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Heterotopic ossification

Discussion in 'LIBRARY General Topics' started by Josephine, Aug 2, 2017.

  1. Josephine

    Josephine FORUM ADMIN, NURSE DIRECTOR Administrator
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    HO is one of those mystery things; we have no idea why some people get it and some don't. Sadly it is a tough thing to treat.

    It looks something like this - identical images, just I outlined in yellow the areas of new abnormal growth in the second image. (This would be a grade 3)

    aflagsforworship.co.uk_jo_pic_images_heterotlt.jpg ...... aflagsforworship.co.uk_jo_pic_images_heterorxr.jpg

    There are grades of HO called the Brooker's scale and treatment will, of course, depend upon the degree of it:
    Grade 1 Islands of bone within the soft tissues about the hip

    Grade 2 Bone spurs in the pelvis or the proximal end of the femur with at least 1 cm between the opposing bone surfaces

    Grade 3 Bone spurs from the pelvis or proximal end of the femur with <1 cm between opposing bone structures

    Grade 4 Radiographic ankylosis (fusion)​

    HO Booker grades-vert.jpg

    - The first approach is usually NSAIDs which calm the process down and hopefully prevent it escalating.
    - Then also/or radiotherapy to arrest the process.
    - And finally, surgery might be deemed necessary in grades 2/3 to excise the aberrant bone.

    Basic action on your part would be to find a chap who has some experience in treating this. You really don't want to end up with a 'have a go, Joe' type!

    There is a significant treatise on the subject here
     
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  2. Josephine

    Josephine FORUM ADMIN, NURSE DIRECTOR Administrator
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    Further Outpatient Care of Heterotopic Ossification


    HO knee.jpg

    Physical Therapy

    The use of physical therapy (PT) in HO has long been controversial. Rossier and co-investigators noted occasional transverse microfractures on sections of HO that they thought might be caused by spasticity or by overly aggressive PROM (passive range of motion). Since then, the debate between resting the joint and aggressive ROM has continued.

    In the literature, however, the developing consensus appears to be that aggressive ROM and continued mobilization, once acute inflammatory signs have subsided, are indicated, because they help to maintain ROM and (in more extensive HO) they may lead to the formation of a pseudarthrosis. Resting the joint appears more likely to lead to decreased ROM or to ankylosis.

    During the acute inflammatory stage, the patient should rest the involved joint in a functional position, and the physical therapist should initiate gentle PROM as soon as possible.

    The role of continuous PROM machines has not been studied in this situation. For patients with incomplete SCI or head injuries, maintaining ROM may be difficult because of pain from ROM exercises.

    Medical Issues/Complications
    The use of joint manipulation has been reported in patients with HO who, because of limited joint ROM, have functional limitations. However, such manipulation is controversial owing to the risk of the formation of new hematoma and because of the chance that long-bone fracture will occur in patients with secondary osteoporosis.

    Nonarticular complications of HO are rare, but they have been reported. These complications include ulnar nerve compression with HO at the elbow, vascular (predominantly venous) compression with or without associated deep venous thrombosis (DVT), and lymphatic obstruction leading to lymphedema.

    Prophylaxis
    Although no effective protocol had previously been developed for preventing HO after SCI, the authors' studies, based on the well-documented beneficial effect of NSAIDs in the prevention of HO after total hip arthroplasty, showed that the following drugs can also be helpful in reducing the incidence and severity of HO after SCI
    • The nonselective NSAID indomethacin SR prescribed for 3 weeks in a dose of 75 mg/d, after SCI, reduced the incidence of HO by 2-3 times.
    • A 25 mg/d prescription of the selective COX-2 inhibitor rofecoxib decreased the risk of HO formation by 2.5 times.
    These positive results with NSAIDs in the prevention of HO may be an important step forward in the clinical management of this condition.

