FOP Disease: How the Body Builds a Second Skeleton

Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder in which the body’s soft tissues, including muscles, tendons, and ligaments, gradually turn into bone. It affects roughly one in every one to two million people worldwide, making it one of the rarest conditions known to medicine. A single mutation in one gene drives the entire disease, and the resulting extra bone forms a kind of second skeleton that progressively locks joints in place over a person’s lifetime.

The Mutation Behind the Second Skeleton

FOP traces back to a mutation in a gene called ACVR1, which encodes a receptor on the surface of cells that normally helps regulate bone growth. The most common form of FOP involves one specific change in that receptor: an arginine amino acid at position 206 gets swapped for a histidine. This single substitution is found in all classic cases of FOP, whether inherited or arising spontaneously, making it one of the most precisely targeted disease-causing mutations known in the human genome.¹

The mutated receptor misbehaves in a way that has taken researchers years to untangle. Originally, scientists proposed two possible explanations: the receptor might be stuck in an “always on” mode, or it might overreact to normal bone-growth signals. More recent work has pointed to a third, more specific problem. The mutated receptor responds to a signaling molecule called Activin A, which the normal receptor ignores entirely. In healthy tissue, Activin A plays roles in inflammation and tissue repair but does not trigger bone formation. In someone with FOP, the mutated receptor treats Activin A as an instruction to start building bone.² This means that the very inflammatory signals the body sends to heal an injury become the signals that create unwanted bone, which is a cruel twist that explains why trauma and inflammation are so dangerous for people with FOP.³

The Earliest Warning Sign Most Doctors Miss

One of the most reliable early clues that a baby has FOP is a malformation of the big toes. Infants with classic FOP are born with short, inward-turning big toes on both feet, a condition known as congenital bilateral hallux valgus. This toe abnormality is present from birth, before any heterotopic bone has formed, and it can be spotted on a routine newborn exam if someone knows to look for it.⁴

The problem is that most clinicians never see a case of FOP in their entire career, and misdiagnosis is extremely common. The soft-tissue swellings that mark the disease’s first flare-ups often get mistaken for tumors, and biopsies are sometimes performed. Biopsying a flare-up is one of the worst things that can happen, because the surgical trauma itself triggers more bone growth at the biopsy site. Recognizing the toe malformation as an early diagnostic marker can spare children from these damaging misadventures and set them on a path toward correct management much sooner.

What Triggers Flare-Ups

FOP does not progress at a constant rate. Instead, it advances through episodic flare-ups: painful swellings in soft tissue that can last days to months and often end with new heterotopic bone locked in place. These flare-ups typically begin during the first decade of life and continue unpredictably throughout a person’s lifetime.⁵

A comprehensive survey of people with FOP found that roughly 88% reported at least some flare-ups triggered by identifiable causes, including injury, viral illness, and overuse. One especially concerning trigger is intramuscular injection: about a quarter of those surveyed said they had experienced a flare-up after an intramuscular shot, and in more than 80% of those cases the flare-up led to permanent bone formation at the injection site.⁶ This is why people with FOP are advised to avoid intramuscular immunizations entirely; vaccines are given subcutaneously instead, and dental injections require special planning.

Flare-ups can also occur without any obvious trigger. A child might wake up with a painful lump on the back or shoulder that seemingly appeared overnight. The unpredictability is one of the disease’s more psychologically taxing features. Falls, muscle stretching, fatigue, and even emotional stress have all been implicated, though the exact threshold that tips normal tissue repair into runaway bone formation remains poorly understood.

How the Disease Marches Through the Body

FOP follows a broadly predictable anatomical pattern. Bone formation tends to start in the neck, shoulders, and upper back during childhood, then moves into the arms, hips, and legs over time. The jaw is commonly affected, and fusion of the jaw joint can make it difficult or impossible to open the mouth fully. One case report of a pediatric patient undergoing surgery described temporomandibular joint fusion with a mouth opening of only about two centimeters, along with cervical spine fusion and thoracic heterotopic bone.⁷

The spine is a frequent site of involvement, and cervical vertebrae can fuse early in the disease. As the trunk becomes encased in heterotopic bone, the rib cage loses flexibility, leading to thoracic insufficiency syndrome, a condition where the chest cannot expand enough for normal breathing. Autopsy and clinical studies of patients with advanced disease have confirmed widespread heterotopic ossification along with right heart dysfunction, likely from the chronic strain of pumping blood through a body with increasingly stiff lungs.⁸ Cardiopulmonary complications are the leading cause of death in FOP, usually by middle age.

