I05 Sclerostin - A key bone regulatory molecule

Abstract

Sclerostin is an osteocyte-expressed, extracellular cystine-knot protein that is lacking in patients with sclerosteosis, a rare condition characterized by excessive bone formation. Sclerosteosis patients exhibit very high bone mass (lumbar spine Z scores up to +14) and are anecdotally resistant to bone fracture. Homozygous patients commonly develop symptoms associated with cranial nerve entrapment from excessive bone formation but do not show signs of heterotopic bone formation or metabolic abnormalities. Carriers demonstrate moderately elevated bone mass without associated untoward symptoms of excessive bone formation. Sclerostin knockout mice recapitulate many of the features of the excessive bone formation seen in sclerosteosis patients. Sclerostin acts by down modulating signaling through two osteogenic pathways (the Wnt and BMP pathways) and is consequently believed to negatively regulate the anabolic output from cells in the osteoblast lineage Treatment of rodents with monoclonal antibodies that block the function of sclerostin results in significant increases in bone formation, bone mass and bone strength. Further, antibodies to sclerostin can reverse the bone loss in rodents associated with ovariectomy, chronic inflammatory conditions and steroids. In primates, sclerostin antibodies cause a dose-dependent increase in circulating markers of bone formation as well as increasing bone mineral density and bone strength in both trabecular and cortical bone. Sclerostin antibodies also accelerate bone repair in both rodent and primate fracture repair models. Mechanistic studies have shown that primarily acts to stimulate bone formation through a modeling rather than a remodeling pathway. A Phase 1 clinical study demonstrated that a humanized antibody to sclerostin increased markers of bone formation and also inhibited a marker of bone resorption in a dose-dependent manner. Sclerostin inhibition provides an opportunity to evaluate therapies to increase bone mass to reduce fracture and accelerate fracture healing.