Search Results (36)

Heterotopic ossification (HO) refers to the pathological formation of bone in soft tissues, typically following trauma, surgical procedures, or as a result of genetic disorders. Notably, injuries to the central nervous system significantly increase the risk of HO, a condition referred to as neurogenic HO (NHO). This review outlines the cellular and molecular mechanisms driving HO, focusing on the inflammatory response, progenitor cell reprogramming, and current treatment strategies. HO is primarily fuelled by a prolonged and dysregulated inflammatory response, characterized by sustained expression of osteoinductive cytokines secreted by M1 macrophages. These cytokines promote the aberrant differentiation of fibro-adipogenic progenitor cells (FAPs) into osteoblasts, leading to ectopic mineralization. Additional factors such as hypoxia, BMP signalling, and mechanotransduction pathways further contribute to extracellular matrix (ECM) remodelling and osteogenic reprogramming of FAPs. In the context of NHO, neuroendocrine mediators enhance ectopic bone formation by influencing both local inflammation and progenitor cell fate decisions. Current treatment options such as nonsteroidal anti-inflammatory drugs (NSAIDs), radiation therapy, and surgical excision offer limited efficacy and are associated with significant risks. Novel therapeutic strategies targeting inflammation, neuropeptide signalling, and calcium metabolism may offer more effective approaches to preventing or mitigating HO progression. Full article

Background/Objectives: The aim of this study was to evaluate the impact of inhomogeneity correction (IC) of dose distribution on the dosimetric and radiobiological efficacy of radiation treatment for heterotopic ossification (HO). Methods: This study involved a retrospective analysis of 21 patients treated using a homogeneous dose distribution plan for hip prophylactic HO. These IC-off plans were evaluated against an IC-on dose distribution plan. Dosimetric and corresponding radiobiological parameters (gEUD, LQ-EUD, LQ, EQD2 for α/β = 3 and 10 Gy) were calculated. These parameters were compared for both treatment plans. Additionally, Monte Carlo simulations were performed using mean and standard deviation values from baseline data to generate 10,000 synthetic datasets, allowing for robust statistical modeling of variability in dose distributions and biological outcomes. Results: The homogeneous (IC-off) plans demonstrated overestimation of dose conformity and uniformity, reflected in lower HI values (0.10 ± 0.05 vs. 0.18 ± 0.05) and higher D_90%–D_98% coverage. Radiobiologically, these plans yielded higher gEUD (7.02 Gy vs. 6.80 Gy) and EQD2 values across all α/β scenarios (e.g., EQD2_{[α/β=3]_gEUD} = 14.07 Gy vs. 13.35 Gy), with statistically significant differences (p < 0.001). Although IC-on plans demonstrated steeper dose gradients (higher GIs), this came at the expense of internal dose variability and potentially compromised biological effectiveness. Conclusions: Our results suggest that plans without IC deliver suboptimal biological effectiveness if continued preferentially in routine HO prophylaxis. With advanced radiation dose calculation algorithms available in all centers, inhomogeneity-corrected doses warrant prospective validation. Full article

Heterotopic ossification (HO) refers to an abnormal process characterized by the aberrant development of bone within soft tissues, leading to significant impairments in patients’ mobility and overall quality of life. Macrophages, as a crucial element of the immune system, are instrumental in the different stages of heterotopic ossification through their dynamic polarization state (pro-inflammatory M1 and anti-inflammatory M2 phenotypes) and secretion of different cytokines. This review explores novel mechanisms of M1 and M2 macrophage-mediated heterotopic ossification, emphasizing the involvement of the inflammatory microenvironment, osteogenic factors, and osteogenic signaling pathways. In addition, we explore promising therapeutic strategies targeting macrophage polarization and function, including agents that modulate the inflammatory microenvironment, such as IL-1 inhibitors, parovastatin, and metformin, as well as agents that affect macrophage osteogenic signaling, such as TGF-βRII-Fc, Galunisertib, and Ruxolitinib. A more comprehensive understanding of these mechanisms may open up new avenues for developing novel approaches to reducing HO in high-risk patients. Full article