    Surgical Intervention
    Once HO has developed to the point that it interferes significantly with the functional capacity of the patient, the only treatment option remaining is surgery, which most commonly is required at the hip. Ensure that the HO has reached maturity before resection, because resection of immature HO leads to recurrence rates of nearly 100% (although a study by Gen et al disagrees with this assertion, suggesting instead that early excision [< 6 mo] of the ossification does not affect recurrence).

    Hemorrhage may be a significant problem at the time of surgery, with an average blood loss of 2100ml reported. Post-surgical infection may lead to amputation; therefore, great care must be taken at the time of surgery. Initiate a pre-surgery program to eliminate any possible nidus of bacteremia or infections (eg, decubitus ulcers, urinary tract infections).

    The usual surgical technique used on HO occurring anteriorly at the hip is anterior wedge resection. Postoperatively, position the joint properly with foam wedges so that the surgical correction can be maintained and any strain on the incision or pressure sores can be prevented. Start gentle PROM about 72 hours post-operation, and increase therapy intensity gradually to incorporate retraining in functional activities. Patient selection and careful identification of functional goals are critical for successful surgical intervention.

    Other Treatment

    Radiation therapy
    • Radiation therapy has been studied mostly in connection with the prevention of HO in patients at high risk for recurrence following hip arthroplasty.
    • The most common use in the rehabilitation setting is for the prevention of postoperative recurrence, but the optimal dosage, frequency, and timing have not been established.
    • Mesenchymal stem cells that may be in muscle and that transform into bone-forming cells are highly radiosensitive. Little is known of radiation therapy's effect on HO after SCI when it is used as a primary treatment. One reason that radiation therapy has not been established as a treatment for HO is a risk of local induction of malignancy. However, radiation has been used in Europe by Sautter-Bihl and colleagues as a primary treatment for early HO after SCI; no adverse effects were noted.
    Medication Summary
    Today, the medical treatment of HO is directed at early HO. In the later stages of the development of mature bone, medical treatment is ineffective. Etidronate (Didronel) is the only available medication for the treatment of HO after SCI. Treatment with NSAIDs may be required initially, until the resolution of inflammation and the normalization of CRP levels.

    Nonsteroidal anti-inflammatory agents
    Presumed to have direct and indirect effects on the formation of HO. Direct effect refers to the inhibition of the differentiation of mesenchymal cells into osteogenic cells, and indirect effect refers to the inhibition of posttraumatic bone remodeling by suppression of the prostaglandin-mediated inflammatory response.

    Bisphosphonates
    The bisphosphonate group of compounds has properties similar to naturally occurring pyrophosphate, which may be a regulator of calcification. Etidronate disodium is the most extensively studied of this class of drugs for the treatment of HO. Etidronate acts by
    (1) inhibiting precipitation of calcium phosphate from unsaturated solutions,
    (2) delaying aggregation of apatite crystals into layers, and
    (3) blocking conversion of calcium phosphate into hydroxyapatite.​

    Apparently, predisposition to the inflammatory process and mineralization decreases with time, although it is not understood why. This phenomenon may be why there is no massive rebound bone formation after cessation of etidronate. Thus, the effectiveness of etidronate depends entirely on when and how long it is given, and the drug does not affect HO that has already formed.

    Etidronate disodium (Didronel)
    Reduces bone formation and does not alter renal tubular reabsorption of calcium. The effects of etidronate increase as the dose increases. Agent does not appear to affect fracture healing.

    Further Outpatient Care
    • Monitoring of HO maturationMonitoring of HO maturation should be performed regularly.
    • In patients with functional limitations for whom surgery is a consideration, radiography should be performed every 4-6 months.
    • CT scanning and MRI may offer more precise delineation of ectopic bone, which may be helpful in preoperative planning.
    Deterrence
    As previously stated, the prophylactic use of medications to prevent HO has been studied in individuals with SCI, with promising outcomes. NSAIDs do have a role in the prevention of HO and in the prevention of postoperative recurrence after the excision of HO. Radiation therapy also may be used to prevent recurrence postoperatively in some patients.

