Effect of Burosumab on Muscle Function and Strength, and Rates of ATP Synthesis in Skeletal Muscle in Adults With XLH

Abstract

Context: In clinical trials, burosumab ameliorates symptoms of pain, fatigue, and stiffness and improves performance on certain muscle function studies in patients with X-linked hypophosphatemia (XLH).

Objective: This work aimed to determine if burosumab increases adenosine triphosphate (ATP) synthesis in skeletal muscle of treatment-naive adults with XLH, and if so, whether that correlates with improved muscle function.

Methods: Ten untreated, symptomatic adults with XLH had ATP synthesis rates measured in 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 4 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: All symptoms improved with treatment. Performance on the 6-Minute Walk Test (6MWT) and Sit to Stand (STS) tests also improved. Muscle strength and ATP synthesis rates did not change over the 3 months of the study. When individuals whose performances on the 6MWT and STS test were at or better than the median outcome for those tests were compared to those whose outcomes were below the median, no difference was observed in the rate of change in ATP synthesis. Intracellular muscle concentrations of phosphate were normal.

Conclusion: The improvement in the 6MWT and STS test without changes in muscle strength or ATP synthesis rates suggests that reductions in pain, fatigue, and stiffness may partly explain the improved performance. Intracellular phosphate in skeletal muscle is insulated from hypophosphatemia in XLH.

Keywords: X-linked hypophosphatemia; burosumab; muscle ATP synthesis; muscle function.

Figure 1.

Schematic outline of the study design.

Figure 2.

A, Least square (LS) mean values (95% CI) for serum phosphorus at visits 1, 4, and 5. B, LS mean values (95% CI) for tubular maximum reabsorption rate of phosphate/glomerular filtration rate (TmP/GFR) at visits 1, 4, and 5. **P less than or equal to .01; ***P less than or equal to .001; ****P less than or equal to .0001.

Figure 3.

A, Least square (LS) mean values (95% CI) for pain score at visits 1, 4, and 5. B, LS mean values (95% CI) for fatigue score at visits 1, 4, and 5. C, LS mean values (95% CI) for stiffness score at visits 1, 4, and 5. D, LS mean values (95% CI) for Knee injury and Osteoarthritis Outcome Score (KOOS) at visits 1, 4, and 5. Ranges for these patient reported outcomes are as follows: pain, 6 to 30, higher values reflect more pain; fatigue score 7 to 35, higher values reflect more fatigue; stiffness, 5 to 25 with higher scores reflecting less stiffness. Raw score ranges from 0% = severe disabling joint problems to 100% = no knee symptoms. *P less than .05; **P less than or equal to .01; ***P less than or equal to .001.

Figure 4.

A, Least square (LS) mean values (95% CI) for distance walked in the 6-Minute Walk Test (6MWT) at visits 1, 4, and 5. B, LS mean values (95% CI) in seconds for Timed Up and Go (TUG) at visits 1, 4, and 5. C, LS mean values (95% CI) for number of repetitions for Sit to Stand at visits 1, 4, and 5. *P less than .05; **P less than or equal to .01. If there is no * in a figure, it means there are no significant differences between values at any time point.

Figure 5.

A, Least square (LS) mean values (95% CI) in kg-force for hip flexion at visits 1, 4, and 5. B, LS mean values (95% CI) in kg-force for hip extension at visits 1, 4, and 5. C, LS mean values in kg-force (95% CI) for hip abduction at visits 1, 4, and 5. D, LS mean values (95% CI) in kg-force for knee flexion at visits 1, 4, and 5. E, LS mean values (95% CI) in kg-force for knee extension at visits 1, 4, and 5. The line with solid circles represents the values for the left joint and the line with open squares the values for the right joint. In B, *P less than .05 for the right hip at visit 5 vs visit 4. In D, *P less than .05 for the left knee at visit 5 vs visit 1. If there is no * in a figure, it means there are no significant differences between values at any time point.

Figure 6.

A, Least square (LS) mean values (95% CI) for muscle phosphate expressed as μmol/g of muscle at visits 1, 4, and 5. B, LS mean values (95% CI) for adenosine triphosphate (ATP) synthesis rate expressed as μmol/g/min at visits 1, 4, and 5. If there is no * in a figure, it means there are no significant differences between values at any time point.

Figure 7.

Upper panel: lease square (LS) mean values (95% CI) of adenosine triphosphate (ATP) synthesis rate expressed as μmol/g/min at visits 1, 4, and 5 for those participants who performed at or better than the median result for the 6-Minute Walk Test (6MWT) test for the 10 participants (line with circles) or below the median score (line with squares). Lower panel: LS mean values (95% CI) of ATP synthesis rate expressed as μmol/g/min at visits 1, 4, and 5 for those participants who performed at or better than the median result for the Sit to Stand test (line with circles) or below the median score (line with squares). If there is no * in a figure, it means there are no significant differences between values at any time point.