Abstract: BACKGROUND: Several observational studies have found a strong association between thyroid function and its related disorders and osteoporosis, but the causal relationship is unclear.
OBJECTIVE: To ascertain the causal relationship between genetically predicted thyroid function and its associated disorders, as well as osteoporosis, through the Mendelian randomization analysis with extensive pooled genetic data.
METHODS: Pooled data from genome-wide association studies were employed to investigate the causal relationship between thyroid function and its associated disorders and osteoporosis. This was achieved through the utilization of the inverse variance weighting method as the primary Mendelian randomization analysis method, in conjunction with the MR-Egger method, weighted median method, simple model method, and weighted model method. A two-step mediated Mendelian randomization analysis was used to calculate the mediating effect of drug-mediated thyroid dysfunction on osteoporosis and the mediating proportion. Subsequently, sensitivity analyses were conducted using the MR-Egger intercept test and MR-PRESSO to detect multiplicity, Cochran’s Q test to detect heterogeneity, and leave-one-out to perform sensitivity analyses.
RESULTS AND CONCLUSION: (1) The results of the inverse variance weighting method showed that thyroid function had an effect on bone mineral density, and that thyrotropin, free triiodothyronine on bone mineral density, free thyroxine, and subclinical hyperthyroidism all had a causal effect on bone mineral density. (2) In addition, mediation analyses revealed a potential mediating effect of carbimazole in the causal relationship between hyperthyroidism and the risk of developing osteoporosis, as well as a potential mediating effect of levothyroxine sodium in the causal relationship between hypothyroidism and the risk of developing osteoporosis. (3) In conclusion, thyrotropin, which is high in the normal range, has been demonstrated to increase bone mineral density. Conversely, free triiodothyronine and free thyroxine, which are also high within the normal range, as well as subclinical hyperthyroidism, have been shown to decrease bone mineral density. The risk of developing osteoporosis is partially mediated by the pathway of taking the therapeutic medication in the context of pharmacologic treatment of thyroid dysfunction. (4) The present study primarily focuses on European population data. However, given the commonality of the genetic background and the generalizability of genome-wide data analysis methods, it is of significant importance to explore the pathogenesis of osteoporosis in the Chinese population, develop effective interventions, and provide genetic counseling.

Key words: thyroid function, thyroid dysfunction, osteoporosis, bone metabolism, bone mineral density, genetics, Mendelian randomization, analysis of mediation