Effective Dosing of Burosumab in XLH

X-linked hypophosphatemia (XLH) is a rare, lifelong genetic disorder caused by inactivating mutations in the PHEX gene, leading to elevated levels of fibroblast growth factor 23 (FGF23), which induces renal phosphate wasting. The resultant hypophosphataemia disrupts bone mineralisation, causing rickets, skeletal deformities, growth failure, and chronic pain.

Historically, treatment has relied on oral phosphate and activated vitamin D analogues, which are burdensome and only partially effective. Burosumab (Crysvita), a monoclonal antibody that targets and neutralizes FGF23, is a transformative therapy for XLH. It has been shown to normalise serum phosphate levels, improve growth parameters, and reduce rickets severity. However, real-world data on optimal dosing regimens remain limited.

This study is a multi-centre, pragmatic, retrospective observational analysis conducted across paediatric metabolic bone centres in England. The objective is to assess whether a starting dose of less than 0.8 mg/kg of Burosumab is effective in achieving biochemical control and to characterise dosing variation and outcomes across centres. The current standard dose recommended by the European Medicines Agency (EMA) is 0.8 mg/kg every two weeks, but clinical experience and historical trial data suggest that a proportion of patients may achieve biochemical control on lower doses.

This study will review data from paediatric patients with a diagnosis of XLH who have received at least 12 months of continuous Burosumab treatment under paediatric dosing criteria. Patients will be included regardless of whether they subsequently transitioned to adult dosing, provided their data under paediatric treatment can be clearly delineated.

Data will be extracted from existing clinical records by each participating centre. These records form part of routine care and include biochemistry (serum phosphate, calcium, alkaline phosphatase, creatinine, parathyroid hormone; and urinary calcium, phosphate, and creatinine), auxology (height, weight, sitting height), treatment timelines, imaging findings (notably nephrocalcinosis), and documented adverse effects. Data will be submitted in pseudonymised form through a secure portal hosted by the University of Nottingham.

Data Quality and Registry Procedures:

A data dictionary has been developed to define all collected variables, including normal ranges and units, and to standardise input across sites.

Data validation and consistency checks will be performed at the time of upload, using range and logic rules.

Where needed, study investigators may request clarification or source verification from submitting centres for apparent anomalies or missing data.

All data will be stored on encrypted and access-controlled servers. Backups are performed daily, and all transmissions are encrypted.

Data will be reviewed centrally, and queries raised where missing, inconsistent, or out-of-window data are identified.

A formal statistical analysis plan has been developed. It includes descriptive analyses (means, medians, ranges, and SDs), between-group comparisons using parametric or non-parametric tests as appropriate, and subgroup analyses based on starting dose, PTH status, and age at treatment initiation.

No direct patient contact is involved. Ethical approval will be obtained and, in accordance with UK Health Research Authority guidance and GDPR, individual consent is not required because the study uses fully pseudonymised data collected as part of usual care.

Sample size justification: A minimum of 35 patients started on less than 0.8 mg/kg is required to ensure that the 95% confidence interval for the estimated proportion achieving biochemical control does not cross zero, based on a conservative effect estimate of 10%. Inclusion of additional patients treated at or above 0.8 mg/kg enables robust secondary and comparative analyses.

Missing data strategy: Where values are not available for key time points, interpolation from adjacent data will be used when possible (e.g., to estimate a 6-month height using 3- and 9-month values).

The study is being coordinated by the University of Nottingham and led by Dr James Law Honorary Clinical Associate Professor and Dr Pooja Sachdev, Clinical Associate Professor in Paediatric Endocrinology and Diabetes. Collaborators include national experts in metabolic bone disease. No external funding has been received; centres are contributing data using existing staff and infrastructure.

This study aims to improve understanding of the real-world use of Burosumab and support optimisation of dosing strategies to ensure effective, safe, and cost-conscious care for children with XLH.