Pharmacologic or genetic targeting of peripheral nerves prevents peri-articular traumatic heterotopic ossification.

Heterotopic ossification (HO) is a pathological process that commonly arises following severe polytrauma, characterized by the anomalous differentiation of mesenchymal progenitor cells and resulting in the formation of ectopic bone in non-skeletal tissues. This abnormal bone growth contributes to pain and reduced mobility, especially when adjacent to a joint. Our prior observations suggested an essential role of NGF (Nerve Growth Factor)-responsive TrkA (Tropomyosin Receptor Kinase A)-expressing peripheral nerves in regulating abnormal osteochondral differentiation following tendon injury. Here, we utilized a recently developed mouse model of hip arthroplasty-induced HO to further validate the role of peripheral nerve regulation of traumatic HO. Nerve ingrowth was either modulated using a knockin transgenic animals with point mutation in TrkA, or local treatment with an FDA-approved formulation of long acting Bupivacaine which prevents peripheral nerve growth. Results demonstrate exuberant sensory and sympathetic nerve growth within the peri-articular HO site, and that both methods to reduce local innervation significantly reduced heterotopic bone formation. TrkA inhibition led to a 34% reduction in bone volume, while bupivacaine treatment resulted in a 50% decrease. Mechanistically, alterations in TGFß and FGF signaling activation accompanied both methods of local denervation, and a shift in macrophages from M1 to M2 phenotypes was observed. In sum, these studies reinforce the observations that peripheral nerves play a role in the etiopathogenesis of HO, and that targeting local nerves represents a potential therapeutic approach for disease prevention.

Effectiveness of indomethacin in preventing Heterotopic Ossification: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Heterotopic ossification (HO) is a frequent complication of joint trauma or surgery, commonly occurring after hip replacements, acetabular or other joint injuries, or surgeries. Indomethacin has long been used to prevent HO and is considered the first-line therapy. However, its effectiveness and necessity for HO prevention are still debated due to mixed evidence about its efficacy and potential side effects. METHODS: Following PRISMA guidelines, this systematic review and meta-analysis evaluated randomized controlled trials using the PICO framework. Searches were conducted across PubMed, Embase, Cochrane Library, and Web of Science. Data were extracted and assessed based on the evidence levels of the selected articles. This study was registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY). RESULTS: This analysis included 665 patients, with 347 in the Indomethacin group and 318 in the No Indomethacin group. The outcomes analyzed-HO, Gastrointestinal Side Effects, and Bone Ununion-indicated that indomethacin effectively prevents HO. The meta-analysis revealed that the Indomethacin group experienced a significant reduction in the occurrence of grade I-II HO compared to the No Indomethacin group, but not for grade III-IV HO. Gastrointestinal side effects were notably higher in the Indomethacin group. The incidence of bone nonunion was higher in the Indomethacin group, although not statistically significant. CONCLUSIONS: The meta-analysis suggests that indomethacin is effective in preventing HO, particularly for Brooker grade I-II, rather than Brooker grade III-IV. Special attention should be given to gastrointestinal complications when using indomethacin. Further prospective randomized controlled studies are required to confirm these findings.

Personalizing Prophylactic Radiotherapy for Hip Heterotopic Ossification: An AMSTAR-2 Compliant Review of Meta-analyses.

BACKGROUND/AIM: Heterotopic ossification (HO) is a common complication following total hip arthroplasty. Various prophylactic treatments have been proposed, including radiotherapy (RT). This review summarizes the evidence from meta-analyses on the efficacy of RT in preventing hip HO. MATERIALS AND METHODS: A literature search was conducted on PubMed. The quality of the meta-analyses was assessed using the AMSTAR-2 tool. RESULTS: Seven meta-analyses were included. One meta-analysis reported a significant reduction in HO occurrence after RT compared to the control group. Comparing RT and non-steroidal anti-inflammatory drugs, one and two meta-analyses showed significantly greater efficacy of RT in preventing severe HO and better outcomes in patients receiving drugs, respectively. Regarding RT settings, the postoperative and preoperative RT were each supported by one meta-analysis. Furthermore, two meta-analyses showed an advantage of multi-fractionated RT over single fraction RT. The overall confidence rate of the meta-analyses was moderate, low, and critically low in one, three, and three meta-analyses, respectively. CONCLUSION: RT is a confirmed prophylactic intervention for HO. However, the precise optimization of timing, dosage, and fractionation requires elucidation. Future research should focus on the development of predictive models through large-scale data collection and advanced analytics to refine individualized treatment strategies and assess RT comparative effectiveness with drugs.

