Variation in cortical thickness (CT) in four quadrants of the human second metacarpal was investigated in a sample (100 males and 72 females, skeletal age 20 to 50+ years) from a 19th-century cemetery. Both left and right elements were studied (total N = 344). Multivariate analysis of covariance (MANCOVA) (for age, sex, and side, controlling for absolute size) was used to test the hypothesis of equality of thickness in the dorsal, palmar, medial, and lateral quadrants. Differences in regional CT posits localized regulation of resorption and formation adapting bone shape to functional loads, with implications for activity-modulation of skeletal senescence. The palmar cortex was found to be uniformly thicker in both sexes and both sides, and at all ages (young, middle, and old adult); the medial, lateral, and dorsal cortices did not differ significantly. Patterns of age-related loss occurring preferentially at the endocortical surface differed between men and women, with women showing significant declines across all age groups for all quadrants, and males only small decrements after middle age. The greater CT in the palmar quadrant corresponds to the region of maximum compressive strain in the second metacarpal for functions involving full flexion (grasping). Although the palmar cortex is thicker at all ages, women lose mass in that quadrant at the same rate as in other quadrants, suggesting that function does not offer protection against endocrinologically-mediated depletion of bone mass (postmenopausal osteopenia).