Sclerostin Antibody Treatment Increases Bone Mass and Normalizes Circulating Phosphate Levels in Growing Hyp Mice

Abstract

X‐linked hypophosphatemia (XLH), caused by a loss‐of‐function mutation in the phosphate regulating gene with homology to endopeptidase located on the X chromosome (PHEX), is the most common form of vitamin D‐resistant rickets. Loss of functional PHEX results in elevated fibroblast growth factor 23 (FGF23) levels, impaired phosphate reabsorption, and inhibited skeletal mineralization. Sclerostin, a protein produced primarily in osteocytes, suppresses bone formation by antagonizing Wnt signaling and is reported to be elevated in XLH patients. This study used the Hyp mouse model to investigate sclerostin's role in the pathophysiology of XLH by evaluating the use of a monoclonal antibody to sclerostin in a mouse model of XLH, the Hyp mouse. Male and female wild‐type and Hyp littermates were injected with 25 mg/kg of vehicle or sclerostin antibody (Scl‐Ab) twice weekly, beginning at 4 weeks of age and euthanized at 8 weeks of age. Scl‐Ab treatment increased serum phosphate levels and suppressed circulating levels of intact FGF23 in treated wild‐type and Hyp mice of both sexes. Cortical area, trabecular bone volume fraction (BV/TV), metaphyseal apparent density, and the peak load increased with Scl‐Ab treatment in both sexes. This short‐term treatment study suggests that Scl‐Ab treatment can effectively improve some of the pathologies associated with XLH, including normalization of phosphate, and that sclerostin may play a role in regulating FGF23 and phosphate metabolism in XLH. © 2019 American Society for Bone and Mineral Research.

Development of Enthesopathies and Joint Structural Damage in a Murine Model of X-Linked Hypophosphatemia

“…Similar mechanisms have been described when mineralization of osteoid is inhibited by administration of bisphosphonate etidronate (Irie et al, 2008). It is worth noting that a recent study suggests a key role of sclerostin in FGF23 regulation, phosphate metabolism and XLH pathobiology (Carpenter and Ross, 2020).…”

Sclerostin and Osteocalcin: Candidate Bone-Produced Hormones

“…Accordingly, urinary calcium excretion was reduced, serum phosphorus was elevated, and serum FGF-23, which promotes phosphate excretion, was low in Sost -/- mice ( 14 ). In wild-type mice and in a mouse model of X-linked hypophosphatemia, sclerostin-neutralizing antibody treatment (4 weeks, 2 doses/week, 25 mg/kg) significantly increased serum phosphate and decreased circulating FGF-23 ( 123 ). Therefore, sclerostin deficiency leads to alterations in mineral metabolism to enhance absorption and reduce excretion of calcium and phosphorus.…”

Sclerostin and Its Associations With Bone Metabolism Markers and Sex Hormones in Healthy Community-Dwelling Elderly Individuals and Adolescents

“…The clinical importance of sclerostin was initially highlighted by sclerosteosis and van Buchem disease, two sclerosing bone disorders caused by lossof-function mutations of the SOST gene (encoding sclerostin), and further proved by the phenotypical characterization of increased bone mass and bone formation in disease-related animal models (Li et al, 2008;Van Lierop et al, 2011Boudin et al, 2017). Based on positive results of experiments in mice and human, two monoclonal antisclerostin antibodies, romosozumab and blosozumab, have been developed as new therapies for osteoporosis and their significant effects in increasing bone mineral density (BMD) and reducing fracture risks were demonstrated (McClung et al, 2014;Recknor et al, 2015;Cosman et al, 2016;Ominsky et al, 2017;Carpenter and Ross, 2019).…”