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JCI Insight Jul 2022Heterotopic ossification (HO) is the formation of ectopic bone that is primarily genetically driven (fibrodysplasia ossificans progressiva [FOP]) or acquired in the... (Review)
Review
Heterotopic ossification (HO) is the formation of ectopic bone that is primarily genetically driven (fibrodysplasia ossificans progressiva [FOP]) or acquired in the setting of trauma (tHO). HO has undergone intense investigation, especially over the last 50 years, as awareness has increased around improving clinical technologies and incidence, such as with ongoing wartime conflicts. Current treatments for tHO and FOP remain prophylactic and include NSAIDs and glucocorticoids, respectively, whereas other proposed therapeutic modalities exhibit prohibitive risk profiles. Contemporary studies have elucidated mechanisms behind tHO and FOP and have described new distinct niches independent of inflammation that regulate ectopic bone formation. These investigations have propagated a paradigm shift in the approach to treatment and management of a historically difficult surgical problem, with ongoing clinical trials and promising new targets.
Topics: Bone and Bones; Humans; Myositis Ossificans; Ossification, Heterotopic
PubMed: 35866484
DOI: 10.1172/jci.insight.158996 -
Pediatric Endocrinology Reviews : PER Jun 2013Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition characterized by congenital malformations of the great toes and progressive... (Review)
Review
Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition characterized by congenital malformations of the great toes and progressive heterotopic endochondral ossification (HEO) which is the most catastrophic of HEO disorders in humans. Flare-ups of FOP are episodic; immobility is cumulative. Heterozygous activating mutations in activin receptor IA/activin-like kinase-2 (ACVRI/ ALK2), a bone morphogenetic protein (BMP) type I receptor, exist in all sporadic and familial cases of FOP. The discovery of the FOP gene established a critical milestone in our understanding of FOP, and revealed a highly conserved therapeutic target in the BMP signaling pathway. This discovery has advanced efforts to develop novel therapies for this disabling disorder of tissue metamorphosis. While effective treatment of FOP will likely be based on interventions that modulate overactive ACVR1/ALK2 signaling, or that specifically block postnatal HEO, current management is focused on early diagnosis, assiduous avoidance of injury or iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function.
Topics: Animals; Disease Models, Animal; Humans; Myositis Ossificans
PubMed: 23858627
DOI: No ID Found -
Journal of Bone and Mineral Research :... Oct 2022Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive heterotopic ossification (HO), often heralded by flare-ups,... (Randomized Controlled Trial)
Randomized Controlled Trial
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive heterotopic ossification (HO), often heralded by flare-ups, leading to reduced movement and life expectancy. This placebo-controlled, double-blind trial (NCT02190747) evaluated palovarotene, an orally bioavailable selective retinoic acid receptor gamma agonist, for prevention of HO in patients with FOP. Patients experiencing a flare-up were enrolled in two cohorts: (1) patients ≥15 years were randomized 3:1 to palovarotene 10/5 mg (weeks 1-2/3-6) or placebo; (2) patients ≥6 years were randomized 3:3:2 to palovarotene 10/5 mg, palovarotene 5/2.5 mg (weeks 1-2/3-6), or placebo. Cohort data were pooled. The primary endpoint was the proportion of responders (no/minimal new HO at flare-up body region by plain radiograph) at week 6. Change from baseline in HO volume and new HO incidence were assessed by computed tomography (CT) at week 12. Tissue edema was assessed by magnetic resonance imaging (MRI) or ultrasound. Forty patients (aged 7-53 years) were enrolled (placebo: n = 10; palovarotene 5/2.5 mg: n = 9; palovarotene 10/5 mg: n = 21). Disease history was similar between groups. In the per-protocol population, the proportion of responders at week 6 by plain radiograph was 100% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 88.9% with placebo (Cochran-Armitage trend test: p = 0.17). At week 12, the proportions were 95.0% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 77.8% with placebo (Cochran-Armitage trend test: p = 0.15). Week 12 least-squares mean (LSmean) new HO volume, assessed by CT, was 3.8 × 10 mm with palovarotene 10/5 mg; 1.3 × 10 mm with palovarotene 5/2.5 mg; 18.0 × 10 mm with placebo (pairwise tests versus placebo: p ≤ 0.12). Palovarotene was well-tolerated. No patients discontinued treatment or required dose reduction; one patient had dose interruption due to elevated lipase. Although these findings were not statistically significant, they support further evaluation of palovarotene for prevention of HO in FOP in larger studies. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Humans; Myositis Ossificans; Ossification, Heterotopic; Pyrazoles; Stilbenes
PubMed: 35854638
DOI: 10.1002/jbmr.4655 -
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 -
Journal of Medical Case Reports Dec 2022Myositis ossificans circumscripta is a self-limiting, benign, ossifying lesion that can affect any type of soft tissue. It is most commonly found in muscles as a...
