Verteporfin attenuates trauma-induced heterotopic ossification of Achilles tendon by inhibiting osteogenesis and angiogenesis involving YAP/ß-catenin signaling.

Heterotopic ossification occurs as a pathological ossification condition characterized by ectopic bone formation within soft tissues following trauma. Vascularization has long been established to fuel skeletal ossification during tissue development and regeneration. However, the feasibility of vascularization as a target of heterotopic ossification prevention remained to be further clarified. Here, we aimed to identify whether verteporfin as a widely used FDA-approved anti-vascularization drug could effectively inhibit trauma-induced heterotopic ossification formation. In the current study, we found that verteporfin not only dose dependently inhibited the angiogenic activity of human umbilical vein endothelial cells (HUVECs) but also the osteogenic differentiation of tendon stem cells (TDSCs). Moreover, YAP/ß-catenin signaling axis was downregulated by the verteporfin. Application of lithium chloride, an agonist of ß-catenin, recovered TDSCs osteogenesis and HUVECs angiogenesis that was inhibited by verteporfin. In vivo, verteporfin attenuated heterotopic ossification formation by decelerating osteogenesis and the vessels densely associated with osteoprogenitors formation, which could also be readily reversed by lithium chloride, as revealed by histological analysis and Micro-CT scan in a murine burn/tenotomy model. Collectively, this study confirmed the therapeutic effect of verteporfin on angiogenesis and osteogenesis in trauma-induced heterotopic ossification. Our study sheds light on the anti-vascularization strategy with verteporfin as a candidate treatment for heterotopic ossification prevention.

Heterotopic ossification following total hip arthroplasty. Which is the predominant risk factor: surgical approach or post-operative prophylaxis?

PURPOSE: To investigate the impact of surgical approach and post-operative prophylaxis on heterotopic ossification (HO) development after total hip arthroplasty (THA). METHODS: A retrospective analysis of 312 patients who underwent THA between January 2009 and April 2016. Patients were categorized by surgical approach (direct lateral or posterolateral), prosthesis type, and post-operative prophylaxis (Etoricoxib 60 mg daily for two weeks). Two orthopaedic surgeons independently assessed radiographs at serial intervals, and HO was graded as per Brooker classification. Bivariate analysis and regression modelling were performed to assess the associations and confounding effects of different variables, RESULTS: Bivariate analysis identified factors correlated with higher HO incidence: absence of prophylaxis, older age, longer symptom evolution, and lower pre-surgery physical activity. Regression modelling showed a correlation between the direct-lateral approach, post-operative prophylaxis, symptom evolution, and higher HO incidence. CONCLUSION: Patients with longer symptom evolution before surgery and without post-operative prophylaxis are at higher risk of developing HO. While the direct lateral approach showed higher HO rates, the difference was insignificant. A two-week prophylactic regimen of Etoricoxib 60 mg daily after THA effectively reduced HO formation. Pharmacological prophylaxis should be evaluated case-by-case, considering patient characteristics and risk factors.

Berberine and aspirin prevent traumatic heterotopic ossification by inhibition of BMP signalling pathway and osteogenic differentiation.

Heterotopic ossification (HO) is a pathological process that often occurs in soft tissues following severe trauma. There is no effective therapy for HO. The BMP signalling pathway plays an essential role in the pathogenesis of HO. Our previous study showed that AMPK negatively regulates the BMP signalling pathway and osteogenic differentiation. The present study aims to study the effect of two AMPK activators berberine and aspirin on osteogenic differentiation and HO induced by traumatic injury. The effects of two AMPK activators, berberine and aspirin, on BMP signalling and osteogenic differentiation were measured by western blot, ALP and Alizarin red S staining in C3H10T1/2 cells. A mouse model with Achilles tenotomy was employed to assess the effects of berberine and aspirin on HO using µCT and histological analysis. First, our study showed that berberine and aspirin inhibited phosphorylation of Smad1/5 induced by BMP6 and the inhibition was attributed to the down-regulation of ALK2 expression. Second, the combination of berberine and aspirin yielded more potent effects on BMP signalling. Third, we further found that there was an additive effect of berberine and aspirin combination on osteogenic differentiation. Finally, we found that berberine and aspirin blocked trauma-induced ectopic bone formation in mice, which may be through suppression of phosphorylation of Smad1/5 in injured tissues. Collectively, these findings indicate that berberine and aspirin inhibit osteogenic differentiation in C3H10T1/2 cells and traumatic HO in mice, possibly through the down-regulation of the BMP signalling pathway. Our study sheds a light on prevention and treatment of traumatic HO using AMPK pharmacological activators berberine and aspirin.

