Patients with X-linked hypophosphatemia (XLH) often report symptoms of fatigue and weakness particularly after exertion, in addition to their skeletal complaints. In previous trials using KRN23 (same drug as burosumab/Crysvita®), patients report these symptoms improve. The investigators wish to test this hypothesis directly by measuring muscle energy when patients begin treatment with Crysvita® for the first time.

X-linked hypophosphatemia is a skeletal dysplasia. The mineralized tissue complications of XLH have been the focus of investigative studies seeking to understand its pathogenesis, as well as studies directed at new therapies. However, in addition to their skeletal complaints, patients with XLH have among their most frequent symptoms, fatigue and weakness, which manifest as both a generalized sense of a lack of energy as well as a more specific feeling that their muscular function is impaired. Objectively, patients complain of fatigue after exertion, when otherwise they do not think they should expect to feel so spent. These symptoms occur in individuals who otherwise have good cardiovascular and respiratory health, so co-morbidities are unlikely to explain these pervasive complaints. Anecdotally, the investigators open-label trial data using KRN23 suggest that these symptoms are dramatically ameliorated by treatment with the drug. In a recent study¹, the investigators found that when stressed by a low-phosphate diet, rates of insulin-stimulated myocyte Adenosine triphosphate (ATP) flux were reduced by 50% in an experimental model of systemic hypophosphatemia (the NaPi2a knockout mouse). Moreover, ATP synthetic flux correlated directly with cellular and mitochondrial phosphate uptake in two rodent myocyte cell lines, as well as in freshly isolated myocyte mitochondria. As direct evidence that these preclinical findings are relevant to human hypophosphatemic genetic syndromes we studied a patient with Heredity Hypophosphatemic Rickets with Hypercalciuria (HHRH) who was not being treated at the time of our experiment. In this patient who had a 50% reduction in serum phosphate, muscle ATP content was also significantly reduced ¹. Both of these parameters normalized completely with oral phosphate repletion ¹. These data strongly support the hypothesis that reduced muscle ATP flux may underlie the myopathy seen in patients with XLH. The investigators propose to directly test this hypothesis, in patients about to begin treatment with Crysvita® for the first time.

Muscle tissue phosphorus concentration and ATP flux rates will be assessed in the right gastrocnemius of the lower leg using 31P-NMR (nuclear magnetic resonance) spectroscopy over the course of the 3 month study. The study consists of 5 visits total over 3 months. At visits 1,4 and 5, patients will undergo magnetic resonance (MR) spectroscopy assessments and functional testing along with blood and urine analysis. At visits 1,2 and 3 patients will receive Burosumab/Crysvita® by subcutaneous injection.

Inclusion Criteria:

1. 18-65 years of age
2. Diagnosis of XLH
3. eGFR ≥ 50 (estimated glomerular filtration rate)
4. Normal serum calcium
5. Phosphate ≤ 2.5 mg/dl
6. Deemed clinically appropriate for starting therapy with Burosumab/Crysvita® (based on the treating physician's evaluation)
7. Deemed appropriate for MR Spectroscopy

Exclusion Criteria:

1. Patients with fixed skeletal abnormalities which would prevent them from successfully completing study-related functional assessments
2. Patients unwilling to stop therapy with supplemental phosphate and calcitriol 2 weeks prior to enrollment.
3. Patients who have undergone an orthopaedic procedure within the previous 6 months involving implantation of metal hardware

3 months (time of consent to completion of visit 5)