Graves' disease and bone mineral density: a meta-analysis and UK Biobank.

To investigate the association between Graves' disease (GD) and bone mineral density by integrating a meta-analysis with a large-scale cross-sectional analysis in the UK Biobank. We systematically searched PubMed, Web of Science, and Cochrane Library for cohort and cross-sectional studies. The pooled findings were then examined in the UK Biobank using multivariable linear regression models with adjustment for age, BMI, lifestyle factors, vitamin D, calcium, and sex. The meta-analysis (14 studies, 3,643 participants) showed that GD patients had significantly lower bone mineral density than controls (Mean Difference = -0.09, 95% CI [-0.10, -0.07], P < 0.001) and higher serum calcium (Standard Mean Difference = 0.37, 95% CI [0.18, 0.57], P = 0.023). However, substantial between-study heterogeneity was observed (I2 = 92.1%), indicating considerable variation across studies. Meta-regression and subgroup analyses identified postmenopausal women, older age (>50 years), and lower BMI as key factors amplifying the association. In the UK Biobank (n = 42374), after rigorous adjustment for all covariates, the association was substantially attenuated and remained statistically significant only at the ribs (P < 0.05), while other skeletal sites, including the lumbar spine and femoral neck, showed no significant differences. This dual-evidence approach provides suggestive, rather than definitive, evidence that GD is associated with reduced BMD. The meta-analysis suggested widespread BMD reductions in GD patients. However, due to the limited number of confirmed GD cases, the fully adjusted UK Biobank analysis adopted a broader exposure definition of hyperthyroidism and observed a nominally statistically significant association only at the ribs, with no significant differences detected at other skeletal sites. Given the limited replication of the meta-analysis findings and the high heterogeneity observed in the meta-analysis, we advocate for a risk-stratified approach to BMD screening that prioritizes postmenopausal women, older adults, and individuals with low BMI, rather than routine screening for all GD patients. These findings underscore the need for prospective studies with standardized protocols to clarify the skeletal impact of GD and to guide evidence-based bone health management.