Etidronate for Prevention of Ectopic Mineralization in Patients With Pseudoxanthoma Elasticum

J Am Coll Cardiol. 2018 Mar 13;71(10):1117-1126. doi: 10.1016/j.jacc.2017.12.062.

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 (TBRfemoral). 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 TBRfemoral 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Bone Density / drug effects
  • Bone Density Conservation Agents / administration & dosage
  • Bone Density Conservation Agents / adverse effects
  • Bone Density Conservation Agents / pharmacokinetics
  • Calcium / blood
  • Calcium / metabolism
  • Drug Monitoring / methods
  • Etidronic Acid* / administration & dosage
  • Etidronic Acid* / adverse effects
  • Etidronic Acid* / pharmacokinetics
  • Female
  • Femur / diagnostic imaging
  • Humans
  • Male
  • Middle Aged
  • Peripheral Arterial Disease* / blood
  • Peripheral Arterial Disease* / diagnosis
  • Peripheral Arterial Disease* / etiology
  • Peripheral Arterial Disease* / prevention & control
  • Phosphates / blood
  • Positron-Emission Tomography / methods
  • Pseudoxanthoma Elasticum* / complications
  • Pseudoxanthoma Elasticum* / diagnosis
  • Pseudoxanthoma Elasticum* / drug therapy
  • Pseudoxanthoma Elasticum* / physiopathology
  • Tomography, X-Ray Computed / methods
  • Treatment Outcome
  • Vascular Calcification* / diagnosis
  • Vascular Calcification* / drug therapy
  • Vascular Calcification* / etiology

Substances

  • Bone Density Conservation Agents
  • Phosphates
  • Etidronic Acid
  • Calcium