Heterotopic ossification (HO) refers to the formation of bone tissue outside the normal skeletal system. According to its pathogenesis, HO is divided into hereditary HO and acquired HO. There currently lack effective approaches for HO prevention or treatment. A deep understanding of its pathogenesis will provide promising strategies to prevent and treat HO. Studies have shown that the hypoxia-adaptive microenvironment generated after trauma is a potent stimulus of HO. The hypoxic microenvironment enhances the stability of hypoxia-inducible factor-1α (HIF-1α), which regulates a complex network including bone morphogenetic proteins (BMPs), vascular endothelial growth factor (VEGF), and neuropilin-1 (NRP-1), which are implicated in the formation of ectopic bone. In this review, we summarize the current understanding of the triggering role and underlying molecular mechanisms of the hypoxic microenvironment in the initiation and progression of HO, focusing mainly on HIF-1 and it's influenced genes  BMP, VEGF, and NRP-1. A better understanding of the role of hypoxia in HO unveils novel therapeutic targets for HO that reduce the local hypoxic microenvironment and inhibit HIF-1α activity.

/pdf/the-hypoxic-microenvironment-a-driving-force-for-heterotopic-q11igtkzeo.pdf

The hypoxic microenvironment: a driving force for heterotopic ossification progression.

Objective To (1) investigate the extent to which recently published meta-analyses report trial funding, author–industry financial ties and author–industry employment from included randomised controlled trials (RCTs), comparing Cochrane and non-Cochrane meta-analyses; (2) examine characteristics of meta-analyses independently associated with reporting funding sources of included RCTs; and (3) compare reporting among recently published Cochrane meta-analyses to Cochrane reviews published in 2010. Design Review of consecutive sample of recently published meta-analyses. Data sources MEDLINE database via PubMed searched on 19 October 2018. Eligibility criteria for selecting articles We selected the 250 most recent meta-analyses listed in PubMed that included a documented search of at least one database, statistically combined results from ≥2 RCTs and evaluated the effects of a drug or class of drugs. Results 90 of 107 (84%) Cochrane meta-analyses reported funding sources for some or all included trials compared with 21 of 143 (15%) non-Cochrane meta-analyses, a difference of 69% (95% CI 59% to 77%). Percent reporting was also higher for Cochrane meta-analyses compared with non-Cochrane meta-analyses for trial author–industry financial ties (44% versus 1%; 95% CI for difference 33% to 52%) and employment (17% versus 1%; 95% CI for difference 9% to 24%). In multivariable analysis, compared with Cochrane meta-analyses, the odds ratio (OR) for reporting trial funding was ≤0.11 for all other journal category and impact factor combinations. Compared with Cochrane reviews from 2010, reporting of funding sources of included RCTs among recently published Cochrane meta-analyses improved by 54% (95% CI 42% to 63%), and reporting of trial author–industry financial ties and employment improved by 37% (95% CI 26% to 47%) and 10% (95% CI 2% to 19%). Conclusions Reporting of trial funding sources, trial author–industry financial ties and trial author–industry employment in Cochrane meta-analyses has improved since 2010 and is higher than in non-Cochrane meta-analyses.

https://bmjopen.bmj.com/content/bmjopen/10/5/e035633.full.pdf

Reporting of drug trial funding sources and author financial conflicts of interest in Cochrane and non-Cochrane meta-analyses: a cross-sectional study.

Heterotopic ossification (HO) is prevalent after total hip arthroplasty (THA). Oral nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 (COX-2) inhibitors have reduced the incidence of HO; however, to the authors' knowledge, no studies have reported the incidence and severity of HO with a pain protocol highlighted by celecoxib in the pre- and postoperative period with a posterolateral approach. Between October 2014 and October 2015, a retrospective study was conducted of 687 consecutive primary THAs with minimum 1-year follow-up performed between January 2009 and December 2013. All patients underwent a posterolateral THA with a multimodal pain protocol consisting of preoperative celecoxib; local steroid infiltration intraoperatively; postoperative celecoxib, dexamethasone, and ketorolac; and aspirin or warfarin thromboprophylaxis. For all patients, pre- and postoperative radiographs were examined and classified for HO using the Brooker classification. Interobserver reliability was calculated for both incidence of HO and Brooker classification. Overall, HO was present around 98 (14.3%) THAs. The incidence of Brooker I, II, and III HO was 38 (5.5%), 47 (6.8%), and 12 (1.7%), respectively. No patients required surgical excision or had radiographic evidence of Brooker IV HO. Multivariate logistic regression identified male sex and hypertrophic osteoarthritis as significant risk factors. The use of aspirin for thromboprophylaxis significantly reduced the incidence of HO. This study found the overall incidence of HO when using celecoxib during a posterior THA to be 14.3%, which is similar to what others have reported with the direct lateral approach and with other COX-2 inhibitors for a posterior approach. Risk factors include male sex and preoperative hypertrophic osteoarthritis. [Orthopedics. 2018; 41(1):e92-e97.].

Incidence of Heterotopic Ossification Following a Multimodal Pain Protocol in Total Hip Arthroplasty With the Posterior Approach

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 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.

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

A systematic review and meta-analysis of naproxen for prevention heterotopic ossification after hip surgery.

This meta-analysis aimed to assess whether the specific nonsteroidal anti-inflammatory drug (NSAID) naproxen has a role in reducing the occurrence of heterotopic ossification after hip surgery. Potential studies were identified in the following electronic databases: PubMed, EMBASE, Web of Science, Cochrane Library, and Google. We included studies involving hip surgery patients in which the intervention group received naproxen and the control group received placebo. The occurrence of heterotopic ossification and complications were the final outcomes. Stata 13.0 was used for the meta-analysis. Four randomized controlled trials (RCTs) involving 269 patients were ultimately included in this meta-analysis. The use of naproxen was associated with a significant reduction in the occurrence of heterotopic ossification at 1.5-, 3-, 6-, and 12-month follow-ups (P   0.05). Our analysis indicates that naproxen can decrease the occurrence of heterotopic ossification without increasing complications in hip surgery patients. Due to the limited number of studies included, more high-quality RCTs are needed to identify the optimal dose of naproxen.

/pdf/efficacy-of-naproxen-prophylaxis-for-the-prevention-of-4k5h8gjv9c.pdf

Efficacy of naproxen prophylaxis for the prevention of heterotopic ossification after hip surgery: a meta-analysis

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Efficacy of naproxen prophylaxis for the prevention of heterotopic ossification after hip surgery: a meta-analysis