While conventional treatment combining phosphate supplementation with active vitamin D is effective for a large number of people with X-linked hypophosphatemia (XLH), some patients develop treatment-associated complications or fail to respond, a review study reports.
In these cases, considerable hope is being placed on treatment with Crysvita (burosumab), according to the study, titled “X-linked hypophosphatemia: Management and treatment prospects,” published in the journal Joint Bone Spine.
Phosphate is required for the development and growth of bones and teeth, as well as for regulation of several cellular processes.
XLH, which caused by mutations in the PHEX gene, is characterized by high levels of fibroblast growth factor 23 (FGF23), which is necessary for regulating phosphate levels in the body, and decreased phosphate reabsorption in the kidneys. Due to the resulting low levels of phosphate in the blood, people with XLH often develop rickets and osteomalacia (softer-than-normal bones), bone pain, and failure to thrive, among other complications.
This conventional strategy lowers levels of alkaline phosphatase (an indicator of bone disorders) within about one year, correcting bone deformities, increasing growth, and decreasing the number of dental abscesses.
However, there are limitations to this strategy including the persistence of low phosphate levels, a risk of secondary hyperparathyroidism (high levels of the parathyroid hormone), and hypercalciuria — high calcium levels in urine — which can cause kidney dysfunction.
Crysvita, approved for children and adults with XLH in the U.S. and Europe, is an antibody against FGF23. Studies have shown that this therapy, developed and marketed by Ultragenyx Pharmaceutical and Kyowa Kirin, helps maintain normal blood phosphate levels, increases vitamin D levels, eases rickets, and leads to significant functional improvements.
“Considerable hope is therefore being placed in the recent licensing of the FGF23 antagonist burosumab [Crysvita] for the treatment of XLH in children,” the investigators wrote.
However, because Crysvita’s approval is still recent, no long-term data are available, particularly pertaining to complications. As such, the conventional strategy with phosphate and vitamin D supplementation remains the first-line approach in children with a known family history or early diagnosis of XLH.
Crysvita is considered for patients who fail to respond to conventional treatment for at least one year, for children with XLH diagnosed later in life (after 7–8 years old), and for children who develop hyperparathyroidism or nephrocalcinosis — deposition of calcium salts in the kidney — during conventional therapy.
Add-on therapies can be given to children with XLH, such as supplementing with a growth hormone for shorter children. When combined with conventional treatment, a growth hormone appears to provide larger growth-rate increases if given before puberty. Another option in children is to undergo surgery to realign their lower limbs during growth.
The management of adults with XLH is different from children.
As patients go through adolescence and reach adulthood, conventional treatment may not be effective against certain XLH complications such as osteoarthritis (inflammation in joints). As a result, it can be difficult to decide the course of treatment, the researchers said. Current consensus is that treatment should be provided to patients with bone pain, fractures, Looser zones (also known as psuedofractures), and to those who require orthopedic surgery.
In adults, an active vitamin D analog is the mainstay of treatment, though the dosage is lower than in children. Phosphate supplements may also be given.
Results of a Phase 3 clinical trial (NCT02526160) in adults showed that treatment with Crysvita eased stiffness, decreased pain, and improved bone healing.
However, as in children, more data are needed on the long-term effect of Crysvita in adults, the scientists said, adding that education plays a big role in XLH treatment, and both the patient and his or her family must be carefully informed to ensure treatment adherence.
“In addition, information on advances in research and treatments in the field of phosphate regulation should be given regularly,” they wrote.
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