Giving New Life Through X-linked Hypophosphatemia Research

Episode 6


After a lifetime of treating her rare bone disease, X-linked hypophosphatemia, a patient is at the end of her rope. Due to a genetic variation of the X chromosome — specifically the PHEX gene — there’s an imbalance of phosphate levels in her body. Because of its domino effect on bone development and mineralization, the patient is in pain, she’s frustrated, and nothing seems to help. So when a clinical trial opportunity presents itself, Dr. Suzanne Jan de Beur, a professor of medicine and the Chief of Endocrinology and Metabolism at the University of Virginia, is unsure the patient will want to participate. While the decision to participate is surprising, the results of the clinical trial are astonishing.

Suzanne Jan de Beur, M.D.

Suzanne Jan de Beur, MD, is Chief of the Division of Endocrinology and Metabolism at University of Virginia School of Medicine. Dr. Jan de Beur holds the Gerald D Aurbach Endowed Chair in Medicine and is Professor of Medicine at University of Virginia School of Medicine.

Dr. Jan de Beur graduated from Cornell University and Cornell Weill Medical College. She completed the Osler Medical Residency at the Johns Hopkins Hospital and her fellowship in Endocrinology and Metabolism at the Johns Hopkins University School of Medicine.

As a Physician-Scientist and a practicing Endocrinologist, her clinical and research work focus on understanding rare and metabolic bone diseases at the basic level and translating these observations to the bedside. She identified and characterized the molecular basis of several disorders of mineral metabolism including pseudohypoparathyroidism, progressive osseous heteroplasia, and tumor induced osteomalacia. Her work has led to important new treatments for X-linked hypophosphatemia, tumor induced osteomalacia and osteogenesis imperfecta.

She is an internationally recognized expert in osteoporosis and rare bone diseases and has contributed to many clinical guidelines for the care of patients with these disorders.   

Dr. Jan de Beur is a member of several professional and honorific societies including the Endocrine Society, the American Society of Bone and Mineral Research (ASBMR) and the Association of Osteobiology.  She is a Past President of the American Society of Bone and Mineral Research and a Fellow of the ASBMR.  Dr. Jan de Beur is the recipient of the Shirley Hohl Award and the Boy Frame Award of the American Society of Bone and Mineral Research.




Giving New Life Through X-linked Hypophosphatemia Research

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

Dr. Suzanne Jan de Beur: So when I think about my patient, when we kind of really hit a wall, I remember myself standing outside the exam room. I was going in and just mentally preparing myself knowing that when I open that door, you know, I’m going to encounter a patient that’s frustrated, that’s in pain, that’s probably sitting in a room with the lights out, probably not going to look me in the eye. Because I’m frustrated and she’s frustrated because she’s having an incredible amount of pain, and I’ve been treating her and I have been tinkering around with her doses, going up, going down, and none of this is making a wit of difference to her. She’s still in pain. She’s still fatigued. She feels like she has no life and I’m frustrated because I have nothing else to offer her.

Dr. Bhardwaj: 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. Suzanne Jan de Beur, a professor of medicine and the Chief of Endocrinology and Metabolism at the University of Virginia.

Dr. Jan de Beur is a scientific advisor, consultant, and investigator for clinical trials for Ultragenics and Kyowa Kirin, Inc. which includes the treatment, burosumab, referenced in this episode. She has received no compensation for her participation in this podcast and the views represented are her own.

Dr. Jan de Beur just described a scenario that probably keeps most doctors up at night.

A patient is suffering.

Treatment isn’t working.

Frustration is mounting.

Our patient has X-linked hypophosphatemia, or XLH, a rare bone disease. It’s caused by a genetic variation of the X chromosome — specifically the PHEX gene — responsible for regulating phosphate levels in the body.

When the PHEX gene goes awry, it leads to an imbalance in phosphate, causing a domino effect on bone development.

Dr. Jan de Beur: This results in poor mineralization of bone. The bone becomes soft. It breaks. So people have fractures, bone deformity, short stature, dental issues that cause dental loss, and then over time, this leads to areas that become calcified or mineralized that shouldn’t be. And this causes stiffness and pain and decreased range of motion. So this is really a lifelong disorder that presents in childhood and this all can lead to lots of pain and lots of disability later in life.

Dr. Bhardwaj: The standard of care for XLH is oral phosphate and active vitamin D supplements.

These work to increase phosphate levels and enhance its absorption in the intestines.

But it’s an imperfect solution.

Dr. Jan de Beur: In the pathophysiology of this disorder, basically the kidney becomes a phosphorus sieve. We are trying to pour phosphorus in a leaky bucket. So we’re pouring phosphorus in, they’re peeing phosphorus out. So it’s really a balancing act of trying to pour enough phosphorus in as it’s being peed out. Trying to get enough calcitriol in to absorb phosphorus in the GI tract, and trying to get enough in the patient’s bloodstream to help with growth, to help with mineralization, to keep the bowing deformity from happening.

