Achondroplasia (ACH), is a skeletal dysplasia disorder with an incidence of one in every 10,000 to 30,000 births, globally affecting over 250,000 individuals [1]. Clinical manifestations include a range of medical and psychosocial difficulties throughout life, such as disproportionately short stature, rhizomelic shortened limbs, deformities of the lower extremity, characteristic facial configuration (relatively large cranium size, forehead protrusion, flat nasal bridge, midface hypoplasia, and relative mandible protrusion), macrocephaly, narrow foramen magnum, ventricular enlargement, upper airway stenosis, otitis media, a narrow thorax, vertebral hyperlordosis, spinal kyphosis, and potential complications like hypotonia, hearing deficit, spinal canal stenosis, sleep apnea, and sudden infant death [2–4].
ACH is an autosomal dominant genetic disease caused by a mutation in Fibroblast Growth Factor Receptor 3 (FGFR3). Chondrocytes and mature osteoblasts express FGFR3, which regulates linear bone growth. A gain-of-function mutation in the FGFR3 gene, which is a negative regulator of endochondral ossification, sets off a signalling cascade that includes the receptor becoming more stable, dimerization becoming stronger, and tyrosine kinase activity becoming stronger. These events happen too quickly and stop bones from growing normally [1, 5, 6].
Despite the limited therapeutic options (growth hormone and surgical lengthening) to increase ACH height, both had limited effects and complications, and neither of them addressed the underlying ACH pathophysiology [7]. Therefore, a promising treatment option for ACH is to counteract FGFR3's negative effects on chondrocytes. The endogenous C-type natriuretic peptide (CNP) and its natriuretic peptide receptor 2 (NPR2) can stop FGFR3 signaling, which can cause endochondral ossification and promote endochondral bone growth. [8, 9].
Vosoritide, a modified human recombinant CNP analog, binds to the receptor to raise the level of cyclic guanosine monophosphate (cGMP) inside cells, stopping the FGFR3 signalling cascade [10]. The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) approved Vosoritide in 2021 for the treatment of ACH children with open epiphyses who are ≥ 5 years old in the United States of America (USA), ≥ 2 years old in the European Union (EU), Brazil, and Australia, and from birth in Japan [11]. Vosoritide expanded the previously restricted range of ACH treatment options.
Although vosoritide's side effects are mostly mild and easy to handle, patients may discontinue it if they cannot tolerate daily injections and manage injection-site reactions, including pain. Moreover, although it greatly speeds up the annualized growth velocity (AGV), the response to vosoritide can vary across regions and institutions and vary in both magnitude and timing depending on the dose, duration, and timing of these assessments. Providers must inform patients and their families about the data from the vosoritide clinical trial. International consensus guidance is required to support the use of vosoritide in clinical practice [11–13].
Although its first approved medications in 2021 have efficacy and safety, there's a shortage of practical guidance. Due to the rarity of ACH, there are only a limited number of patients. Therefore, it is crucial to investigate the different aspects of utilizing vosoritide in clinical settings and share the knowledge acquired from early experiences in the published clinical trials.
Therefore we conducted this systematic review and dose-related meta-analysis aim to provide a more robust understanding of the potential benefits and risks associated with vosoritide and comprehensively evaluating their efficacy and safety through the following objectives: systematically analyzing data from relevant randomized controlled trials (RCTs) until April 2024 to examine the effect of different vosoritide doses on height from baseline (represented as z-scores), annualized growth velocity (AGV), the upper-to-lower body segment ratio (ULBR), changes in growth velocity (a measure of linear growth over time), and safety profiles (the frequency of adverse effects)