Author + information
- Received December 14, 2017
- Accepted December 19, 2017
- Published online March 5, 2018.
- Guido Kranenburg, MDa,
- Pim A. de Jong, MD, PhDb,
- Jonas W. Bartstra, MDa,
- Suzanne J. Lagerweij, MDb,
- Marnix G. Lam, MD, PhDb,
- Jeannette Ossewaarde-van Norel, MD, PhDc,
- Sara Risseeuw, MDc,
- Redmer van Leeuwen, MD, PhDc,
- Saskia M. Imhof, MD, PhDc,
- Harald J. Verhaar, MD, PhDd,
- Job J. de Vries, BScb,
- Riemer H.J.A. Slart, MD, PhDe,
- Gert Luurtsema, PhDe,
- Annemarie M. den Harder, MDb,
- Frank L.J. Visseren, MD, PhDa,
- Willem P. Mali, MD, PhDb and
- Wilko Spiering, MD, PhDa,∗ ()
- aDepartment of Vascular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
- bDepartment of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
- cDepartment of Ophthalmology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
- dDepartment of Geriatric Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
- eMedical Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- ↵∗Address for correspondence:
Dr. Wilko Spiering, Department of Vascular Medicine, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands.
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)
This study was supported by the Dutch Innovation Fund of Health Insurers (Innovatiefonds Zorgverzekeraars), Dutch Foundation PXE Fund, Dutch Eye Association, and Foundation Friends of University Medical Center Utrecht. UNI-Pharma Kleon Tsetis Pharmaceutical Laboratories SA (Greece) provided all etidronate and placebo capsules for free, as manufacturer of the finished product (OSTOPOR hard capsules, 400 mg/capsule). UNI-Pharma SA was not involved in the design, the execution, the analysis, or the reporting of the Treatment of Ectopic Mineralization in Pseudoxanthoma Elasticum trial. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received December 14, 2017.
- Accepted December 19, 2017.
- 2018 American College of Cardiology Foundation
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