Dr. Bhardwaj: This treatment begins at diagnosis, which usually happens in childhood and continues until the patient’s bones have fully developed.

It’s a demanding regimen.

Dr. Jan de Beur: So unfortunately, they have to take phosphorus four or five times a day and trying to get a toddler and a youngster and a teenager to take medications four and five times a day is a really uphill battle. Phosphorus does not taste good and it can cause diarrhea.

Dr. Bhardwaj: As a child our patient adhered to the standard regimen of phosphate and vitamin D supplements, a treatment commonly phased out in adulthood.

But her symptoms were tenacious, so as an adult she was advised to continue with the supplements.

Yet, despite a steadfast routine, relief remained elusive.

During their first meeting, Dr. Jan de Beur was struck by how much pain this patient was experiencing.

Dr. Jan de Beur: So when we met, I remember it well. You know, she was kind of slumped over in her chair. I was sitting on a stool next to her and just really trying to get an idea about how she was feeling, what was going on. She was extremely fatigued. She was in a lot of pain, her bones ached.

And when I tried to distill what type of pain she was having, it was clear to me she was having many different types of pain. That was keeping her from really doing much at all. She would not go out. She could barely work. She would barely look me in the eye. You know, she was slumped over and just really, seemed a little angry and I understand why. Because she really just did not have a life.

Dr. Bhardwaj: Dr. Jan de Beur tinkered with the dosage of the supplements. But it didn’t help.

Dr. Jan de Beur: You know, I really, over time, as we tinkered with calcitriol and phosphorus, really just felt like I was at the end of what I could offer. We were making no progress and I was frustrated and she was frustrated too. Yeah, I mean, it’s a terrible feeling just to kind of be at the end of what you can offer.

Dr. Bhardwaj: But there was another option.

Dr. Jan de Beur: So I was starting a clinical trial of a medication called burosumab, which focuses on neutralizing FGF23.

Dr. Bhardwaj: The hormone FGF23, or fibroblast growth factor 23, acts like a traffic cop, regulating the movement of phosphate in the body.

However, in XLH, FGF23 causes the kidneys to excrete more phosphate, leading to persistently low levels and contributing to weakened bones and other health issues.

Burosumab steps in as a regulator, tempering FGF23’s activity, allowing for improved phosphate retention, and ultimately fostering better bone development.

And although this sounds like a promising alternative, Dr. Jan de Beur was almost certain her patient wouldn’t agree.

Dr. Jan de Beur: And I thought about patients that I could offer this to. And, you know, I thought about her and I thought, there is just no way she will think about doing this, not in a second. She does not trust me. She’s frustrated. I’ve really made no progress with her. I can’t imagine in a million years, she would agree to go in this clinical trial.

Dr. Bhardwaj: But Dr. Jan de Beur still met with her patient to float this possibility.

Dr. Jan de Beur: So I went and I explained the clinical trial and I was shocked. You could have knocked me off my stool when she said, yes, I want to do it. And I was shocked because, you know, I thought that she would for sure not want to do it, but then it really hit home with me. You know, she is suffering so much. She wants to try something new. We’re just nowhere and she wants to try something different.

Dr. Bhardwaj: The patient enrolled in the clinical trial and the results were almost immediate.

Dr. Jan de Beur: She came into the clinical research unit, I almost felt like, you know, invasion of the body snatchers. Who is this woman that looks just like my patient, but acts completely differently?! She came in with this baseball hat that she had bejeweled and decorated. She told me about taking her grandchildren out to the park, how she had thought about starting a childcare business. She just seemed completely different. She had so much more energy. Her pain was so much better. I was really shocked how well she was doing in just such a short period of time.

Dr. Bhardwaj: The medication was eventually approved in the United States to treat XLH in children and adults. Our patient has been taking it as a monthly injection ever since.

Dr. Jan de Beur: She seems like a completely different person to me. She is writing a children’s book for kids with XLH. She travels with her husband. She started a business that’s thriving. She is just happy and up and joking and laughing and she’s just the life of the party. I don’t feel like she’s gotten her life back. I think she has a better life than she’s ever had.

Dr. Bhardwaj: Dr. Jan de Beur says that we can all learn a lot from this patient’s journey.

Dr. Jan de Beur: I think there’s a couple takeaways, one takeaway for me is that don’t ever underestimate people’s willingness to participate in a clinical trial and offer everybody the chance to participate. My other takeaway is that, you know, there is hope for adults with X-linked hypophosphatemia that are experiencing debilitating pain, fatigue, that are really affecting their life.

And I’ve seen it multiple times that with newer treatments that really this can be improved and life can improve. I didn’t feel like I even knew who my patient was until I saw what she was like on burosumab treatment or on this newer treatment. So I guess the takeaway from this is that, you know, when you hit a roadblock, and at the time that I hit the roadblock with her, I didn’t have anything, but now we have newer treatments that I would have such a low threshold for trying it in people that are not doing well on standard of care.

Dr. Bhardwaj: Thanks to Dr. Jan de Beur 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 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 Kyowa Kirin, Inc.

Thanks for listening!