The effects of denbufylline, a xanthine derivative with selective inhi
bitory activity on the phosphodiesterase (PDE) 4 isoenzyme, on bone lo
ss in Walker 256/S-bearing rats and on mineralized nodule formation an
d osteoclastlike cell formation in bone marrow culture systems were ex
amined. Serial oral administrations of denbufylline inhibited the decr
ease in the bone mineral density of femurs from Walker 256/S bearing r
ats, without influence on the healthy rats. Denbufyllin restored the b
one mass and the number of osteoclasts and osteoblasts per trabecular
surface in the femur metaphysis. Among PDE inhibitors, only PDE4-selec
tive inhibitors increased the number of mineralized nodules and decrea
sed the number of osteoclastlike cells in the in vitro bone marrow cul
ture systems, and dibutyryl cyclic AMP mimicked these effects in the i
n vitro systems. These results suggest that the PDE4 isoenzyme may pla
y an important role in bone turnover through cyclic AMP and that its i
nhibitors are candidates for therapeutic drugs for the bone loss disea
ses. (C) 1997 Elsevier Science Inc.