ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Bone Miner Res. 2020;35(3):596–60.

In brief: Antibody treatment against the Wnt antagonizing sclerostin substantially improves FGF23 levels, serum phosphate and mechanical bone properties in a murine model of X-linked hypophosphatemic rickets, suggesting a role of sclerostin in phosphate metabolism.

Commentary: Associations between the expression of the Wnt-antagonist sclerostin and FGF23 have been suggested in recent human and murine studies, although a direct interaction was not proven so far.

Based on the hypothetical interactions between the two osteocyte-derived endocrine factors, Carpenter and Ross used the well-established murine Hyp model for XLH to investigate effects of sclerostin inhibiting antibodies (SclAb) on increased FGF23 expression and its sequelae during skeletal growth. In line with their initial assumption, Scl-Ab treatment increased circulating phosphate and decreased intact FGF23 levels in both WT and Hyp mice with a more pronounced effect in the disease model. SclAb did not normalize the impaired growth or osteoid but increased bone mass and strength in Hyp and wildtype mice to a comparable extent. Thus, these data could prove a partial rescue of the Hyp phenotype by SclAb treatment. Although sclerostin clearly has to be added to the list of regulating factors in the still poorly understood pathogenesis of XLH, the distinct regulatory pathways remain unclear. Confounding effects such as increased 1,25-OH-Vitamin D levels in SclAb treatment further complicate the interpretation of the study’s results.

Nevertheless, the pharmacologic inhibition of sclerostin represents a novel therapeutic perspective in the treatment of XLH and FGF23-related hypophosphatemia. While beneficial effects might be limited on phosphate levels and bone strength, combined approaches with established agents such as Burosumab might give hope to further optimize the pharmacological treatment of XLH.