Role of serum leptin, insulin, and estrogen levels as potential mediators of the relationship between fat mass and bone mineral density in men versus women

Although fat mass is related to bone mineral density (BMD), the potential mechanism(s) of this effect remain to be defined. Thus, we assessed the role of the candidate hormones, leptin, insulin, and estrogen in mediating fat mass effects on the skeleton. Specifically, we related these hormones and fat mass to BMD at the total hip, mid-lateral spine, and mid-distal radius in a sample of 137 premenopausal women (age range 21-54 years), 165 postmenopausal women (34-93 years), and 343 men (23-90 years) recruited from the general population. Fat mass and BMD were significantly related in pre- and postmenopausal women at multiple sites, whereas this relationship was only weakly present in men at the total hip. Serum leptin levels were also significantly related to BMD in the women, but not in the men. Insulin was associated with hip BMD in the women, and bioavailable estradiol (E₂) was correlated with BMD at all sites in men and in postmenopausal women. In the women, adjusting for leptin reduced the strength of the association between fat mass and BMD, with further adjustments for insulin or bioavailable E₂ having no additional effects. Adjusting for leptin in the men had no consistent effect on the relationship between fat mass and BMD. Collectively, these data suggest that there is a sexual dimorphism in the relationship of fat mass and leptin to BMD, with both being positively associated with BMD in women but not in men. In women, leptin may also mediate at least part of the protective effect of fat mass on the skeleton.