Adaptation of bone to mechanical stresses normally produces a bone architecture that combines a proper resistance against failure with a minimal use of material. This adaptive process is governed by mechanosensitive osteocytes that transduce the mechanical signals into chemical responses, i.e. the osteocytes release signaling molecules, which orchestrate the recruitment and activity of bone forming osteoblasts and/or bone resorbing osteoclasts. Computer models have shown that the maintenance of a mechanically-efficient bone architecture depends on the intensity and spatial distribution of the mechanical stimulus as well as on the osteocyte response. Osteoporosis is a condition characterized by a reduced bone mass and a compromized resistance of bone against mechanical loads, which has led us to hypothesize that mechanotransduction by osteocytes is altered in osteoporosis. One of the major causal factors for osteoporosis is the loss of estrogen, the major hormonal regulator of bone metabolism. Loss of estrogen may increase osteocyte-mediated activation of bone remodeling, resulting in impaired bone mass and architecture. In this review we highlight current insights on how osteocytes perceive mechanical stimuli placed on whole bones. Particular emphasis is placed on the role of estrogen in signaling pathway activation by mechanical stimuli, and on computer simulation in combination with cell biology to unravel biological processes contributing to bone strength.