Real-World Assessment of Osteoporosis-Related Polymorphisms: Negative Findings for Osteoporosis and an Exploratory Association with Vitamin D

Osteoporosis develops silently and is strongly influenced by both genetic and environmental factors. This study investigated whether three well-established osteoporosis-related polymorphisms—SOST rs1513670, LRP5 rs3736228, and ESR1 rs6929137—derived from a commercial genetic testing panel (HelloGene™) were primarily associated with osteoporosis prevalence and/or incidence and secondarily with bone-related biochemical markers in a Korean population. A total of 843 adults who completed genetic testing at Seoul St. Mary’s Hospital and subsequently underwent bone mineral density (BMD) assessment were included. Logistic and linear regression models were applied to evaluate associations between genotypes, osteoporosis diagnosis, and serum calcium and 25-hydroxyvitamin D levels. None of the examined SNPs showed significant associations with osteoporosis status. However, the SOST variant demonstrated a statistically significant association with serum vitamin D concentration (β = −4.836, p = 1.7 × 10−6), with TC and CC genotype carriers exhibiting markedly lower vitamin D levels than TT carriers. LRP5 and ESR1 variants showed no significant relationships with either osteoporosis or vitamin D. These findings suggest a hypothesis-generating finding between SOST-mediated WNT signaling and vitamin D metabolism, even in the absence of measurable effects on clinical osteoporosis.