Approach Considerations
A therapeutic option that may lower the number of body regions with new ossification or the formation of new ossification may substantially enhance a patient’s quality of life. [1, 2] Palovarotene was approved by the FDA in Auguest 2023 and is an oral selective retinoic acid receptor γ agonist developed to diminish FOP heterotopic ossification formation. [34] Patients require close monitoring, as Hsiao et al have illuminated, [35] as adverse events may produce depression or/and anxiety and, potentially, heighten pain perception. [36]
Medical Care
Fibrodysplasia ossificans progressiva (FOP) should be diagnosed during the neonatal period. [37] Early treatment of fibrodysplasia ossificans progressiva helps avoid the factors of aggravation, slow the progression of the disease, and provide the children with improved quality of life. The first effective medical therapy, palovarotene, was approved by the FDA for fibrodysplasia ossificans progressiva in August 2023. Bisphosphonates and corticosteroids are only beneficial during the flares. Systemic steroids are sometimes used for acute flare-ups. Iontophoresis with steroids or acetic acid may improve diminished range of motion.
Palovarotene
Palovarotene (Sohonos) was the first drug approved for fibrodysplasia ossificans progressiva (FOP). It is indicated for reduction in volume of new heterotopic ossification in adults and pediatric patients aged ≥8 years for females and ≥10 years for males with fibrodysplasia ossificans progressiva (FOP).
In patients with fibrodysplasia ossificans progressiva, abnormal bone formation, including heterotrophic ossification, is driven by a gain-of-function mutation in the bone morphogenetic protein (BMP) type I receptor ALK2 (ACVR1). Palovarotene is an orally bioavailable retinoic acid receptor agonist, with particular selectivity at the gamma subtype of RAR.
Approval was based on 18-month data from the phase 3 multicenter, open-label MOVE trial that included 107 adult and pediatric patients, over 10% of the world's population with FOP. All received oral palovarotene and were compared with untreated individuals from a prior natural history study of the condition. Palovarotene reduced annualized heterotopic ossification volume by 54% (p = 0.039). [38]
Other therapies
Gene therapy may hold promise in fibrodysplasia ossificans progressiva treatment. Inflammatory mediators play a role in fibrodysplasia ossificans progressiva and represent a possible therapeutic target. [39] The discovery of the FOP gene reveals a highly conserved target in the transforming growth factor-beta/bone morphogenetic protein signaling pathway and compels therapeutic approaches for the development of small-molecule signal transduction inhibitors for activinlike kinase-2. [40] Effective therapies for fibrodysplasia ossificans progressiva may be based on blocking activinlike kinase-2 or blocking of activin receptor IA/activin–like kinase 2 signaling. [41]
One report (involving 3 patients) suggested that a combined formulation of propranolol and ascorbic acid (known as FOPCon) may be beneficial in the prophylaxis of flare-ups. [42] However, the International Clinical Counsel (ICC) on Fibrodysplasia Ossificans Progressiva, which seeks to help delineate best practices, [35] recommends that FOPCon not be promoted as or purported to be a definitive therapy for fibrodysplasia ossificans progressiva. [43] The ICC has determined the evidence for efficacy and safety is insufficient. The organization strongly recommends caution for both patients and medical practitioners against making therapeutic conclusions for current practice; however, it suggests further insights may be gained from continued investigation and validation. Further, until the safety and efficacy of FOPCon has been further investigated, it should be considered investigational and patients receiving it should be treated under protocols associated with formal clinical trials, including discussion of potential risks and benefits.
A summary of the ICC treatment guidelines for medical professionals is as follows [44] :
-
Deep tissue trauma: Deep tissue trauma must be avoided. This includes intramuscular injections, if at all possible.
-
Stabilization and treatment: For stabilization and procedures, venipuncture, subcutaneous medications, and intravenous medications are acceptable; again, intramuscular infections should be avoided if possible.
-
Intubation precautions: Significant precautions should be taken with intubation procedures. The jaw should be protected. Expert anesthesiologist consultation should be obtained because the jaw and neck may be completely or partially locked.
-
Further consultations: It is strongly recommended to obtain further consultations with expert physicians regarding the significant potential risks of any surgical or medical interventions being considered.
A complete version of these guidelines is available at The Medical Management of Fibrodysplasia Ossificans Progressiva: Current Treatment Considerations.
Surgical Care
Patients with fibrodysplasia ossificans progressiva (FOP), a rare disorder, may require oral surgical and anesthetic procedures to control oral pain. The importance of a minimally invasive surgical technique and appropriate anesthetic management has been stressed. [45]
The experience using general anesthesia has been favorable, with awake nasal fiberoptic intubation evaluated as desirable for airway management. [46]
-
Widespread tumors and indurations mainly in the scapular area, found on radiographic examination to consist of heterotopic bone formation.
-
Typical hallus valgus deformity.
-
Proliferation of fibroblasts within the muscle with partial replacement of the muscle fibers.
