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Background Disproportionate short stature is one of the most characteristic clinical traits of achondroplasia, a condition with a significant impact on patients’ autonomy that results in a series of limitations leading to poorer health-related quality of life. Limb lengthening surgery is an effective therapeutic alternative for increasing the stature of persons with achondroplasia. The purpose of this study was to evaluate the cost-effectiveness of bone lengthening in patients with achondroplasia and to estimate the economic impact of the procedure on the Spanish health system by means of a Markov model. Results Patients with achondroplasia who undergo a limb lengthening procedure gain, on average, 5.954 quality-adjusted life years (QALYs) more than unoperated patients (27.197 vs. 21.243 QALYs). As the procedure entails a mean incremental cost of €49,480, the resulting incremental cost-effectiveness ratio (ICER) is €8,310/QALY. The probabilistic sensitivity analysis (PSA) performed yielded a mean quality of life gain of 6.287 QALYs and a mean cost increase of €49,131, which translates into an ICER of €7,814/QALY. The budget impact analysis was based on the hypothesis that all patients with achondroplasia born every year in the country used as a reference (Spain, n  = 15) undergo the procedure. Under this assumption, a cumulative cost increase of €8,896,196 can be estimated over a 15-year period (€8,836,931 following the PSA). Conclusions Limb lengthening surgery in patients with achondroplasia can be considered a cost-effective intervention according to the most commonly accepted willingness-to-pay thresholds in Spain and other Western countries.

Background Achondroplasia, caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene, is the most common skeletal dysplasia. The Lifetime Impact of Achondroplasia Study in Europe (LIAISE; NCT03449368) aimed to quantify the burden of achondroplasia among individuals across a broad range of ages, including adults. Methods Demographic, clinical and healthcare resource use data were collected from medical records of achondroplasia patients enrolled in 13 sites across six European countries in this retrospective, observational study. Descriptive statistics or event rates per 100 person-years were calculated and compared across age groups as well as by history of limb lengthening. Patient-reported outcomes (quality of life [QoL], pain, functional independence, work productivity and activity impairments) were evaluated using questionnaires at the time of enrolment. An exploratory analysis investigated correlations between height (z-score or centimetres) and patient-reported outcomes. Results Overall, 186 study patients were included, with a mean age of 21.7 ± 17.3 years (range 5.0–84.4). At least one complication or surgery was reported for 94.6% and 72.0% of patients, respectively, at a rate of 66.6 and 21.5 events per 100 person-years. Diverse medical and surgical complications were reported for all ages in a bimodal distribution, occurring more frequently in the youngest and oldest age groups. A total of 40 patients had previously undergone limb lengthening (capped at 20% per the study protocol). The most frequent surgery types varied by age, in line with complication profiles. Healthcare resource use was high across all age groups, especially among the youngest and oldest individuals, and did not differ substantially according to history of limb lengthening. Compared to general population values, patients reported impaired QoL particularly for physical functioning domains. In addition, patients reported difficulty carrying out daily activities independently and pain starting in childhood. Patient height correlated with multiple patient-reported outcomes. Conclusions The findings of this study suggest that, across an individual’s lifetime, achondroplasia is associated with multisystem complications, reduced QoL and functionality, and increased pain. These results highlight the large amount of healthcare resources that individuals with achondroplasia require throughout their lifespans and provide novel insights into current achondroplasia management practices across Europe. Trial registration ClinicalTrials.gov, NCT03449368, Submitted 14 December 2017 – prospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT03449368

Background: Guided bone regeneration (GBR) is a widely used technique in oral and maxillofacial surgery to restore lost bone. The aim of this study is to evaluate the effectiveness of titanium occlusive barriers in GBR for increasing bone volume in both vertical and horizontal dimensions. Methods: A prospective analysis was conducted on 11 patients (15 cases) undergoing bone augmentation with titanium barriers combined with bone graft biomaterials for dental implant placement. Bone gain was assessed using pre- and postoperative low-dose cone beam computed tomography (CBCT) measurements in vertical and horizontal planes. Histological analyses evaluated the quality and vascularization of the regenerated bone. Results: Significant bone volume increases were observed, with a mean vertical gain of 7.60 mm (SD 0.23) and a horizontal gain of 5.44 mm (SD 0.39). Histological examination confirmed well-vascularized regenerated bone with minimal residual graft material, effective integration, and the formation of keratinized gingiva. Conclusions: Titanium occlusive barriers in GBR provide a reliable and minimally invasive method for substantial bone regeneration, showing advantages such as ease of handling and reduced invasiveness. Additional studies are recommended to validate these findings and evaluate long-term outcomes.

