Burden and Treatment of Achondroplasia: A Systematic Literature Review

Abstract

Background Achondroplasia is the most common form of skeletal dysplasia. Recent advances in therapeutic options have highlighted the need for understanding the burden and treatment landscape of the condition. This systematic literature review (SLR) aimed to identify health-related quality of life (HRQoL)/utilities, healthcare resource use (HCRU), costs, efficacy, safety and economic evaluation data in achondroplasia and to identify gaps in the research. Methods Searches of MEDLINE, Embase, the University of York Centre for Reviews and Dissemination (CRD), the Cochrane Library and grey literature were performed. Articles were screened against pre-specified eligibility criteria by two individuals and study quality was assessed using published checklists. Additional targeted searches were conducted to identify management guidelines. Results Fifty-nine unique studies were included. Results demonstrated a substantial HRQoL and HCRU/cost-related burden of achondroplasia on affected individuals and their families throughout their lifetimes, particularly in emotional wellbeing and hospitalisation costs and resource use. Vosoritide, growth hormone (GH) and limb lengthening all conferred benefits for height or growth velocity; however, the long-term effects of GH therapy were unclear, data for vosoritide were from a limited number of studies, and limb lengthening was associated with complications. Included management guidelines varied widely in their scope, with the first global effort to standardise achondroplasia management represented by the International Achondroplasia Consensus Statement published at the end of 2021. Current evidence gaps include a lack of utility and cost-effectiveness data for achondroplasia and its treatments. Conclusions This SLR provides a comprehensive overview of the current burden and treatment landscape for achondroplasia, along with areas where evidence is lacking. This review should be updated as new evidence becomes available on emerging therapies. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-023-02549-3.

Skeletal overgrowth in a pre-pubescent child treated with pan-FGFR inhibitor

“…Germline mutations in FGFR 1–3 cause at least 20 congenital skeletal disorders [ 37 ], with achondroplasia, caused by activating (gain-of-function) mutations in FGFR3 resulting in constitutive activation of the MAPK pathway in chondrocytes which leads to inhibition of endochondral ossification [ 2 , 3 ]. Interestingly, patients with achondroplasia have been treated with recombinant human growth hormone (GH), a key regulator of IGF-I production [ [26] , [27] , [28] ] and although GH-induced production of IGF-I is believed to be a key mechanism for increasing growth velocity, final height remains suboptimal [ 31 , [38] , [39] , [40] ]. A potential mechanism for the positive effects of IGF-I was demonstrated in an immortalized mouse chondrocyte cell line model for achondroplasia where IGF-1 prevented constitutively activated FGFR3-mediated apoptosis [ 31 ].…”

“…A potential mechanism for the positive effects of IGF-I was demonstrated in an immortalized mouse chondrocyte cell line model for achondroplasia where IGF-1 prevented constitutively activated FGFR3-mediated apoptosis [ 31 ]. However, enhanced GH-induced IGF-I production itself does not appear to be sufficient to override the inhibitory osteogenic effects of activated FGFR-3, and a number of other therapeutics are currently under study [ [38] , [39] , [40] ]. Indeed, several FGFR inhibitors have been evaluated in vitro and in achondroplasia mouse models with variable results and toxicities [ [41] , [42] , [43] ].…”

The Role of Genetic Testing for Short Stature Now and in the Future

“…For example, vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and treats achondroplasia (caused by variants in FGFR3 , which impairs endochondral ossification, and is approved by the European Medicines Agency and the US Food and Drug Administration . Furthermore, while treatment with vasoritide has not been found to be associated with improved patient health-related quality of life, self-help seminars and patient education interventions have . Thus, genetic testing for short stature could also lead to interventions that improve patient quality of life and have meaningful clinical benefit.…”

“…7 Furthermore, while treatment with vasoritide has not been found to be associated with improved patient health-related quality of life, self-help seminars and patient education interventions have. 8 Thus, genetic testing for short stature could also lead to interventions that improve patient quality of life and have meaningful clinical benefit.…”