BACKGROUND
Myositis ossificans circumscripta is a self-limiting, benign, ossifying lesion that can affect any type of soft tissue. It is most commonly found in muscles as a solitary lesion. A history of recent trauma has been reported in approximately 50% of cases. Clinically, MOC presents as a painful swelling, which rapidly increases in size. The pain and inflammatory symptoms spontaneously disappear after approximately 2-6 weeks, and the mass stabilizes or decreases. Radiologically, myositis ossificans circumscripta can be divided into two phases. The first is the acute phase, which is followed by the mature phase 2-6 weeks later. During the acute phase, the radiological aspect does not show any specific abnormality. In the mature phase, plain radiographs and computed tomography show blurred calcifications around a hypodense center. We describe here the first case of myositis ossificans circumscripta, with appropriate follow-up, occurring during sunitinib exposure.
CASE PRESENTATION
We report a case of myositis ossificans circumscripta in a 34-year-old man (ethnicity unknown) receiving sunitinib for metastatic alveolar soft part sarcoma of the left thigh after surgery and radiotherapy. Four months after the first dose of sunitinib, the patient experienced painful swelling in the surgical scar area. Magnetic resonance imaging showed diffuse and marked edema of the anterior compartment of the thigh, without nodular lesions circumscribing a central core, and without bone signal abnormality. The increased visibility of the intermuscular fascia and convergence of normal muscle fibers (black hole effect), without the displacement seen in tumors, were suggestive of myositis. Therefore, antiangiogenic treatment was discontinued, and the symptoms rapidly resolved within a few days. Three weeks after the discontinuation of sunitinib, the inflammatory findings completely disappeared. Two months after the diagnosis of myositis ossificans circumscripta, plain radiographs and computed tomography showed an extensive calcified mass measuring > 12 cm. The continuation of favorable clinical outcomes was confirmed.
CONCLUSIONS
To the best of our knowledge, this is the first case of myositis ossificans circumscripta with appropriate follow-up occurring during sunitinib exposure. Owing to multimodal treatment of sarcoma, we cannot rule out the radiotherapy and surgery causality.
Topics: Humans; Adult; Sunitinib; Pain
PubMed: 36474288
DOI: 10.1186/s13256-022-03664-5 -
QJM : Monthly Journal of the... Nov 2021
Topics: COVID-19; COVID-19 Vaccines; Humans; Myositis Ossificans; SARS-CoV-2; Vaccination
PubMed: 34109386
DOI: 10.1093/qjmed/hcab161 -
Human Gene Therapy Aug 2022Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease, in which soft connective tissue is converted into heterotopic bone through an... (Review)
Review
Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease, in which soft connective tissue is converted into heterotopic bone through an endochondral ossification process. Patients succumb early as they gradually become trapped in a second skeleton of heterotopic bone. Although the underlying genetic defect is long known, the inherent complexity of the disease has hindered the discovery of effective preventions and treatments. New developments in the gene therapy field have motivated its consideration as an attractive therapeutic option for FOP. However, the immune system's role in FOP activation and the as-yet unknown primary causative cell, are crucial issues which must be taken into account in the therapy design. While gene therapy offers a potential therapeutic solution, more knowledge about FOP is needed to enable its optimal and safe application.
Topics: Activin Receptors, Type I; Feasibility Studies; Genetic Therapy; Humans; Myositis Ossificans; Ossification, Heterotopic
PubMed: 35502479
DOI: 10.1089/hum.2022.023 -
Journal of Bone and Mineral Research :... Mar 2023Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely disabling genetic disorder of progressive heterotopic ossification (HO). The single-arm,...
