Effects of XT-44, a phosphodiesterase 4 inhibitor, in osteoblastgenesis and osteoclastgenesis in culture and its therapeutic effects in rat osteopenia models

We have reported that denbufylline, a phosphodiesterase 4 (PDE4) inhibitor, inhibits bone loss in Walker256/S tumor-bearing rats, suggesting therapeut ic potentiality of a PDE4 inhibitor in osteopenia. In the present study, ef fects of a new PDE4 inhibitor, 1-n-butyl-3-n-propylxanthine (XT-44), in bon e were evaluated in cell cultures and animal experiments. In rat bone marro w culture, XT-44 stimulated mineralized-nodule formation, whereas it inhibi ted osteoclast-like cell formation in mouse bone marrow culture. In Walker2 56/S-bearing rats (6-week-old female Wistar Imamichi rats), rapid decrease in bone mineral density (BMD) was prominent, and oral administration of XT- 44 (0.3 mg/kg, every 2 days) inhibited the decrease in BMD. In the second a nimal experiment, female Wistar rats (6-week-old) were sciatic neurectomize d, and XT-44 was orally administered to these rats every 2 days for 4 weeks . XT-44 administration (0.3 mg/kg) recovered BMD in these neurectomized ani mals. Furthermore, 19-week-old, female Wistar rats were ovariectomized (OVX ), and 15 weeks after surgery, these rats were orally administered XT-44 ev ery 2 days for 8 weeks. XT-44 treatment (1 mg/kg) increased the BMD of OVX rats. These results indicate that XT-44 could be a candidate as a therapeut ic drug for treating osteopenia including osteoporosis.