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.

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.

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.

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).

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.

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.

Incidence and Risk Factors for Heterotopic Ossification in a Matched Cohort Adolescent Population Undergoing Hip Arthroscopy.

BACKGROUND: Heterotopic ossification (HO) is a known complication after hip arthroscopy in adults, positively associated with larger cam resection, male sex, older age, and obesity, and negatively associated with nonsteroidal anti-inflammatory drug (NSAID) use and capsular closure. However, it has not been well-documented in adolescents. The purpose of this study was to determine the incidence and risk factors for the development of HO in adolescent patients undergoing hip arthroscopy. METHODS: Clinical and operative records from a pediatric institution were queried to identify patients aged 21 years or younger who underwent hip arthroscopy between 2008 and 2018. The 27 cases that developed HO were matched 1:4 on age and sex with 107 controls. The bivariate analysis assessed the relationship between demographic and perioperative factors on the development of HO. Multivariable logistic regression evaluated the association between prophylactic NSAID use (indomethacin 75 mg, 3 wk) and HO, controlling for surgeon and extent of cam resection (change in alpha angle). RESULTS: Twenty-seven of 595 (4.5%) hips that underwent hip arthroscopy developed HO within 2 years of surgery. Prophylactic indomethacin was not significantly associated with developing HO [30% (8/27), P=0.83], after controlling for surgeon and extent of cam resection-nor were age, sex, and body mass index percentile. Of patients who developed HO, a smaller proportion underwent reoperation for HO excision among those who received prophylactic indomethacin than those who did not [13% (1/8) vs. 63% (12/19), P=0.03]. CONCLUSIONS: The incidence of HO within 2 years of hip arthroscopy in this adolescent population was 4.5%. Although studies in the adult hip arthroscopy population have pointed to a protective role of NSAIDs (eg, indomethacin) in radiographic HO, the effect was less certain in this adolescent sample. Larger studies are important to further evaluate the role of prophylactic NSAIDs and variations in arthroscopic technique in developing HO. LEVEL OF EVIDENCE: Level III-therapeutic, case-control study.

Heterotopic Ossification Prophylaxis Following Operative Fixation of Acetabular Fractures: A Systematic Review.

INTRODUCTION: Heterotopic ossification (HO) is a well-recognized complication following operative fixation of acetabular fractures with a range of severity and clinical consequences. The purpose of this review was to: (1) report the incidence of heterotopic ossification (HO) formation following operative fixation of acetabular fractures; (2) determine the effectiveness of prophylactic treatments for HO; and (3) assess the radiographic severity of HO with and without prophylactic treatment. MATERIALS AND METHODS: A literature search for peer-reviewed articles was conducted utilizing a variety of research databases. PRISMA guidelines were followed and included in this review were full-length, English language manuscripts published before September 2019, using the following search criteria: "heterotopic ossification AND acetabulum OR acetabular." Studies that reported HO as one of the reported outcomes were included. Articles were excluded if radiographic HO was not reported and if it was evaluated in surgeries other than those involved in acetabular fractures. Extracted data included, but was not limited to: type of prophylaxis; incidence of HO; severity of HO based on the Brooker classification; and statistical significance. A methodologic quality appraisal of the included studies was also conducted. A total of 54 full-text studies with 5,890 patients with operatively fixed acetabular fractures met inclusion criteria. There were four level I studies, four level II study, 26 level III studies, and 20 level IV studies. RESULTS: The overall incidence of HO after acetabular fracture surgery was 28.4%. The rate of HO formation was: 34.9% without prophylaxis, 28.3% with non-steroidal anti-inflammatory drugs (NSAID) prophylaxis, and 21.2% with radiation therapy (RT). Patients receiving a combination of both RT and NSAIDs developed HO 21.8% of the time. The rate of radiographic severe HO was 13.9% (range, 0-75%) in patients without prophylaxis, 9.4% (range, 0-50%) with NSAID prophylaxis, 5.7% (range, 0-12.8%) with RT prophylaxis, and 11.7% (range, 0-18.5%) with the combination of RT and NSAIDs. CONCLUSION: With the current literature collected in this systematic review, there was a lower incidence and severity of heterotopic bone formation following acetabular fracture fixation using radiation prophylaxis compared to NSAIDs or no treatment. The available literature is heterogeneous in fracture characteristics, surgical approaches, and prophylactic regimens with a general lack of randomized control trials. Further prospective studies are required to make definitive claims on the optimal prophylactic strategy to prevent heterotopic ossification.

