The development of bone changes induced in rats by recombinant human granulocyte colony-stimulating factor is suppressed by bisphosphonate

M. Suzuki1,2, K. Adachi2, T. Sugimoto2, H. Nakayama1 and K. Doi1

1Department of Veterinary Pathology, Faculty of Agriculture, The University of Tokyo, Bunkyo-ku, Tokyo, Japan and 2Toxicology Laboratory, Chugai Pharmaceutical Co., Ltd., Gotemba-shi, Shizuoka, Japan

Offprint requests to: Dr. Masami Suzuki, Toxicology Laboratory, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba-shi, Shizuoka 412-8513, Japan

Summary. We have previously demonstrated that high doses of recombinant human granulocyte colony-stimulating factor (rhG-CSF) induce bone changes characterized by osteoclastic bone resorption and osteogenesis due to intramembranous ossification in rats. In this communication we examined the effects of a pretreatment with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (AHPrBP), which is a powerful inhibitor of osteoclastic bone resorption, on bone changes induced by rhG-CSF in order to investigate the relation between osteoclastic bone resorption and osteogenesis. AHPrBP (5 mg/kg/day) was subcutaneously given to 6-week-old rats for 2 days. From the following day of the final injection of AHPrBP, rats received a subcutaneous injection of rhG-CSF (1,000 µg/kg/day) for 14 days, and the femur and tibia were evaluated histopathologically. By the analysis of peripheral blood leukocyte counts, spleen weights and bone marrow findings, the pretreatment with AHPrBP had no effect on the activation of hematopoiesis related to the major pharmacological activity of rhG-CSF. In the rats treated with rhG-CSF alone, accelerated osteoclastic bone resorption and osteogenesis due to intramembranous ossification were observed in the trabeculae of metaphyseal spongiosa. The accelerated osteoclastic bone resorption induced by rhG-CSF was suppressed by the pharmacological activity of AHPrBP. Furthermore, the osteogenesis induced by rhG-CSF was also suppressed by AHPrBP. These results suggest that the osteogenesis induced by rhG-CSF is a sequential reaction of accelerated osteoclastic bone resorption, and moreover that the main action of rhG-CSF on bone is an acceleration of osteoclastic bone resorption. Histol. Histopathol. 14, 679-686 (1999)

Key words: Granulocyte colony-stimulating factor, Osteoclastic bone resorption, Osteogenesis, Intra-membranous ossification, Bisphosphonate

DOI: 10.14670/HH-14.679