Genetic abnormalities in 30 people in a Dutch fishing village and about a hundred South African Afrikaners have provided the clues needed to develop sclerostin inhibitors as a potential new treatment for osteoporosis.
Professor Socrates Papapoulos, from the Leiden University Medical Center in The Netherlands, described the progressive bone overgrowth that occurred during the first three decades of life in the Dutch patients with van Buchem disease and the Afrikaners with sclerosteosis.
Complications include entrapment of cranial nerves and increased intracranial pressure, but these individuals also have bones of unusual strength that are resistant to fracture, Professor Papapoulos told delegates.
The disorders have been traced to different autosomal recessive defects in the SOST gene that result in impaired secretion of sclerostin, a glycoprotein produced only by mature osteocytes.
“Sclerostin inhibits Wnt signalling and bone formation, and is the most attractive target for the development of new therapeutics,” he said.
“Inhibition of sclerostin in animal models has a truly anabolic effect, promoting new bone formation without increasing resorption and leading to trabecular and cortical bone formation and increased bone mass and strength.”
Two humanised antibodies to sclerostin, romosozumab and blosozumab, have been investigated in phase I and II clinical studies.
“Subcutaneous injection every two or four weeks for up to two years showed impressive increases in BMD at the spine and the hip which exceeded previously reported increases with any other monotherapy,” he said.
“The studies confirmed the transient dissociation of bone formation and resorption with treatment.”
A large phase III study of romosozumab, with fracture outcomes, is currently underway in about 10,000 patients and will explore the safety of the drug.
Because of the apparent specificity of sclerostin for osteocyte function, it’s hoped the side effect profile will be favourable.
“Most currently-available agents do not stimulate the formation of new bone, which is essential for the management of patients with severe disease, and only modestly reduce the risk of non-vertebral fractures,” Professor Papapoulos said.
“We need new agents capable of stimulating new bone formation for such patients.”