Damage and recovery of the bone and bone marrow following methotrexate chemotherapy

The bone marrow microenvironment is home to mesenchymal and haematopoietic stem cells, and the interaction between these cell types and their respective progeny allows the maintenance of a steady-state functioning marrow, bone formation and turnover throughout life. Unfortunately, cancer chemotherapy, which commonly includes the anti-metabolite methotrexate (MTX), is a serious risk factor that disrupts homeostasis of the bone marrow and compromises bone formation, leading to myelosuppression and bone loss. MTX has been shown to cause significant damage to the bone marrow and reduce bone volume in both clinical and animal studies. Although the severity of damage to the bone marrow and the degree of ensuing recovery of marrow cell populations are dependent on the MTX dose and length of treatment, in order to re-establish the depleted marrow cavity, haematopoietic stem cells maintained at endosteal niche sites are induced to enter the cell cycle and differentiate down the appropriate lineage. Associated with damaged bone marrow stromal cells and a differentiation switch to adipogenesis at the expense of osteogenesis, are bone loss, increased marrow fat and fracture risk. This chapter will discuss mechanisms of how MTX chemotherapy causes myelosuppression, bone loss and marrow adiposity as reported in both clinical and animal studies, and will summarise changes in the relationship between cells of the mesenchymal and haematopoietic lineages in relation to MTX-induced damage and recovery of the bone and bone marrow.