Not every tissue is affected equally. The diaphragm, the tongue, the heart muscle, and the smooth muscle of internal organs are spared. The extraocular muscles that move the eyes are also spared. This selectivity has long puzzled researchers, and the identity of the specific progenitor cells that get hijacked into forming bone remains an active area of investigation.⁹

Neurological Symptoms That Often Go Unrecognized

FOP is usually thought of strictly as a bone disorder, but neurological symptoms are far more common than many clinicians realize. A survey of people with FOP found that about half reported chronic neurological issues. Neuropathic pain, the burning or electric-shock-type pain that comes from nerve damage, was significantly more common than in the general population. Among women with FOP, neuropathic pain was roughly ten times more common than among men with the disease. About a quarter of those surveyed reported recurrent severe headaches, with women again disproportionately affected, and about a third of female respondents said their neurological symptoms worsened during menstrual periods.¹⁰

These findings suggest that the ACVR1 mutation may have effects on the nervous system that go beyond simple nerve compression from heterotopic bone. The sex-linked pattern and hormonal influence on symptoms point to a more complicated biological story that researchers are still working to understand. For patients, the practical takeaway is that nerve pain and sensory abnormalities are a recognized part of the disease and should be managed proactively rather than dismissed as unrelated.

Living with FOP

The cumulative burden of FOP extends well beyond the medical. An international survey of patients and their families found that decreased joint function was closely tied to reduced quality of life and a growing need for home modifications, assistive devices, and personal care support. Nearly half of primary caregivers reported at least a mild to moderate impact on their own health or psychological wellbeing, and most caregivers and adult patients said the disease had influenced their career decisions.¹¹

Children with FOP often lose the ability to raise their arms above their heads during elementary school years. By adolescence, many have significant restrictions in how far they can turn their heads or bend at the waist. Some become wheelchair-dependent as bridges of bone lock the hips or knees. Each lost degree of motion is permanent; once a joint is fused by heterotopic bone, no therapy or surgery can restore it. This progressive, irreversible loss of independence makes early recognition and careful flare-up prevention all the more important.

Why Surgery Is Almost Never an Option

In most orthopedic conditions, a surgeon can remove problematic bone and restore movement. In FOP, the opposite happens. Surgical trauma provokes a massive inflammatory response in the surrounding tissue, which the mutant ACVR1 receptor converts directly into new bone formation. Removing heterotopic bone from a fused joint in a person with FOP reliably produces even more bone than was taken out, often in a worse position. For this reason, surgery is avoided except in life-threatening emergencies.

Even necessary medical procedures pose serious risks. Anesthesia in someone with FOP can be extremely challenging. Jaw fusion and cervical spine immobility make conventional intubation, the process of placing a breathing tube, dangerous or impossible. Clinicians who have managed these cases describe using fiberoptic techniques to thread a breathing tube through the nose while the patient remains awake, since forcing the jaw open or extending the neck could trigger new bone growth.¹² Severe restrictive lung disease adds another layer of risk, because the rigid chest wall leaves very little room for error in ventilation. Any procedure that requires general anesthesia in a person with FOP demands a highly experienced team and meticulous planning.

Current Symptom Management

Without a cure, the day-to-day management of FOP focuses on preventing flare-ups and reducing their severity when they occur. Updated medical guidelines recommend a short course of oral corticosteroids at the onset of a flare-up to reduce inflammation, swelling, and tissue infiltration by immune cells.¹³ Nonsteroidal anti-inflammatory drugs and muscle relaxants are sometimes added for pain. None of these stop heterotopic bone from forming once the process is underway; they are comfort measures and damage-limitation strategies.

Fall prevention is a central part of daily life. Families childproof homes extensively. Contact sports, playground equipment, and any activity with a meaningful fall risk are off the table. Dental care is planned with extreme caution to avoid overstretching the jaw. Vaccinations are rerouted away from intramuscular sites. This level of constant vigilance is exhausting for families, and it is one reason why caregiver burnout is so common.

