Etidronate for Prevention of Ectopic Mineralization in Patients With Pseudoxanthoma Elasticum

Abstract

Background: In pseudoxanthoma elasticum (PXE), low pyrophosphate levels may cause ectopic mineralization, leading to skin changes, visual impairment, and peripheral arterial disease.

Objectives: The authors hypothesized that etidronate, a pyrophosphate analog, might reduce ectopic mineralization in PXE.

Methods: In the Treatment of Ectopic Mineralization in Pseudoxanthoma Elasticum trial, adults with PXE and leg arterial calcifications (n = 74) were randomly assigned to etidronate or placebo (cyclical 20 mg/kg for 2 weeks every 12 weeks). The primary outcome was ectopic mineralization, quantified with ¹⁸fluoride positron emission tomography scans as femoral arterial wall target-to-background ratios (TBR_femoral). Secondary outcomes were computed tomography arterial calcification and ophthalmological changes. Safety outcomes were bone density, serum calcium, and phosphate.

Results: During 12 months of follow-up, the TBR_femoral increased 6% (interquartile range [IQR]: -12% to 25%) in the etidronate group and 7% (IQR: -9% to 32%) in the placebo group (p = 0.465). Arterial calcification decreased 4% (IQR: -11% to 7%) in the etidronate group and increased 8% (IQR: -1% to 20%) in the placebo group (p = 0.001). Etidronate treatment was associated with significantly fewer subretinal neovascularization events (1 vs. 9, p = 0.007). Bone density decreased 4% ± 12% in the etidronate group and 6% ± 9% in the placebo group (p = 0.374). Hypocalcemia (<2.20 mmol/l) occurred in 3 versus 1 patient (8.1% vs. 2.7%, p = 0.304). Eighteen patients (48.6%) treated with etidronate, compared with 0 patients treated with placebo (p < 0.001), experienced hyperphosphatemia (>1.5 mmol/l) and recovered spontaneously.

Conclusions: In patients with PXE, etidronate reduced arterial calcification and subretinal neovascularization events but did not lower femoral ¹⁸fluoride sodium positron emission tomography activity compared with placebo, without important safety issues. (Treatment of Ectopic Mineralization in Pseudoxanthoma elasticum; NTR5180).

Keywords: PXE; arterial calcification; bisphosphonates; etidronate.