Effect of burosumab on muscle function and strength, and rates of ATP synthesis in skeletal muscle in adults with X-linked Hypophosphatemia

Abstract

Context: Burosumab, a neutralizing antibody to FGF23, is approved for the treatment of X-linked hypophosphatemia. In clinical trials burosumab improves symptoms of pain, fatigue and stiffness and improves performance on certain muscle function studies.

Objective: Determine if burosumab would increase ATP synthesis in skeletal muscle of treatment-naïve adults with XLH and if so whether that correlated with improved muscle function.

Methods: Ten symptomatic adults, who had not received any treatment for XLH for years, had ATP synthesis rates assessed in the soleus/gastrocnemius muscle complex of the right calf using the 31P magnetic resonance spectroscopy saturation transfer technique. Baseline muscle function tests and symptoms of pain, fatigue, stiffness and lower extremity joint pain were quantified. All participants were treated with burosumab, 1 mg/kg every four weeks for 12 weeks. ATP synthesis rates and muscle function tests were repeated 2-weeks (“peak”) and 4-weeks (“trough”) after the third dose of burosumab.

Results: Pain, fatigue, stiffness and lower extremity joint pain all improved with treatment. Performance on the 6-Minute Walk and Sit to Stand tests also improved significantly. Performance on the Timed Up and Go test did not significantly improve (p = 0.057). Muscle strength, measured by dynamometry, did not change significantly in either the upper or lower extremities during the study. ATP synthesis rates did not change over the three months of study in the group as whole. In a sub-analysis comparing individuals whose performances on the 6-Minute Walk Test and Sit to Stand tests were at or better than the mean outcome for those tests, to those whose outcomes were below the mean, no difference was observed in the rate of change in ATP synthesis rates. Despite profound and prolonged hypophosphatemia at baseline, intracellular muscle concentrations of phosphorus were normal.

Conclusion: The improvement in the 6-Minute Walk Test and Sit to Stand tests without any observed change in either upper or lower extremity muscle strength or ATP synthesis rates, suggests that improvement in pain, fatigue and stiffness may explain, at least in part, the improved performance on these two tests. The preserved intracellular phosphate levels suggests that adaptive mechanisms are present in skeletal muscle that insulate intracellular phosphorus from life-long FGF23-mediaed hypophosphatemia.