(3.16) Treatment of osteoporosis in Osteogenesis Imperfecta type V with Monoclonal Anti-Sclerostin Antibody Romosuzumab

Osteogenesis Imperfecta (OI) is a hereditary connective tissue disorder characterized by bone fragility. IFITM5 gene mutation has been found in all patients with OI type V (< 5% of all OI cases), but its etiologic mechanism remains unclear. OI-V clinical phenotype includes fracture susceptibility of variable severity, metaphyseal changes at birth, radial head dislocation, mineralized interosseous membranes, and hyperplasic callus. Short stature, blue sclerae, fractures at birth, and scoliosis may be rarely observed. Dentinogenesis imperfecta is absent.

Case(s) Description :

42-year-old female with OI-V diagnosed at 6 months, vitamin D deficiency, osteoporosis and nephrolithiasis. Genetic testing revealed heterozygous mutation of IFITM5 gene, variant c.-14C >T (Non-coding). She has had >300 fractures (most after birth, less after age 17). Patient underwent multiple orthopedic surgeries, including bilateral intramedullary femoral rods. Physical exam evidenced short stature, scoliosis, bone deformities, white sclerae, and no teeth abnormalities. She is wheelchair bound since childhood. DXA scan at age 20 (01/2001) revealed lowest Z score of -7.1 at the spine. After age 21, she developed approximately 50 fractures - mostly non-traumatic fractures of shoulder and ribs after sneezing or coughing, but also femoral and hip fractures. Patient received pamidronate for 3 years in her early 20s, and then had drug holiday until her 40s. 11/2020 DXA scan 1/3 radius BMD 0.687, T score and Z-Score -2.2. Spine measurements not obtained due to positioning issues, and no hip measurements due to femoral rods. She received 1 dose of zoledronic acid (ZA) in 01/2021. CT scan 02/2022: Subacute acetabular fracture, as well as displaced distal left intramedullary rod fracture. Subsequently received 10 doses of Romosuzumab (RZ), completed in 11/2022. 02/2023 DXA scan 1/3 radius BMD 0.737, T score 0.7, Z score 1.1. During 10-month treatment course with RZ, and for 4 months after, patient did not develop any fractures. After medication was discontinued, she received another dose of ZA in 02/2023, but unfortunately developed recurrent rib and shoulder fractures since March 2023.

Discussion :

In preclinical studies and small human trials, anti-sclerostin antibodies (ASA) have been shown to stimulate bone formation, reduce bone resorption, and increase BMD in adults with OI. Regardless, their use in OI remains off-label, and bisphosphonates are still the cornerstone of medical therapy. This paves the way for further studies assessing the efficacy, safety, and tolerability of ASA in patients with OI. Likewise, the bone formation mechanism of IFITM5 and its in vivo regulatory measures need to be elucidated to advance the understanding and treatment of OI-V.