Diagnosis of skeletal fragility due to Loeys-Dietz syndrome and treatment with romosozumab followed by denosumab

Abstract

Loeys–Dietz syndrome (LDS) is an autosomal dominant, inherited connective tissue disorder caused by a pathogenic variant in TGF-β signaling-related genes. LDS is associated with a high risk of low bone mineral density (BMD) and fractures.

We present a case report of a 43-year-old premenopausal woman with skeletal fragility who was diagnosed with LDS type 4 due to a large heterozygous deletion in the TGFB2 gene. Upon initial referral, she was evaluated for secondary osteoporosis. Although mild abnormalities in calcium metabolism, menstrual irregularities, and lack of exercise were observed, they were not associated with this condition. However, a thorough family history and physical examination raised the suspicion of Marfan syndrome and related disorders, which were subsequently confirmed using genetic testing. Treatment with romosozumab for 1 year increased the lumbar spine BMD from 0.750 g/cm² (Z-score −2.1) to 0.881 g/cm² (Z-score −1.0) and the femoral neck BMD from 0.407 g/cm² (Z-score − 3.0) to 0.428 g/cm² (Z-score − 2.6), with a slight increase in total hip BMD from 0.525 g/cm² (Z-score −2.6) to 0.527 g/cm² (Z-score −2.4). Subsequent therapy with denosumab for 1 year further improved the lumbar spine BMD to 0.939 g/cm² (Z-score, −0.5), femoral neck BMD to 0.496 g/cm² (Z-score, −2.0), and total hip BMD to 0.552 g/cm² (Z-score, −2.2). To our knowledge, this is the first case report of an improvement in BMD with romosozumab, followed by denosumab, for skeletal fragility due to LDS. Our findings suggest that this treatment regimen may be an effective therapeutic option for the management of skeletal fragility in patients with LDS.