Growth parameters in children with achondroplasia: A 7-year, prospective, multinational, observational study.

PURPOSE: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control. METHODS: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing. RESULTS: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants <1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants <1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged <1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward. CONCLUSION: This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.

Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: BioMarin Pharmaceutical.

Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study.

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.

Computed tomography and histological evaluation of xenogenic and biomimetic bone grafts in three-wall alveolar defects in minipigs.

OBJECTIVES: This study aimed to compare the performance of a xenograft (XG) and a biomimetic synthetic graft (SG) in three-wall alveolar defects in minipigs by means of 3D computerised tomography and histology. MATERIALS AND METHODS: Eight minipigs were used. A total of eight defects were created in the jaw of each animal, three of which were grafted with XGs, three with SGs, and two were left empty as a negative control. The allocation of the different grafts was randomised. Four animals were euthanised at 6 weeks and four at 12 weeks. The grafted volume was then measured by spiral computed tomography to assess volume preservation. Additionally, a histological analysis was performed in undecalcified samples by backscattered scanning electron microscopy and optical microscopy after Masson's trichrome staining. RESULTS: A linear mixed-effects model was applied considering four fixed factors (bone graft type, regeneration time, anatomic position, and maxilla/mandible) and one random factor (animal). The SG exhibited significantly larger grafted volume (19%) than the XG. The anterior sites preserved better the grafted volume than the posterior ones. Finally, regeneration time had a positive effect on the grafted volume. Histological observations revealed excellent osseointegration and osteoconductive properties for both biomaterials. Some concavities found in the spheroidal morphologies of SGs were associated with osteoclastic resorption. CONCLUSIONS: Both biomaterials met the requirements for bone grafting, i.e. biocompatibility, osseointegration, and osteoconduction. Granule morphology was identified as an important factor to ensure a good volume preservation. CLINICAL RELEVANCE: Whereas both biomaterials showed excellent osteoconduction, SGs resulted in better volume preservation.

Guided Bone Regeneration: Novel Use of Fixation Screws as an Alternative to Using the Buccoapical Periosteum for Membrane Stabilization With Sutures-Two Case Reports.

Guided bone regeneration (GBR) requires a stable graft-membrane complex. This article presents a novel technique that uses membrane fixation screws to serve as anchors for membrane stabilization sutures without the need for periosteal dissection and biting of the buccoapical periosteum. This technique may be a viable alternative when there is a preference to avoid the complexities of periosteal suturing and direct membrane fixation using tacks or screws. The technique, which utilizes anchoring screws as mooring lines, can be used at the time of tooth extraction as well as for ridge augmentation of an edentulous site in preparation for future dental implant placement. Two case reports are presented that illustrate the feasibility of the technique, in which the integrity and stability of a resorbable membrane is preserved prior to final closure, suggesting that screws used as anchors for stabilization sutures might be a predictable option when addressing challenging horizontal defects requiring GBR.

Transferring emergence profile and position of interim restorative implant fixture. A novel digital technique.

The present technical article describes a protocol to digitally reproduce the emergence profile of an interim implant prosthesis (IP) and to transfer its macrogeometry into the definitive restoration. The purpose of this protocol was to minimize alterations in the gingival architecture developed during the interim restorative phase of a single implant that could potentially jeopardize its esthetic outcome. The process included obtaining an intraoral scan with the interim IP in situ, a duplicate of this intraoral scan that was used to capture the exact position of the implant, and an extraoral scan of the prosthesis. These data could then be imported into IOS software to create a model where the patients' soft tissue was incorporated with precision, allowing for the fabrication of a definitive crown with an optimal soft tissue adaptation. As there are few articles in the scientific literature that have reported a consistent method to replicate the emergence profile of an interim IP, the present technical article aims to highlight the potential of utilizing the emergence profile of an interim IP created by IOS software.

CBCT analysis of mandibular incisor area and feasibility of immediate implant placement. An alveolar housing study.

BACKGROUND: Immediate implant placement (IIP) has shown predictable outcomes when specific requirements are met. The aim of the present study was to radiographically evaluate the dimensions of mandibular incisors and the alveolar bone to further determine the feasibility of IIP in this area. MATERIALS AND METHODS: A total of 404 intact mandibular incisor CBCT images from 101 patients (42 males, 59 females; mean age 49 ± 16.84 years) were analyzed. The mesiodistal tooth width and the distance between the incisal edge (IE), cementoenamel junction (CEJ), facial bone crest (BC), root apex (RA), and fenestration point (F) were registered, together with the alveolar bone width at 1 and 3 mm below BC. Finally, the angular discrepancy between the dental and the alveolar bone long axis (BLA) was recorded as the tooth torque (TT). RESULTS: The CEJ to BC distance was 3.23 ± 1.67 mm. The RA to F mean distance was 15.02 ± 3.97 mm. The mean alveolar bone buccolingual widths at 1 and 3 mm below the facial BC were 7.12 ± 0.82 and 6.32 ± 0.71 mm in the lateral and central incisors, respectively (P 0.001). The buccolingual width was less than 6 mm in more than 33% of the central incisors, but only in 3% of the lateral incisors, displaying increased alveolar width. The average was 165.66 ± 7.47 degrees. CONCLUSIONS: The results presented in this study point toward the need for careful consideration of the requirements for anterior mandibular IIP for success and predictability purposes.

International expert opinion on the considerations for combining vosoritide and limb surgery: a modified delphi study.

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.

The Ribroast Technique™: An Alternative Method to Stabilize a Resorbable Collagen Membrane for Guided Bone Regeneration.

Stabilization of the graft-membrane complex during guided bone regeneration is a critically important aspect of implant dentistry. Several articles in the dental literature have introduced the utilization of periosteal biting stabilization sutures, rather than fixation screws and pins, to stabilize a bioabsorbable collagen membrane. This article reviews the concept of stabilization using sutures in periodontal regeneration and describes an alternative method, the Ribroast technique™, to stabilize a bioabsorbable membrane, whereby single periosteal biting horizontal mattress sutures are placed along the length of the defect to achieve sufficient stabilization. Two cases are presented that highlight the utility of this technique. Guidelines and limitations for the use of periosteal biting sutures are also discussed along with considerations and protocols that may be useful for improving treatment outcomes.