Background: Strontium (Sr) enriched biomaterials have been used to improve bone regeneration in vivo. However, most studies provide only two experimental groups. The aim of our study was to compare eleven different bone sample groups from osteoporotic and healthy rabbits' femoral neck, as it is the most frequent osteoporotic fracture in humans. Methods: Osteoporotic bone defects were filled with hydroxyapatite 30% (HA) and tricalcium phosphate 70% (TCP), 5% Sr-enriched HA 30 /TCP 70 , HA 70 /TCP 30 , or Sr-HA 70 /TCP 30 granules and were compared with intact leg, sham surgery and healthy non-operated bone. Expression of osteoprotegerin (OPG), nuclear factor kappa beta 105 (NFkB-105), osteocalcin (OC), bone morphogenetic protein 2/4 (BMP-2/4), collagen I (Col-1α), matrix metalloproteinase 2 (MMP- 2), tissue inhibitor of matrix metalloproteinase 2 (TIMP-2), interleukin 1 (IL-1) and interleukin 10 (IL-10) was analyzed by histomorphometry and immunohistochemistry. Results: Our study showed that Sr-HA 70 /TCP 30 induced higher expression of all above-mentioned factors compared to intact leg and even higher expression of OC, MMP-2 and NFkB-105 compared to Sr-HA 30 /TCP 70 . HA 70 /TCP 30 induced higher level of NFkB-105 and IL-1 compared to HA 30 /TCP 70 . Conclusion: Sr-enriched biomaterials improved bone regeneration at molecular level in severe osteoporosis and induced activity of the factors was higher than after pure ceramic, sham or even healthy rabbits.