Osteocytic alterations in CKD-associated osteomalacia appear to differ according to aluminum deposition, suggesting distinct microenvironmental and canalicular phenotypes

Abstract Osteomalacia is a severe mineralization defect characterized by increased osteoid matrix and delayed mineral apposition. In chronic kidney disease, particularly in patients on hemodialysis, aluminum deposition has been implicated as a risk factor. However, it remains unclear whether osteomalacia and aluminum-associated osteomalacia represent distinct variants. We compared clinical, biochemical, histomorphometric and osteocytic features between hemodialysis patients with osteomalacia with and without aluminum deposition. This is a cross-section study of 27 hemodialysis patients with osteomalacia, 15 without and 12 with aluminum deposition, defined by solochrome azurine staining as stainable aluminum in ≥30% of the mineralization front. Clinical/biochemical data and bone histomorphometry were assessed. Osteocytic proteins, osteopontin, and apoptosis were evaluated by immunohistochemistry, globally and separately in mineralized matrix and osteoid. Osteocyte morphology and canaliculi were assessed by Ploton-Silver staining (n=4/group). Patients without aluminum showed higher parathyroid hormone and total alkaline phosphatase, greater osteoid volume (p=0.0214) and fibrosis (p=0.0251), whereas those with aluminum had higher phosphorus. Globally, osteopontin was higher in aluminum-associated osteomalacia (p=0.0334), whereas RANKL (p=0.0164) and CD44 (p<0.0001) were higher without aluminum. In mineralized bone only CD44 differed (p<0.0001); in osteoid, FGF23, MEPE, CD44 and E11 were higher without aluminum (all p<0.05). Patients without aluminum also showed more canaliculi per osteocyte (16 vs. 14, p=0.0468), with unchanged mean canalicular length (p=0.113) and more slender osteocyte bodies. After adjustment for parathyroid hormone, alkaline phosphatase and phosphorus, aluminum status remained associated with CD44 globally (p=0.0016) and in mineralized bone (p=0.0041), and with osteoid FGF23 (p=0.0171) and MEPE (p=0.0468), but not with RANKL, osteopontin or osteoid E11. Our findings suggest that osteomalacia and aluminum-associated osteomalacia represent distinct variants, with aluminum potentially affecting osteocyte function, the canalicular network, and osteopontin expression. Part of the differences may nevertheless reflect the distinct biochemical milieu of the two groups.