Aims: Hormone replacement therapy (HRT) reverses the menopausal decline in bone mineral density (BMD).We investigate if part of this response is through modulation of Interleukin-6 (IL-6) activity, which is known to be reduced by HRT. Methods: We have examined the association of the -174 G/C functional promoter polymorphism of the IL-6 gene with the BMD response to HRT (Prempak C: 0.625mg oestrogen per day and 0.15mg norgestrel). 65 women were genotyped for the IL-6 polymorphism, and differences in genotype related to changes in BMD over a one year follow up period. Results: Baseline BMD (0.75 g/cm²) was independent of IL-6 genotype. The rise in BMD with HRT (5% ± 3%, p < 0.00005 by paired t-test) was genotype-dependent, with BMD rising least amongst those of GG genotype (6% ± 3% for ≥1 C allele vs 4% ± 2% GG, p=0.03). In the HRT group, BMD rose most amongst those with the putatively ‘lowest IL-6’ genotype combination- namely ≥ 1 ACE I allele and ≥ 1 IL-6 C allele (n=14) (7% ± 3%), when compared with other genotype combinations (4% ± 2%) (n=16) (p=0.003). Conclusion: These are the first data to demonstrate an influence for IL-6 genotype in influencing response to oestrogen therapy, rather than its physiological withdrawal.

Aims: To examine the relationship between the Interleukin 6 (IL-6) −174 G> C promoter polymorphism and exercise-induced femoral cortical bone resorption. Methods: The skeletal response to exercise was assessed in 130 male Caucasian army recruits. Five cross-sectional magnetic resonance images of the right femur were obtained before and after a 10 week period of basic physical training, and changes in cross-sectional cortical area calculated. Recruits were genotyped for the −174 G> C IL-6 promoter polymorphism. Results: Genotype frequencies (GG 36%, GC 47%, CC 22 17%) were in Hardy-Weinberg Equilibrium. The mean percentage change in proximal femoral cross sectional cortical area was strongly IL-6 genotype-dependent, with GG homozygotes losing 6.8 ± 3.82% in cortical area, GC gaining +5.5 ± 4.88%, and CC gaining +17.3 ± 9.46% (p=0.007 for linear trend). These changes persisted throughout the right femur and were significant in the femur as a whole (p=0.03). Conclusion: This study demonstrates a linear relationship between a functional polymorphism in the IL-6 gene and femoral cortical remodelling during strenuous physical exercise. Previous studies have suggested an important role for IL-6 in the regulation of bone mass in postmenopausal women, and in the invasion of bone by metastatic tumour deposits. These data extend these observations to the regulation of bone mass in healthy males, supporting a fundamental role for IL-6 in the regulation of bone mass and bone remodelling in humans.