Burosumab and 1-25 (OH) Vitamin D on Human Osteoblasts (HYPO-BLASTES)

Effect of Burosumab and 1-25 (OH) Vitamin D on Human Osteoblasts From Patients Requiring Craniosynostosis Surgery for Idiopathic Reason or Due to Hypophosphatemic Rickets (HR)

FGF23 is the cornerstone of phosphate / calcium / vitamin D metabolism: it is synthesized mainly by osteocytes and acts as a phosphaturizing agent, inhibitor of dihydroxyvitamin D, and inhibitor of synthesis and secretion of PTH in most tissues.

The specific role of FGF23 on bone has yet to be demonstrated. In osteoblasts, overexpression of FGF23 in vitro suppresses not only osteoblastic differentiation but also the synthesis of the mineralized matrix independently of its systemic action on phosphate metabolism. In osteoblasts, FGF23 also regulates the secretion of osteopontin by directly suppressing transcription of alkaline phosphatase.

In some diseases such as hypophosphatemic rickets (HR), the direct role of FGF23 on bone has not yet been studied to our knowledge, whereas these genetic hypophosphatemias are secondary to overexpression of FGF23, whether an activating mutation of FGF23 or inhibitory mutations of its inhibitors (DMP1 and PHEX). However, patients with X-linked hypophosphatemic rickets (XLH) have higher circulating FGF23 levels than healthy controls and these levels are higher in treated patients.

Management of XLH consists primarily of correcting the native vitamin D defect by prescribing active vitamin D analogs as well as phosphate supplementation to improve bone mineralization and decrease dental complications, growth, and bone deformities. Recently, a new therapeutic option has been developed for XLH, burosumab, a human monoclonal antibody that binds and inhibits FGF23 activity. The use of burosumab is currently authorized in France in some pediatric patients with severe forms of XLH.

Independently of the indirect bone effects of phosphate correction and vitamin D levels, the direct role of burosumab on bone cells has never been studied. The objective of this project is to study the osteoblastic biology of patients with RH compared to control patients, and to evaluate the direct impact of the treatments used in this pathology on human osteoblasts.

Study Overview

• Status: Recruiting
• Conditions: Craniosynostoses
• Intervention / Treatment: Biological: osteoblast biology study

• Study Type: Observational
• Enrollment (Estimated): 20

Contacts and Locations

• Study Contact: Name: Federico DI ROCCO, MD; Phone Number: +33 04 72 35 75 72; Email: federico.dirocco@chu-lyon.fr
• Study Contact Backup: Name: Justine BACCHETTA, MD; Phone Number: +33 0427856178; Email: justine.bacchetta@chu-lyon.fr

Study Locations

• France
  • Bron, France, 69500
    • Recruiting
    • Centre de référence des craniosténoses et malformations cranio-faciales Service de neurochirurgie Pédiatrique
    • Contact: Justine BACCHETTA, MD; Email: justine.bacchetta@chu-lyon.fr
    • Contact: Federico DI ROCCO, MD; Email: federico.dirocco@chu-lyon.fr
    • Principal Investigator: Federico DI ROCCO, MD
    • Sub-Investigator: Justine BACCHETTA, MD
    • Sub-Investigator: Aurélia BERTHOLET-THOMAS, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

patients with craniosynostosis, idiopathic (control patients) or due to HR

Description

Inclusion Criteria:

• Children from 4 months-old to 18 years-old
• Patients requiring craniosynostosis surgery followed by reference centers for rare diseases of calcium and phosphate metabolism / craniofacial malformations
• Patients and parent / holder of parental authority who have been informed of the study and do not object to participate

Exclusion Criteria:

• Patient being treated with oral corticosteroid or having received more than 3 months of corticosteroid treatment before surgery.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
control patients; Patients with idiopathic craniosynostosis	Biological: osteoblast biology study; Describe the in-vitro action of burosumab and vitamin D on human osteoblastogenesis from osteoblasts from patients with craniosynostosis due to HR
HR patients; Patients with craniosynostosis due to HR	Biological: osteoblast biology study; Describe the in-vitro action of burosumab and vitamin D on human osteoblastogenesis from osteoblasts from patients with craniosynostosis due to HR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of osteoblastic cells obtained at the end of differentiation	The analysis of osteoblastic differentiation obtained from the bone cells from patients with burosumab and/or 1-25 (OH) vitamin D (HR patients vs idiopathic craniosynostosis)	Day 0

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Federico DI ROCCO, MD, Hospices Civils de Lyon Centre de référence des craniosténoses et malformations cranio-faciales Service de neurochirurgie Pédiatrique

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2020
• Primary Completion (Estimated): April 4, 2026
• Study Completion (Estimated): April 4, 2026

Study Registration Dates

• First Submitted: November 7, 2019
• First Submitted That Met QC Criteria: November 7, 2019
• First Posted (Actual): November 12, 2019

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 14, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Congenital Abnormalities; Musculoskeletal Diseases; Bone Diseases; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Bone Diseases, Developmental; Dysostoses; Synostosis; Craniosynostoses
• Other Study ID Numbers: 69HCL19_0773; 2019-A02762-55 (Other Identifier: ID-RCB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No