Bone Abstracts

Achondroplasia is the most common form of short-limbed dwarfism with a frequency of 1 in 10,000 to 30,000 births. Although it can be inherited in a autosomal dominant manner, 80% of the cases are sporadic. Achondroplasia is classified as one of the FGFR3 chondrodysplasias and more than 97% occur from an activating mutation at residue 380 (p.R380G) of the FGFR3 gene. Current treatment of achondroplasia is mainly directed at prevention and treatment of its complications (obstructive sleep apnea, foramen magnum stenosis, kyphosis, lordosis, genu varum, lumbar spinal stenosis etc.) and involves symptomatic management, surgical intervention, and lifelong follow-up. Short stature is another major problem. Although it is a demanding process, surgical limb lengthening can achieve substantial height enhancement. Growth hormone has been shown to increase adult height +2.8 to 3.2 cm in females and +3.5 to 7.0 cm in males according to Japanese observational studies. The effect is modest, but it will serve as a benchmark for treatments under investigation. Since achondroplasia occurs from activation of FGFR3, which in turn decreases chondrocyte proliferation and differentiation, current nonsurgical strategies are aimed at either directly blocking FGFR3 activation or regulating other signaling pathways that control these cells. Some of the therapies aimed at FGFR3 signaling are tyrosine kinase inhibitors, FGFR3-specific monoclonal antibodies that target the extracellular domain to block ligand binding, and soluble decoy receptors or aptamers that can bind and sequester FGFs. Examples of therapies targeting non-FGFR3 signaling pathways are PTH/PTHrP, meclozine, statins, and CNP. At present, the most promising is the stabilized CNP analog vosoritide since it enhances long bone growth as well as flattens the skull in achondroplasia model mice. The drug is currently undergoing Phase 2 and 3 clinical trials. Recent studies have suggested mTOR and CREB as signaling molecules downstream of FGFR3 and CNP, respectively. Further studies of signaling pathways downstream of or those that interact with FGFR3 will likely lead to new therapeutic strategies not only for skeletal growth but also for other complications of FGFR3 chondrodysplasias.

Disclosure: Biomarin: consultation fee, Novo Nordisk: consultation fee, Lilly: speaker’s bureau.

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