    Complications

    • Potential complications associated with surgical intervention in patients with HO include hemorrhage and postsurgical infections (see Surgical Intervention).
    • HO in patients with SCI may lead to other complications, such as pressure sores and DVT.
    Prognosis
    Approximately 20-30% of patients with SCI develop clinically evident HO, and 3-8% of them develop severe functional limitations.

    Patient Education
    Patient and family education is an important part of the treatment process in individuals with HO. Physical therapists may instruct patients and family members, if needed, to complete ROM exercises as instructed by the physician. Patients should also be taught to watch for signs of other potential complications when dealing with heterotopic ossification (in order, for example, to prevent pressure sores in patients with SCI).
     
  3. Josephine

    Josephine FORUM ADMIN, NURSE DIRECTOR Administrator
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    Prophylaxis of heterotopic ossification – an updated review
    Evan O Baird and Qian K Kang
    Journal of Orthopaedic Surgery and Research 20 April 2009


    Abstract
    Heterotopic ossification (HO) is defined as the process by which trabecular bone forms outside of the skeletal structure, occupying space in soft tissue where it does not normally exist. The current popular prophylactic treatment modalities include non-steroidal anti-inflammatory drugs (NSAIDs) and radiation therapy, although the literature remains inconclusive as to which is superior. Additionally, both treatments can lead to adverse effects to the patient.

    Recently there have been several studies attempting to identify new aspects of the aaetiology of heterotopic bone formation and introduce new prophylactic modalities with increased efficacy and fewer side effects.

    Background
    Heterotopic ossification (HO) is defined as the process by which trabecular bone forms outside of the skeletal structure, occupying space in soft tissue where it does not normally exist. This misplaced growth occurs between muscle planes and not within the muscle fibres themselves. Furthermore, though the new bone often abuts existing skeletal structure, it does not interfere with the configuration of the periosteum [1].

    The heterotopic ossification of muscles, ligaments and tendons is a potential complication following trauma, elective surgery, neurological injury and severe burns[2]. The most common site for the formation of HO is following open-reduction internal-fixation (ORIF) for acetabular fracture, followed by the hip after total hip arthroplasty (THA)[3, 4]. Following THA, the incidence of HO has been reported as being between 5 and 90%, though only 3 to 7% of patients experience clinically significant HO; that is, to an extent that the outcome of the surgery is affected and as designated a grade of III or IV as originally described by Brooker in reference to the hip joint (Table 1)[5, 6]. Reported incidence is lower following primary total knee arthroplasty (TKA), and has been reported as between 3.8 and 39% for all Brooker classification grades, but as one study reported only 1% of patients were symptomatic[5].

    Table 1
    Brooker classification of heterotopic ossification [6]

    [TABLE="class: brtb_item_table"][TBODY][TR][TD="height: 5px"]Grade 1[/TD][TD]Islands of bone within the soft tissues about the hip[/TD][/TR]
    [TR][TD]Grade 2[/TD][TD]Bone spurs from the pelvis or proximal end of the femur, leaving at least one centimetre between opposing bone surfaces[/TD][/TR]
    [TR][TD]Grade 3[/TD][TD]Bone spurs from the pelvis or proximal end of the femur, reducing the space between opposing bone surfaces to less than one centimetre[/TD][/TR]
    [TR][TD]Grade 4[/TD][TD] Apparent bone ankylosis of the hip[/TD][/TR][/TBODY][/TABLE]
    This article is meant to serve as a review and an update on the literature regarding current prophylaxis modalities as well as treatments under investigation for prevention of heterotopic ossification. It is our hope that these new methods will be more effective and with fewer side effects than their predecessors, allowing far fewer patients to suffer with the debilitating effects of this disease.

    Mechanisms of heterotopic ossification
    The aetiology of HO can be divided into the three headings of
    - neurological
    - genetic
    - traumatic with orthopaedic procedures included in this last group[5].

