Safer, More Effective Therapies Needed for Hypophosphatemic Rickets, Turkish Study Reports

Higher doses of phosphate and vitamin D supplements seem to reduce bone deformities in young people with hypophosphatemic rickets (HR), a Turkish nationwide study reports. However, such increased doses also may cause a disorder called nephrocalcinosis, in which the levels of calcium in the kidneys become abnormally high.

In patients with kidney stones, developing nephrocalcinosis may lead to symptoms such as blood in the urine, fever and chills, nausea and vomiting, and severe pain.

These findings reflect the challenges of current HR treatments — and highlight the need for safer and more effective therapies for the disease — in which the bones become painfully soft and bend easily, the scientists said.

The study, “Nationwide Turkish Cohort Study of Hypophosphatemic Rickets,” was published in the Journal of Clinical Research in Pediatric Endocrinology.

HR is a rare disorder that can be caused by different mutations leading to the overproduction of a hormone called fibroblast growth factor 23 (FGF23). High levels of FGF23 prevent the kidneys from reabsorbing phosphate and block the production of vitamin D. That, in turn, leads to chronic hypophosphatemia — low blood levels of phosphate — as well as osteomalacia and rickets, both of which are characterized by softer and weaker bones.

X‐linked hypophosphatemia (XLH), the most common form of HR, is caused by mutations in the PHEX gene, which codes for an enzyme that controls the production of FGF23.

Conventional treatments for HR include combinations of phosphate and active vitamin D (calcitriol) supplements.

“Unfortunately this therapy was unsuccessful in a significant proportion of patients in respect to healing of rickets and improvement in deformities, and can be associated with treatment related side effects,” the investigators wrote.

Here, scientists from Turkey reported the findings of a nationwide study that documented the clinical outcomes of 166 children and adolescents with HR who were being followed at 24 clinical centers in the country. The patients, ages 0-18, were followed for a mean period of 6.7 years, and nearly all were treated with calcitriol and phosphate supplements.

Genetic tests involving 75 of the children and adolescents revealed that the majority (80%) had a PHEX mutation.

Analyses based on 91 children and adolescents who completed at least three years of treatment showed that the blood levels of phosphate and parathyroid hormone (PTH), which controls the levels of calcium, tended to increase over time.

During follow-up, approximately a third (36%) of 159 patients who did not have a specific diagnosis underlying HR had a reduction in bone leg deformities. Although doses of phosphate supplements were similar, the children and adolescents having less significant bone deformities received higher doses of calcitriol than the other participants in the first and third years.

Safety analyses showed that 27 patients ended up developing nephrocalcinosis at some point during follow-up. These participants had received higher doses of both calcitriol and phosphate supplements, the results showed.

“HR treatment and follow-up is challenging and our results showed an association between higher treatment doses and NC,” the researchers wrote. “However, higher calcitriol doses appear to improve bone deformities.”

The scientists concluded: “Safer and more efficacious therapies are needed.”