In patients with osteosarcoma several causative factors are implicated in the occurrence of osteoporosis, such as no weight-bearing, pre- and post-surgical immobilization, and neoadjuvant and adjuvant chemotherapy. Nevertheless, osteoporotic fractures are a rare complication in young patients. We report the case of a spontaneous greenstick fracture of the distal tibia occurring during adjuvant chemotherapy in a 12-year-old Caucasian girl. Among the various drugs, the main role of methotrexate was investigated. A review of the literature is also presented along with a discussion about the role of preventive agents able to reduce the occurrence of osteopenia and/or osteoporosis following cancer treatment.