Multidisciplinary Approach Key for XLH, Experts Say in Webinar

Multidisciplinary Approach Key for XLH, Experts Say in Webinar
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A multidisciplinary approach based on pediatrics, orthopedics, and functional therapy specialties is crucial for managing and treating children and adults living with X-linked hypophosphatemia (XLH), experts emphasized on a recent webinar hosted by the European Pediatric Orthopedic Society (EPOS).

In the webinar, “8th EPOS Webinar on Lower Limb: X-linked hypophosphatemic rickets (XLH): pediatric perspectives, clinical aspects and treatment,” a pediatric endocrinologist and two orthopedists discussed the clinical, radiographic, and functional aspects of the disease, as well as treatment options.

XLH is complex with high disease burden

XLH is characterized by abnormally high blood levels of FGF23, a bone-derived hormone, preventing the kidneys from reabsorbing phosphate — an important mineral for bone and teeth development — into the bloodstream and leading to chronic hypophosphatemia (low blood levels of phosphate).

Hypophosphatemia causes a number of symptoms, such as osteomalacia — soft and weak bones — skeletal deformities, fractures, stunted growth, and early osteoarthritis (joint cartilage damage).

“XLH is much more than just rickets or lower limb deformities,” said Adalbert Raimann, MD, a pediatric endocrinologist at Medical University of Vienna’s Comprehensive Center for Pediatrics and the Vienna Bone and Growth Center, in Austria. He also is involved in the treatment of the largest group of XLH patients in the country.

Notably, the XLH-associated defect in bone mineralization also leads to dental abscesses (buildup of pus in the teeth), which when not managed by a dentist with some expertise in XLH, may lead to the “extraction of nearly all teeth” by age 10 to 12, Raimann said.

As such, a basic assessment of a patients with XLH includes at least seven disciplines, he added, with pediatrics, orthopedics/pediatric orthopedics, and functional therapy as key players in treatment.

“You need to work together and every discipline has to bring in a specialty which the other probably can’t compensate,” he said.

Despite standard treatments, nearly all adults (97%) and most children (80%) with XLH have bone or joint pain, with pain killers being taken at least once a week by 67% of adult patients. In addition, more than 80% of patients have walking problems and short stature.

Raimann said that quality of life data from his own patients also showed that the physical domain is particularly impaired in children with XLH, even when compared with those with brittle bone disease, “because they have so much chronic pain and burden of disease.” About 10,000–25,000 people in Europe alone are estimated to live with XLH (excluding U.K. numbers), he added.

Joachim Horn, MD, PhD, the chief of the Children’s Orthopedics section at the Oslo University Hospital, in Norway, also said that XLH became one of the conditions prioritized by the European Reference Network on Rare Bone Diseases due to its frequency and gravity, thereby supporting the improvement of its diagnosis and management.

Treatment options

Standard treatment includes a combination of high-dose oral phosphate supplements and active vitamin D compounds, such as calcitriol, which helps to lessen rickets but does not target the underlying cause of the disease.

In addition, treatment dose and schedule have to be tightly controlled to prevent potential side effects; a task that has proven challenging, as not all patients comply to the sometimes highly-demanding recommendations, Raimann said.

Crysvita (burosumab), marketed by Ultragenyx Pharmaceutical and Kyowa Kirin, became the first and only disease-modifying therapy approved for XLH in 2018. The therapy works by blocking FGF23, thereby boosting phosphate reabsorption in the kidneys.

Besides achieving normal phosphate levels in the blood, Crysvita-treated patients also show significant improvements in bone fracture healing and in growth. However, “linear growth is not that much improved and deformities which are not directly rickets-derived neither,” Raimann said.

Regardless of treatment, patients are unable to achieve normal growth due to bone deformities, which just from “a matter of angle cost a lot of centimeters,” the pediatrician added.

That is when orthopedics comes in. Orthopedics aims to correct XLH-associated bone deformities mainly through guided growth, a minimally-invasive surgical procedure, and osteotomy, a surgical procedure in which the bone is cut to be repositioned.

Christof Radler, MD, the head of pediatric orthopedics at the Orthopedic Hospital Speising Vienna, said that guided growth “takes quite a long time, but it does work very nicely.” Horn recommended that guided growth should be applied “as early as possible,” with ages 3 and 4 as a good time to start.

While this method can be repeated upon deformity recurrence, it cannot correct all bone deformities. Still, “osteotomies of course are a good choice,” said Radler.

However, “recurrence has been recognized as a problem [of osteotomies] for quite a long time,” especially in younger children, he added.

A 2008 study in which Radler was involved showed that 90% of XLH patients had bone deformity recurrence after the first intervention and 60% after a second intervention. Still, he believes that at that time, patients were not as metabolically well-controlled with medication as nowadays, which may have contributed to the observed higher rates of recurrence.

In addition, several studies have highlighted that bone fixations can help correct the deformity and limit recurrence, but not completely.

Further data need to be collected to learn more about the specifics of this rare disease and to provide better care to these patients, said Raimann.

“We have to find partners in all disciplines for this very multidisciplinary disorder, especially [in terms of] orthopedics, pediatrics, and adult medicine,” he said, with the latter focusing on giving adult patients the best possible quality of life and mobility.

“This is probably more important than choice of pharmacological treatment and sometimes maybe even more important than the choice of this or that surgical approach.”

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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José holds a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.

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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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