Breakthrough Therapy for a Rare Metabolic Bone Disease

Breakthrough Therapy for a Rare Metabolic Bone Disease
Burosumab may enable near-normal lives for children with XLH.

New medications for treating genetic metabolic bone diseases are driving results of a magnitude seldom seen in pediatric drug trials. For victims of three rare disorders – osteogenesis imperfecta, hypophosphosphatasia and X-linked hypophosphataemia (XLH) – the impact ranges from more tolerable treatment regimens that lower fracture rates to a dramatic change in disease outcomes.

Monroe Carell Jr. Children’s Hospital at Vanderbilt is one of few centers to specialize in the treatment of children with rare metabolic bone diseases and is a top research site in the field. Jill Simmons, M.D., pediatric endocrinologist and director of the Program for Pediatric Metabolic Bone Disorders, joined Vanderbilt in 2006. “I love this patient population and it’s exciting to work in an area where the progress is so visible. Over the years, I have watched these kids develop more normally, do more physically, and receive treatment that doesn’t disrupt their lives,” Simmons said.

One of the most dramatic developments has been driven by burosumab treatment for XLH. With a Phase 3 multisite trial completed in 2019, the evidence is clear that burosumab vastly improves rickets, lower extremity bowing, linear growth, pain and physical function for the majority of patients.

“Over the years, I have watched these kids develop more normally, do more physically, and receive treatment that doesn’t disrupt their lives.”

Attacking Bone Mineralization Deficiency

Most metabolic bone disorders result from (usually hereditary) genetic mutations that prevent skeletal bone mineralization. In XLH, the body oversecretes fibroblast growth factor (FGF-23). This turns the kidneys into a sieve for phosphorus, preventing bone mineralization. The resulting osteomalacia manifests in skeletal deformities like rickets, bowing and short stature in children. Adults with XLH have poorly healing fractures, chronic pain, and often, limited mobility.

Until recently, XLH treatment consisted of four to six daily oral boluses of phosphorus as well as one to two times daily calcitriol. This therapy surfeits the bloodstream with phosphorus to try to outrun depletion in the kidneys. But the side effects of nausea and diarrhea are significant and compliance often suffers, Simmons says – even with good compliance, improvement is marginal.

In contrast to this compensatory strategy, burosumab, a human monoclonal antibody, works by targeting the root of the problem, FGF-23. With reduced volumes of this protein in circulation, the kidneys are able to naturally reabsorb more phosphorus.

The Burosumab Victory

The phase 3 burosumab trial included 61 patients, ages one to 12, enrolled across 16 sites and assigned to conventional or burosumab therapy. The primary endpoint was changed in rickets severity at 40 weeks. Results were published in Lancet.

Radiographic evidence showed the 29 children receiving burosumab experienced double the improvement of conventional therapy in rickets and lower extremity bowing. Mild to moderate adverse events were more frequent with the treatment group but were generally consistent with subcutaneous injection.

“Now we have a disease-specific treatment for XLH that works for patients across their lifespan.”

“Now we have a disease-specific treatment for XLH that works for patients across their lifespan,” Simmons said. “We’ve seen it reverse rickets, decrease lower extremity bowing and even result in healing of previously non-healing fractures. These results are achieved through twice-monthly subcutaneous injections at home versus requiring frequent oral medication that induces nausea and diarrhea.”

Trials on several promising new drugs to treat hypophosphosphatasia and osteogenesis imperfecta are also complete or in progress, Simmons said, with most drugs working to improve osteoblast function and reduce osteoclasts. Simmons hopes these will enable these kids to suffer fewer broken bones and spend less time sitting on the sidelines of life.