    Though the aetiology has been classified, the exact pathophysiology of HO remains unknown. Several contributory factors have been suggested. Prostaglandin activity, specifically PGE-2, as well as hypercalcemia, tissue hypoxia, alterations in sympathetic nerve activity, prolonged immobilization and imbalances between parathyroid hormone activity and calcitonin have all been shown to contribute to HO formation[7]. These factors help to enable the improper differentiation of pluripotent mesenchymal stem cells into osteoblastic precursors[5].

    Furthermore, numerous risk factors have been identified in several studies. Those studied in association with hip arthroplasty include a history of HO in the ipsilateral or contralateral hip, post-traumatic arthritis, hypertrophic osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diffuse idiopathic skeletal hyperostosis, osteonecrosis, Paget disease and male sex[8, 9].

    Commonly used prophylactic modalities

    NSAIDs
    The prophylactic effectiveness of indomethacin following elective lower limb surgery is well-accepted, and has been shown to help prevent HO, lessen the extent of the development of HO and assist in preventing inflammation associated with acute HO; it is currently part of a widely-employed prophylaxis protocol[1, 5, 24, 25, 26, 27]. The drug is a simple and low cost option for prophylaxis. It is important to note that several trials have shown that aspirin does not appear to have the same beneficial effects as indomethacin[27, 28]. The drug works by inhibiting prostaglandin-mediated bone remodeling and also by directly inhibiting the differentiation of osteoprogenitor cells[1, 24, 25].

    A Cochrane Review was conducted in 2004, comprising 16 randomized controlled trials analyzing the effectiveness of prevention of HO with the use of NSAIDs[28]. The use of NSAIDs peri-operatively was shown to reduce the risk of developing heterotopic bone formation by 59% over placebo.

    Another systematic review by Neal, et al. demonstrated a 57% reduction in the risk of HO when NSAIDs were used as prophylaxis[27]. The statistical data from this study leads the authors to predict that for every 100,000 THAs performed in the US each year, perioperative NSAID use has the potential to prevent anywhere from 10 to 20,000 cases of heterotopic bone formation. Though both review studies demonstrated a significant reduction in incidence of HO, neither addressed clinical outcomes of pain and physical function among treatments. However not all trials have seen such a benign side-effect profile with the use of NSAIDs.

    NSAID complications
    Karunakar et al[26]. conducted a randomized, prospective double-blind placebo-controlled clinical trial on the effect of indomethacin after the operative treatment of fractures of the acetabulum. Though as the authors point out the study is lacking in power, it is significant in that it was determined that there was no significant difference in the incidence of HO between the indomethacin and placebo treatment groups.

    However, it was noted that one of the indomethacin patients developed gastrointestinal hemorrhage and one had a perforated ulcer, while 13 total patients withdrew from the study due to side effects of the medication, compared with only 1 withdrawing in the placebo treatment. Others such as Banovac[24] have used misoprostol to aid in the prevention of gastrointestinal complications. Another problem with non-selective (i.e. those actively inhibiting cyclo-oxygenase 1 and 2, or COX-1 and COX-2) NSAIDs such as indomethacin is increased perioperative bleeding secondary to inhibition of COX-1, leading to reduced production of thromboxane A2, which is essential to platelet aggregation[29].


    Fransen et al. followed up her 2004 Cochrane review with a randomized controlled trial comparing postoperative pain and physical function in patients taking either ibuprofen or placebo following total hip arthroplasty and revision total hip arthroplasty surgery[30]. Though the overall risk of HO was reduced by 31% (as assessed radiographically) with use of ibuprofen, the study demonstrated no clinically significant difference in either pain or physical function 6 to 12 months postoperatively.

    Further, though the risk reduction is impressive, the raw data (i.e. number of patients affected) does not suggest as large an impact on the actual incidence of Brooker Grade 3 and 4 HO. Among those patients in the ibuprofen treatment set, 2.5% developed Brooker Grade 3 or 4 HO, whereas the placebo treatment demonstrated an incidence of 6%[30]. Further, there was a significant increase in major bleeding complications in the ibuprofen treatment group, again serving to emphasize untoward side effects of this treatment modality[30].

