Did you mean: myositis ossificans
-
Insights Into Imaging Jun 2023Bizarre parosteal osteochondromatous proliferation (BPOP) is a surface-based bone lesion belonging to the group of benign chondrogenic tumors. The aim of this review is... (Review)
Review
Bizarre parosteal osteochondromatous proliferation (BPOP) is a surface-based bone lesion belonging to the group of benign chondrogenic tumors. The aim of this review is to familiarize the readers with imaging features and differential diagnosis of BPOP, also addressing pathological presentation and treatment options. The peak of incidence of BPOP is in the third and fourth decades of life, although it can occur at any age. Hands are the most common location of BPOP (55%), followed by feet (15%) and long bones (25%). On imaging, BPOP appears as a well-marginated mass of heterotopic mineralization arising from the periosteal aspect of the bone. Typical features of BPOP are contiguity with the underlying bone and lack of cortico-medullary continuity, although cortical interruption and medullary involvement have been rarely reported. Histologically, BPOP is a benign bone surface lesion characterized by osteocartilaginous proliferation with disorganized admixture of cartilage with bizarre features, bone and spindle cells. Differential diagnosis includes both benign-such as florid reactive periostitis, osteochondroma, subungual exostosis, periosteal chondroma and myositis ossificans-and malignant lesions-such as periosteal chondrosarcoma and surface-based osteosarcoma. Treatment consists of surgical resection. Local recurrences are common and treated with re-excision.Critical relevance statement Bizarre parosteal osteochondromatous proliferation is a benign mineralized mass arising from the periosteal aspect of bone cortex. Multi-modality imaging characteristics, pathology features and differential diagnosis are here highlighted to familiarize the readers with this entity and offer optimal patient care.
PubMed: 37336832
DOI: 10.1186/s13244-023-01455-0 -
Biomolecules Apr 2024The formation of bone outside the normal skeleton, or heterotopic ossification (HO), occurs through genetic and acquired mechanisms. Fibrodysplasia ossificans... (Review)
Review
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 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.
Topics: Humans; Ossification, Heterotopic; Cellular Senescence; Myositis Ossificans; Animals; Activin Receptors, Type I
PubMed: 38672501
DOI: 10.3390/biom14040485 -
Biomolecules Mar 2024Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized. (Review)
Review
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.
Topics: Humans; Myositis Ossificans; Ossification, Heterotopic; Cell Differentiation; Signal Transduction; Inflammation
PubMed: 38540775
DOI: 10.3390/biom14030357 -
Nature Medicine Oct 2023Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2... (Randomized Controlled Trial)
Randomized Controlled Trial
Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET-CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 .
Topics: Adult; Humans; Myositis Ossificans; Positron Emission Tomography Computed Tomography; Ossification, Heterotopic
PubMed: 37770652
DOI: 10.1038/s41591-023-02561-8 -
Orthopadie (Heidelberg, Germany) Nov 2023Fibrodysplasia ossificans progressiva (FOP) is a very rare, severe genetic disorder triggered by a gain-of-function mutation in the ACVR1 gene that codes for the... (Review)
Review
BACKGROUND
Fibrodysplasia ossificans progressiva (FOP) is a very rare, severe genetic disorder triggered by a gain-of-function mutation in the ACVR1 gene that codes for the type I bone morphogenetic protein (BMP) receptor ACVR1 (activin A receptor-type 1), also known as ALK2 (activin receptor-like kinase-2). It leads to the onset and progression of heterotopic ossification (HO) in soft and connective tissue. HO is often preceded by episodes of soft tissue swelling or flare-ups. Flare-ups, characteristic of FOP, may be induced by trauma, infection, vaccination, or other medications, as well as surgical procedures or may occur spontaneously. As patients age, they develop severe mobility limitations due to progressive HO formation, including immobility, causing a shortened life expectancy. FOP's first characteristic clinical sign is the congenital malformation of one or both big toes with valgus axis deviation, which is present in almost all patients. To confirm the diagnosis, molecular genetic analysis of the ACVR1 gene is possible.
AIM OF THE RECOMMENDATIONS
This white paper aims to provide an overview of the necessary prerequisites and conditions for the care of patients with FOP and positively contribute to patients with FOP by improving the overall availability of knowledge. To achieve this, relevant aspects of the care of the very rare disease FOP are presented, from the initial diagnosis to the care in regular care based on the authors' knowledge (German FOP network) and the international FOP Treatment Guidelines. The recommendations presented here are addressed to all actors and decision-makers in the health care system and are also intended to inform patients and the public.
Topics: Humans; Myositis Ossificans; Mutation; Ossification, Heterotopic; Bone Morphogenetic Proteins; Delivery of Health Care
PubMed: 37603129
DOI: 10.1007/s00132-023-04425-y -
BMC Medical Research Methodology Nov 2023The design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an...
BACKGROUND
The design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by skeletal malformations and progressive heterotopic ossification (HO). Palovarotene is a selective retinoic acid receptor gamma agonist. Here, we describe the methodology of three studies in the palovarotene clinical development program in FOP and discuss insights that could inform future research, including endpoint suitability and the impact of trial design.
METHODS
PVO-1A-001 (NCT02322255) was a prospective, protocol-specified, longitudinal FOP natural history study (NHS). PVO-1A-201 (NCT02190747) was a randomized, double-blind, placebo-controlled phase II trial; PVO-1A-202 (NCT02279095) was its open-label extension. Trial designs, including treatment regimens and imaging assessments, were refined between PVO-1A-201 and PVO-1A-202, and within PVO-1A-202, based on emerging data as the studies progressed. Palovarotene doses were administered using a flare-up treatment regimen (higher dose for 2/4 weeks, followed by lower dose for 4/≥8 weeks; from flare-up onset), with or without accompanying chronic (daily) treatment. Flare-up and disease progression outcomes were assessed, including incidence and volume of new HO during flare-ups and/or annually, as well as other clinical, patient-reported, and exploratory outcomes. Safety was monitored throughout all studies.
