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Estrogen deficiency induced bone loss is associated with increased bone turnover in rats and humans. The respective roles of increased bone turnover and altered balance between bone formation and bone resorption in mediating estrogen deficiency-induced cancellous bone loss was investigated in ovariectomized rats. Ovariectomy resulted in increased bone turnover in the distal femur. However, cancellous bone was preferentially lost in the metaphysis, a site that normally experiences low strain energy. No bone loss was observed in the epiphysis, a site experiencing higher strain energy. The role of mechanical strain in maintaining bone balance was investigated by altering the strain history. Mechanical strain was increased and decreased in long bones of ovariectomized rats by treadmill exercise and functional unloading, respectively. Functional unloading was achieved during orbital spacef light and following unilateral sciatic neurotomy. Increasing mechanical loading reduced bone loss in the metaphysis. In contrast, decreasing loading accentuated bone loss in the metaphysis and resulted in bone loss in the epiphysis. Finally, administration of estrogen to ovariectomized rats reduced bone loss in the unloaded and prevented loss in the loaded limb following unilateral sciatic neurotomy in part by reducing indices of bone turnover. These results suggest that estrogen regulates the rate of bone turnover, but the overall balance between bone formation and bone resorption is inf luenced by prevailing levels of mechanical strain.Ovarian hormone deficiency is the most important risk factor for postmenopausal osteoporosis (1, 2). Bone loss also occurs in premenopausal women following ovariectomy (OVX) (3) or treatment with gonadotrophin-releasing hormone agonists (4). Estrogen replacement therapy prevents bone loss in postmenopausal and ovariectomized women, suggesting that 17␤-estradiol is the gonadal hormone that is essential for normal bone balance.The mechanism for the skeletal effects of estrogen are incompletely understood but have been the subject of intense study in laboratory animal models (5). The rat has proven to be especially useful. OVX and gonadotrophin-releasing hormone agonists result in bone loss in rats, and these changes are prevented by estrogen treatment (6-9). These observations suggest similar skeletal mechanisms of action of estrogen in rats and humans. Furthermore, the skeletal changes in rats in response to partial estrogen agonists have accurately predicted the differential responses of pre-and postmenopausal women to tamoxifen treatment (10, 11).The bone loss in postmenopausal women and ovariectomized women and rats is associated with elevated bone turnover (6,(12)(13)(14). However, the bone loss is not uniform; cancellous bone is at a greater risk than cortical bone (7,14,15). In addition, there is site specificity in the loss of cancellous bone. For example, cancellous bone is lost more rapidly from the proximal tibial metaphysis than from vertebral bodies (16). Also, bone is preferenti...