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

Overview

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.

Full Title of Study: “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)”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: October 2, 2022

Interventions

  • 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

Arms, Groups and Cohorts

  • control patients
    • Patients with idiopathic craniosynostosis
  • HR patients
    • Patients with craniosynostosis due to HR

Clinical Trial Outcome Measures

Primary Measures

  • Number of osteoblastic cells obtained at the end of differentiation
    • Time Frame: Day 0
    • 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)

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 4 Months

Maximum Age: 18 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Hospices Civils de Lyon
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Federico DI ROCCO, MD, Principal Investigator, Hospices Civils de Lyon Centre de référence des craniosténoses et malformations cranio-faciales Service de neurochirurgie Pédiatrique
  • Overall Contact(s)
    • Federico DI ROCCO, MD, federico.dirocco@chu-lyon.fr

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