Efficacy of ibuprofen and indomethacin as prophylaxis of heterotopic ossification: a comparative study.

The prophylactic action of non-steroidal anti-inflammatory drugs (NSAIDs) in heterotopic ossification (HO) was first described following analgesic therapy with indomethacin. Following that evidence, several compounds have been successfully used for prophylaxes of HO. Ibuprofen has been also proposed for the prevention of HO following THA. The present study compared the administration of ibuprofen for three weeks versus indomethacin as prophylaxis for HO following primary THA. In all THA procedures, pre- and post-operative protocols were conducted in a highly standardized fashion. The type of HO prophylaxis (indomethacin 100 mg/daily or ibuprofen 100 mg/daily) was chosen according to a chronological criterion: from 2017 to 2019 indomethacin was used, whereas from 2019 to 2022 ibuprofen was administered. In case of allergy or intolerance to NSAIDs, no prophylaxis was performed, and patients were included as a control group. All patients who underwent an anteroposterior radiography of the pelvis at a minimum of 12 months following THA were considered for inclusion. On admission, the age and sex of the patients were recorded. Moreover, the causes of osteoarthritis and the date of surgery were recorded. The grade of HO was assigned by a blinded assessor who was not involved in the clinical management of the patients. The modified Brooker Staging System was used to rate the efficacy of the interventions. Data from 1248 patients were collected. 62% (767 of 1248 patients) were women. The mean age was 67.0 ± 2.9 years. The mean follow-up was 21.1 ± 10.8 months. In the ibuprofen group, 73% of patients evidenced Brooker 0, 17% Brooker I, and 10% Brooker II. In the indomethacin group, 77% of patients evidenced Brooker 0, 16% Brooker I, 6% Brooker II. No patient in the ibuprofen and indomethacin group developed Brooker III or IV. In the control group, 64% of patients evidenced Brooker 0, 21% Brooker I, 3% Brooker II, and 12% Brooker III. No patient in the control group developed Brooker IV HO. Concluding, three weeks of administration of ibuprofen demonstrated similar efficacy to indomethacin in preventing HO following primary THA. The prophylaxis with ibuprofen or indomethacin was more effective in preventing HO compared to a control group who did not receive any pharmacological prophylaxis.

Chemoprophylaxis for heterotopic ossification following hip arthroscopy: A systematic review.

INTRODUCTION: Heterotopic ossification (HO) is a known complication diagnosed following hip arthroscopy. PURPOSE/HYPOTHESIS: This study sought to review the current literature on chemoprophylaxis for HO following hip arthroscopy and to describe what agents and doses are being utilized. STUDY DESIGN: Systematic Review. METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines on the use of chemoprophylactic medications for HO prevention following hip arthroscopy. Mechanical and radiation prophylaxis were not included in the current analysis. RESULTS: A total of 203 studies were identified, of which 15 were included with 6463 patients. There was one randomized control trial (RCT) and 4 additional comparative studies. The most commonly utilized chemoprophylactic agents were the following: naproxen (n â€‹= â€‹8), celecoxib (n â€‹= â€‹3), indomethacin (n â€‹= â€‹3), aspirin (n â€‹= â€‹1), etoricoxib (n â€‹= â€‹1), and etodolac (n â€‹= â€‹1), and non-specific non-steroidal anti-inflammatory drugs (NSAIDs) (n â€‹= â€‹1). Naproxen was either given at a dose of 500 â€‹mg once or twice daily for 2-4 weeks. RCTs and additional comparative studies showed significant HO prevention using chemoprophylactic agents following hip arthroscopy. CONCLUSIONS: HO is a known and common complication following hip arthroscopy. The current systematic review found significant heterogeneity across the literature with respect to specific chemoprophylactic agents and their dosing regimens aimed to reduce the incidence and severity of HO following hip arthroscopy. Additionally, this review demonstrates that most studies that utilize chemoprophylaxis use NSAIDs with successful reduction in the incidence of HO. LEVEL OF EVIDENCE: Level IV Evidence.

