Bone turnover increases with age. In a previous study, we reported on bone metabolism in young and elderly women and men. The aim of the present investigation was to evaluate potential age- and gender-related changes in cathepsin K, a cysteine protease that plays an important role in the degradation of the organic matrix of bone. Twenty-five healthy premenopausal women, 24 young healthy men, 26 elderly women, and 25 elderly men participated in the study. Elderly women and men had significantly lower cathepsin K levels than younger ones. In both men and women, serum levels of cathepsin K were negatively correlated with age. In men there was a statistically significant negative correlation between serum levels of cathepsin K and osteoprotegerin, which inhibits osteoclast differentiation and activation. No association was found between serum levels of cathepsin K and bone-specific alkaline phosphatase, osteocalcin, or 25-hydroxy vitamin D. Thus, the age-related increase in OPG, which markedly inhibits the expression of cathepsin K, may also reduce serum levels of cathepsin K. Despite the age-related increase in bone resorption, this study shows lower cathepsin K values in elderly women and men than in younger subjects. It might be speculated that a different enzyme could compensate for the decline in cathepsin K during old age.