Osteoglycin and Sclerostin Imbalance in Hypophosphatasia: Bone-Derived Markers of Mineralization and Systemic Involvement.

Hypophosphatasia (HPP) is a rare inherited disorder caused by deficient tissue-nonspecific alkaline phosphatase (TNSALP) activity and classically characterized by impaired mineralization processes, although growing evidence suggests broader systemic involvement beyond bone. This cross-sectional study aimed to characterize circulating levels of osteoglycin and sclerostin in patients with HPP and to explore their relationships with TNSALP activity and systemic clinical-biochemical profiles. This cross-sectional study included 25 genetically confirmed HPP patients and 25 age- and sex-matched controls without cardiovascular disease. Circulating osteoglycin and sclerostin were measured by ELISA, and clinical, metabolic, renal, inflammatory, cardiovascular, and bone-related variables were assessed. HPP patients showed lower osteoglycin and higher sclerostin levels compared with controls. Osteoglycin was mainly associated with ALP activity and mineral-related variables, while sclerostin showed broader associations involving glycemic, inflammatory, renal, and cardiovascular domains. In multivariable analyses, osteoglycin was linked to ALP, renal and inflammatory markers, whereas sclerostin was associated with glycemic, mineral, inflammation, and circulatory markers. Overall, osteoglycin variability appeared mainly driven by mineral-related factors, while sclerostin was more influenced by metabolic and inflammatory domains. In conclusion, HPP is associated with an imbalance in circulating bone-derived proteins, characterized by reduced osteoglycin and increased sclerostin, suggesting systemic alterations in bone-related signaling beyond impaired mineralization.