RESULTS
Overall, 114 and 58 individuals with FOP were enrolled in the NHS and phase II trials, respectively. Results of the NHS and PVO-1A-201 were published in 2022; complete results of PVO-1A-202 will be publicly available in due course. Together the studies yielded important information on endpoint suitability, including that low-dose whole-body computed tomography was the optimum imaging modality for assessing HO progression annually and that long study durations are needed to detect substantial changes in functional and patient-reported outcomes.
CONCLUSIONS
A flexible clinical development program is necessary for underexplored rare diseases to overcome the many challenges faced. Here, the NHS provided a longitudinal evaluation of FOP progression and interventional trials were based on emerging data. The studies described informed the design and endpoints implemented in the phase III MOVE trial (NCT03312634) and provide a foundation for future clinical trial development.
TRIAL REGISTRATION
NCT02322255 (registered 23/12/2014); NCT02190747 (registered 15/07/2014); NCT02279095 (registered 30/10/2014).
Topics: Humans; Myositis Ossificans; Ossification, Heterotopic; Prospective Studies; Rare Diseases; Randomized Controlled Trials as Topic; Clinical Trials, Phase II as Topic
PubMed: 37957586
DOI: 10.1186/s12874-023-02080-7 -
Frontiers in Pediatrics 2023Circumscribed or pseudomalignant myositis ossificans (MO) is a rare and benign condition characterized by heterotopic bone formation in soft tissues. The clinical...
INTRODUCTION
Circumscribed or pseudomalignant myositis ossificans (MO) is a rare and benign condition characterized by heterotopic bone formation in soft tissues. The clinical presentation of MO, imaging investigations, histological findings, and treatment strategies are unclear, especially in the pediatric population.
MATERIALS AND METHODS
A literature search was conducted in PubMed, Scopus, and Google Scholar electronic databases to identify original articles and reviews in English or French of traumatic and non-traumatic MO. Studies were selected by 2 independent reviewers following the PRISMA recommendation and descriptive data were extracted. We harvest in each case the sex, age at diagnosis, location, presence of initial trauma, pre-emptive diagnosis, modalities of imagery used, realized biopsy, treatment performed, and type of follow-up.
RESULTS
Sixty pediatric cases of MO were identified between 2002 and 2023. Twenty-three patients (38.3%) were diagnosed with idiopathic/pseudomalignant and 37 patients (61.7%) with circumscribed. The mean age at diagnosis was 9.5 years (range 0.2-17 years), with a male-to-female ratio of 1:1. The initial pre-emptive diagnosis was neoplasia in 13 patients (21.7%). The biopsy was percutaneous in 9 patients (15%) and incisional in 7 patients (11.7%). Histological analysis was achieved in 35 cases (57%). Surgical excision was the first line treatment in 46.7% of patients, and non-surgical in the remaining patients. The follow-up strategy was clinical in 16 patients (26.7%) or based on imaging investigation in 23 patients (38.3%).
DISCUSSION
Although MO in children is described as a rare pathology, identifying the benignity of the condition is essential to avoid unnecessary invasive treatment and to avoid delaying the treatment of a potentially life-threatening entity. It seems that there is no consensus established concerning the proper imaging for diagnosis. Clinicians should acknowledge that the absence of a triggering trauma tends to direct the investigation and the management toward a surgical attitude. Conservative management is key, however, surgical excision can be proposed on matured lesions on a case-by-case basis. The absence of recurrence is not excluded. Therefore, a close clinical follow-up is suggested for all cases. The true benefit of a radiological is questioned in a question known to be self-resolving.
PubMed: 38161430
DOI: 10.3389/fped.2023.1295212 -
Biomolecules Sep 2023Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive disabling heterotopic ossification (HO) at extra-skeletal...
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive disabling heterotopic ossification (HO) at extra-skeletal sites. Here, we developed adeno-associated virus (AAV)-based gene therapy that suppresses trauma-induced HO in FOP mice harboring a heterozygous allele of human () while limiting the expression in non-skeletal organs such as the brain, heart, lung, liver, and kidney. AAV gene therapy carrying the combination of codon-optimized human ACVR1 (ACVR1) and artificial miRNAs targeting Activin A and its receptor ACVR1 ablated the aberrant activation of BMP-Smad1/5 signaling and the osteogenic differentiation of skeletal progenitors. The local delivery of AAV gene therapy to HO-causing cells in the skeletal muscle resulted in a significant decrease in endochondral bone formation in mice. These mice showed little to no expression in a major AAV-targeted organ, the liver, due to liver-abundant miR-122-mediated repression. Thus, AAV gene therapy is a promising therapeutic strategy to explore in suppressing HO in FOP.
Topics: Animals; Humans; Mice; Activin Receptors, Type I; Activins; Dependovirus; Myositis Ossificans; Osteogenesis
PubMed: 37759764
DOI: 10.3390/biom13091364 -
Biomolecules Jan 2024Fibrodysplasia 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... (Review)
Review
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 (, also known as ) 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.
Topics: Animals; Mice; Ligands; Mutation; Myositis Ossificans; Ossification, Heterotopic; Signal Transduction; TOR Serine-Threonine Kinases; Humans; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 38397384
DOI: 10.3390/biom14020147