Defining the Relationships between Bone, Calcium, and Cholesterol

Elevated cholesterol is a well-established driver of cardiovascular disease, while osteoporosis and bone loss contribute significantly to morbidity through fracture risk. Emerging evidence suggests a clinically relevant but underexplored link between cholesterol metabolism, serum calcium, and bone health. Observational studies in humans and pre-clinical data in mice indicate consistent associations between serum calcium and LDL-cholesterol, as well as an inverse relationship between bone mineral density and cardiovascular outcomes. However, the causal direction of these relationships remains unclear, and the extent to which co-morbid hypercholesterolemia and hypercalcemia amplify cardiovascular risk has not been defined. We hypothesize that elevated LDL-C promotes bone demineralization, increasing serum calcium, and thereby conferring additive cardiovascular risk. To test this, we propose a two-pronged approach: (1) pre-clinical experiments in mouse models to manipulate serum calcium and cholesterol independently, complemented by Mendelian Randomization analyses in humans to determine causal directionality, and (2) epidemiological and experimental studies to assess the cardiovascular impact of concurrent elevations in calcium and cholesterol, leveraging the Michigan Genomics Initiative and established mouse models of atherosclerosis and bone loss. Together, these studies will provide the first rigorous evaluation of the cholesterol–calcium–bone axis, clarify its mechanistic basis, and establish the clinical significance of these interrelated conditions. By integrating pre-clinical and population-based approaches, this work has the potential to identify novel risk factors and therapeutic targets, reshape our understanding of cardiovascular–bone health interactions, and inform strategies for prevention and treatment of two highly prevalent chronic diseases.