    One method of circumventing the pitfalls of NSAIDs use is by employing COX-2 selective NSAIDs, such as meloxicam. Weber et al. have shown that use of this selective NSAID following total hip arthroplasty was associated with a 17% reduction in intraoperative and postoperative (first 24 hours following surgery) blood loss[29]. Furthermore, fewer gastrointestinal side-effects have been noted as a result of preferential use of COX-2 selective NSAIDs [31, 32, 33, 34, 35]. As noted in additional File 1, more recent studies have highlighted the both these advantages as well as efficacy comparable to that of traditional, non-selective NSAIDs[32, 34, 35, 36, 37].

    However, it is notable that the practice of prescribing COX-2 specific NSAIDs is not without consequences, as several trials have shown an increased risk of cardiovascular events associated with their use [38, 39, 40]. Despite this, a few trials have shown either no increased risk for cardiovascular events when compared to non-slective NSAID use[41, 42] (albeit with lower rates of GI side effects) or a decreased risk (in the case of celecoxib[43]) as shown in one study. Due to the current lack of evidence for safety of routine use of COX-2 selective NSAIDs as prophylaxis for postoperative HO, indomethacin remains the gold standard of treatment when employing NSAIDs therapy[44].

    A serious problem with the use of high-dose indomethacin and other NSAIDS for HO prophylaxis is that while new heterotopic bone may be prevented from forming, the formation of bone for healing the fracture site may also be impaired. Thus, the large number of reports of nonunion or malunion as well as poor ligament healing[5, 25, 45]. One such study by Burd et al. noted 29% incidence of nonunion of long bone fractures following indomethacin prophylaxis, whereas in the radiation arm the incidence was just 7%[25]. Of note, there were no instances of acetabular nonunion. In a study by Persson et al., 142 patients were followed for formation of HO following THA. Of the 11 that underwent a revision procedure secondary to aseptic loosening, 10 belonged to the indomethacin group[46].

    Radiation Therapy
    Studies by Cooley and Goss[47] in 1958 and later those by Craven and Urist[48] in 1971 demonstrated the effects of irradiation therapy on bone growth and repair. After demonstrating the inhibiting influence of the radiation on bone repair of rat bone and seeing that the effects were more pronounced when the treatment was initiated closer to the time of the fracture, the authors hypothesized that the early osteoprogenitor cells involved in bone repair were more radiosensitive than the more mature cells seen later[4]. In 1981, Coventry et al. established the utility of radiotherapy (RT) as prophylactic treatment for HO by irradiating the hips of 42 patients who had undergone hip surgery[49] 48 hips, each designated as high risk for the formation of HO, were treated with a 20 Gy dose of radiation.

    Of those treated, 19% developed ectopic bone, noting that patients treated earlier enjoyed lower rates of HO, though data specifics were not included. Today, RT is used prophylactically (albeit in much smaller doses) both pre- and postoperatively for the prevention of HO following bone fracture or manipulation secondary to trauma or operative treatment[3, 4, 50]. Recently, Childs et al. noted that based on a retrospective cohort study of 263 patients having experienced traumatic acetabular fracture, HO was discovered in 5.3% of patients receiving RT, while 60% of patients who did not receive treatment developed some degree of ectopic bone[51]. Further, a study by Chao et al. has demonstrated RT to be capable of preventing HO in high-risk patients, specifically those in whom a history of HO exists[52].

    Several studies comparing preoperative to postoperative radiation therapy (RT) were reviewed by Balboni et al. in a critical review of RT for HO prophylaxis[4]. Studies cited by the authors suggest that there is not a statistically significant difference between employing preoperative (<4 hours preoperatively) or postoperative (<72 hours postoperatively) RT. In particular the authors cite Gregoritch et al[50] and Seegenschmiedt et al[53] In Gregoritch's study 122 patients undergoing THA and deemed at a high risk of HO were treated with either preoperative or postoperative RT. The authors reported no significant difference among the treatment arms, noting a 28% incidence in the postoperative treatment and 26% incidence in the preoperative treatment.. They calculated a 5% incidence of clinically significant (Brooker Grade 3 or 4) HO in the postoperative group and a 2% incidence in the preoperative group.

