The aim of the present study was to determine the safety and efficacy of combined therapy with raloxifene (RLX) and clodronate (CLD) in postmenopausal women. We enrolled 45 women with postmenopausal osteoporosis. The patients were randomly assigned to two different therapeutic groups: RLX 60 mg/day (n = 23) and RLX 60 mg/day plus CLD 100 mg intramuscularly (i.m.) once every 10 days (n = 22); 1 g of calcium and 800 IU of vitamin D3 were also given daily to both groups. Lumbar and femoral bone mineral density (BMD) were assessed at baseline and after 12 months of therapy using the dual X-ray absorptiometry technique (Norland XR36). We measured the bone turnover markers NTx and CTx, bone alkaline phosphatase (BAP) and osteocalcin at baseline and after 12 months of therapy. Our data demonstrate that 1 year of combined RLX+CLD therapy induced a higher increase in lumbar BMD than treatment with RLX alone as well as a major decrease in bone resorption markers, suggesting an additive effect of CLD on bone mass and inhibition of bone turnover. Furthermore, after 1 year of therapy levels of bone formation markers (osteocalcin and BAP) had increased in both groups, but the increase in osteocalcin and BAP was significantly higher in the RLX+CLD treated group, suggesting that, in addition to its inhibitory effects on resorption, CLD might also have stimulatory effects on mature osteoblast activity.