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.

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).

Selective versus non-selective NSAIDs as prophylaxis for heterotopic ossification following hip arthroplasty: a meta-analysis.

BACKGROUND: Some patients have demonstrated evidence of heterotopic ossification (HO) following total hip arthroplasty (THA). Selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) are used as prophylaxis for HO following THA. This meta-analysis compared selective versus non-selective NSAIDs as prophylaxis for HO following THA. MATERIAL AND METHODS: The present study was conducted according to the PRISMA 2020 guidelines. All the clinical investigations comparing selective versus non-selective NSAIDs as prophylaxis for HO following THA were accessed in February 2022. An assessment of the methodological quality and statistical analyses were performed through the risk of bias summary tool of the Review Manager 5.3 software (Cochrane Collaboration, Copenhagen). The modified Brooker staging system was used to rate the efficacies of the interventions. RESULTS: Data from 8 studies and 1526 patients were collected. 60.8% were female. No difference was found in the sample size, mean age, and percentage of females between the two groups at baseline. No statistically significant difference was found between selective and non-selective NSAIDs in term of efficacy. 72% (1078 of 1502) of the patients were classified as Brooker 0, 21% (322 of 1502) as Brooker I, 5% (80 of 1502) as Brooker II, 1% (16 of 1502) as Brooker III, and 0.1% (2 of 1502) as Brooker IV. CONCLUSION: Selective and non-selective NSAIDs were equally effective when used as prophylaxis for HO following THA. LEVEL OF EVIDENCE: Level III, systematic review and meta-analysis.

Inhibition of IL-17 prevents the progression of traumatic heterotopic ossification.

Traumatic heterotopic ossification (HO) is the abnormal formation of bone in soft tissues as a consequence of injury. However, the pathological mechanisms leading to traumatic HO remain unknown. Here, we report that aberrant expression of IL-17 promotes traumatic HO formation by activating ß-catenin signalling in mouse model. We found that elevated IL-17 and ß-catenin levels are correlated with a high degree of HO formation in specimens from patients and HO animals. We also show that IL-17 initiates and promotes HO progression in mice. Local injection of an IL-17 neutralizing antibody attenuates ectopic bone formation in a traumatic mouse model. IL-17 enhances the osteoblastic differentiation of mesenchymal stem cells (MSCs) by activating ß-catenin signalling. Moreover, inhibition of IL-17R or ß-catenin signalling by neutralizing antibodies or drugs prevents the osteogenic differentiation of isolated MSCs and decreases HO formation in mouse models. Together, our study identifies a novel role for active IL-17 as the inducer and promoter of ectopic bone formation and suggests that IL-17 inhibition might be a potential therapeutic target in traumatic HO.

NSAIDs for Prophylaxis for Heterotopic Ossification After Total Hip Arthroplasty: A Bayesian Network Meta-analysis.

