Unexpected Therapies for Fibrodysplasia Ossificans Progressiva Offer New Hope

Episode 4


A local pool in the summer is teeming with kids. A 9-year-old does a cannonball into the shallow end. As she surfaces, a stab of pain shoots through her hip. As days pass, what seems like a straightforward bump takes a complicated turn. Dr. Edward Hsiao, an endocrinologist and Director of the UCSF Metabolic Bone Clinic at the University of California, describes how after discovering a new bone growth at the site of the pain and several rounds of major (and unsuccessful) interventions, the child is diagnosed with fibrodysplasia ossificans progressiva. This extremely rare bone disorder has a devastating impact on a patient’s life. But thanks to unexpected areas of research, patients have new reasons to hope.

Edward Hsiao, MD/PhD

Edward Hsiao, MD, PhD, is a Full Professor and Director of the UCSF Metabolic Bone Clinic at the University of California, San Francisco. His research is driven by a bedside-to-bench-back to-bedside approach, using clinical observations and patient samples to inspire the research with the long-term goal of improving the care of patients with all types of skeletal disorders, such as fibrodysplasia ossificans progressiva (FOP). His laboratory uses a combination of human stem cell and mouse models to study how genetics and hormone signaling contributes to the normal formation of key skeletal tissues such as bone, cartilage, muscle, and fat. The lab also uses human induced pluripotent stem cells and genomics to understand the regulators of human disease. He sees patients with metabolic and rare bone diseases in the UCSF Metabolic Bone Clinic. He is a site investigator in interventional trials for an experimental compound to block heterotopic ossification in FOP, and he serves as a volunteer member of the International Clinical Council on FOP, the International FOP Association Medical Registry Advisory Board, and the FD/MAS Alliance. Outside of work and the lab, he enjoys hiking, archery, and spending time with his family.



Unexpected Therapies for Fibrodysplasia Ossificans Progressiva Offer New Hope

Dr. Raj Bhardwaj: This episode of DDX was produced in partnership with the American Society for Bone and Mineral Research and sponsored by Ipsen Biopharmaceuticals, Inc.

The details of this case have been changed to protect patient confidentiality.

A local pool is teeming with kids. Amid the laughter, a 9-year-old hurls herself into the shallow end with a cannonball. But as she surfaces, a stab of pain shoots through her hip.

Maybe she banged it on the pool floor — nothing major, right?

However, as days pass, what seems like a straightforward bump takes a complicated turn, exposing a diagnosis that nobody saw coming.

This is DDX, a podcast from Figure 1 about how doctors think. I’m Dr. Raj Bhardwaj.

This season is all about the treatment of bone diseases.

Today, a case from Dr. Edward Hsiao, an endocrinologist and Director of the UCSF Metabolic Bone Clinic at the University of California.

Dr. Hsiao is also the site investigator for clinical trials sponsored by Ipsen, which includes the drug discussed in this episode, palovarotene. He has received no compensation for his participation in this podcast and the views represented are his own.

Now, let’s return to the little girl at the swimming pool.

Dr. Edward Hsiao: So this is a very intriguing patient. She was 9 at the time that she first developed symptoms. And up until then, she was the usual happy child that was doing quite well from a health standpoint. At age 9, while she was playing, she actually jumped into a swimming pool, the shallow end of a swimming pool, and afterwards, she developed this right sided hip pain. And although there wasn’t any obvious trauma, she began to walk with a limp and developed a progressive stiffness and pain in her leg.

Dr. Bhardwaj: Our patient had a pelvis X-ray. It revealed that she had calcium deposits, forming in the muscle of her right hip, at the site of her original injury.

Dr. Hsiao: At the time, she was initially managed with different types of medication and physical therapy, and she subsequently underwent preoperative radiation therapy of that hip and then surgical resection to try to remove the heterotopic ossification.

Dr. Bhardwaj: Four weeks after her surgery, she was limping again.

She returned to her doctor.

What they found was shocking.

Dr. Hsiao: All of this extra bone actually came back, I think the family was very worried and very frustrated.

Dr. Bhardwaj: Even after they tried to remove the bone in her hip muscle through surgery, it just grew back.

Dr. Hsiao: And so they subsequently did a second surgery to try to resect the bone. And this one received additional radiation and steroids and anti-inflammatory medications to try to tamper it down and reduce the risk of bone forming again.

Dr. Bhardwaj: But this didn’t work either.

Just weeks later, she found herself limping and dealing with the pain again. The next visit to the doctor uncovered something totally unexpected.

Dr. Hsiao: After the second surgery, the bone formed back again. And at that point, they started to really get worried because this was a process that was going on, and it was recurring.

Dr. Bhardwaj: The child’s radiologist had a hunch about what might be going on.

Dr. Hsiao: One of the things that the radiologists had pointed out was like, this could, there’s a large amount of bone formation. You might want to consider a genetic diagnosis of FOP.

Dr. Bhardwaj: Fibrodysplasia ossificans progressiva, or FOP, is an extremely rare disorder, characterized by the abnormal formation of bone in muscles, tendons, and ligaments.

The way it attacks the body is dramatic and catastrophic.

Patients slowly lose mobility as the muscles and ligaments in their body are replaced by bone.

Many are largely immobilized by the time they reach their twenties. It’s a relentless and devastating process.

