BACKGROUND Orthopedic surgeons and dentists often implant materials to repair bone tissue defects and restore physiological functions of bone organs. The clinical success depends on adequate bone formation in operation sites. However, the real cause of osteogenesis has not yet been fully elucidated. To investigate the bone response to implanted materials, this study examined the bone tissue reaction in rat femoral medullary canal, which received gelatin and collagen as foreign-body materials. METHODS A total of 36 six-month-old Sprague-Dawley rats were randomly and meanly divided into three groups. In the gelatin group, the bilateral femora received gelatin material; in the collagen group, they were implanted with type I collagen, and in the control group, the femora suffered from sham operation with no materials inserted. After 2, 4, 8, and 12 weeks, specimens were harvested and subjected to a series of examinations. RESULTS After 2 weeks of healing, a significant upregulation of both alkaline phosphatase and osteocalcin by both kinds of implanted materials relative to the control (sham implantation group) was seen in gene expression analysis. Strong reactivity of osteoprotegerin and receptor activator of NFκB ligand was detected in the two test groups in immunohistochemistry at 4 weeks of healing. Also, micro-CT revealed an increase in cortical bone thickness in the two test groups as compared to the control group. Densitometry showed increased bone mineral density in the bone receiving materials after 12 weeks, leading to the enhanced maximum load in the test groups. CONCLUSIONS These results indicated that the implanted materials led to an osteogenesis response in rat femoral medullary canal. Thus, we probably should reconsider the potential cascades of tissue reaction when utilizing orthopedic and dental implants and other materials to recover bone related-organ function and repair bone defects.