Effect of paricalcitol on circulating parathyroid hormone in X-linked hypophosphatemia: a randomized, double-blind, placebo-controlled study

Abstract

Context: Hyperparathyroidism occurs frequently in X-linked hypophosphatemia (XLH) and may exacerbate phosphaturia, potentially affecting skeletal abnormalities.

Objective: The objective of the study was to suppress elevated PTH levels in XLH patients.

Design: This was a prospective, randomized, placebo-controlled, double-blind, 1-year trial of paricalcitol, with outcomes measured at entry and 1 year later.

Setting: PATIENTS were recruited from the investigators' clinics or referred from throughout the United States. Data were collected in an in-patient hospital research unit.

Patients: Subjects with a clinical diagnosis of XLH and hyperparathyroidism were offered participation and were eligible if they were 9 years old or older and not pregnant, and their serum calcium level was less than 10.7 mg/dL, their 25-hydroxyvitamin D level was 20 ng/mL or greater, and their creatinine level was 1.5 mg/dL or less.

Intervention: The intervention for this study was the use of paricalcitol or placebo for 1 year.

Main outcome measures: Determined prior to trial onset was the change in PTH area under the curve. Secondary outcomes included renal phosphate threshold per glomerular filtration rate, serum phosphorus, serum alkaline phosphatase activity, and (99m)Tc-methylenediphosphonate bone scans.

Results: PTH area under the curve decreased 17% with paricalcitol, differing (P = .007) from the 20% increase with placebo. The renal phosphate threshold per glomerular filtration rate increased 17% with paricalcitol and decreased 21% with placebo (P = .05). Serum phosphorus increased 12% with paricalcitol but did not differ from placebo. Paricalcitol decreased alkaline phosphatase activity in adults by 21% (no change with placebo, P = .04). Bone scans improved in 6 of 17 paricalcitol subjects, whereas no placebo-treated subject improved. Hypercalciuria developed in six paricalcitol subjects and persisted from baseline in one placebo subject.

Conclusions: Suppression of PTH may be a useful strategy for skeletal improvement in XLH patients with hyperparathyroidism, and paricalcitol appears to be an effective adjunct to standard therapy in this setting. Although paricalcitol was well tolerated, urinary calcium and serum calcium and creatinine should be monitored closely with its use.

Trial registration: ClinicalTrials.gov NCT00417612.

Figures

Figure 1.

Flow diagram of the progress of study subjects through enrollment, recruitment, and retention.

Figure 2.

Changes in major outcome variables over the year of intervention as percentages of baseline values. Data are plotted as observed means and SEM of the respective groups. A, PTHauc. B, TmP/GFR. C, Fasting serum phosphorus (Pi) level. D, Fasting serum 1,25(OH)2D level. E, Fasting circulating intact FGF23 level (picograms per milliliter). F, Fasting circulating alkaline phosphatase activity in the adult patients. Active therapy subjects are shown in diagonal fill, and placebo-treated subjects are shown in white. *, Differs from placebo (P ≤ .05); **, differs from placebo (P < .01).

Figure 3.

Changes in safety measures and secondary outcome variables, as percentages of baseline values, at the 1-year evaluation. Data are plotted as observed means and SEM of the respective groups. A, Fasting serum calcium level. B, Fasting serum creatinine level. C, Twenty-four-hour urinary calcium excretion. Active therapy subjects are shown in diagonal fill, and placebo treated subjects are shown in white. **, Differs from placebo (P < .01).

Figure 4.

A and C, Relationship of TmP/GFR (milligrams per deciliter) to PTHauc at baseline (r = −0.56; P = .002) (A) and after 1 year of therapy (placebo: r = −0.82, P = .013; paricalcitol, r = 0.42; P = .09) (C). B and D, Relationship of TmP/GFR to serum FGF23 level (picograms per milliliter) at baseline (r = −0.54; P = .004) (B) and after 1 year of therapy (placebo: r = −0.67, P = .07; paricalcitol, r = 0.04; P = .9) (D). The posttreatment data are shown by treatment group: solid symbols and solid lines represent the data from the active treatment group, and open symbols and broken lines represent the data from the placebo group.