What makes FOP particularly challenging is that the formation of extra bone can be triggered by events as seemingly innocuous as minor trauma or injury.

In the case of our patient, bumping her hip when she jumped into the shallow end of a swimming pool was enough.

And multiple surgeries were too.

FOP usually manifests during early childhood, although our patient didn’t have her first occurrence until she was 9 years old.

And its presentation can vary among individuals.

But so much is still unknown about the disease; FOP flare-ups can be challenging to predict.

What we do know is that the genetic underpinnings of FOP involve variations in the ACVR1 gene, which impacts bone and tissue development.

But let’s return to our patient.

At the radiologist’s suggestion, she was referred to genetics.

Dr. Hsiao: She was subsequently referred to genetics and at the genetics office was noted to have malformed great toes. What was missing was that first joint of her toe, which resulted in a malformation.

Dr. Bhardwaj: The ACVR1 gene throws a wrench into the usual bone and tissue development.

And its impact can be seen during fetal development, specifically in the malformation of the big toes.

Dr. Hsiao: Between that clinical finding of the malformed great toes and her history of heterotopic ossification, they sent a genetic test for the gene ACVR1, which when mutated can induce heterotopic ossification. So she was ultimately diagnosed with fibrodysplasia ossificans progressiva.

Dr. Bhardwaj: A tiny tweak in a single amino acid can spark conditions like FOP, turning soft tissues into bone.

This diagnosis drastically transformed our patient’s life, highlighting the profound impact of even the smallest genetic changes.

Dr. Hsiao: So I think if we were to talk with her, I think her life would have changed significantly. When we talk to patients with FOP one of the things that they note is that, I used to be able to run, but now I can’t run with my friends, and for a child, that’s a big deal.

Dr. Bhardwaj: Any slight bump or injury could trigger bone formation in muscle.

Dr. Hsiao: I think the other aspect is as she has gotten older, the recognition that her independence is slowly being taken away from her.

Dr. Bhardwaj: There’s no cure for FOP.

Until recently, treatment mainly involved managing symptoms, steering clear of triggers that could spark bone formation, using steroids to tamp down inflammatory responses, and trying to manage the relentless pain.

Enter a surprising twist in treatment — a class of drugs known as retinoic acid medications or retinoids, akin to the acne treatment Accutane or isotretinoin. Known for its toxic side effects, these drugs disrupt the mineralization of cartilage, the initial phase of bone formation during fetal development. While pregnant individuals taking them risk limb malformations in their babies, for patients dealing with FOP, this posed a unique and unexpected opportunity.

Dr. Hsiao: And so the question became, could you actually use this type of toxicity as a treatment for patients with FOP?

Dr. Bhardwaj: Initially designed as a treatment for lung emphysema, the retinoid medication palovertine, showed good tolerance among patients.

This sparked interest in its potential as a safe treatment for FOP. But how does this tie into our patient’s story?

Dr. Hsiao: So as she got older she became a good candidate for palovertine, because I think one of the things that you want to do is to potentially block as much bone formation as early as possible.

Dr. Bhardwaj: Palovarotene, like any drug, has risks.

One notable concern is its potential to stunt growth in children by curbing the amount of bone formation.

And it’s possible that palovarotene could prevent any normal bone fractures from healing.

It’s a delicate balance when prescribing such medications — where benefits must be weighed against potential setbacks.

Our patient was prescribed palovarotene and takes it daily. She increases the dosage if there’s a chance of an FOP flare-up with some physical mishap.

Palovarotene has been recently approved as a treatment for FOP in the U.S. and Canada based on promising clinical trials.

Dr. Hsiao: So the patients who received the palovarotene had 50 to 60% less new heterotopic ossification as compared to the patients who were in the control group and did not receive palovarotene.

Dr. Bhardwaj: There’s a lot that doctors can learn from this 9-year-old girl’s case.

Dr. Hsiao: The diagnostic journey is important. In the past, a lot of patients have had misdiagnoses that they’ve ended up with biopsies that triggered additional heterotopic ossification. I think it’s worthwhile thinking that, if you see something like the abnormal toes and the swellings that you should think about patients with FOP because avoiding those situations, avoiding those biopsies really can be life changing for these patients.

Dr. Bhardwaj: FOP is exceptionally rare, impacting one in 1.4 million people, with about 1,000 identified patients and a significant number still undiagnosed.

Now, what about palovarotene — it might not just be for FOP, but could potentially have broader applications in treating various bone diseases.

Dr. Hsiao: One of the things we don’t know is whether palovarotene might actually be helpful for other types of heterotopic ossification occurring after hip replacement surgeries, or hip fractures, or elbow fractures. And then there are other rare conditions that actually have abnormal bone formation. So there is a potential that this may be useful on a much broader scale.

Dr. Bhardwaj: Those are exciting areas for future research.

Thanks to Dr. Hsiao for speaking with us.

This is DDX, a podcast by Figure 1. Figure 1 is an app that lets doctors share clinical images and knowledge about difficult-to-diagnose cases.

I’m Dr. Raj Bhardwaj, host and story editor of DDX.

Head over to figure1.com/ddx where you can find full show notes, speaker bios and photos.

This episode of DDX was produced in partnership with the American Society for Bone and Mineral Research and sponsored by Ipsen Biopharmaceuticals, Inc.

Thanks for listening!