Lonafarnib clinical trials demonstrate uncoupling of the muscle-bone unit in Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford Progeria Syndrome (HGPS) is a devastating ultrarare genetic premature aging disease resulting in early atherosclerosis and death during adolescence due to heart failure. Structures of mesenchymal origin, including bone, fat, and muscle, create a progressive skeletal dysplasia, lifelong failure to thrive, and unique bone phenotype. Characterizing the interaction between muscle and bone has emerged as a powerful tool for defining drivers of bone disease in other conditions but has not been previously explored in HGPS. We examined the "muscle-bone unit" using radial pQCT in youth with HGPS aged 2 to 18 years before and after treatment with lonafarnib, a farnesyltransferase inhibitor that extends HGPS lifespan. Untreated radii displayed highly abnormal shapes in 70% of individuals spanning all ages. Compared to controls, HGPS forearm muscle and radial area were lower (p<0.001) and grew more slowly (muscle β=1.4 cm2/year vs. 0.3 cm2/year in HGPS; radius β=5.8 mm2/year vs. 0.5 mm2/year in HGPS). Fat area decreased with age (β=-0.2 cm2/year, p<0.001) and muscle area, normalized for either BMI or radial length, was reduced in HGPS (p=0.02 and p=<0.001, respectively). These normalized outcomes were similar to controls at younger ages but diverged as patients aged. Radial architectural changes were present even before changes in muscle area and represent a pattern distinct from the normal aging process and other muscle-wasting pediatric conditions. Lonafarnib therapy did not normalize the muscle-bone phenotype after 24 months, although some individuals (25%) had partial normalization of radial shape. These results demonstrate that the muscle-bone unit is uncoupled in children with HGPS. Normal muscle mass for body size at younger ages implies that there is an opportunity for early treatment to avoid impending pathology. New strategies are needed to ameliorate this phenotype in HGPS, and this study provides a benchmark for gauging future therapies.