Somatomedin-C (Sm-C) or insulin-like growth factor-I, GH and physical fitness decline with age. Physical fitness and muscle strength are important determinants of bone density, and the age-related decline in bone density may be related in part to a decline in fitness and muscle strength. Also, Sm-C has been shown to stimulate osteoblasts in vitro and may effect skeletal muscle mass. We postulated that the age-related decline in GH and Sm-C levels may be related to an age-related decline in physical fitness and/or muscle strength, and the effect of physical fitness and muscle strength on bone may be mediated by Sm-C. We, therefore, examined the relationship between circulating GH and Sm-C levels and physical fitness, as determined by predicted maximal oxygen uptake (VO2max) in 134 normal women, 34 of whom were postmenopausal. In a subgroup of 62 women overall muscle strength was estimated as the sum of the Z-sores for biceps, quadriceps, and grip strength. Overall muscle strength correlated with GH levels (r = 0.28; P < 0.02), but not with Sm-C levels. There was a significant positive relationship between plasma Sm-C levels and VO2max in all women (r = 0.47; P < 0.001) and in the postmenopausal group alone (r = 0.50; P < 0.01). Although there was a significant negative relationship between Sm-C and age (r = -0.36; P = 0.001), VO2max was a better independent predictor than age (r = 0.47; P = 0.0001). To examine the hypothesis that Sm-C may be mediating part of the effects of physical fitness on bone we examined the relationship between Sm-C and bone mineral density in the femoral neck, lumbar spine, and distal radius of 108 premenopausal and 69 postmenopausal normal women. Although there was a positive relationship between plasma Sm-C levels and bone mineral density at all sites measured, this was not independent of the effect of physical fitness. Thus, the agerelated decline in plasma Sm-C levels may relate to an agerelated decline in physical fitness rather than an effect of aging alone. It remains to be shown if Sm-C plays a role in the effects of fitness and strength on bone density.