Pregnancy and lactation induce drastic changes in skeletal physiology due to the increased calcium demand by fetal/infant growth. Although both clinical and animal studies have suggested that reproduction leads to long-lasting skeletal changes to exert protective effects on mechanical functions of maternal skeleton when subjected to estrogen deficiency, the underlying innate compensatory mechanisms at the cellular level remain unknown. Recent studies have suggested that osteocytes, the presumed mechano-sensors in bone, can actively remodel their peri-lacunar/canalicular bone matrix during lactation, and thus affecting bone’s mechano-sensitivity. Therefore, our first goal of this thesis was to determine both immediate and long-term effects of reproduction and lactation on bone mechano-sensitivity and osteocyte microenvironment in a rat model. Our study demonstrated an improved bone mechano-responsiveness in rats during lactation, possibly resulting from the elevated lactation-associated osteocyte peri-lacunar/canalicular remodeling (PLR) activities. Furthermore, when subjected to estrogen deficiency, the history of reproduction and lactation may prime the microenvironment of osteocytes through active PLR, leading to elevated mechano-sensitivity to protect maternal skeleton against estrogen deficiency. In addition to mechano-sensitivity and osteocytes, regulation of bone marrow adipocytes (BMAs) during reproduction and lactation may also contribute to exerting protective effects on skeletal metabolic homeostasis. Therefore, our second goal of this thesis was to investigate the immediate and long-term effects of reproduction and lactation on adipogenic capacity of mesenchymal progenitors and BMAs by both rat and mouse models. Our study in the inducible AdipoqCreER:TdTomato mice suggested a functional adaptation in BMAs through dynamic lipid alterations during one reproductive cycle. Moreover, when subjected to estrogen deficiency, rats with reproductive history showed lower adipogenic capacity and marked reduction in BMAs than virgins, indicating a protective effect of lactation history against estrogen-deficiency-induced bone marrow adiposity later in life. Taken together, this work explored the amazing functional adaptive mechanisms, at the cellular level, that protect women with a history of lactation from postmenopausal risks, providing important insights for osteoporosis prevention, management, and treatment in postmenopausal women by considering their lactation history.