This study aimed to quantify horizontal and vertical bone gain using superimposition of preoperative and postoperative cone beam computed tomography (CBCT) in severe alveolar ridge defects treated with a modified guided bone regeneration (GBR) technique based on customized titanium occlusive barriers with a window design, combined with autologous blood clot and β-tricalcium phosphate (β-TCP). In this prospective case series, 13 patients (28 defects) were treated. Customized titanium barriers were digitally designed based on CBCT data and manufactured by laser sintering. The barriers were fixed over the defects and filled with a mixture of an autologous blood clot and β-TCP, providing an osteoconductive scaffold within a stable regenerative compartment. A standardized window-based follow-up protocol was applied during healing, including irrigation and controlled deepithelialization. Primary outcomes were horizontal and vertical bone gain, assessed by pre- and postoperative CBCT superimposition. Histological evaluation was performed at the time of implant placement. After 8 months, significant bone gain was observed, with a mean horizontal gain of 4.50 ± 2.02 mm and a mean vertical gain of 4.40 ± 2.82 mm (p < 0.0001), confirmed by linear mixed-effects models and patient-level sensitivity analyses (p < 0.001). Histological analysis revealed well-vascularized newly formed bone with active osteoblasts and no inflammatory response. Keratinized gingiva formation was observed at all sites. One minor complication (mild screw loosening) was recorded and successfully resolved. This study is presented as a prospective case series; therefore, the results should be interpreted as exploratory evidence and do not allow direct comparisons or conclusions regarding equivalence or superiority over other GBR techniques. The present report specifically evaluates the regenerative phase prior to functional loading; therefore, although implants were placed according to protocol, implant survival and long-term functional outcomes were not assessed and cannot be inferred from these data. Within the limitations of this prospective case series, customized titanium occlusive barriers with a window design demonstrated promising results for horizontal and vertical bone augmentation and keratinized gingiva formation, without the need for autologous bone grafts or primary wound closure.

Background: Bone resorption following tooth loss poses significant challenges for dental implant success. Guided bone regeneration (GBR) techniques, particularly in vertically deficient ridges, often require complex procedures and soft tissue management. This case report introduces a modified occlusive barrier with a window, combined with tricalcium phosphate, to address these challenges. Methods: A 26-year-old female with significant bone loss in the mandibular anterior region underwent GBR using a digitally designed titanium occlusive barrier. The barrier was fabricated using CAD/CAM technology and secured with screws. A blood clot mixed with tricalcium phosphate was used to promote bone regeneration. Postoperative care included regular irrigation, de-epithelialization, and follow-up over six months. Implant placement and histological analysis were performed to evaluate outcomes. Case Presentation: The patient achieved 8.8 mm of vertical and 7.6 mm of horizontal bone regeneration. Histological analysis confirmed the presence of mature, mineralized bone, and keratinized gingiva. The implant was successfully placed, and a fixed prosthesis was restored after four months, with stable results at a three-year follow-up. Conclusion: This technique demonstrates effective bone and soft tissue regeneration in a single procedure, eliminating the need for autologous bone grafts and secondary surgeries. The use of a digitally designed occlusive barrier offers precision, reduces morbidity, and simplifies the surgical process, suggesting a promising advancement in GBR. Further studies are needed to validate these findings.

Background Achondroplasia is the most common form of skeletal disorder with disproportionate short stature. Vosoritide is the first disease-specific, precision pharmacotherapy to increase growth velocity in children with achondroplasia. Limb surgery is a standard approach to increase height and arm span, improve proportionality and functionality, as well as correcting deformities. The aim of this study was to gain expert opinion on the combined use of vosoritide and limb surgery in children and adolescents with achondroplasia. Methods An international expert panel of 17 clinicians and orthopaedic surgeons was convened, and a modified Delphi process undertaken. The panel reviewed 120 statements for wording, removed any unnecessary statements, and added any that they felt were missing. There were 26 statements identified as facts that were not included in subsequent rounds of voting. A total of 97 statements were rated on a ten-point scale where 1 was ‘Completely disagree’ and 10 ‘Completely agree’. A score of ≥ 7 was identified as agreement, and ≤ 4 as disagreement. All experts who scored a statement ≤ 4 were invited to provide comments. Results There was 100% agreement with several statements including, “Achieve a target height, arm span or upper limb length to improve daily activities” (mean level of agreement [LoA] 9.47, range 8–10), the “ Involvement of a multidisciplinary team in a specialist centre to follow up the patient” (mean LoA 9.67, range 7–10), “ Planning a treatment strategy based on age and pubertal stage” (mean LoA 9.60, range 8–10), and “ Identification of short- and long-term goals, based on individualised treatment planning” (mean LoA 9.27, range 7–10), among others. The sequence of a combined approach and potential impact on the physes caused disagreement, largely due to a lack of available data. Conclusions It is clear from the range of responses that this modified Delphi process is only the beginning of new considerations, now that a medical therapy for achondroplasia is available. Until data on a combined treatment approach are available, sharing expert opinion is a vital way of providing support and guidance to the clinical community.

