The formation, maintenance, and repair of bone tissue involve close interlinks between two stem cell types housed in the bone marrow: the hematologic stem cell originating osteoclasts and mesenchymal stromal cells (MSCs) generating osteoblasts. In this review, we consider malfunctioning of MSCs as essential for osteoporosis. In osteoporosis, increased bone fragility and susceptibility to fractures result from increased osteoclastogenesis and insufficient osteoblastogenesis. MSCs are the common precursors for both osteoblasts and adipocytes, among other cell types. MSCs' commitment towards either the osteoblast or adipocyte lineages depends on suitable regulatory factors activating lineage-specific transcriptional regulators. In osteoporosis, the reciprocal balance between the two differentiation pathways is altered, facilitating adipose accretion in bone marrow at the expense of osteoblast formation; suggesting that under this condition MSCs activity and their microenvironment may be disturbed. We summarize research on the properties of MSCs isolated from the bone marrow of control and osteoporotic post-menopausal women. Our observations indicate that intrinsic properties of MSCs are disturbed in osteoporosis. Moreover, we found that the regulatory conditions in the bone marrow fluid of control and osteoporotic patients are significantly different. These conclusions should be relevant for the use of MSCs in therapeutic applications.