Decoding the Calcification Paradox: How Estrogen , Chronic Disease and Ethnicity Affect Bone–Cardiovascular Health Across the Lifespan All Ages

The calcification paradox, where low bone mineral density (BMD) is associated with the development of cardiovascular calcification and vice versa, highlights a complex relationship between skeletal fragility and cardiovascular calcification. Most studies investigating this paradox have focused on older populations, with aging often assumed to be the primary driver, potentially overlooking some critical mechanisms present across different ethnic groups (Black and White population), estrogen in young women and chronic kidney disease (CKD) in children. This review explores the multifactorial nature of the calcification paradox, emphasizing the roles of hormonal status, CKD, and examining how paradox may manifest differently in Black populations and in children with CKD, diverging from the classical paradox, which is low BMD associated with cardiovascular calcification. We suggest that estrogen deficiency is a pivotal factor in women, modulating the receptor activator of nuclear factor kappa-B (RANK)/ its ligand (RANKL)/ osteoprotegerin (OPG) signalling axis and impacting both bone resorption and cardiovascular calcification. In children with CKD, vitamin D deficiency is associated with the calcification paradox, characterised by abnormalities in bone metabolism and microarchitecture alongside cardiovascular calcification. The pattern of this paradox may also be modulated by active vitamin D analogue concentrations. Moreover, ethnic differences further complicate this relationship, with evidence showing that vitamin D metabolism, BMD, and vascular calcification interact differently between racial groups, particularly between Black and White populations. However, these factors-,including disturbances in 25-hydroxyvitamin D (25(OH)D) across ethnic groups, estrogen deficiency in younger women, and CKD in children, do not fully account for the occurrence of the calcification paradox. Other effects, such as inflammation, likely interact with tissue processes in bones and vessels, as well as lifestyle factors, and should be studied in relation to previously identified contributors to help explain the paradox across different age groups.