Background: Achondroplasia is the most common short-limbed skeletal dysplasia resulting from gain-of-function pathogenic variants in fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Most treatment options are symptomatic, targeting medical complications. Infigratinib is an orally bioavailable, FGFR1–3 selective tyrosine kinase inhibitor being investigated as a direct therapeutic strategy to counteract FGFR3 overactivity in achondroplasia. Objectives: The main objective of PROPEL is to collect baseline data of children with achondroplasia being considered for future enrollment in interventional studies sponsored by QED Therapeutics. The objectives of PROPEL 2 are to obtain preliminary evidence of safety and efficacy of oral infigratinib in children with achondroplasia, to identify the infigratinib dose to be explored in future studies, and to characterize the pharmacokinetic (PK) profile of infigratinib and major metabolites. Design: PROPEL (NCT04035811) is a prospective, noninterventional clinical study designed to characterize the natural history and collect baseline data of children with achondroplasia over 6−24 months. PROPEL 2 (NCT04265651), a prospective, phase II, open-label study of infigratinib in children with achondroplasia, consists of a dose-escalation, dose-finding, and dose-expansion phase to confirm the selected dose, and a PK substudy. Methods and analysis: Children aged 3−11 years with achondroplasia who completed ⩾6 months in PROPEL are eligible for PROPEL 2. Primary endpoints include treatment-emergent adverse events and change from baseline in annualized height velocity. Four cohorts at ascending dose levels are planned for dose escalation. The selected dose will be confirmed in the dose-expansion phase. Ethics: PROPEL and PROPEL 2 are being conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, principles of the Declaration of Helsinki, and relevant human clinical research and data privacy regulations. Protocols have been approved by local health authorities, ethics committees, and institutions as applicable. Parents/legally authorized representatives are required to provide signed informed consent; signed informed assent by the child is also required, where applicable. Discussion: PROPEL and PROPEL 2 will provide preliminary evidence of the safety and efficacy of infigratinib as precision treatment of children with achondroplasia and will inform the design of future studies of FGFR-targeted agents in achondroplasia. Registration: ClinicalTrials.gov: NCT04035811; NCT04265651.

Purpose Achondroplasia, as the most common form of disproportionate short stature, potentially impacts the health-related quality of life (HRQOL) and functioning of people with this condition. Because there are no psychometrically validated patient-reported outcome (PRO) condition-specific instruments for achondroplasia, this study selected and tested available generic, disease-specific and under development questionnaires for possible use in multinational clinical research. Methods A three-step approach was applied. First, a literature review and clinician/expert opinions were used to select relevant PRO questionnaires. Second, focus group discussions, including a group cognitive debriefing for piloting of the questionnaires with children/adolescents with achondroplasia and their parents, were performed in Spain and Germany. Third, a field-test study was conducted to test the psychometric properties of these instruments. Results Six questionnaires were identified as potentially relevant in children with achondroplasia. In each country, five focus groups including a cognitive debriefing were conducted, and the results narrowed the possibilities to three instruments as most appropriate to assess HRQOL (the generic PedsQL, the height-specific QoLISSY, and the achondroplasia-specific APLES). Results of the field study indicate the QoLISSY and the PedsQL questionnaires to be most appropriate for use in clinical research at this time. Conclusion This selection study is a step forward in assessing the impact of achondroplasia on HRQOL. Of the instruments examined, the QoLISSY and the PedsQL both capture items relevant to children with achondroplasia and have met the psychometric validation criteria needed for use in research. The APLES instrument is a promising tool that should be revisited upon psychometric validation.

There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings. This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 μg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11. All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22–1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred. Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be. BioMarin Pharmaceutical.

Purpose Achondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported. Methods After completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 μg/kg/day. Results In children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected. Conclusion Vosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.