Association Between Tranexamic Acid Use and Heterotopic Ossification Prevalence After Elbow Trauma Surgery: A Propensity-Score-Matched Cohort Study.

BACKGROUND: Heterotopic ossification (HO) is a common complication of elbow trauma that can affect limb mobility. Inflammation is an initiating factor for HO formation. Tranexamic acid (TXA) can reduce the inflammatory response after orthopaedic surgery. However, evidence regarding the effectiveness of TXA use for HO prevention after elbow trauma surgery is lacking. METHODS: This retrospective observational propensity-score-matched (PSM) cohort study was conducted from July 1, 2019, to June 30, 2021, at the National Orthopedics Clinical Medical Center, Shanghai, People's Republic of China. A total of 640 patients who underwent surgery following elbow trauma were evaluated. The present study excluded patients with an age of <18 years; those with a history of elbow fracture; those with a central nervous system injury, spinal cord injury, burn injury, or destructive injury; and those who had been lost to follow-up. After 1:1 matching on the basis of sex, age, dominant arm, injury type, open injury, comminuted fracture, ipsilateral trauma, time from injury to surgery, and nonsteroidal anti-inflammatory drug use, the TXA group and the no-TXA group comprised 241 patients each. RESULTS: In the PSM population, the prevalence of HO was 8.71% in the TXA group and 16.18% in the no-TXA group (with rates of 2.07% and 5.80% for clinically important HO, respectively). Logistic regression analyses showed that TXA use was associated with a lower rate of HO (odds ratio [OR], 0.49; 95% CI, 0.28 to 0.86; p = 0.014) than no TXA use, as well as with a lower rate of clinically important HO (OR, 0.34; 95% CI, 0.11 to 0.91; p = 0.044). None of the baseline covariates significantly affected the relationship between TXA use and HO rate (p > 0.05 for all). Sensitivity analyses supported these findings. CONCLUSIONS: TXA prophylaxis may be an appropriate method for the prevention of HO following elbow trauma. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

TNFα-dependent mTOR activity is required for tenotomy-induced ectopic ossification in mice.

INTRODUCTION: Ectopic ossifications often occur in skeletal muscles or tendons following local trauma or internal hemorrhage, and occasionally cause severe pain that limits activities of daily living. However, mechanisms underlying their development remain unknown. MATERIALS AND METHODS: The right Achilles tendon in 8-week-old female or male mice was dissected. Some mice were injected intraperitoneally either with phosphate-buffered saline, dimethyl sulfoxide, cimetidine, rapamycin, celecoxib or loxoprofen for 10 weeks. One week after surgery, immunohistochemical analysis was performed for mTOR, TNFα or F4/80. Ten weeks after surgery, ectopic ossification at the tenotomy site was detected by 3D micro-CT. RESULTS: Ectopic ossification was seen at dissection sites in all wild-type mice by dissection of the Achilles tendon. mTOR activation was detected at dissection sites, and development of ectopic ossification was significantly inhibited by administration of rapamycin, an mTOR inhibitor, to wild-type mice. Moreover, administration of the histamine 2 blocker cimetidine, which reportedly inhibits ectopic ossification in tendons, was not effective in inhibiting ectopic ossification in our models. TNFα-expressing F4/80-positive macrophages accumulate at dissection sites and that ectopic ossification of the Achilles tendon dissection was significantly inhibited in TNFα-deficient mice in vivo. Ectopic ossification is significantly inhibited by administration of either celecoxib or loxoprofen, both anti-inflammatory agents, in wild-type mice. mTOR activation by Achilles tendon tenotomy is inhibited in TNFα-deficient mice. CONCLUSION: The TNFα-mTOR axis could be targeted therapeutically to prevent trauma-induced ectopic ossification in tendons.

Inhibition of NF-κB Signaling-Mediated Crosstalk Between Macrophages and Preosteoblasts by Metformin Alleviates Trauma-Induced Heterotopic Ossification.