Background: The effectiveness of hip hemiarthroplasty in managing femoral neck fractures in individuals with cerebral palsy has seldom been reported. Objectives: Given the complex neuromuscular issues associated with cerebral palsy (CP), this retrospective study aims to document the outcomes and characterize the complications of hip hemiarthroplasty for fractures of the femoral neck in a series of patients with CP, emphasizing the role of precision medicine in management. Methods: Six cases of hip hemiarthroplasty in six male patients with cerebral palsy and displaced femoral neck fractures have been reviewed in this study. The patients’ mean age at the time of surgery was 55.6 ± 14.1 years (range, 33–71). All the patients were independent indoor ambulators before their femoral neck fracture and had various medical comorbidities. Five patients had intellectual disabilities. Results: The mean clinical and radiographic follow-ups for the patients included in this series were 91.5 and 71.3 months, respectively. All the patients developed significant heterotopic ossification (HO) around the operated hip, which was observed as early as the second week postoperatively on radiographs. HO progressed throughout the follow-up for all the patients. One patient had an early postoperative dislocation with femoral stem loosening, which was managed by implant revision. Another patient had an acetabular protrusion, leading to the loss of their weight-bearing ability and mobility due to pain. Four patients were deceased at a mean of 86.5 months after the index surgery. Conclusions: After considering the preliminary evidence provided with this small case series, this study suggests the overall guarded outcomes of hip hemiarthroplasty in patients with CP. Given the 100% rate of heterotopic ossification, a precision medicine framework with consideration for HO prophylaxis may be recommended after hip hemiarthroplasty in patients with CP. It may also be reasonable to scrutinize a personalized risk assessment approach in this patient subset regarding decision making, surgical approach, and rehabilitation program. The clinical outcomes and the risks of complications following hemiarthroplasty should be sensibly presented to patients with cerebral palsy and their caregivers to achieve reasonable postoperative expectations. Full article

Duchenne muscular dystrophy (DMD) is a severe genetic muscle disease occurring due to mutations of the dystrophin gene. There is no cure for DMD. Using a dystrophin^−/−utrophin^−/− (DKO-Hom) mouse model, we investigated the PGE2/EP2 pathway in the pathogenesis of dystrophic muscle and its potential as a therapeutic target. We found that Ep2, Ep4, Cox-2, 15-Pgdh mRNA, and PGE2 were significantly increased in DKO-Hom mice compared to wild-type (WT) mice. The EP2 and EP4 receptors were mainly expressed in CD68⁺ macrophages and were significantly increased in the muscle tissues of both dystrophin^−/− (mdx) and DKO-Hom mice compared to WT mice. Osteogenic and osteoclastogenic gene expression in skeletal muscle also increased in DKO-Hom mice, which correlates with severe muscle heterotopic ossification (HO). Treatment of DKO-Hom mice with the EP2 antagonist PF04418948 for 2 weeks increased body weight and reduced HO and muscle pathology by decreasing both total macrophages (CD68⁺) and senescent macrophages (CD68⁺P21⁺), while increasing endothelial cells (CD31⁺). PF04418948 also increased bone volume/total volume (BV/TV), the trabecular thickness (Tb.Th) of the tibia trabecular bone, and the cortical bone thickness of both the femur and tibia without affecting spine trabecular bone microarchitecture. In summary, our results indicate that targeting EP2 improves muscle pathology and improves bone mass in DKO mice. Full article

Background: Complications such as periprosthetic fractures necessitate challenging revision surgeries. In particular, femoral stem revisions can be complicated by poor bone quality, making primary stability and leg length restoration difficult to achieve. Modular fluted tapered stems (MFTSs) have emerged as a viable option for these complex cases. This study aims to describe a reproducible three-step technique for femoral stem revision using MFTSs. The technique focuses on (1) obtaining distal primary stability, (2) restoring leg length, and (3) ensuring overall implant stability. Materials and methods: We conducted a retrospective analysis of ten patients who underwent revision THA using this three-step technique, with a minimum follow-up of 12 months. The mean patient age was 70.7 years, and the average follow-up was 24.2 months. Limits were the small sample size, the lack of clinical outcomes and the short-term follow-up. Results: There was no subsidence, a mean leg length discrepancy of 4 mm (p: 0.604), and no dislocations. However, heterotopic ossifications (HOs) were observed in 25% of patients, although no trochanteric migrations occurred. One patient experienced an intraoperative femoral fracture, which was successfully treated. Conclusions: This three-step approach can break down the revision procedure, making it more accessible to surgeons. The findings suggest that this technique is effective in achieving reliable outcomes in femoral stem revisions, potentially improving the standard of care for patients requiring complex THA revisions. Full article

Introduction: Heterotopic ossifications (HOs) are a well-known complication following total hip arthroplasty. Yet only little is known about the development of HOs following a femoral fracture and intramedullary stabilization in polytraumatized patients. Thus, the present study aimed to investigate whether the development of HOs is being observed more frequently in patients suffering polytrauma compared to those with single-extremity trauma. Materials and Methods: The retrospective outcome study was conducted at our level I trauma center. All patients admitted from 2010 to 2020 were included if they (1) presented with multiple injuries (≥2 body regions), (2) had an Injury Severity Score ≥16, (3) suffered a femoral fracture, and (4) were treated with intramedullary stabilization. Furthermore, a control group was established to match the polytrauma group (sex, age), who were suffering from single-extremity trauma (femoral fracture) which was treated with intramedullary stabilization. Subsequently, X-rays of the hip were performed and evaluated for up to one-year post-trauma. Results: Our study group consisted of 36 patients in total (91.7% male; mean age 39.4 ± 17.4 years, range: 18–82 years). The polytrauma (PT) group included 12 patients (mean age 39.5 years, median ISS 28), whereas the control group (single-extremity-trauma) included 24 patients (mean age 39.3 years). We documented HOs in nine (75%) patients in the PT group vs. five (20.8%) patients in the single-extremity group (p = 0.03). Conclusion: In this study, we were able to demonstrate that heterotopic ossifications are being observed significantly more frequently in patients suffering from polytrauma in comparison to patients with single-extremity trauma following intramedullary stabilization after a femoral fracture. Full article

