Rickets severity predicts clinical outcomes in children with X-linked hypophosphatemia: Utility of the radiographic Rickets Severity Score

Tom D. Thacher, John M. Pettifor, Peter Tebben, Ana L. Creo, Alison Skrinar, Meng Mao, Chao Yin Chen, Ting Chang, Javier San Martin, Thomas O. Carpenter

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

The Rickets Severity Score (RSS) was used to evaluate X-linked hypophosphatemic rickets (XLH), a genetic disorder mediated by increased circulating FGF23. The reliability of the RSS was assessed using data from a randomized, phase 2 clinical trial that evaluated the effects of burosumab, a fully human anti-FGF23 monoclonal antibody, in 52 children with XLH ages 5 to 12 years. Bilateral knee and wrist radiographs were obtained at baseline, week 40, and week 64. We evaluated the relationships of the RSS to the Radiographic Global Impression of Change (RGI-C), serum alkaline phosphatase (ALP), height Z-score, 6-minute walk test (6MWT) percent predicted, and the Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI). The RSS showed moderate-to-substantial inter-rater reliability (weighted kappa, 0.45–0.65; Pearson correlation coefficient (r), 0.83–0.89) and substantial intra-rater reliability (weighted Kappa, 0.66; r = 0.91). Baseline RSS correlated with serum ALP (r = 0.47). Baseline RSS identified two subgroups (higher [RSS ≥1.5] and lower RSS [RSS <1.5]) that discriminated between subjects with greater and lesser rachitic disease. Higher RSS was associated with more severe clinical features, including impaired growth (Z-score, −2.12 vs −1.44) and walking ability (6MWT percent predicted, 77% vs 86%), more severe self-reported pain (29.9 [more severe] vs 45.3 [less severe]) and less physical function (29.6 [more severe] vs 40.9 [less severe]). During burosumab treatment, greater reductions in RSS corresponded to higher RGI-C global scores (r = −0.65). Improvements in RSS correlated with decreased serum ALP (r = 0.47). These results show the reliability of the RSS in XLH, and demonstrate that higher RSS values are associated with greater biochemical, clinical, and functional impairments in children with XLH.

Original languageEnglish (US)
Pages (from-to)76-81
Number of pages6
JournalBone
Volume122
DOIs
StatePublished - May 1 2019

    Fingerprint

Keywords

  • Children
  • Clinical trial
  • Metabolic bone disease
  • Radiology
  • Validation

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

Cite this

Thacher, T. D., Pettifor, J. M., Tebben, P., Creo, A. L., Skrinar, A., Mao, M., Chen, C. Y., Chang, T., San Martin, J., & Carpenter, T. O. (2019). Rickets severity predicts clinical outcomes in children with X-linked hypophosphatemia: Utility of the radiographic Rickets Severity Score. Bone, 122, 76-81. https://doi.org/10.1016/j.bone.2019.02.010