Cystinosis-associated metabolic bone disease across ages and CKD stages 1-5D/T.

Abstract

The pathophysiology of cystinosis-associated metabolic bone disease is complex. We hypothesized a disturbed interaction between osteoblasts and osteoclasts. Binational cross-sectional multicenter study. Hospital clinics. One hundred and three patients with cystinosis (61% children) with chronic kidney disease (CKD) stages 1-5D/T. Ten key bone markers. Skeletal complications occurred in two-thirds of the patients, with adults having a five-fold increased risk compared to children. Patients with CKD stages 1-3 showed reduced z-scores for serum phosphate and calcium, suppressed fibroblast growth factor 23 (FGF23) and parathyroid hormone levels in conjunction with elevated bone-specific alkaline phosphatase levels. Serum phosphate was associated with estimated glomerular filtration rate, combined phosphate and active vitamin D treatment, and native vitamin D supplementation, while serum calcium was associated with age and dosage of active vitamin D. Sclerostin was generally elevated in children, and associated with age, FGF23 levels, and treatment with active vitamin D and growth hormone. The osteoclast marker tartrate-resistant acid phosphatase 5b was increased, and associated with age and treatment with active vitamin D. The ratio of soluble ligand of receptor activator of nuclear factor-κB (sRANKL) and osteoprotegerin (OPG), a surrogate for the regulation of osteoclastogenesis by osteoblasts, was decreased and associated with phosphate and 1,25(OH)2D3 levels. These changes were only partly corrected after transplantation. Bone health in cystinosis deteriorates with age, which is associated with increased osteoclast activity despite counterregulation of osteoblasts via OPG/RANKL, which in conjunction with elevated sclerostin levels and persistent rickets/osteomalacia may promote progressive bone loss.