Palovarotene and the First Approved Therapy

For decades, FOP had no disease-specific treatment. Palovarotene, a drug that activates a receptor for retinoic acid (a derivative of vitamin A), became the first therapy developed specifically for FOP. It works on a different part of the bone-formation process than the ACVR1 mutation itself: rather than blocking the initial aberrant signal, it interferes with the cartilage-to-bone conversion step that produces heterotopic bone. Palovarotene was studied in phase 2 and phase 3 clinical trials to determine whether it could reduce new bone formation during flare-ups.¹⁴

Regulatory outcomes have varied by country. Canada granted approval in 2022, and some other markets have followed, though the drug’s path has not been straightforward. Safety concerns, particularly effects on bone growth in children, have complicated its use in younger patients who arguably have the most to gain from early treatment. Because FOP typically begins in childhood, this tension between potential benefit and growth-related side effects remains unresolved.

Garetosmab and the Activin A Approach

The discovery that Activin A is the key driver of heterotopic bone formation in FOP opened a new therapeutic avenue. Garetosmab is a monoclonal antibody that binds and neutralizes Activin A, aiming to block the disease at its source rather than downstream. In a randomized, placebo-controlled phase 2 trial, garetosmab produced striking results: new bone lesion activity was reduced by about 97% compared to placebo, and the volume of new heterotopic bone dropped by roughly 90%.¹⁵

Flare-ups were also less frequent and shorter in duration. A post hoc analysis showed that 35% of patients on garetosmab reported flare-ups during the treatment period, compared to 71% on placebo. When flare-ups did occur in the treatment group, their median duration was about 15 days versus 48 days for placebo. Fewer garetosmab-treated patients needed rescue corticosteroids.¹⁶ These are early-phase results in a small number of patients, and longer-term data will be needed, but the magnitude of the effect has generated considerable optimism in the FOP community.

Small Molecules in the Pipeline

Beyond antibodies, several groups are developing oral drugs that target the mutant ACVR1 receptor directly. One compound, BCX9250, acts as a potent inhibitor of the ACVR1 kinase. In mouse models of FOP, oral dosing reduced heterotopic bone volume to about 8% of what untreated animals developed, a reduction comparable to palovarotene in the same model.¹⁷

Another compound, RK783, takes a similar approach. In two different FOP mouse models, oral RK783 prevented the infiltration of immune cells and the differentiation of progenitor cells into cartilage and bone, effectively shutting down heterotopic bone formation in muscle tissue.¹⁸ A third class of compounds, macrocyclic kinase inhibitors, has been designed for even more selective targeting of the mutant receptor, aiming to minimize off-target effects on normal bone signaling pathways.¹⁹

All of these small molecules are still in preclinical or early clinical stages. The appeal of an oral pill that could be taken daily to prevent flare-ups is obvious, especially for children, but translating mouse results into human efficacy is never guaranteed. The FOP research pipeline is nonetheless broader than it has ever been, with multiple mechanistic approaches being pursued simultaneously.

Tracking the Disease Before Bone Forms

One of the frustrations of managing FOP is that by the time heterotopic bone is visible on a standard X-ray or CT scan, it is already formed and permanent. Researchers have explored earlier imaging methods to catch the process before bone solidifies. A specialized PET/CT scan using a radioactive sodium fluoride tracer has shown promise as a way to detect increased bone-forming activity in muscle tissue during flare-ups, potentially before hard bone has appeared. Elevated tracer uptake in a particular area may predict where heterotopic bone will develop, giving clinicians a potential window to intervene.²⁰

This type of early detection could become especially valuable as more treatments reach clinical trials. If a drug’s goal is to prevent bone formation rather than reverse it, you need a way to measure whether it is working before the bone shows up. Imaging that can detect the precursor activity gives trial designers and clinicians a tool they have not previously had, and it may eventually help patients and their doctors decide when to start or intensify treatment during a suspected flare-up.

Why FOP Research Matters Beyond FOP

FOP affects a tiny number of people, but the science behind it has implications for a much larger population. Heterotopic ossification, the formation of bone in soft tissue, occurs in people without FOP as well. It is a common complication after hip replacement surgery, severe burns, traumatic brain injuries, and blast injuries in combat. The biology is not identical to FOP, but many of the same signaling pathways are involved. Compounds developed for FOP may eventually find uses in preventing post-surgical or post-traumatic heterotopic bone in the general population. For the researchers working on this ultra-rare disease, the small patient community has punched well above its weight in advancing the understanding of how bone forms where it should not.