    In Seegenschmiedt's study, 161 patients were randomized to receive either preoperative or postoperative RT. Of those treated, 4 (5%) failures were noted in the postoperative group, compared with 11 (19%) in the preoperative group. However, the authors noted that the majority of failures in the preoperative group occurred in patients with pre-existing Brooker Grade 3 or 4 HO which had not been removed prior to treatment. Thus, the authors conclude that there both pre- and postoperative treatment are equally effective.

    Childs et al. had similar results regarding timing of treatment in a study evaluating postoperative RT for HO prophylaxis following traumatic acetabular fractures[51]. Of 152 patients studied, 58 received radiation within 24 hours of surgery, 41 within 48 hours, 53 within 72 hours, 13 within 4 days and 4 were delayed longer than 4 days. The authors noted no increase in HO when prophylactic RT was initiated anywhere from one to four days postoperatively.

    There are several potential side effects of RT, the most concerning of which is the theoretical effect of carcinogenesis; however there has yet to be a documented case of a radiation-induced tumor after RT for HO prophylaxis[4]. This positive outcome is thought to be the effect of both low doses of radiation as well as an older patient population – as the latency period for induction of malignancy following RT is from 15 to 24 years, it is a possibility that there are too few patients that survive long enough after treatment for the carcinogenic effects to be realized[4, 50]. Therefore, as this treatment option is employed for younger patients, this concern is worth considering.

    Another possible complication of RT (and one that also plagues indomethacin treatment, as mentioned above) is the risk of bony nonunion, as has been demonstrated when trochanteric osteotomy is necessary to remove the prosthesis during a revision procedure[4, 49, 54]. Rates of nonunion range from 12–30% after RT[4], with the highest in Lo et al., in which the authors noted that of the 6 patients in whom osteotomy was necessary, 2 developed a nonunion[54]. In non-irradiated trochanteric osteotomy, the rate of nonunion is diminished, occurring only 2–15% of the time[4]. Therefore some authors have advocated the use of shielding to prevent nonunion[9, 50].

    Finally, radiation dose to the testis is also a concern with the use of radiation prophylaxis. Animal studies have shown that reversible oligospermia can be induced with doses as low as 20 to 70 cGy, and doses of 120 cGy have been shown to cause permanent azoospermia[4]. The same study also measured effective testicular dose, showing an average of 25.1 cGy, with a 54% reduction to 11.3 cGy using a testicular shield. For this reason it is recommended that testicular shields always be used during this treatment and that patients be made aware of the risks involved with this treatment modality.

    Regarding which of these treatments (ie NSAIDs or RT) is most effective, several trials have found both are effective means of prophylaxis following arthroplasty and trauma. They point out that clinical decisions should not be made based on efficacy but rather on factors such as availability, side effects and cost [55, 56, 57]. Strauss et al. (2008) recommend that, when accounting for efficacy and all costs associated with the use of NSAIDs versus RT (including patient disability due to HO) for prophylaxis, RT has the advantage due to a lower incidence of serious side effects[58]. This attitude is not supported universally, though several other trials have found an advantage in efficacy using RT rather than NSAID therapy[9, 59].

    Kölbl et al[59] conducted a trial in which 301 patients were randomized to either an NSAID treatment arm, a single 5 Gy fraction of RT or a 7 Gy fraction of RT. 113 patients were randomized to the NSAID arm, 95 to the 5 Gy arm and 93 to 7 Gy. The data from the study supported the 7 Gy therapy as being the most effective postoperative treatment schedule in prevention of clinically significant (Brooker 3 or 4) heterotopic ossification. A study by Pakos et al[9] had similar results, demonstrating a difference in effective HO prophylaxis for Brooker grade 3 and 4, albeit only a 1.2% absolute risk reduction.