Non-steroidal anti-inflammatory drugs (NSAID) have been recommended to prevent of heterotopic ossification (HO) after total hip arthroplasty (THA), but debates are still ongoing. The present Bayesian network meta-analysis of randomized clinical trials (RCTs) compared all available pathways of NSAID treatment as prophylaxis for HO after THA. The present Bayesian network meta-analysis was conducted according to The PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions guidelines. All randomized clinical trials comparing two or more interventions to prevent HO after THA were considered for analysis. HO was classified according to Brooker. The quality of the methodological assessment was performed through the risk of bias summary tool of the Review Manager Software 5.3 (The Cochrane Collaboration, Copenhagen). The network meta-analysis was performed through a STATA routine for Bayesian hierarchical random-effects model analysis, with log odd ratio (LOR) effect measure. Data from 26 studies (6396 THAs; 58% females) were collected. The mean follow-up was 10.50 ± 5.7 months. ANOVA showed good comparability among mean age and gender (P > 0.5). Celecoxib demonstrated the highest rate of Brooker class 0 (LOR 6.96), followed by diclofenac (LOR 6.94). Naproxen demonstrated the lowest rate of Brooker I HO (LOR 2.82), followed by celecoxib (LOR 3.52). Celecoxib demonstrated lowest rate of Brooker class II HO (LOR 1.66), class III (LOR), and class IV (LOR 0.25). The equation for global linearity detected no statistically significant inconsistency (P > 0.5) in all the comparisons. The present Bayesian network meta-analysis encourages the use of celecoxib as a prophylaxis for HO. These conclusions must be interpreted in light of the limitations of the present study. Future investigations are required to establish more definitely the role of celecoxib.Level of Evidence: I, Bayesian network analysis of RCTs.

Heterotopic Ossification Following Direct Anterior Total Hip Arthroplasty With and Without Postoperative Analgesic Nonsteroidal Anti-inflammatories.

BACKGROUND: Heterotopic ossification (HO) can result in poorer clinical outcomes following total hip arthroplasty (THA). Multiple modes of intervention have been evaluated for HO prevention, including the use of nonsteroidal anti-inflammatories. Additionally, multimodal pain management strategies including celecoxib have become more prominent. Therefore, this study aims to evaluate the influence of celecoxib as part of postoperative analgesia on the risk of developing HO following the direct anterior approach (DA) for THA. METHODS: A retrospective query identified primary DA THAs performed by a single surgeon between 2013 and 2020. Patients were grouped according to those who received 3 weeks celecoxib upon discharge, and those who did not. Radiographs were used to categorize patients according to the Brooker classification system for HO. Preoperative and 2-week, 6-week, 3-month, and 1-year postoperative X-rays were evaluated. RESULTS: A total of 688 DA THAs were included, demonstrating a 9.6% (n = 66) incidence of HO with Brooker classification: 1: 5.7% (n = 39); 2: 2.6% (n = 18); 3: 1.2% (n = 8); and 4: 0.1% (n = 1). Patients who did not receive celecoxib had a 14.3% (52/364) rate of HO following THA (odds ratio 4.53, P < .001) vs only 4.3% (14/324) in the celecoxib group (odds ratio 0.22, P < .001). Overall, 9 patients (1.3%) went on to develop significant HO (Booker 3 or greater): 8 (2.2%) in the control group and 1 (0.3%) in the celecoxib group (P < .001). CONCLUSION: Our findings suggest a significant reduction in the formation of HO following DA THA when using postoperative analgesic celecoxib as part of a multimodal pain protocol. Future prospective randomized studies are needed to identify ideal dosage, duration, and formulation to reduce the risk of HO while optimizing multimodal pain management.

Low-Dose Aspirin Administered for Venous Thromboembolism Prophylaxis Reduces the Incidence of Heterotopic Ossification in Total Joint Arthroplasty.

BACKGROUND: Heterotopic ossification (HO) is a common complication following total joint arthroplasty (TJA). However, the pathophysiology of HO is not entirely understood. Inflammation may play a significant role in the pathogenesis of HO as nonsteroidal anti-inflammatory drugs are effective in the prevention of HO. The purpose of this study is to examine if aspirin (ASA), when used as venous thromboembolism (VTE) prophylaxis, influenced the rate of HO formation following TJA. METHODS: We queried our longitudinally maintained database to identify all patients who underwent primary total hip arthroplasty (THA) or total knee arthroplasty (TKA) for osteoarthritis between January 2016 and June 2018 with at least 3-month radiographic follow-up. In total, 1238 THAs and 1051 TKAs were included for analysis. Radiographs were reviewed and HO formation graded according to the Brooker classification. Patient demographic and VTE prophylaxis data were collected and reviewed for accuracy. Univariate and multivariate analysis was performed to evaluate the effect of ASA on HO formation. RESULTS: The overall rate of HO was 37.5% after THA and 17.4% after TKA. Patients receiving ASA were less likely to develop HO after THA (34.8% vs 45.5%; P < .001), as well as HO after TKA (13.4% vs 18.4%; P = .047) compared to patients receiving non-ASA VTE prophylaxis. The rate of HO formation trended to be lower, albeit not statistically significantly, in patients receiving low-dose ASA (81 mg) vs high-dose ASA (325 mg). CONCLUSION: Patients undergoing primary TJA receiving ASA for VTE prophylaxis were less likely to develop HO compared to patients who were administered non-ASA VTE prophylaxis.

