Combo Therapy with Growth Hormone Could Improve Bone Development in XLH, Mouse Study Suggests

If combined with an approach that targets hallmark abnormalities in X-linked hypophosphatemia (XLH), treatment with growth hormone could normalize bone growth and structure in these patients, a study in mice suggests.

The study, “MAPK inhibition and growth hormone: a promising therapy in XLH,” was published in The FASEB Journal.

A protein called fibroblast growth factor 23 (FGF23) is important in the regulation of phosphorus levels in the body and in bone growth. Due to mutations in the PHEX gene, people with XLH have abnormally high levels of FGF23, which suppresses phosphate reabsorption in the kidneys and increases its excretion in urine.

Researchers in Spain assessed whether reducing FGF23 levels could improve body weight and bone growth in a mouse model of XLH. Rather than directly target FGF23, they used a compound known as PD0325901, which blocks the MAPK (mitogen-activated protein kinase) pathway used by FGF23 to inhibit phosphate reabsorption.

Mice received treatment with PD0325901 or growth hormone (GH), or both. Of note, growth hormone is used to promote body growth in children with XLH.

If untreated, mice with XLH showed growth deficits and marked alterations in the growth plate — the growing tissue of long bones — as well as impaired bone mineralization.

Results showed that PD0325901, with or without growth hormone, reduced FGF23 levels compared to untreated mice with XLH. Also, treatment alone or combined led to similar body weight gains in comparison with healthy animals.

Mice treated with only PD0325901 showed accelerated growth, improvement in rickets (soft, weak bones), and almost normal growth plates. Treatment with only growth hormone accelerated growth and improved bone mineralization, but it did not normalize the structure of the growth plate and the trabecular bone (sponge-like bone found at the ends of long bones).

“Thus,” the researchers wrote, “the use of GH might potentially increment the risk of bone deformities in pediatric patients with XLH.”

But when the treatments were combined, the animals showed accelerated growth, normalized growth plate, and improved structure of the cortical bone (the bone’s outer surface).

“Therefore, our data suggest that a combined treatment with a MAPK pathway inhibitor plus GH is the most effective treatment to improve growth and bone structure in the animal model of XLH,” the scientists said. Such treatment could “facilitate a well-ordered growth of bone and, at the same time, would have the potential of reducing the risk of fractures.”

Further studies will be needed to see whether these findings could be translated to children with XLH.