    Combination Therapy
    Another option for HO prophylaxis is to combine NSAIDs and RT. Both Pakos et al[9] and Piatek et al[60] found combination therapy to be effective, with Pakos' study of 54 patients having only 1 develop clinically significant HO, though with an overall incidence of 20.4%. This rate is noticeably higher than that produced by several other studies, notably Kölbl et al[59], in which the overall rate of HO formation was 11.6% in the 7 Gy RT arm, with no instances of Brooker grade 3 or 4 HO. Piatek's[60] study had only 1 of 24 patients to develop any HO. Very few studies have examined this treatment modality combination, and there is still a considerable amount of discussion regarding whether or not it is worth pursuing[61]. Though Piatek's study in particular is promising, larger trials must be implemented to discover the true utility or lack thereof of a combined prophylaxis protocol.

    Methods under investigation
    Indomethacin use has led to the development of gastric ulcers and even gastrointestinal hemorrhage[24, 26] in some patients, as well as bony nonunion[5, 25, 45] as a result of its systemic effects. Radiation therapy carries with it the risks of carcinogenesis[4, 50], gonadal dysfunction[4], and bony nonunion[4, 49, 54], as with NSAID therapy. Since the development and use of NSAIDs and RT for HO prophylaxis, there have been several studies attempting to pinpoint new aspects of HO aetiology and thus direct the development of new prophylactic modalities with increased efficacy and fewer side effects[1, 2, 62, 63, 64].

    Noggin
    Though the exact aetiology of HO is not yet fully understood, it is possible that the over-expression of certain bone morphogenetic proteins (BMPs) may have an influence on the formation of ectopic bone[2], most notably in skeletal muscle. BMP-4 in particular has been demonstrated to be elevated in diseases such as fibrodysplasia ossificans progressive (FOP), a disease characterized by the progressive ossification of soft tissue, especially muscle, tendons and ligaments[2, 65]. A study by Kan et al[66] demonstrated experimentally that over-expression of BMP-4 via a particular gene promoter was able to induce a FOP-like phenotype.

    In addition to the upregulation of BMPs, the downregulation of BMP antagonists such as Noggin, an extracellular peptide that binds and antagonizes BMPs, may play a role in the development of heterotopic bone[2, 62, 66, 67, 68]. Hannallah et al[2] have shown that retroviral delivery of Noggin into HO-predisposed muscle stem cells in mice (those expressing BMP-4) is able to reduce HO by 53–99% in a dose-dependent manner. This study also showed that tissue in which Noggin had been delivered exhibited an 83% decrease in area of HO following trauma (Achilles tenotomy). Aspenberg et al[62] also demonstrated the efficacy of Noggin delivery in prevention of HO, using both wild-type and engineered strains of the peptide and Glaser et al[68] demonstrated that direct delivery of Noggin as well as systemic delivery via adenovirus vector was effective in blocking BMP-4-induced heterotopic ossification. A unique study performed by Weber et al. utilized mutant forms of BMPs that worked in a similar way to BMP antagonists (like Noggin), but even more effectively[29].

    Current research suggests that local and some forms of systemic delivery of Noggin is effective in combating formation of heterotopic bone in animal models. Our hope is that Noggin will prove capable of doing the same in humans, particularly at surgical sites, in light of the high rates of heterotopic bone formation following procedures such as hip and knee arthroplasty.

