To determine the effects of HRT with or without clodronate on bone mineral density (BMD) change and bone turnover markers. Prospective, partly randomized trial. Kuopio University Hospital, Finland. 167 osteoporotic women (61+/-2.7 years; T-score<or=-2.5 SD). Estradiol 2 mg+NETA 1 mg, randomization to additional 800 mg clodronate (n=55, HT+C-group) or placebo (n=55, HT-group); if contraindications to HRT, clodronate (n=57, C-group). BMD by DXA after 1, 3 and 5 years, serum osteocalcin (OC) and bone-specific alkaline phosphatase (BAP) at the baseline and after 3 years. After 5 years, adjusted lumbar BMD increased by 4.2% in the HT-group and 3.7% in the HT+C-group. The C-group showed a decrease of -1.1%, the total difference being 5.3% and 4.8% between HT, HT+C vs. C-group, respectively (p<0.001). In the femoral neck, the adjusted 5-year BMD benefit was 1.3% and 2.4% in the HT- and HT+C-groups, respectively, the net loss of BMD in the C-group was -3.3% (p<0.05 between HT+C vs. C). By 3 years, OC decreased by 55.0%, 70.3% and 53.8% in the HT-, HT+C- and C-groups, respectively (p<0.001 vs. baseline). The significant decreases of BAP were 39.4% in the HT-group, 42.1% in the HT+C-group and 30.2% in the C-group with no significant differences between the groups after adjustments. In postmenopausal women with osteoporosis, HRT increased spinal and femoral BMD, but the combination of HRT and clodronate did not offer an extra gain of bone mass.