Variation in trabecular microarchitecture is widely accepted as being regulated by both functional (mechanical loading) and genetic parameters, although the relative influence of each is unclear. Studies reporting inter-site differences in trabecular morphology (volume, number and structure) reveal a complex interaction at the gene–environment interface. We report inter- and intra-site variation in trabecular anatomy using a novel model of contralateral (left vs right) and ipsilateral (head vs base) comparisons for the human second metacarpal in a sample of n = 29 historically known 19th century EuroCanadians. Measures of bone volume fraction, structure model index, connectivity, trabecular number, spacing and thickness as well as degree of anisotropy were obtained from 5-mm volumes of interest using three-dimensional microcomputed tomography. We hypothesized that: (i) the more diverse loading environment of metacarpal heads should produce a more robust trabecular architecture than corresponding bases within sides and (ii) the ipsilateral differences between epiphyses will be larger on the right side than on the left side, as a function of handedness. Analysis of covariance (Side × Epiphysis) with Age as covariate revealed a clear dichotomy between labile and constrained architectures within and among anatomical sites. The predicted variation in loading was accommodated by changes in trabecular volume, whereas trabecular structure did not vary significantly by side or by epiphysis within sides. Age was a significant covariate only for females. We conclude that environmental and genetic regulation of bone adaptation may act through distinct pathways and local anatomies to ensure an integrated lattice of sufficient mass to meet normal functional demands.