    Pulsed Electromagnetic Fields (PEMF)
    Based on the assumption that local hypoxia has a role in the development of HO[69, 70], a study by Kociæ et al[64] has suggested that the use of pulsed electromagnetic fields (PEMF) could prevent HO by increasing the rate of circulation and oxygenation of soft tissue surrounding a traumatic or surgical site. Group A consisted of 131 hips in 117 patients that were administered PEMF treatments starting 3 days postoperatively and interferential current starting approximately 14 days postoperatively. Group B also contained 131 hips in 117 patients, but these patients were treated with PEMF and interferential current, both starting 14 days postoperatively, as well as kinesitherapy. Group C consisted of 79 hips in 66 patients who had only kinesitherapy during postoperative rehabilitation. Group A had an overall HO incidence of 16.7%, Group B 43.5%, and Group C 50.6%. Brooker grade 3 and 4 was evident in none of the Group A patients, in 6.1% of Group B patients and in 26.6% of Group C patients.

    Free Radical Scavengers
    Oxidative stress occurs when the production of Reactive Oxygen Species (also referred to as free radicals) are created at a faster rate than that at which they are eliminated[1, 71]. Large quantities of free radicals are produced both as a result of the ischemia/reperfusion syndrome and the so-called disuse phenomenon. The ischemia/reperfusion syndrome is a result of isometric muscle contractions (secondary to muscle hypertonia and contractures) effectively occluding the muscle's arterial supply and inducing a state of ischemia. Patients may be started on an exercise regimen to aid in reperfusion of the tissue, simultaneously causing free radical generation[1].

    Vanden Bossche describes well the disuse phenomenon. Muscle atrophy occurs largely as a result not of degradation of existing proteins, but of the decrease in protein synthesis, weakening repair mechanisms[1, 71]. However, a reduction in antioxidants available to the tissue also plays a role, complicated by the release of myoglobin-derived iron in muscle, which is able to catalyze oxidative processes responsible for further protein damage[1]. Moreover, the metabolic rate of the muscle involved is also a consideration, with higher metabolism being associated with a higher rate of production of free radicals, and thus increased tissue damage[1, 72].

    Knowing that heterotopic bone formation is noted to be present following both of these conditions, Vanden Bossche et al[1] indirectly links the production and action of free radicals to the process of heterotopic ossification. Drawing on the theory of the involvement of hypoxia in the pathophysiology of HO, the study examined the use of allopurinol and N-acetylcysteine (A/A) as free radical scavengers to prevent ectopic bone formation.

    Using a rabbit model, they used 10 animals each in 4 different treatments: placebo, indomethacin, A/A free radical scavengers, or a combination of free radical scavengers and indomethacin. They immobilized the left hind leg of each animal to induce HO. This study demonstrated a significant difference between the efficacy of indomethacin and the increased efficacy of A/A on prevention of HO, as well as a statistical difference between the A/A and placebo group. However, no statistical significance was noted between the indomethacin and placebo groups. Also of note was that there was not significant difference in efficacy between the A/A group and the combination A/A, indomethacin group.

    Conclusion
    Though radiation therapy and NSAIDs remain the most widely used therapeutic modalities in the setting of post-surgical heterotopic ossification prophylaxis, it is evident that they bring with them many hazards and shortcomings. While they represent comparatively cheap and easily administered treatments, they are plagued with the propensity to cause bony nonunion, gastrointestinal disturbances, and in the case of radiation therapy, carcinogenesis. Though proponents of COX-2 selective NSAIDs have sought to correct many of these ills, there is as of yet not enough evidence of their safety for the authors to recommend their adoption without reservation.

    Noggin (a bone morphogenetic protein inhibitor), pulsed electromagnetic fields (PEMF), and free radical scavengers in the form of allopurinol and N-acetylcysteine are three new methods being evaluated to take the place of radiation and NSAID therapy as the predominant method of prophylaxis. While research into alternative prophylactic modalities is currently in its infancy, the three mentioned here have thus far shown promise for fewer associated side effects and better control of heterotopic bone formation. It is the hope of the authors that these modalities will be further developed and made available for routine use, leading to fewer post-surgical complications and better outcomes overall.

    Copyright
    © Baird and Kang; licensee BioMed Central Ltd. 2009
    This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
     
  4. Josephine

    Josephine FORUM ADMIN, NURSE DIRECTOR Administrator
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    References
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