ESPE Abstracts (2023) 97 P1-28

ESPE2023 Poster Category 1 Bone, Growth Plate and Mineral Metabolism (46 abstracts)

Effects of romosozumab on bone ultrastructure and density in a patient with primary osteoporosis caused by a novel heterozygous WNT1 mutation

Rodrigo Montero-Lopez 1 , Alexandra Blaschitz 1 , Katharina Tischlinger 1 , Marlene Wimleitner 1 , Thomas Hörtenhuber 1 , Markus Klinger 2 , Daniel Cejka 3 & Wolfgang Högler 1

1Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria. 2Institute of Nuclear Medicine, Kepler University Hospital, Linz, Austria. 3Department of Internal Medicine III, Nephrology, Transplantation Medicine, Rheumatology, Geriatrics, Ordensklinikum Linz-Elisabethinen, Linz, Austria

Background: Genetic defects in the Wnt signaling pathway lead to early-onset osteoporosis (EOOP). Romosozumab is a monoclonal antibody against sclerostin, an inhibitor of the Wnt/ß-catenin pathway. Romosozumab has shown great efficacy in adult osteoporosis, however its effect in patients with Wnt-related EOOP is unknown. In monoallelic loss-of-function WNT1 mutations, romosozumab could potentially stimulate the defective Wnt signaling pathway and improve BMD and architecture. Here we present evidence in support of this hypothesis, demonstrating effective romosozumab treatment in a patient with EOOP due to a heterozygous WNT1 mutation.

Case: A 40-year-old Caucasian man presented with a history of long-bone fractures from moderate trauma since early childhood, and back pain from multiple vertebral fractures. He had no deformities and no extraskeletal symptoms. Whole Exome Sequencing identified a novel, heterozygous variant in WNT1 (c.761C>A). At age 40 years, DXA-measured bone mineral density (BMD) was very low, both in the lumbar spine (LS-BMD Z-score -6.8) and in the femoral neck (FN-BMD Z-score -4.1). Volumetric BMD assessed by HRpQCT (XCT-II) in the distal tibia (22.0 mm from tibial plafond) was very low (Tt.vBMD Z-score -3.8), especially in trabecular bone (Tb.vBMD Z-score -4.1), compared to healthy controls (unpublished reference data). Trabecular bone was more severely affected (Tb.N Z-score -5.4, BV/TV Z-score -4.0, Tb.Sp Z-score +9.2) than cortical bone (30% diaphyseal tibia; Ct.vBMD Z-score +1.0, Ct.Ar Z-score -4.9, Ct.Th Z-score -3.2). After one year of romosozumab therapy (210 mg s.c., once monthly; together with colecalciferol (2000-4800 IU/d) and calcium carbonate (1000-2000 mg/d)), aBMD by DXA had substantially increased (LS-BMD +41%, FN-BMD +24%). Volumetric BMD by XCT-II increased both globally (Tt.vBMD +5.4%) and in trabecular and cortical compartments (Tb.BMD +7.5%, Ct.vBMD +0.7%). Trabecular (Tb.Th +1.6%, Tb.N +0.9%, Tb.Sp -0.8%) and cortical structural parameters (Ct.Ar +0.6%, Ct.Th +1.5%) improved to a lesser extent. No fractures were reported, but subjective improvements in muscle and bone pain. Serum calcium and parathyroid hormone levels were maintained within normal range. No cardiovascular events were reported.

Discussion: Romosozumab treatment for 12 months substantially improved bone mass, volumetric BMD and bone structure, with greatest changes in trabecular bone. These findings are consistent with prior romosozumab studies in ovariectomized animals. The observed improvements in aBMD were equal or superior to those reported with antiresorptive therapy in a WNT1-related EOOP patient of similar age. Based on this single-case experience, romosozumab may be an effective treatment option for primary osteoporosis caused by WNT1 mutations.

Volume 97

61st Annual ESPE (ESPE 2023)

The Hague, Netherlands
21 Sep 2023 - 23 Sep 2023

European Society for Paediatric Endocrinology 

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