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Insulin-like growth factor-I (IGF-I) clearly plays a role in bone metabolism and maintenance, as evidenced by in vitro and animal studies. In clinical studies, the age-related decrease in IGF-I parallels the age-related decrease in bone mineral density (BMD), but several age-adjusted cross-sectional studies show no consistent association of IGF-I and BMD. We report here a cross-sectional study of serum IGF-I and BMD levels in 483 men and 455 postmenopausal women not using estrogen; subjects were 55 years of age and older, community-dwelling, ambulatory, and unselected for bone density. IGF-I was measured by a highly specific radioimmunoassay. BMD was measured at the lumbar spine and hip using dual-energy X-ray absorptiometry. Men had higher IGF-I and BMD levels than women. In age-adjusted and age-stratified models, IGF-I was associated with BMD only in women (test for interaction, p < 0.0001). Gender differences persisted in gender-specific multiple regression analyses adjusted for age, body mass index, thiazide diuretic use, current smoking, alcohol intake, physical activity, and weight change; IGF-I was significantly associated with BMD at the spine (p = 0.0001) and hip(p = 0.02) in women, but not in men (p's > 0.6). Circulating estradiol levels were not associated with IGF-I levels in either gender; testosterone was inversely associated with IGF-I and only in men. This striking gender difference has not been described previously. Its etiology is unknown. The answer could lead to improved understanding of gender differences in osteoporosis and in response to treatment with IGF-I or growth hormone.