Heterotopic ossification (HO) is a pathological condition that occurs in soft tissues following severe trauma. The exact pathogenesis of HO remains unclear. Studies have shown that inflammation predisposes patients to the development of HO and triggers ectopic bone formation. Macrophages are crucial mediators of inflammation and are involved in HO development. The present study investigated the inhibitory effect and underlying mechanism of metformin on macrophage infiltration and traumatic HO in mice. Our results found that abundant levels of macrophages were recruited to the injury site during early HO progression and that early administration of metformin prevented traumatic HO in mice. Furthermore, we found that metformin attenuated macrophage infiltration and the NF-κB signaling pathway in injured tissue. The monocyte-to-macrophage transition in vitro was suppressed by metformin and this event was mediated by AMPK. Finally, we showed that inflammatory mediator's regulation by macrophages targeted preosteoblasts, leading to elevated BMP signaling, and osteogenic differentiation and driving HO formation, and this effect was blocked after the activation of AMPK in macrophages. Collectively, our study suggests that metformin prevents traumatic HO by inhibiting of NF-κB signaling in macrophages and subsequently attenuating BMP signaling and osteogenic differentiation in preosteoblasts. Therefore, metformin may serve as a therapeutic drug for traumatic HO by targeting NF-κB signaling in macrophages.

Role of aspirin in the prevention of heterotopic ossification following total hip replacement: a systematic review and meta-analysis.

BACKGROUND: To systematically investigate if aspirin (ASA), used as venous thromboembolism (VTE) prophylaxis, plays a role in the prevention of heterotopic ossification (HO) following total hip arthroplasty (THA) and if ASA dosage impacted the rate of HO. METHODS: Eligible studies published from January 2000 to July 2022 were identified from the computerized searching of PubMed, Scopus and Web of Science. HO was defined according to Brooker Classification. Pooled risk ratios (OR) and 95% confidence interval (CI) were estimated under a random-effect model. Additionally, combined HO incidences were compared according to ASA dosage (a regular dose of 325 bid vs. a low dose of 81 mg bid/162 mg qd). RESULTS: Thirteen studies were included. ASA administered for VTE prophylaxis was significantly associated with a reduced risk of all-grade HO following THA (univariate, OR: 0.50, 95% CI: 0.34-0.74, P < 0.001; multivariate, OR: 0.60, 95% CI: 0.49-0.73, P < 0.001). Similar results could be observed for high-grade HO (univariate, OR: 0.57, 95% CI: 0.36-0.89, P = 0.015; multivariate, OR: 0.50, 95% CI: 0.27-0.92, P = 0.026). There was a non-significant trend towards a higher incidence of HO formation for low-dose ASA (31%, 95% CI: 29-34%), compared with regular-dose ASA (21%, 95% CI: 11-33%) (P = 0.069 under test of interaction). CONCLUSIONS: ASA can be an effective option for HO prophylaxis. More well-designed trials with long-term follow-ups are encouraged to confirm the current findings and to investigate the effect of ASA dosage on HO reduction.

Is External Beam Radiation Therapy Really Associated With Low Rates of Heterotopic Ossification After Acetabular Surgery?

OBJECTIVES: Describe rate of postoperative heterotopic ossification (HO) after acetabular surgery in patients who received external beam radiation (XRT) as HO prophylaxis. DESIGN: Retrospective. SETTING: Level I trauma center. PATIENTS/PARTICIPANTS: Consecutive series of patients who presented to a single, level I, academic trauma center over a 10-year period (2008-2018) for surgical fixation of an acetabular fracture. Patients eligible for inclusion were those who underwent surgical fixation of an acetabular fracture through a posterior (Kocher-Langenbeck), combined anterior and posterior, or extensile exposure. Patients were excluded if an isolated anterior approach was performed or if an acute total hip arthroplasty was performed at the time of index surgery. INTERVENTION: XRT. MAIN OUTCOME: Severe HO (Brooker class III or IV). RESULTS: The severe HO (Brooker class III or IV) rate for entire cohort was 12% (44 of 361 patients). Of these 44 patients, 30 patients were classified as Brooker III and 14 patients were classified as Brooker IV. The Brooker IV rate for the entire cohort was 4% (14 of 361 patients). Severe HO rates showed a declining trend over the period examined, with a risk reduction of -1.0% per year (95% confidence interval -2.1% to 0.2%; P = 0.10). CONCLUSION: To our knowledge, this is the largest single consecutive series on acetabular fracture patients who received XRT as HO prophylaxis. The overall severe HO rate was 12%, which is similar to other comparably large series data on patients who did not receive XRT after surgical fixation acetabular fractures. Although these data suggest that XRT may not be beneficial when used universally for all patients, comparative studies are required to rule out the benefits of XRT for preventing HO in this population. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Indomethacin for heterotopic ossification prophylaxis following surgical treatment of elbow trauma: a randomized controlled trial.

