports, Pakos et al.  performed a meta-analysis. Out of the results of that report, radiation seems to be slightly more effective to prevent significant Brooker grades 3/4 as compared to NSAIDs in a dose-dependent manner.
As described following THA, radiation therapy is also one of the therapeutic options in preventing HO following acetabular fracture care by open reduction and internal fixation. Haas et al.  were able to demonstrate an effective treatment strategy to prevent formations of clinically significant HO according to Brooker.
There has been some controversy about the timing of perioperative radiation therapy in current literature. Meanwhile, some investigators also found beneficial effects when applied as short as 4 h before the surgical procedure. Others were able to demonstrate even more profit when applied after surgery [96, 97]. Generally, radiation therapy affects the resident osteogenic progenitor cells. During surgery, large amounts of cells might be spread in soft tissues around the approach which may be influenced by radiation therapy. One step in the pathology of HO is perceived as a differentiation of pluripotential stem cells into osteogenic progenitor cells. This formation starts within the first 20 h and peaks around 2 days following traumatic events . This might be one explanation of the now accepted method of radiation therapy following surgery in some departments. When using radiation therapy, postoperative application within a maximum of 72 h after surgery should be favoured . Besides logistical planning, costs of the radiation therapy should be considered.
However, concerns regarding the effectiveness or superior outcome of radiation in patients sustaining acetabular fractures as compared to patients treated by NSAIDs, led to a number of investigations and comparisons of both strategies.
A study by Moore et al.  included 75 patients who underwent ORIF of acetabular fractures and received either 25 mg indomethacin three times daily or radiation in a dose of 8 Gy within 3 days after surgery. In their randomised study, the investigators found similar results following both treatment strategies with regard to the respective Brooker grade. However, the authors also highlighted the cost efficacy of both strategies and experienced much higher costs due to radiation therapy. Furthermore, there seemed to be some logistical problems with radiation therapy due to intrahospital transports and scheduling. Furthermore, radiation therapy might not always be available especially in smaller hospitals.
In contrast, a recently published meta-analysis by Blokhuis et al.  showed evidence for the use of radiation therapy for HO prophylaxis after surgical treatment of acetabular fractures. Comparing the incidence of significant Brooker grades (3 and 4), the investigators were able to show a significant increased number of patients following indomethacin treatment as compared to radiation. However, the authors also stated that there is great diversity in the current literature and in the included studies, particularly due to different study designs, randomisation and therapeutic strategies.
In addition to the beneficial effects of NSAIDs and radiation, the combination of both has been investigated in a limited number of studies. Published literature regarding the combination of both, NSAIDs and radiation, deal with THA but also acetabular fracture care.
A recent report described the effectiveness of the combined therapy following THA in high risk patients. Pakos et al.  investigated the effect of a single dose of 7 Gy combined with indomethacin over a 15-day period. The investigators sufficiently reduced the risk of recurrent HO in patients suffering from recurrent HO or severe osteoarthritis.
Another study, dealing with patients following acetabular fracture care, was performed by Piatek et al. . The combination of both, NSAIDs and external radiation, significantly reduced the risk of HO. When compared to NSAID or radiation therapy only, the investigators assumed that the combination therapy was associated with the lowest risk of HO. No patient out of the study population (n = 24) sustained Brooker grade 3/4. Finally, the investigators compared their results with current literature. Also compared to published results, there was a low incidence and decreased Brooker grades in the combined group. Out of these results, the authors believe that a combined therapy should be used in high-risk patients with recurrent HO, extensive approach during acetabular fracture care or in patients undergoing surgical excision. However, randomised trials concerning the combination of NSAIDs and radiation therapy are lacking and should be the focus of further investigations.
In summary, NSAIDs and radiation therapy seem to be beneficial concerning the prevention of HO following acetabular surgery and decision making should be dependent on local conditions and possibilities. Oral application of NSAIDs seems to be more comfortable. Furthermore, cost factors involving radiation have to be considered.
In contrast to the field of THA or acetabular fracture care, reports about radiation in case of HO at the elbow are limited in current literature. However, some case series are available. McAuliffe et al.  performed an outcome study following resection of HO and postoperative radiation. In their report, the postoperative arc of motion (103°) compared favourably with the intraoperative status and was therewith significantly increased as compared to preoperative status with 12°. Therefore, the authors concluded that radiation therapy is beneficial in these patients. However, sample sizes of published reports are small and there is no general recommendation for radiation therapy. Viola et al.  recommend a single dose of 7 Gy within 72 h following the injury, where applicable (Table 4).
The role of surgical interventions in HO has been the focus in a number of studies. Despite the anticipated beneficial effect of the resection, high recurrence rates and complications, compared to routine procedures, have been described . In general, surgical excision is only recommended in clinically relevant and high grades of HO leading to severe functional, neuronal, vascular or painful impairments (Fig. 2).
The optimal timing of resection is debatable but there is evidence that the lesion should be well organised and is supposed to demonstrate only minor biological activity. Beside this, no joint swelling should be present . Surgical resection of HO should be followed by a strict periperative regimen including NSAIDs or radiation or both which leads to significantly improved ROM and reduced radiographic visible HO .
Surgical resection of symptomatic HO is recommended in clinically relevant HO (Brooker grades 3 and 4), around the hip joint. Cobb et al.  investigated 53 patients suffering from HO following THA. The investigators not only found an increase of ROM but also pain relief in the follow-up. However, in patients who underwent surgical resection solely because of pain, no significant improvement could be observed. Furthermore, some functional outcome parameters such as stair climbing or ability to walk were not significantly improved in the study population.
There are some reports about the outcome following surgical resections of HO around the elbow joint. Taken together, there is consensus about the limited success for bone resection. As described, most authors recommend a waiting period of up to 18 months before resection .
However, timing of resection may also depend on the localisation of the HO. Jupiter et al.  performed an outcome study following resection of post-traumatic proximal radioulnar synostosis. Following their results, early excision may be beneficial in terms of early physical training as well as the overall period of disability.
The development of heterotopic ossifications is a multifactorial process. Some patient specific as well as surgical risk factors have been found including male gender, traumatic brain injury and extensive soft tissue damage. The influence of implant surgery including arthroplasty but also fracture care has been analysed in a number of studies. Moreover, associations of the type and extension of surgical approaches were revealed. The knowledge of the pathophysiology on molecular and cellular level led to the recommended strategies including NSAIDs, radiation and the combination of both. Extensive studies were performed to analyse the effectiveness and advantages of the different concepts. Thereby, different classification systems of heterotopic ossifications were developed. Up to date, Brooker’s system is most commonly used around the hip joint; a general classification system is missing. Beside the non-surgical therapy, surgical excision has been discussed controversially; to date there is consensus about the limited indication. Thereby, only heterotopic ossifications of high grade resulting in profound clinical impairments should be resected. Still, there is ambiguity about the optimal timing of surgical resection.
The authors gratefully thank Mr. HP Stiefel for his important intellectual comments.
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