Sclerostin Antibody–Induced Changes in Bone Mass Are Site Specific in Developing Crania

Abstract

Sclerostin antibody (Scl‐Ab) is an anabolic bone agent that has been shown to increase bone mass in clinical trials of adult diseases of low bone mass, such as osteoporosis and osteogenesis imperfecta (OI). Its use to decrease bone fragility in pediatric OI has shown efficacy in several growing mouse models, suggesting translational potential to pediatric disorders of low bone mass. However, the effects of pharmacologic inhibition of sclerostin during periods of rapid growth and development have not yet been described with respect to the cranium, where lifelong deficiency of functioning sclerostin leads to patterns of excessive bone growth, cranial compression, and facial palsy. In the present study, we undertook dimensional and volumetric measurements in the skulls of growing Brtl/+ OI mice treated with Scl‐Ab to examine whether therapy‐induced phenotypic changes were similar to those observed clinically in patients with sclerosteosis or Van Buchem disorder. Mice treated between 3 and 14 weeks of age with high doses of Scl‐Ab show significant calvarial thickening capable of rescuing OI‐induced deficiencies in skull thickness. Other changes in cranial morphology, such as lengths and distances between anatomic landmarks, intracranial volume, and suture interdigitation, showed minimal effects of Scl‐Ab when compared with growth‐induced differences over the treatment duration. Treatment‐induced narrowing of foramina was limited to sites of vascular but not neural passage, suggesting patterns of local regulation. Together, these findings reveal a site specificity of Scl‐Ab action in the calvaria with no measurable cranial nerve impingement or brainstem compression. This differentiation from the observed outcomes of lifelong sclerostin deficiency complements reports of Scl‐Ab treatment efficacy at other skeletal sites with the prospect of minimal cranial secondary complications. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

Spaceflight-Associated Vascular Remodeling and Gene Expression in Mouse Calvaria

“…However the gene expression of sclerostin, a potent inhibitor of bone formation, is higher in the spaceflight group based on our previous results (Macaulay et al, 2017) implying the possibility of both anabolic and catabolic activity of sclerostin. This is in contrast to previous reports that show that loss of sclerostin increases cranial bone growth and regeneration and sclerostin antibodies are used to increase bone mass in clinical trials of osteoporosis and osteogenesis imperfecta (Kang et al, 2018;Scheiber et al, 2019) suggesting that other mechanisms may be involved in bone formation.…”

Molecular Basis for Craniofacial Phenotypes Caused by Sclerostin Deletion

“…While Sost −/− mice show pathological bone accrual resulting in midfacial hypoplasia, candidates for romosozumab therapy would be long past any window where excessive mineralization would curtail facial growth. This conclusion is also supported by a study in which a function-blocking sclerostin antibody was delivered to mice with an osteogenesis imperfecta phenotype; even in very young mice treated with high doses of the sclerostin antibody, minimal alterations in cranial morphology were detected (Scheiber et al 2019).…”

Modeling the Impact of Microgravity at the Cellular Level: Implications for Human Disease

“…The BMP family of proteins regulates the expression of an important mechanosensing protein, sclerostin, found exclusively in osteocytes (Poole et al, 2005;Kamiya et al, 2016), whereby mechanical unloading increases sclerostin protein expression to promote bone resorption and cause a loss of bone density (Robling et al, 2008) -a phenotype that closely mimics both osteoporosis and osteonecrosis. Thus by applying the unique mechanical unloading environment offered by both real and simulated-microgravity to bone (specifically, osteoporosis) research has led to the introduction of the FDA approved drug, Evenity, a monoclonal antibody that works as an anabolic agent to increase bone mass via the sclerostin pathway (Scheiber et al, 2019).…”