BACKGROUND: Heterotopic ossification is a frequent complication following surgical treatment of elbow trauma. The use of indomethacin to prevent heterotopic ossification is reported in the literature; however, its effectiveness is controversial. The purpose of this randomized, double-blind, placebo-controlled study was to determine whether indomethacin is effective in reducing the incidence and severity of heterotopic ossification after surgical management of elbow trauma. METHODS: Between February 2013 and April 2018, 164 eligible patients were randomized to receive postoperative indomethacin or placebo medication. The primary outcome was the incidence of heterotopic ossification on elbow radiographs at 1-year follow-up. Secondary outcomes included the Patient Rated Elbow Evaluation score, Mayo Elbow Performance Index score, and Disabilities of the Arm, Shoulder and Hand score. Range of motion, complications, and nonunion rates were also obtained. RESULTS: At 1-year follow-up, there was no significant difference in the incidence of heterotopic ossification between the indomethacin group (49%) and the control group (55%) (relative risk, 0.89; P = .52). There were no significant differences in postoperative Patient Rated Elbow Evaluation, Mayo Elbow Performance Index, and Disabilities of the Arm, Shoulder and Hand scores or range of motion (P = .16). The complication rate was 17% in both the treatment and control groups (P > .99). There were no nonunions in either group. CONCLUSION: This Level I study demonstrated that indomethacin prophylaxis against heterotopic ossification in the setting of surgically treated elbow trauma was not significantly different from placebo.

STING contributes to trauma-induced heterotopic ossification through NLRP3-dependent macrophage pyroptosis.

Trauma-induced heterotopic ossification (HO) is featured by aberrant bone formation at extra-skeletal site. STING is a master adaptor protein linking cellular damage to immune responses, while its role in HO remains elusive. A murine burn/tenotomy model was used to mimic trauma-induced HO in vivo. We demonstrated elevated STING expression in macrophages in inflammatory stage after burn/tenotomy, and STING inhibition significantly alleviated HO formation. Activated NLRP3-dependent macrophage pyroptosis was also found in inflammatory stage after burn/tenotomy. Either STING or NLRP3 suppression reduced mature HO by weakening macrophage pyroptotic inflammation, while protective effects of STING were abolished by NLRP3 overexpression. Further, in vitro, we also found a prominent STING level in pyroptotic BMDMs. STING suppression relieved macrophage pyroptotic inflammation, while abolished by NLRP3 overexpression. Our results reveal that STING poses regulatory effects on trauma-induced HO formation, via modulating NLRP3-dependent macrophage pyroptosis. Targeting STING-NLRP3 axis represents an attractive approach for trauma-induced HO prevention.

Surgical Resection Combined with Adjuvant Radiotherapy and Non-Steroidal Anti-Inflammatory Drugs in the Treatment of Heterotopic Ossification Following Total Hip Arthroplasty.

Heterotopic ossification (HO) is a well-known complication following total hip arthroplasty (THA), with an average incidence of 30%. Patients are classified according to Brooker's staging system. In advanced stages (III and IV), HO may limit hip motion and cause intolerable pain. For these symptomatic stages, surgical excision is mandatory, usually combined with prophylaxis of recurrence with non-steroidal anti-inflammatory drugs (NSAIDs) and/or radiotherapy. We present the case of a 70-year-old woman who developed Stage IV HO after undergoing THA for left hip osteoarthritis. Surgical excision of the HO was performed eighteen months after THA, with adjuvant radiotherapy and indomethacin. After two years of follow-up, the patient had a good hip function with no recurrence of HO. Several authors have studied the effect of NSAIDs and radiotherapy in HO prophylaxis and in HO treatment but there is lack of reports concerning the combination of the two strategies with surgery in the postoperative period. We therefore report this successful case of post-THA HO treatment with surgical excision and post-operative radiotherapy and NSAIDs.