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely disabling genetic disorder of progressive heterotopic ossification (HO). The single-arm, open-label, phase 3 MOVE trial (NCT03312634) assessed efficacy and safety of palovarotene, a selective retinoic acid receptor gamma agonist, in patients with FOP. Findings were compared with FOP natural history study (NHS; NCT02322255) participants untreated beyond standard of care. Patients aged ≥4 years received palovarotene once daily (chronic: 5 mg; flare-up: 20 mg for 4 weeks, then 10 mg for ≥8 weeks; weight-adjusted if skeletally immature). The primary endpoint was annualized change in new HO volume versus NHS participants (by low-dose whole-body computed tomography [WBCT]), analyzed using a Bayesian compound Poisson model (BcPM) with square-root transformation. Twelve-month interim analyses met futility criteria; dosing was paused. An independent Data Monitoring Committee recommended trial continuation. Post hoc 18-month interim analyses utilized BcPM with square-root transformation and HO data collapsed to equalize MOVE and NHS visit schedules, BcPM without transformation, and weighted linear mixed-effects (wLME) models, alongside prespecified analysis. Safety was assessed throughout. Eighteen-month interim analyses included 97 MOVE and 101 NHS individuals with post-baseline WBCT. BcPM analyses without transformation showed 99.4% probability of any reduction in new HO with palovarotene versus NHS participants (with transformation: 65.4%). Mean annualized new HO volume was 60% lower in MOVE versus the NHS. wLME results were similar (54% reduction fitted; nominal p = 0.039). All palovarotene-treated patients reported ≥1 adverse event (AE); 97.0% reported ≥1 retinoid-associated AE; 29.3% reported ≥1 serious AE, including premature physeal closure (PPC)/epiphyseal disorder in 21/57 (36.8%) patients aged <14 years. Post hoc computational analyses using WBCT showed decreased vertebral bone mineral density, content, and strength, and increased vertebral fracture risk in palovarotene-treated patients. Thus, post hoc analyses showed evidence for efficacy of palovarotene in reducing new HO in FOP, but high risk of PPC in skeletally immature patients. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Humans; Myositis Ossificans; Bayes Theorem; Ossification, Heterotopic; Pyrazoles
PubMed: 36583535
DOI: 10.1002/jbmr.4762 -
Cells Oct 2019encodes for a bone morphogenetic protein type I receptor of the TGFβ receptor superfamily. It is involved in a wide variety of biological processes, including bone,... (Review)
Review
encodes for a bone morphogenetic protein type I receptor of the TGFβ receptor superfamily. It is involved in a wide variety of biological processes, including bone, heart, cartilage, nervous, and reproductive system development and regulation. Moreover, has been extensively studied for its causal role in fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder characterised by progressive heterotopic ossification. is linked to different pathologies, including cardiac malformations and alterations in the reproductive system. More recently, has been experimentally validated as a cancer driver gene in diffuse intrinsic pontine glioma (DIPG), a malignant childhood brainstem glioma, and its function is being studied in other cancer types. Here, we review ACVR1 receptor function and signalling in physiological and pathological processes and its regulation according to cell type and mutational status. Learning from different functions and alterations linked to is a key step in the development of interdisciplinary research towards the identification of novel treatments for these pathologies.
Topics: Activin Receptors, Type I; Bone Morphogenetic Proteins; Brain Neoplasms; Diffuse Intrinsic Pontine Glioma; Genitalia; Humans; Myositis Ossificans; Ossification, Heterotopic; Polymorphism, Single Nucleotide; Signal Transduction
PubMed: 31683698
DOI: 10.3390/cells8111366 -
Archives of Pathology & Laboratory... Apr 2008One of the most common and important pitfalls in soft tissue pathology are the so-called pseudosarcomas. These lesions are nonneoplastic; however, their rapid growth,... (Review)
Review
One of the most common and important pitfalls in soft tissue pathology are the so-called pseudosarcomas. These lesions are nonneoplastic; however, their rapid growth, hypercellularity, cytologic atypia, and mitotic activity makes them prone to be misinterpreted as sarcoma. The most common of these lesions are fibroblastic/myofibroblastic and matrix-forming proliferations, including nodular fasciitis, proliferative fasciitis and myositis, ischemic fasciitis, massive localized edema, myositis ossificans, and bizarre parosteal osteochondromatous proliferation and related entities. Most of these lesions rarely recur following simple excision; therefore, their accurate recognition helps prevent excessive therapy.
Topics: Diagnosis, Differential; Fasciitis; Humans; Lymphedema; Myositis; Myositis Ossificans; Pathology; Sarcoma; Soft Tissue Neoplasms
PubMed: 18384209
DOI: 10.5858/2008-132-579-POST