[Tranexamic Acid Reduces the Incidence of Heterotopic Ossifications after Elective Primary Total Hip Arthroplasty]. / Kyselina tranexamová snizuje výskyt heterotopických osifikací po primární elektivní TEP kycelního kloubu.

PURPOSE OF THE STUDY Heterotopic ossification is a frequent and a well-known complication after elective primary total hip arthroplasty. Prophylaxis is crucial since once the ossification is mature, the only treatment option is its surgical removal during revision hip surgery. There are pre-, peri- and postoperative prophylactic modalities. Ranking among the perioperative possibilities is the application of tranexamic acid in blood control management. The aim of our study is to prove the positive side effect of tranexamic acid application on reducing the heterotopic ossification ratio. MATERIAL AND METHODS A cohort of 401 total hip replacements was assessed retrospectively in the period from 2012 to 2016. Particular degrees were stratified based on the Brooker classification, sex, laterality and type of implant fixation. The average follow-up period is 6.10 years (range 40 m to 113 m). The hips treated in 2012 are taken as reference and the hips treated in 2016 are exposed to tranexamic acid protocol. Other secondary prophylactic modalities (pharmacological prophylaxis or radiotherapy), tertiary modalities (revision surgery) and trauma patients were excluded from the study. The acquired data were then statistically assessed. RESULTS Tranexamic acid protocol significantly reduces the incidence of heterotopic ossification after elective primary total hip replacement. In our cohort of 401 hips, the overall incidence of HO is 40.6%. The difference between the control group - 49.7% and the exposed group - 30.2% is statistically significant. More importantly, the clinically relevant types (III and IV) were also significantly reduced (12.7% vs. 4.2%). Other associated parameters such as uncemented implant, female sex and right-sided surgery further reduced the incidence of ossifications. DISCUSSION Identification of the risk patient, risk factors and subsequent care to maintain the range of motion, analgesia or potential removal of ossifications remain to be the priority in managing heterotopic ossifications after THA. Preoperative options to reduce the incidence of this complication are limited. Moreover, both the pharmacological prophylaxis and radiotherapy are associated with major complications and strict patient compliance is fundamental. Inclusion of simple tranexamic acid protocol in surgery management significantly reduces the risk of heterotopic ossification. CONCLUSIONS Development and maturation of heterotopic ossification is still intensively explored, but the main biochemical pathways are still unclear. Therefore, there is no causal treatment option nowadays. Individualisation of prophylactic treatment modalities leads to reduction in ossification development. It has been proven that one of these effective modalities is the tranexamic acid application before and after the procedure. This reduction is statistically significant and clinically relevant. Key words: tranexamic acid, total hip replacement, heterotopic ossification, prophylaxis, fixation type.

Mechanism of traumatic heterotopic ossification: In search of injury-induced osteogenic factors.

Heterotopic ossification (HO) is a pathological condition of abnormal bone formation in soft tissue. Three factors have been proposed as required to induce HO: (a) osteogenic precursor cells, (b) osteoinductive agents and (c) an osteoconductive environment. Since Urist's landmark discovery of bone induction in skeletal muscle tissue by demineralized bone matrix, it is generally believed that skeletal muscle itself is a conductive environment for osteogenesis and that resident progenitor cells in skeletal muscle are capable of differentiating into osteoblast to form bone. However, little is known about the naturally occurring osteoinductive agents that triggered this osteogenic response in the first place. This article provides a review of the emerging findings regarding distinct types of HO to summarize the current understanding of HO mechanisms, with special attention to the osteogenic factors that are induced following injury. Specifically, we hypothesize that muscle injury-induced up-regulation of local bone morphogenetic protein-7 (BMP-7) level, combined with glucocorticoid excess-induced down-regulation of circulating transforming growth factor-ß1 (TGF-ß1) level, could be an important causative mechanism of traumatic HO formation.