Context: Higher physiological cortisol levels may increase the risk of age-related osteoporosis. We hypothesized that common polymorphisms in the cortisol synthesis enzyme 11β-hydroxysteroid dehydrogenase (HSD11B) may cause interindividual variations in cortisol levels and age-related bone loss.
Study design and patients: We performed a retrospective study in a cohort of 452 ambulatory patients under evaluation for osteoporosis. We investigated the associations of 16 single-nucleotide polymorphisms (in the HSD11B1 and HSD11B2 genes with a postdexamethasone cortisol (PDC) level and bone mineral density (BMD; primary end points) and fracture risk (secondary end point) in a subgroup of 304 patients. The observed associations with BMD were validated in a subgroup of 148 patients.
Results: The PDC level increased with age (R = 0.274, P < 10(-5), n = 287) and was negatively correlated with BMD at the femoral neck (R = -0.278, P < 10(-5), n = 258). Three genetically linked single-nucleotide polymorphisms (in intron 5 of HSD11B1), rs1000283, rs932335, and rs11811440, were significantly associated with BMD, with rs11811440 having the strongest association. The presence of the minor rs11811440 A allele was correlated with a lower PDC level (R = -0.128, P = .03, n = 304). The A allele was also consistently correlated with a higher spinal BMD in both patient subgroups (R = 0.17, Bonferroni corrected P = .006, n = 452). The correlation with BMD remained significant after adjustment for age, gender, body mass index, and type of osteoporosis and was stronger in patients older than 65 years.
Conclusion: Genetic variations in HSD11B1 may affect the physiological cortisol levels and the severity of age-related osteoporosis. Underlying functional mechanisms remain to be elucidated.