A ossificação heterotópica (OH) é uma complicação frequente após artroplastia total da anca (ATA), com uma incidência média de 30%. Os doentes são classificados de acordo com o sistema de estadiamento de Brooker. Nos estádios avançados (Brooker III e IV), a OH pode restringir a mobilidade da anca e causar dores insuportáveis. Nestes estádios sintomáticos, o tratamento indicado consiste na excisão cirúrgica combinada com profilaxia da recorrência com anti-inflamatórios não esteróides (AINEs) e/ou radioterapia. Apresentamos o caso de uma mulher de 70 anos que desenvolveu OH grau IV após ATA por osteoartrose da anca esquerda. Realizou-se excisão da OH um ano e meio após a ATA, com radioterapia e indometacina adjuvantes. Após dois anos de seguimento, não se verifica recorrência da OH e apresenta uma boa função da anca. O efeito dos AINEs e radioterapia adjuvante na profilaxia e no tratamento da HO está bem estabelecido, mas não há muitos relatos das duas estratégias combinadas com cirurgia no pós-operatório. Descrevemos, portanto, um caso de tratamento de OH pós-ATA com excisão das ossificações e radioterapia e AINEs no pós-operatório.

Heterotopic Ossification Prophylaxis in Acetabular Fracture Surgery: A Systematic Review.

Heterotopic ossification (HO) following acetabular fracture surgery is relatively common. The purpose of this study was to perform a systematic review of the literature regarding HO rates following acetabular surgery and the effectiveness of the various prophylactic measures taken to prevent its occurrence. A search of PubMed, MEDLINE, and Cochrane Database of Systematic Reviews was performed using the search terms ("Acetabular" OR "Acetabulum") AND ("Heterotopic Ossification" OR "HO" OR "Ectopic Ossification"). Inclusion criteria included articles published in English reporting on HO in acetabular fracture surgery. Descriptive statistics were calculated with categorical data presented as frequency with percentages and continuous data as means. Standard weighted means were calculated for all parameters. Sixty-six articles were included in this study with a total of 5,028 patients. HO was identified in 1,511 (30%) of fractures. Indomethacin (27%) and radiation therapy (24%) demonstrated decreased rates of HO formation versus no prophylaxis (36%). In particular, rates of severe HO formation were substantially decreased with radiation therapy (3%) and indomethacin (7%) compared to no prophylaxis (18%). Indomethacin and radiation therapy both appear to decrease HO formation and severity without substantially increasing surgical morbidity. (Journal of Surgical Orthopaedic Advances 32(4):217-224, 2023).

Could temporary external fixation after reduction of displaced acetabular fractures prevent posttraumatic heterotopic ossification?

OBJECTIVES: To recommend appropriate immobilization after the initial reduction of acetabular displaced fractures in order to minimize the risk of heterotopic ossification formation. DESIGN: Retrospective study of patients treated in our surgical department during the years 2005-2018. MATERIALS AND METHODS: There were 94 patients included in statistical analysis. The factors of injury severity, course of surgery and hospitalization and incidence of complications were recorded. The functional and X-ray results were evaluated at least one year after surgery. RESULTS: The patients were divided into the two groups according to the type of fixation after closed reduction, the external fixation (EF) and the skeletal traction (ST) group. According to the type of fracture there were 33 patients with central displacement and 61 patients with posterior displacement. Ossification grade III. And IV. Occur in 20% of our sample. There was greater incidence of Brooker grade III. And IV. Ossification in the ST group, but statistically insignificant, p = 0.57. There was no statistically significant difference in the occurrence of ossifications regarding the severity of the head injury, p = 0.11, or to the severity of the injury p = 0.54. The combination of posterior displacement and ST results in higher risk for ossifications, specifically in our group at 11.48% compared to the combination of posterior displacement and EF where it is 8.2%. CONCLUSION: Skeletal traction for posterior displaced acetabular fracture appears to be a more risky procedure for the development of ossifications than external fixation.

