Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare
premature aging disease, exhibit extraskeletal calcifications detected by
radiographic analysis and on physical examination. The aim of this study was
to describe the natural history and pathophysiology of these abnormal
calcifications in HGPS, and to determine whether medications and/or
supplements tested in clinical trials alter their development. Children from two successive
clinical trials administering 1)
lonafarnib (n=26) and 2) lonafarnib + pravastatin + zoledronic acid (n=37)
were studied at baseline (pre-therapy), one year on therapy, and at
end-of-therapy (3.3–4.3 years after the baseline visit). Calcium
supplementation (oral calcium carbonate) was administered during the first
year of the second trial and was subsequently discontinued. Information on
calcifications was obtained from physical examinations, radiographs, and
serum and urinary biochemical measures. The mineral content of two
skin-derived calcifications was determined by x-ray diffraction. Extraskeletal calcifications
were detected radiographically in 12/39
(31%) patients at baseline. The odds of exhibiting calcifications increased
with age (p=0.045). The odds were unaffected by receipt of lonafarnib,
pravastatin, and zoledronate therapies. However, administration of calcium
carbonate supplementation, in conjunction with all three therapeutic agents,
significantly increased the odds of developing calcifications (p=0.009),
with the odds plateauing after the supplement’s discontinuation.
Composition analysis of calcinosis cutis showed hydroxyapatite similar to
bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were
within normal limits at baseline and on-therapy, PTH increased significantly
after lonafarnib initiation (p<0.001). Both the urinary
calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were
elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients,
respectively, with no significant changes while on-therapy. The mean calcium
× phosphorus product (Ca × Pi) was within normal limits, but
plasma magnesium decreased over both clinical trials. Fibroblast growth
factor 23 (FGF23) was lower compared to age-matched controls (p=0.03). Extraskeletal
calcifications increased with age in children with HGPS
and were composed of hydroxyapatite. The urinary calcium/creatinine ratio
and TRP were elevated for age while FGF23 was decreased. Magnesium decreased
and PTH increased after lonafarnib therapy which may alter the ability to
mobilize calcium. These findings demonstrate that children with HGPS with
normal renal function and an unremarkable Ca × Pi develop
extraskeletal calcifications by an unidentified mechanism that may involve
decreased plasma magnesium and FGF23. Calcium carbonate accelerated their
development and is, therefore, not recommended for routine supplementation
in these children.