When a genetic disease is characterized by the abnormal activation of normal molecular pathways and cellular events, it is illuminating to critically examine the places and times of these activities both in health and disease. Therefore, because heterotopic ossification (HO) in fibrodysplasia ossificans progressiva (FOP) is by far the disease’s most prominent symptom, attention is also directed toward the pathways and processes of bone formation during skeletal development. FOP is recognizable by effects of the causative mutation on skeletal development even before HO manifests, specifically in the malformation of the great toes. This signature skeletal phenotype is the most highly penetrant, but is only one among several skeletal abnormalities associated with FOP. Patients may present clinically with joint malformation and ankylosis, particularly in the cervical spine and costovertebral joints, as well as characteristic facial features and a litany of less common, non-skeletal symptoms, all stemming from missense mutations in the ACVR1 gene. In the same way that studying the genetic cause of HO advanced our understanding of HO initiation and progression, insight into the roles of ACVR1 signaling during tissue development, particularly in the musculoskeletal system, can be gained from examining altered skeletal development in individuals with FOP. This review will detail what is known about the molecular mechanisms of developmental phenotypes in FOP and the early role of ACVR1 in skeletal patterning and growth, as well as highlight how better understanding these processes may serve to advance patient care, assessments of patient outcomes, and the fields of bone and joint biology. Full article

The formation of bone outside the normal skeleton, or heterotopic ossification (HO), occurs through genetic and acquired mechanisms. Fibrodysplasia ossificans progressiva (FOP), the most devastating genetic condition of HO, is due to mutations in the ACVR1/ALK2 gene and is relentlessly progressive. Acquired HO is mostly precipitated by injury or orthopedic surgical procedures but can also be associated with certain conditions related to aging. Cellular senescence is a hallmark of aging and thought to be a tumor-suppressive mechanism with characteristic features such as irreversible growth arrest, apoptosis resistance, and an inflammatory senescence-associated secretory phenotype (SASP). Here, we review possible roles for cellular senescence in HO and how targeting senescent cells may provide new therapeutic approaches to both FOP and acquired forms of HO. Full article

Traumatic heterotopic ossification (HO) is frequently observed in Service Members following combat-related trauma. Estimates suggest that ~65% of wounded warriors who suffer limb loss or major extremity trauma will experience some type of HO formation. The development of HO delays rehabilitation and can prevent the use of a prosthetic. To date there are limited data to suggest a standard mechanism for preventing HO. This may be due to inadequate animal models not producing a similar bone structure as human HO. We recently showed that traumatic HO growth is possible in an ovine model. Within that study, we demonstrated that 65% of sheep developed a human-relevant hybrid traumatic HO bone structure after being exposed to a combination of seven combat-relevant factors. Although HO formed, we did not determine which traumatic factor contributed most. Therefore, in this study, we performed individual and various combinations of surgical/traumatic factors to determine their individual contribution to HO growth. Outcomes showed that the presence of mature biofilm stimulated a large region of bone growth, while bone trauma resulted in a localized bone response as indicated by jagged bone at the linea aspera. However, it was not until the combinatory factors were included that an HO structure similar to that of humans formed more readily in 60% of the sheep. In conclusion, data suggested that traumatic HO growth can develop following various traumatic factors, but a combination of known instigators yields higher frequency size and consistency of ectopic bone. Full article

Fibrodysplasia ossificans progressiva (FOP) is a debilitating genetic disorder characterized by recurrent episodes of heterotopic ossification (HO) formation in muscles, tendons, and ligaments. FOP is caused by a missense mutation in the ACVR1 gene (activin A receptor type I), an important signaling receptor involved in endochondral ossification. The ACVR1^R206H mutation induces increased downstream canonical SMAD-signaling and drives tissue-resident progenitor cells with osteogenic potential to participate in endochondral HO formation. In this article, we review aberrant ACVR1^R206H signaling and the cells that give rise to HO in FOP. FOP mouse models and lineage tracing analyses have been used to provide strong evidence for tissue-resident mesenchymal cells as cellular contributors to HO. We assess how the underlying mutation in FOP disrupts muscle-specific dynamics during homeostasis and repair, with a focus on muscle-resident mesenchymal cells known as fibro-adipogenic progenitors (FAPs). Accumulating research points to FAPs as a prominent HO progenitor population, with ACVR1^R206H FAPs not only aberrantly differentiating into chondro-osteogenic lineages but creating a permissive environment for bone formation at the expense of muscle regeneration. We will further discuss the emerging role of ACVR1^R206H FAPs in muscle regeneration and therapeutic targeting of these cells to reduce HO formation in FOP. Full article