Fifteen years' experience of radiation therapy for resected advanced heterotopic ossification following motor vehicle accidents: outcome and side effects.

BACKGROUND: Surgical resection is the primary treatment for advanced-stage heterotopic ossification (HO), with a high incidence of local recurrence reaching up to 50%. Postoperative radiotherapy (PORT) and indomethacin are commonly used prophylactic strategies following surgery. The study aims to assess the safety and effectiveness of PORT in advanced-stage HO patients having motor vehicle accidents (MVA). METHODS: Medical records of patients having HO following MVA between 2006 and 2021 were retrospectively reviewed. Thirty-nine patients with advanced disease (35 had hip HO and 4 had elbow HO) were included in the study. RESULTS: Excision of HO with joint preservation was performed for 82% of patients, while 18% had a joint replacement. Seven to 8 Gy radiation was given to all patients within 3 days postoperatively. A ninty seven percent of patients regained partially the movement range. The mean follow-up time was 74 months. Six patients had treatment failure, with only one having a recurrence of HO. The 8-year treatment failure-free rate (8-y TFFR) was 79.3±9%, and the 5-year HO failure-free rate (5y-HOFFR) was 97.2±3%. Acute side effects were experienced in 13% of patients but resolved without any consequences. Despite the relatively long follow-up time, we did not report any absolute infertility or secondary malignancies related to the radiation. The testicular mean calculated dose was 33±44 cGy, and the mean measured dose was 58±40 cGy. Of the 35 patients who received radiation to the pelvis, 26 were married, and all did not experience infertility post-treatment. CONCLUSION: PORT proved an effective and safe treatment for advanced-stage HO disease. The treatment failure is mainly related to surgical difficulties due to advanced disease. Treatment using a 3-dimensional or intensity-modulated radiation therapy is not associated with serious side effects like second malignancy or absolute infertility.

Prophylactic Radiotherapy for Prevention of Heterotopic Ossification After Periacetabular Fractures: A Review of Efficacy and Associated Conditions.

Prophylactic radiotherapy (XRT) is a commonly used treatment to decrease heterotopic ossification (HO) in patients with traumatic hip injuries. We conducted a retrospective review of patients at risk for HO who underwent XRT. Of the patients reviewed, 27.3% developed radiographic HO, 11.2% developed symptoms, and 2.0% required resection surgery. Patients were divided into primary (n = 71) and secondary prophylaxis (n = 27) cohorts. In the primary group, 25.0% developed radiographic HO, 5.6% developed symptoms, and 0 required surgery. In the secondary cohort, 33.3% of patients developed new radiographic HO, and 25.9% were symptomatic: four had a Brooker score of 3, and three had a score of 4 (p = 0.03), and 7.4% required surgical resection. (Journal of Surgical Orthopaedic Advances 31(2):113-118, 2022).

Three weeks of indomethacin is not superior to 1 week of meloxicam as prophylaxis for heterotopic ossifications after distal biceps tendon repair with a single-incision technique.

BACKGROUND: The aim of this study was to assess the efficacy of 3 weeks of indomethacin, a nonselective nonsteroidal anti-inflammatory drug, in comparison to 1 week of meloxicam as prophylaxis for heterotopic ossifications (HOs) after distal biceps tendon repair. METHODS: A single-center retrospective study was performed on 78 patients undergoing distal biceps tendon repair between 2008 and 2019. From 2008 to 2016, patients received meloxicam 15 mg daily for the period of 1 week as usual care. From 2016 onward, the standard protocol was changed to indomethacin 25 mg 3 times daily for 3 weeks. All patients underwent a single-incision repair with a cortical button technique. The postoperative rehabilitation protocol was similar for all patients. The postoperative radiographs at 8-week follow-up were assessed blindly by 7 independent assessors. If HOs were present, it was classified according to the Ilahi-Gabel classification for size and according to the Gärtner-Heyer classification for density. Statistical analysis was performed to analyze the difference in HO between the patients who were treated with indomethacin and with meloxicam. RESULTS: Seventy-eight patients, with a mean age of 48.8 years (range 30-72) were included. The mean follow-up after surgery was 12 months (range 2-45). Indomethacin (21 days, 25 mg 3 times per day) was prescribed to 26 (33%) patients. The 52 other patients (67%) were prescribed meloxicam 15 mg daily for 7 days. HOs were seen in 19 patients 8 weeks postoperatively. Five of 26 patients treated with indomethacin developed HO, and 14 of 52 patients treated with meloxicam developed HO (P = .5). Two patients had symptomatic HO with minor restrictions in movement; neither patient was treated with indomethacin. Significantly more HOs were seen in patients with a longer time from injury to surgery (P = .01) The intraclass correlation score for reliability between assessors for HO scoring on postoperative radiographs was good to excellent for both classifications. CONCLUSION: In this study, HOs were seen in 24% of postoperative radiographs. Three weeks of indomethacin was not superior to meloxicam for 1 week for the prevention of HO after single-incision distal biceps tendon repair.

