Effectiveness of Paricalcitol in Reducing Parathyroid Hormone (PTH) Levels in X-linked Hypophosphatemic Rickets

The Role of Parathyroid Hormone in the Pathogenesis of Skeletal Disease in X-linked Hypophosphatemic Rickets (XLH)

The purpose of this study is to determine the effectiveness of paricalcitol, a form of synthetic vitamin D, in lowering parathyroid hormone (PTH) levels and reducing disease symptoms in children and adults with X-linked hypophosphatemic (XLH) rickets.

XLH rickets is a rare inherited disorder in which the bones become painfully soft and bend easily because of a phosphate deficiency. This genetic defect causes the kidneys to allow excretion of an inappropriately high amount of phosphate into the urine. The kidneys are also unable to convert vitamin D into a form usable by the body, resulting in inadequate amounts of active vitamin D. Because vitamin D is needed to absorb calcium and phosphate from the intestine, this deficiency further reduces phosphate levels. Without the sufficient phosphate needed for normal bone growth, individuals with XLH rickets typically develop skeletal malformations, bone pain, and abnormally bowed legs. Hyperparathyroidism, a condition in which the parathyroid glands excrete excess amounts of PTH, also occurs frequently in individuals with XLH rickets, and may play a significant role in the skeletal complications associated with XLH rickets. The purpose of this study is to determine the effectiveness of paricalcitol in lowering PTH levels and reducing disease symptoms in individuals with XLH rickets.

This study will last 12 months. Participants will be randomly assigned to receive either paricalcitol or placebo, taken in the form of two pills daily for the duration of the study. During a baseline 3-day inpatient hospital stay, participants will undergo a physical exam, a cardiac ultrasound, a bone scan, blood collection, and a radiographic skeletal survey. The skeletal survey will include x-rays of various body parts. Participants who are 18 years or younger will not undergo the radiographic skeletal survey. Study visits for all participants will occur every 2 months until the end of the study. These visits will include a physical exam, review of disease symptoms, blood and urine collection, and a check of medication compliance.

Inclusion Criteria:

• Diagnosis of XLH rickets
• Fasting serum calcium of 10.7 mg/dl or less
• Fasting PTH greater than 40 nleq/ml and less than 120 nleq/ml in the mid-molecule PTH assay at screening (upper limit of normal is 25 nleq/ml)
• Willing and able to participate in the trial
• Taking stable dose of standard therapy for XLH rickets for at least 2 months prior to study entry
• Concomitant therapy for XLH rickets will not be an exclusion criteria
• Parent or guardian willing to provide informed consent, if applicable

Exclusion Criteria:

• Concomitant kidney failure (estimated creatinine clearance less than 60 cc/min or serum creatinine greater than 1.5 mg/dl)
• Serum 25-hydroxy vitamin D less than 20 ng/ml. Participants meeting this criterion will receive vitamin D3 supplementation for 3 months and then be rescreened.
• Unable to comply with protocol and appropriate follow-up visits
• Treatment with agents that may affect skeletal metabolism, such as glucocorticoids and anticonvulsants