Skeletal effects of 5-year high-dose cyclical etidronate in patients with pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) is a rare genetic disease characterized by ectopic calcification in the eyes, skin, and arteries. It is caused by pathogenic variants in the ABCC6 gene and leads to reduced plasma levels of inorganic pyrophosphate. Etidronate, a stable analogue of pyrophosphate, has been shown to reduce arterial calcification. However, the long-term skeletal safety of high-dose cyclical etidronate treatment remains unclear. This study aimed to evaluate the skeletal effects of cyclical etidronate administration in adults aged ≥50 years with PXE. This prospective study included patients treated with etidronate (20 mg/kg/day for 14 days every 12 weeks) for ≥1 year and untreated control patients from the Dutch Expertise Center for PXE. Bone density (BD) was measured on whole-body low-dose CT scans in Hounsfield units at the spine and femoral necks. Safety was assessed using bone turnover markers and fracture data. BD changes were compared within treated patients and between the treated and control groups using scanner-adjusted linear mixed models. In total, 71 treated patients (mean age 57.0 ± 7.6 years; 56% female) and 72 untreated patients (mean age 54.2 ± 11.0 years; 69% female) were included. Median etidronate follow-up duration was 5.2 years (IQR 5.1-7.5). Of the 71 treated patients, 66 (93%) completed 5 years of follow-up, and all treated patients completed at least 2.5 years of treatment. In the treated group, BD remained stable during treatment, whereas in the untreated group it declined substantially, resulting in a greater overall loss in the untreated group compared to the treated group. Non-vertebral fracture incidence was low and comparable to controls, and no atypical femur fractures, excessive suppression of bone turnover markers, or medication-related osteonecrosis of the jaw were observed. This study demonstrates that cyclical administration of high-dose etidronate to patients aged ≥50 years with PXE for 5 years did not negatively affect skeletal integrity and metabolism and prevented bone loss at both the spine and the hip.