Palovarotene inhibits the NF-κB signalling pathway to prevent heterotopic ossification.

Heterotopic ossification (HO) is a common disease characterized by pain, dysfunction and calcification. The mechanisms underlying HO have not been completely elucidated. Palovarotene, a retinoic acid receptor γ agonist, significantly inhibits the formation of HO in vivo. However, its specific mechanism of action remains unclear. Therefore, we aimed to evaluate the signalling pathways related to the formation of HO as well as the mechanism of palovarotene action. We constructed in vitro and in vivo models of HO. Osteogenic differentiation of bone mesenchymal stem cells (BMSCs) was observed by alizarin red and alkaline phosphatase staining assays in vitro. X-ray and haematoxylin-eosin staining were performed in vivo. Western blots and reverse transcription-polymerase chain reaction were performed to determine the levels of osteogenic- and inflammation-related genes. Immunofluorescence and immunocytochemistry were used to assess the levels of p65, the core molecule of the nuclear factor κ-B (NF-κB) signalling pathway. We demonstrated that, in vitro, under inflammatory stimulation, pathological calcium deposition increased in BMSCs. The levels of osteogenesis- and inflammation-related genes were also upregulated, along with an enhanced expression of p65. Immunofluorescence assays revealed that p65 entered the nucleus, thereby stimulating the downstream effectors of the NF-κB pathway. The above trends were reversed after palovarotene treatment. In conclusion, the NF-κB signalling pathway played an important role in HO, and palovarotene could alleviate HO by blocking the NF-κB cascade. Our results may provide a theoretical basis for palovarotene in the treatment of HO. Further studies on the side effects of palovarotene are warranted in the future.

Incidence of heterotopic ossification following hip arthroscopy is low: considerations for routine prophylaxis.

PURPOSE: This scoping review aims to map and summarise the available literature on heterotopic ossification (HO) following hip arthroscopy, with particular focus on incidence, distribution as per Brooker classification, efficacy of prophylactic measures and factors that may influence the likelihood of production of HO. METHODS: A computer-based search was performed on PubMed, Embase, Emcare, Cinahl, ISI web of science and Scopus using the terms 'heterotopic ossification' and 'hip arthroscopy'. Articles reporting heterotopic ossification following hip arthroscopy for any condition were included after two-stage title/abstract and full-text screening. RESULTS: Of the 663 articles retrieved, 45 studies were included. The proportion of patients with HO ranged from 0 to 44%. The majority of the cases were either Brooker grade I or II. Of the six studies investigating the effect of NSAID prophylaxis, five reported a significantly lower incidence of heterotopic ossification associated with its use. Weak evidence suggests that an outside-in arthroscopic approach, no capsular closure, male sex and mixed cam and pincer resection may be associated with an increased risk of HO. CONCLUSION: Although there is a large variation in rates of HO following hip arthroscopy in the current literature, the majority of studies report a low incidence. Evidence exists advocating the administration of post-operative NSAIDs to reduce the incidence of HO following hip arthroscopy. This, combined with the low risk of complications, means there is a favourable risk-benefit ratio for prophylactic NSAID used in HA. Future research should work to identify patient clinical and demographic factors which may increase the risk of development of HO, allowing clinicians to risk stratify and select only specific patients who would benefit from receiving NSAID prophylaxis.