ESPEYB19 5. Bone, Growth Plate and Mineral Metabolism Novel treatments for rare skeletal disorders (3 abstracts)
5.1. Targeting TGF-β for treatment of osteogenesis imperfecta
Song IW , Nagamani SC , Nguyen D , Grafe I , Sutton VR , Gannon FH , Munivez E , Jiang MM , Tran A , Wallace M , Esposito P , Musaad S , Strudthoff E , McGuire S , Thornton M , Shenava V , Rosenfeld S , Huang S , Shypailo R , Orwoll E & Lee B
J Clin Invest. 2022 Apr 1;132(7):e152571. doi: 10.1172/JCI152571.Abstract: https://pubmed-ncbi-nlm-nih-gov.proxy.kib.ki.se/35113812/
In brief: Currently, there is no disease-specific therapy for osteogenesis imperfecta (OI) where most children, of all forms of OI, with significant fracture history, are managed by bisphosphonates. Preclinical studies demonstrate that excessive TGF-β signaling is a pathogenic mechanism in OI. In this, phase I study of fresolimumab (TGF-β neutralizing antibody) in 8 adults with OI there were dose-dependent effects on bone mass and turnover.
Commentary: The management of OI typically involves a multidisciplinary approach; currently, there are no approved medical therapies for OI. Treatment of bone fragility is limited to the repurposing of medications that are used to treat osteoporosis. Bisphosphonates (BPNs) have become the standard of care, especially in children. In adults, the benefits and the consequences of long-term treatment with BPNs are less certain. BPNs however, don’t address specific pathogenetic mechanism(s) in OI, and, hence, they have no effect on extraskeletal manifestations. In murine models, excessive TGF-β signaling has been found to be a key driver of pathogenesis and neutralizing TGF-β improves bone mass, bone biomechanical properties, as well as pulmonary abnormalities (1).
A phase I study of fresolimumab, a TGF-β neutralizing antibody, was conducted in 8 adults with OI. Safety and effects on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed.
OI bone demonstrated woven structure, increased osteocytes, high turnover, and reduced maturation. SMAD phosphorylation was the most significantly upregulated molecular event. Gene set enrichment analysis identified the TGF-β pathway as the top-activated signaling pathway, and pathway analyses showed that TGF-β1 was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increases in LS aBMD in participants with OI type IV, whereas participants with OI type III and VIII had unchanged or decreased LS aBMD. No significant adverse events related to the medications were noted.
While promising, treatment with fresolimumab or Losartan as an angiotensin II-receptor agent with anti- TGF-β properties requires investigation in children where bone turnover is higher and previous repurposed medications have not been found to be safe (e.g. denosumab). However, if found effective, anti-TGF-β medications could be the first disease-specific therapy with the potential to significantly impact skeletal and extraskeletal manifestations of OI in children.
Reference: 1. Grafe I, Yang T, Alexander S, Homan EP, Lietman C, Jiang MM, Bertin T, Munivez E, Chen Y, Dawson B, Ishikawa Y, Weis MA, Sampath TK, Ambrose C, Eyre D, Bächinger HP, Lee B. Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta. Nat Med. 2014 Jun;20(6):670–5. doi: 10.1038/nm.3544.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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