Background: Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized. Purpose of review: This review will examine recent findings on the roles of inflammation and the immune system in fibrodysplasia ossificans progressiva (FOP). FOP is a genetic condition of aggressive and progressive HO formation. We also examine how inflammation may be a valuable target for the treatment of HO. Rationale/Recent findings: Multiple lines of evidence indicate a key role for the immune system in driving FOP pathogenesis. Critical cell types include macrophages, mast cells, and adaptive immune cells, working through hypoxia signaling pathways, stem cell differentiation signaling pathways, vascular regulatory pathways, and inflammatory cytokines. In addition, recent clinical reports suggest a potential role for immune modulators in the management of FOP. Future perspectives: The central role of inflammatory mediators in HO suggests that the immune system may be a common target for blocking HO in both FOP and non-genetic forms of HO. Future research focusing on the identification of novel inflammatory targets will help support the testing of potential therapies for FOP and other related conditions. Full article

Heterotopic ossification (HO) is a debilitating pathology where ectopic bone develops in areas of soft tissue. HO can develop as a consequence of traumatic insult or as a result of dysregulated osteogenic signaling, as in the case of the orphan disease fibrodysplasia ossificans progressiva (FOP). Traumatic HO (tHO) formation is mediated by the complex interplay of signaling between progenitor, inflammatory, and nerve cells, among others, making it a challenging process to understand. Research into the pathogenesis of genetically mediated HO (gHO) in FOP has established a pathway involving uninhibited activin-like kinase 2 receptor (ALK2) signaling that leads to downstream osteogenesis. Current methods of diagnosis and treatment lag behind pre-mature HO detection and progressive HO accumulation, resulting in irreversible decreases in range of motion and chronic pain for patients. As such, it is necessary to draw on advancements made in the study of tHO and gHO to better diagnose, comprehend, prevent, and treat both. Full article

Heterotopic ossification (HO) is most dramatically manifested in the rare and severely debilitating disease, fibrodysplasia ossificans progressiva (FOP), in which heterotopic bone progressively accumulates in skeletal muscles and associated soft tissues. The great majority of FOP cases are caused by a single amino acid substitution in the type 1 bone morphogenetic protein (BMP) receptor ACVR1, a mutation that imparts responsiveness to activin A. Although it is well-established that biological sex is a critical variable in a range of physiological and disease processes, the impact of sex on HO in animal models of FOP has not been explored. We show that female FOP mice exhibit both significantly greater and more variable HO responses after muscle injury. Additionally, the incidence of spontaneous HO was significantly greater in female mice. This sex dimorphism is not dependent on gonadally derived sex hormones, and reciprocal cell transplantations indicate that apparent differences in osteogenic activity are intrinsic to the sex of the transplanted cells. By circumventing the absolute requirement for activin A using an agonist of mutant ACVR1, we show that the female-specific response to muscle injury or BMP2 implantation is dependent on activin A. These data identify sex as a critical variable in basic and pre-clinical studies of FOP. Full article

Fibrodysplasia ossificans progressiva (FOP; MIM# 135100) is an ultra-rare congenital disorder caused by gain-of-function point mutations in the Activin receptor A type I (ACVR1, also known as ALK2) gene. FOP is characterized by episodic heterotopic ossification (HO) in skeletal muscles, tendons, ligaments, or other soft tissues that progressively causes irreversible loss of mobility. FOP mutations cause mild ligand-independent constitutive activation as well as ligand-dependent bone morphogenetic protein (BMP) pathway hypersensitivity of mutant ACVR1. BMP signaling is also a key pathway for mediating acquired HO. However, HO is a highly complex biological process involving multiple interacting signaling pathways. Among them, the hypoxia-inducible factor (HIF) and mechanistic target of rapamycin (mTOR) pathways are intimately involved in both genetic and acquired HO formation. HIF-1α inhibition or mTOR inhibition reduces HO formation in mouse models of FOP or acquired HO in part by de-amplifying the BMP pathway signaling. Here, we review the recent progress on the mechanisms of the HIF-1α and mTOR pathways in the amplification of HO lesions and discuss the future directions and strategies to translate the targeting of HIF-1α and the mTOR pathways into clinical interventions for FOP and other forms of HO. Full article